Does CBD Oil Work to Help With Seizures?

  • In a 2017 study in the New England Journal of Medicine, researchers led by Orrin Devinsky, M.D., concluded that among patients with Dravet syndrome, CBD use resulted in a more significant reduction in convulsive-seizure frequency than placebo(1)
  • In a randomized, double-blind, placebo-controlled trial done in the USA, the Netherlands, and Poland in 2018, researchers found that add-on CBD proved efficacious for the treatment of individuals aged 2 to 55 years old with drop seizures associated with Lennox-Gastaut syndrome(2)
  • The studies on CBD in individuals with Dravet and Lennox-Gastaut syndrome contributed to the U.S. Food and Drug Administration’s decision to approve Epidiolex (pharmaceutical-grade pure CBD) as an evidence-based treatment for treatment-resistant epilepsy due to the syndromes(3)
  • For some forms of epilepsy, there is currently no cure or treatment of seizures. Increasing a patient’s quality of life is a significant motive of health professionals for initiating treatment, as shown in a 2018 study published in Epilepsy and Behavior(4).
  • In their most recent update, the Centers for Disease Control and Prevention (CDC) have included epilepsy, along with many other medical and neurological disorders, as a condition that may increase the risk of serious COVID-19 for individuals of any age(5)

Best CBD Oils for Seizures

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    FormOil Tincture
    IngredientsOrganic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier OilOrganic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price Range$89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsOrganic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forNew CBD users
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Patients who are looking for serious CBD oil support
  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
     Extra strong  No other flavors
     Significant benefits with just a few drops
     100% Natural ingredients
  • Features
    Discount pricing available?15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take itUsing 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier OilCoconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price RangeSingle Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsContaminant-free
    AllergensVegan and Gluten-free
    Refund policyWithin 30 days
    Recommended forPatients who are looking for serious CBD oil support
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Organic

Nuleaf Naturals 725mg Full Spectrum CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
Nuleaf Naturals 725mg Full Spectrum CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health conscious
  • Summary

    Natural remedy for various illnesses. There are approximately 300 drops in this 0.5 FL OZ bottle, where 1 drop = 2.4 mg of CBD.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsUSDA Certified Organic Hemp Oil, Full Spectrum Hemp Extract
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take itUnder the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    725mg of CBD per 0.5 FL OZ (15ml)
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    48.33mg to a max of 51.82mg per 1ml
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99.00 - 1-pack, $434.00 - 6-pack
    $/mg CBD
    Price ($/mg)
    1-pack - $0.13, 6-pack - $0.59
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsNo additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    AllergensNot specified
    Refund policyWithin 30 days
    Recommended forHealth conscious
    Countries servedUSA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Parguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...CBD users with different needs
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
     Plenty of concentrations to choose from for all people with various kinds of needs  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
     Has vegan, organic, and gluten-free ingredients
     Affordable pricing
     Affordable pricing
  • Features
    Discount pricing available?15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier OilOrganic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug TestContaining less than 0.3% THC, there are still trace amounts
    FlavoursNatural, Berry, Orange and Mint
    Price Range30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants100% organic, non-GMO, and vegan-certified
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forCBD users with different needs
    Countries servedUSA only (all 50 states)
Check Latest Prices

Why People Are Turning to CBD for Seizures

Cannabidiol (CBD), an active cannabinoid without psychoactive effects and abuse liability, has recently gained interest as a potential treatment option for epilepsy.

Recent legal changes in the status of medical cannabis within several European countries have made CBD more accessible to health care professionals, according to a 2018 study published in the European Journal of Pain(6). 

The authors of a 2014 study in Epilepsy and Behavior noted that many families with children dealing with treatment-resistant epilepsy began to explore the use of CBD-enriched cannabis and reported a successful reduction of seizure frequency(7). 

Studies showed CBD’s antiepileptic efficacy in acute and chronic seizure models in rodents, although the precise mechanisms of action remain unclear(8).

Various studies using purified CBD in animal models of partial and generalized epilepsy also showed anticonvulsant effects(9). The studies were done on rats, gerbils, and mice. 

Meanwhile, small randomized controlled trials and open-label studies of purified CBD in humans with treatment-resistant epilepsy had shown mixed results(10).

In a 2017 study in the New England Journal of Medicine, researchers led by Orrin Devinsky, M.D., concluded that among those with the Dravet syndrome, CBD use resulted in a more significant reduction in convulsive-seizure frequency than placebo(11). 

Dr. Orrin Devinsky is a neurologist specializing in epilepsy treatments and the director of the Comprehensive Epilepsy Center.

The results of the study mentioned were encouraging. On average, convulsive seizures decreased from nearly 13 seizures to about 6 seizures per month with CBD. 

The average change was from nearly 15 to about 14 seizures per month with the placebo. A minority of patients, about 5%, became seizure-free.

However, CBD use was also linked to higher rates of adverse events, including diarrhea, vomiting, fatigue, fever, drowsiness, and abnormal results on liver-function tests.

 In a randomized, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland in 2018, researchers investigated the efficacy of CBD for the treatment-resistant Lennox-Gastaut syndrome (LGS)(12). 

Results indicated that add-on CBD proved efficacious for the treatment of individuals (aged 2 to 55 years old) with drop seizures associated with Lennox-Gastaut syndrome.

Drop seizures (also called atonic seizures or drop attacks) are a type of seizure characterized by a sudden loss of muscle strength, causing the person to fall to the ground(13).

In the said study, the average reduction in drop-seizure frequency during the treatment period was nearly 42% in the high-dose CBD group, about 37% in the low-dose CBD group, and 17% in the placebo group.

The authors also found CBD to be generally well-tolerated. However, 74 of the 86 patients experienced adverse effects, like diarrhea, drowsiness, fever, decreased appetite, and vomiting.

The studies on CBD as add-on anticonvulsant in individuals with Dravet and Lennox-Gastaut syndrome contributed to the U.S. Food and Drug Administration (FDA)’s decision to approve Epidiolex (pharmaceutical-grade pure CBD) as an evidence-based remedy for treatment-resistant epilepsy due to the syndromes(14).

Still, doctors’ attitudes concerning the use of the medical cannabis plant, in general, and CBD for the treatment of epilepsy appear to be divided(15). Also, data about the clinical use of CBD in daily practice are not available.

How CBD Oil Works to Help With Seizures

To understand how CBD works to help with seizures, one must understand how the endocannabinoid system (ECS) works. 

The therapeutic effects of cannabinoids, such as CBD, are realized by their interaction with the body’s ECS and its specialized cannabinoid receptors. 

The ECS, integral to the body’s physiologies, is responsible for regulating a wide range of body functions, including pain sensation, immune response, anxiety, sleep, mood, appetite, metabolism, and memory.

CB1 and CB2 are the two main types of receptors found in specific parts of the human body. These receptors each have particular roles in the ECS.

CB1 receptors are mostly located in the brain and central nervous system. However, they are also found in the reproductive organs, gastrointestinal and urinary tracts, liver, lungs, and retina(16). 

CB1 receptors play a role in motor regulation, memory processing, appetite, pain sensation, mood, and sleep(17). 

The activation of CB1 receptors has also been linked to neuroprotective responses. This activity suggests the cannabinoids with a higher affinity for CB1 receptors could help in the treatment and prevention of neurodegenerative medical conditions, such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.

Meanwhile, CB2 receptors are primarily situated on cells in the immune system and its associated structures.

When CB2 receptors are triggered, they stimulate a response that fights inflammation, reducing pain, and minimizing damage to tissues.

CBD has a very weak affinity for the CB1 and CB2 receptors, and its anti-seizure activity at specific concentrations is brought about by other mechanisms(18).

In particular, the reabsorption of adenosine and the blocking of GPR55 receptors in the brain have been suggested to play an essential role in CBD anti-seizure activity(19).

Adenosine is a neurotransmitter that can stop convulsions and seizures(20). A 2017 study published in Neuropharmacology noted that the therapeutic increase of adenosine effectively prevents epileptic seizures(21). 

GPR55 is a type of protein in the brain. A study found that GPR55 function was enhanced by epilepsy in a manner that made the disease worse. 

However, CBD remained sufficiently potent in epileptic brains, suggesting an anticonvulsant characteristic of CBD(22).

The anticonvulsant properties of CBD may be related in part to CBD-mediated modulation of the ECS(23)

This action is done explicitly through the inhibition of anandamide degradation or decline, resulting in decreased excess brain activity(24).

Anandamide is an endocannabinoid that acts as a neurotransmitter and regulates emotions. 

Research found that endocannabinoids are released by bursts of action potentials, including events resembling spikes, and probably by seizures as well(25).

The Pros and Cons of CBD Oil for Seizures

The Pros

  • CBD’s efficacy as a potential remedy to seizures or the management of epilepsy symptoms has been shown in the studies stated above.
  • CBD is non-addictive, says Nora Volkow, director of the National Institute on Drug Abuse (NIDA) in a 2015 article(26). This characteristic makes CBD safe for daily consumption. 
  • CBD is generally well-tolerated with a good safety profile, the World Health Organization (WHO) stated in a critical review(27).
  • In a 2017 review published in Cannabis and Cannabinoid Research Journal, CBD was considered tolerable at doses of up to 1,500 mg per day(28). 
  • CBD oil may be purchased without a prescription in locations where they are legally available.
  • The FDA has approved Epidiolex, a drug for seizures that has CBD as its main ingredient(29).

The Cons

  • No study validates CBD alone can be used in treating epilepsy and all its symptoms. Studies are too limited to determine whether or not CBD is an effective treatment for conditions other than the ones approved by the FDA(30).
  • As with the use of any natural chemical compound, there are risks involved in using CBD for seizures. 

According to the Mayo Clinic, possible side effects of CBD use include drowsiness or sleepiness, dry mouth, diarrhea, fatigue, and reduced appetite(31).

  • CBD has been shown to alter how the body metabolizes certain medications, as a 2017 research reveals(32).
  • The lack of regulation makes it difficult to determine whether the CBD gummies, tinctures, patches, balms, and gelcaps contain what the product label claims.

A 2017 review published in the Journal of the American Medical Association revealed labeling inaccuracies among CBD products. Some products had less CBD than stated, while others had more(33).

How CBD Oil Compares to Alternative Treatments for Seizures

Epilepsy is a type of neurological condition that can get in the way of everyday life, particularly when seizures occur frequently. 

Medicines and surgical techniques can control seizures in 70% of individuals diagnosed with epilepsy-seizure disorders. 

Unfortunately, for some forms of epilepsy, there is currently no cure or treatment of seizures(34).

However, there are self-management strategies that epilepsy patients can apply to control their seizures better and take care of their health.

These self-management techniques include the following:

  • Get 7 to 8 hours of sleep every night.
  • Follow a well-balanced diet and keep a healthy weight.
  • Find ways to lower stress and get help for emotional problems.

CBD’s therapeutic properties may help with these self-management strategies. 

CBD for Improved Sleep

Sleep deprivation is well-recognized as a precipitant or trigger for seizures and most epilepsies. Meanwhile, studies have shown CBD to be useful at inducing restful sleep. 

A study published in Pharmaceuticals (Basel) in 2012 compared CBD with a sleep aid called nitrazepam(35). 

The authors found that high-dose CBD at 160 milligrams increased the subject’s duration of sleep.

Similarly, a 2017 study published in the Current Psychiatry Reports noted that at moderate to high doses, CBD might have therapeutic potential for the treatment of insomnia(36).

CBD for Brain Health and Body Weight Management

Full-spectrum CBD oil derived from hemp contains Omega-3 fatty acids, which could have an anti-inflammatory effect on the brain and help cognitive function in those with severe epilepsy.

A study published in the Journal of Epilepsy and Clinical Neurophysiology found that the administration of supplements consisting of omega 3 and omega 6 fatty acids to human subjects resulted in a reduction of the number of seizures in refractory epilepsy(37).

Also called by some other names, like uncontrolled, intractable, or drug-resistant epilepsy, refractory epilepsy affects about one-third of people with epilepsy(38). 

A special diet, called a ketogenic diet, might also help control seizures linked to refractory epilepsy. This type of diet is high in fats and low in carbohydrates. 

However, individuals following this diet should work closely with their doctor and take supplements of certain nutrients as needed.

CBD can be beneficial to people who are trying to manage their weight. A study published in Nature Journal has shown that CBD could increase the levels of leptin in the brain(39).

Leptin is the hormone that makes an individual feel full or satiated. The reduced cravings for unhealthy, calorie-dense foods may help individuals achieve their weight loss goals fast.

In another study, researchers found that CBD might interfere with the secretion of cortisol, reducing blood levels significantly(40).

Chronic stress and persistently high cortisol levels may be associated with increased appetite and weight gain(41).

CBD for Reduced Anxiety and Depression

Anxiety, depression, and psychosis may complicate epilepsy, both before certain seizures and also between seizures in individuals with epilepsy. 

These symptoms may be part of the epilepsy syndrome arising as a consequence of surgery or the use or withdrawal of antiepileptic drugs (AEDs)(42)

Results of a study published in the Neuropharmacology Journal indicated that CBD might help block anxiety-induced sleep disturbances through its anti-anxiety effects on the brain(43). 

A 2018 study published in the Frontiers in Immunology Journal showed CBD as a potential remedy to depression(44). 

In the study, researchers found that CBD showed anti-anxiety, antiepileptic, and non-psychoactive properties that might help reduce depression linked to stress.

Best CBD Oils for Seizures

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    FormOil Tincture
    IngredientsOrganic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier OilOrganic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price Range$89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsOrganic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forNew CBD users
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Patients who are looking for serious CBD oil support
  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
     Extra strong  No other flavors
     Significant benefits with just a few drops
     100% Natural ingredients
  • Features
    Discount pricing available?15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take itUsing 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier OilCoconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price RangeSingle Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsContaminant-free
    AllergensVegan and Gluten-free
    Refund policyWithin 30 days
    Recommended forPatients who are looking for serious CBD oil support
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Organic

Nuleaf Naturals 725mg Full Spectrum CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
Nuleaf Naturals 725mg Full Spectrum CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health conscious
  • Summary

    Natural remedy for various illnesses. There are approximately 300 drops in this 0.5 FL OZ bottle, where 1 drop = 2.4 mg of CBD.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsUSDA Certified Organic Hemp Oil, Full Spectrum Hemp Extract
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take itUnder the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    725mg of CBD per 0.5 FL OZ (15ml)
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    48.33mg to a max of 51.82mg per 1ml
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99.00 - 1-pack, $434.00 - 6-pack
    $/mg CBD
    Price ($/mg)
    1-pack - $0.13, 6-pack - $0.59
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsNo additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    AllergensNot specified
    Refund policyWithin 30 days
    Recommended forHealth conscious
    Countries servedUSA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Parguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...CBD users with different needs
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
     Plenty of concentrations to choose from for all people with various kinds of needs  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
     Has vegan, organic, and gluten-free ingredients
     Affordable pricing
     Affordable pricing
  • Features
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    Source
    Source of Hemp
    Kentucky, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier OilOrganic Coconut MCT Oil
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    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug TestContaining less than 0.3% THC, there are still trace amounts
    FlavoursNatural, Berry, Orange and Mint
    Price Range30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
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    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
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    Refund policyWithin 30 days
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How to Choose the Right CBD for Seizures

Full-spectrum CBD hemp oil contains all nutrients from hemp, including trace amounts of THC (tetrahydrocannabinol), terpenes, flavonoids, fatty acids, and essential oils. 

The combination of all these components creates a synergy known as “entourage effect.”(45). 

This phenomenon occurs when the multiple compounds working together achieve more than the sum of what the same compounds could achieve acting individually.

Broad-spectrum CBD oils are like full-spectrum oils without THC. CBD isolates carry only pure, isolated cannabidiol.

If individuals with seizures do not want any amount of THC in their system, broad-spectrum CBD can be used. If they are allergic to specific components of the hemp plant, CBD isolates are the only option.

Regardless of the form of CBD products that individuals choose for their seizures, careful consideration must be employed in selecting the best CBD oil that is right for their lifestyle and preferences.

The following factors are essential to ensure the safety and reliability of the CBD products purchased:

1. Research on the exact legal stipulations applicable to CBD in the area where it would be purchased and used.

2. Purchase only high-quality, non-GMO, organic hemp-derived CBD products from legitimate and reliable CBD brands. 

The majority of companies that manufacture the best CBD oil products grow their hemp from their own farms, or they purchase from licensed hemp producers.

3. When buying from an online store, research product reviews. When buying from a physical store or dispensary, check whether the store is authorized by the government to sell CBD.

4. Knowing the extraction method and carrier oil used in making the CBD oil is also essential.

Researchers of a study indicate that the Supercritical-CO2 extraction process is recognized as safe by the U.S. Food and Drug Administration (FDA) in pharmaceutical manufacturing(46).

The supercritical CO2 extraction method allows for the highest purity and potency because the process does not extract any unwanted ingredients and impurities.

The most natural carrier oils that may be used include MCT oil (medium-chain triglycerides from coconut oil), hemp seed oil, and extra-virgin olive oil.

5. One important thing to look for in CBD products is certification codes. Several certification authorities approve certain products only after some thorough screening tests and third-party lab testing. 

6. Compare a CBD company’s claims about its products’ potency with that of the third-party lab reports. 

7. Consulting with a medical professional experienced in CBD use is ideal before one purchases his or her first bottle of CBD.

CBD Dosage for Seizures

Dosing may depend on several factors, such as the age of the patient, the cause of epilepsy, etiology, seizure type, and other medications that are currently taken(47).

CBD doses up to 50 mg/kg were found to be safe. However, given the lack of data, an upper permissible dose cannot be defined(48). 

Long-term data of CBD use are also limited (49). Thus, no defined timeframe qualifies as CBD treatment failure, as reflected by the doctors’ differing opinions about when to discontinue a CBD treatment. 

How to Take CBD Oil for Seizures

CBD taken orally is swallowed or ingested in the form of capsules, food, or liquid, which are convenient and straightforward ways to take CBD oil (cannabidiol oil), especially for beginners.

CBD oil in these forms gets absorbed through the digestive tract. However, absorption is slow, and dosing is tricky due to the delayed onset (one to two hours) of effect, unknown stomach acids, and recent meals, among other factors.

CBD oil may also be taken sublingually (under the tongue) using a dropper and then allowing the oil to be absorbed into the bloodstream.

In a 2010 review, published in the International Journal of Pharmacy and Pharmaceutical Sciences, researchers found that peak blood levels of most substances given sublingually are achieved in 10 to 15 minutes, which is faster than when those same drugs are ingested orally(50). 

Sublingual absorption is an efficient way of consuming CBD tinctures. According to studies, CBD oil has a sublingual bioavailability of 13% to 19%, with some studies putting it as high as 35%(51). 

Bioavailability is the extent and rate to which a compound or an active drug ingredient is absorbed and becomes readily available for the body to use(52). 

When taking tinctures sublingually, keep the CBD oil under the tongue for 60 to 90 seconds before swallowing it.

If users find the earthy, grassy taste of pure CBD oil unappealing, other CBD brands offer a variety of delicious flavors to explore. 

CBD oil can also be mixed with other foods and beverages that are easy to consume. However, keep in mind that oil and water do not mix.

An additional fat, like milk, may be necessary for the oil to bind and completely dissolve while maintaining the smooth consistency of the drink. 

Given that CBD is a highly lipophilic (soluble in lipids or oils) molecule, it may dissolve in the fat content of food, increasing its solubility and absorption, according to a 2018 study published in the journal Frontiers in Pharmacology(53). 

CBD oil may also be used in massage therapies. According to the Epilepsy Society in the UK, complementary therapies, like herbal remedies and massages, can help promote well-being, reduce stress, and may be used with any antiepileptic drugs currently taken by an individual(54).

There is, however, limited absorption through the skin with topical CBD oil. For topical products, look for keywords on the product labels that indicate that the product uses nano technology, encapsulation, or micellization of CBD.

These words indicate that their formulation can transmit CBD through the dermal layers, rather than just staying on the skin.

Meanwhile, CBD oil vapes are one of the quickest ways to get CBD into the body since it enters the bloodstream through the lungs, without going through the digestive system. 

When inhaling CBD using a vape pen, effects can be felt in minutes. However, the effects last for only 30 minutes to an hour or two. Also, with CBD vapes, it is difficult to determine precisely the amount of CBD is in each draw. 

As a 2018 study published in Molecules indicated, the primary limitations of inhaling are the variability in individuals’ inhalation techniques and respiratory tract irritation during inhalation(55)

Although labels for CBD oil vape products usually indicate the amount per inhale, this amount may vary in individuals. Thus, getting the dose right requires a bit of experimentation at first. 

Vaping is not for everyone. Experts are not sure whether or not vaping causes lung problems. However, they believe that the most likely culprit is a contaminant, not an infectious agent(56).

Possibilities may also include chemical irritation or allergic or immune reactions to various chemicals or other substances in the inhaled vapors.

Individuals contemplating vaping CBD for the first time must proceed with caution and first consult with a doctor experienced in cannabis use.

Seizure vs. Convulsion: What Is the Difference?

Epilepsy is a disorder of the brain. Intellectual disability is relatively common in individuals with epilepsy, with prevalence estimated to be around 25%, according to a 2017 study published in PLoS One(57).

Epilepsy is diagnosed when a person has had at least two seizures, also called epileptic seizures. 

The signs of a seizure typically depend on the type of seizure. In some cases, it is difficult to determine if someone is having a seizure.

A person having a seizure may look confused or seem like they are staring at something that is not there. Other seizures can cause the person to fall, shake, and become unaware of what is going on around them(58). 

The terms seizure and convulsion are often used interchangeably, although they are not the same. 

Seizures are electrical disturbances in the brain, while convulsions are uncontrollable muscle contractions. 

During convulsions, a person has uncontrollable shaking that is rapid and rhythmic, with the muscles contracting and relaxing repeatedly(59).

The Case for Medical Marijuana in Epilepsy

Charlotte Figi was an inspiration to many individuals dealing with the same health conditions. She had Dravet syndrome, a type of severe epilepsy. At age 5, she had as many as 300 seizures a week.

Charlotte’s case has made the use of cannabis oil from medical marijuana an almost-last option for hopeful families looking to treat their children’s epilepsy.

Through the exhaustive personal research and invaluable assistance from a Colorado-based medical marijuana (medical cannabis) group, called Realm of Caring, Charlotte’s mother started complementary therapy with a high concentration CBD:THC strain of cannabis, now known as Charlotte’s Web(60). 

This extract, slowly titrated over weeks and given in conjunction with Charlotte’s existing antiepileptic seizure medications, helped with seizure control. 

Sadly, Charlotte has died after being hospitalized for a seizure that resulted in a cardiac arrest and respiratory failure. She died on April 7, 2020, at age 13.

Epidiolex No Longer A Controlled Substance

GW Pharmaceuticals announced on April 6, 2020, that it received notice from the U.S. Drug Enforcement Administration (DEA) granting the biopharmaceutical company’s petition to deschedule its cannabis-derived drug, Epidiolex(61).

Cannabis has been a Schedule I drug, which has limited the type and scope of research needed to figure out how best to benefit from its medical use.

Under the U.S. Federal Controlled Substances Act, Schedule I drugs have no currently accepted medical use and a high potential for abuse(62).

This latest confirmation means that Epidiolex is no longer subject to the Controlled Substances Act (CSA). 

Epidiolex is the first prescription medicine of highly purified, plant-derived CBD, and the first in a new category of antiepileptic drugs.

“The descheduling of EPIDIOLEX has the potential to further ease patient access to this important therapy for patients living with Lennox-Gastaut Syndrome and Dravet syndrome, two of the most debilitating forms of epilepsy,” says GW Pharmaceuticals in their press release.

COVID-19 and Epilepsy

Currently, there is no substantial scientific evidence to suggest that an individual diagnosed with epilepsy alone is at increased risk of getting the coronavirus disease (COVID-19).

However, in their most recent update, the Centers for Disease Control and Prevention (CDC) have included epilepsy, along with many other medical and neurological disorders, as a condition that may help increase the risk of serious COVID-19 for individuals of any age(63). 

As medical experts continue to learn more about COVID-19 and its impact on health, epilepsy patients are encouraged to consult with a doctor if their current epilepsy treatments or other medical conditions impact their level of risk.

Conclusion

The studies mentioned above showed that CBD might help individuals with epilepsy by potentially reducing convulsive-seizure frequency.

CBD’s anti-anxiety, anti-depressant, anti-stress, sleep-inducing, and appetite-regulating qualities also make it useful in managing epilepsy.

However, studies conducted on CBD and epilepsy are still lacking, and the long-term effects of CBD use remain unknown.

Also, as with the use of any natural chemical compound, there are risks involved in using CBD for seizures. 

Consulting with an epilepsy specialist experienced in cannabis use for advice and guidance is the essential first step for parents looking into trying CBD for seizures.

Individuals dealing with any form of epilepsy can explore, together with their doctors, the possible treatment options with CBD to empower them to make informed decisions that weigh both risks and health benefits.


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  63. CDC. (2020, March 12). op. cit. 

More Info

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Carbamazepine

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination by route of exposure

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological analyses and their interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple qualitative test(s)

         8.2.1.2 Advanced qualitative confirmation test(s)

         8.2.1.3 Simple quantitative method(s)

         8.2.1.4 Advanced quantitative method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple qualitative test(s)

         8.2.2.2 Advanced qualitative confirmation test(s)

         8.2.2.3 Simple quantitative method(s)

         8.2.2.4 Advanced quantitative method(s)

         8.2.2.5 Other dedicated method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analysis

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other fluids

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central Nervous System (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    CARBAMAZEPINE

 

    International Programme on Chemical Safety

    Poisons Information Monograph 100

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Carbamazepine

 

        1.2  Group

 

             Nervous system, antiepileptics, antiepileptics,

             carboxamide derivatives.

 

        1.3  Synonyms

 

             G 32883

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    298-46-4

 

             1.4.2  Other numbers

 

                    ATC code: NO3AF

 

        1.5  Main brand names, main trade names

 

             Biston, Calepsin, Convulsine, Epitol, Finlepsin,

             Hermolepsin, Karbamazepine, Lexin, Mazepine, Neuritol,

             Neurotol, Neurotop, Nordotol, Servimazepine, Sirtal,

             Stazepine, Tegretal, Tegretol, Telesmin, Temporol, Teril,

             Timonil, Trimonil Retard (Index Nominum, 1987).

 

        1.6  Main manufacturers, main importers

 

             Geigy (importer):      Argentine, Australia, Belgium,

                                    Canada, Denmark, France,

                                    Italy, Netherlands, Norway,

                                    Portugal, South Africa, Spain,

                                    Switzerland, UK, USA.

    

             Spofa:          Prague, Czech Republic

    

             Protea:         Glebe, NSW 2037, Australia

    

 

             Arzneitmittelwerk:  8122 Radebeul, Dresden,

                                 Germany 

    

             Lääke:          20101 Abo, Finland 

    

             Fujinawa:       Tokyo, Japan

    

             ICN:            Montreal, Quebec, Canada

    

             Eczacoibasoi:   Istanbul, Turkey

 

             Farmos Group:   20101, Turku, Finland

    

             Servipharm:     4002, Basel, Switzerland

    

             Polfa:          Warszawa, Poland

    

             Orion:          00510, Helsinki, Finland

    

             Taro:           Haifa, Israel

    

             Desitin:        2000 Hamburg, Germany

    

             (Index Nominum, 1992/93; Reynolds, 1996)

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             The principle toxic effects of  carbamazepine are

             depression in level of consciousness, convulsions and ECG

             changes. 

 

        2.2  Summary of clinical effects

 

             Cardiovascular tachycardia, hypotension, conduction

             disorders.

    

             Respiratory:  central respiratory depression.

    

             Eyes:  mydriasis, nystagmus.

    

             Neurological: depressed level of consciousness, ataxia,

             initial hyperreflexia followed by hyporeflexia,

             ophisthotonus, agitation, disorientation, tremor, involuntary

             movements, convulsions.

    

             Gastrointestinal: nausea and vomiting

 

        2.3  Diagnosis

 

             The diagnosis should be considered in any patient with

             access to carbamazepine who presents with a depressed level

 

             of consciousness.  The presence of seizure activity or ECG

             changes makes the diagnosis more likely.  The diagnosis is

             confirmed in laboratory by measurement of  toxic serum

             carbamazepine levels.

 

        2.4  First aid measures and management principles

 

             Management is supportive.  Particular attention is

             directed towards maintenance of the airway and ventilation

             and control of seizures.  Other clinical features that may

             require treatment include hypotension, hypothermia and

             hyponatraemia.

    

             The administration of oral activated charcoal to prevent

             furhter absorption is indicated once the airway is secured. 

             Repeat doses of activated charcoal are effective in enhancing

             elimination of carbamazepine.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Synthetic.

 

        3.2  Chemical structure

 

             Carbamazepine is an iminostilbene derivative that is

             related chemically to the tricyclic antidepressants and is

             structurally similar to phenytoin.

    

             Chemical name: 5H-Dibenz[b,f]azepine-5-carboxamide;

             5-carbamoyl-5H-dibenz[b,f]azepine

    

             Molecular formula of carbamazepine: C15H12N2O.

    

             Molecular weight: 236.26.

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White to yellowish-white

 

             3.3.2  State/form

 

                    Crystal

 

             3.3.3  Description

 

                    Almost odourless, carbamazepine can either have

                    no taste or be slightly bitter.  It is practically

                    insoluble in water and ether but soluble in acetone,

 

                    alcohol, carbon tetrachloride, chloroform,

                    dimethylformamide dioxane, and propylene glycol

    

                    Melting point: 190 to 193°C.

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

                    No data available.

 

             3.4.2  Storage conditions

 

                    Store in airtight containers, below 40°C and,

                    preferably, between 15 and 30°C, and away from light

                    (Budavari, 1996).

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

             4.1.2  Description

 

                    Carbamazepine has both antiepileptic and

                    psychotropic properties.  Accepted indications

                    include:

    

                    Epilepsy: Generalized tonic-clonic (grand mal) and

                    partial (focal) seizures.

    

                    Pain syndromes: Trigeminal neuralgia and

                    glossopharyngeal neuralgia.

    

                    Manic depressive illness unresponsive to lithium. 

    

                    (Reynolds, 1996)

 

        4.2  Therapeutic dosage

 

             4.2.1  Adults

 

                    The dose of carbamazepine should be adjusted

                    according to the needs of each patient.  The

                    therapeutic plasma concentration is 4 to 12 mg/L (20

                    to 50 mmol/L).  The total daily dose should preferably

                    be given as three or four divided doses.

    

                    Epilepsy: the initial oral dose is 200 mg twice a day,

                    increased by 200 mg at weekly intervals until the

 

                    patient responds.  The maintenance dose is 800 mg to

                    1200 mg/day, maximum 1600 mg/day.

    

                    Neuralgia: the initial dose is 100 mg twice a day,

                    with an additional 200 mg every other day until pain

                    is relieved.  The maintenance dose is 200-1200 mg

                    daily, maximum 1600 mg/day.

    

                    Psychosis: initial doses are 400-600 mg per day, to a

                    maximum of 1.6 g/day as needed and tolerated.

    

                    (Reynolds, 1996).

 

             4.2.2  Children

 

                    The safety and efficacy of carbamazepine have

                    not been established in children less than 

                    6-years-old.  Some doctors give an initial dosage of 

                    5 mg/kg daily, which may be increased to 10 to 20 

                    mg/kg daily; the following doses can be used as

                    guidelines:

    

                    less than 1 year old:   100 to 200 mg/day

                    1 to 5 years old:       200 to 400 mg/day

                    5 to 10 years old:      400 to 600 mg/day

                    10 to 15 years old:     600 to 1000 mg/day

    

                    The dosage should not exceed 1 g/day (Reynolds, 1996)

 

        4.3  Contraindications

 

             Hypersensitivity to carbamazepine

             Atrioventricular conduction defects (unless paced)

             Aplastic anaemia

             Acute intermittent porphyria

    

             Caution should be exercised in administering carbamazepine to

             patients with history of cardiac, hepatic, haematologic or

             renal disease or with raised intraocular pressure.

    

             Carbamazepine should not be given with monoamine oxidase

             inhibitors or within two weeks of its cessation.

             (Reynolds, 1996; Morant & Ruppaner, 1997).

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Carbamazepine is given orally in tablet or syrup form.  

             Carbamazepine intoxication occurs from ingestion.

 

        5.2  Inhalation

 

             Not relevant.

 

        5.3  Dermal

 

             Not relevant.

 

        5.4  Eye

 

             Not relevant.

 

        5.5  Parenteral

 

             No data available.

 

        5.6  Other

 

             Rectal.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Absorption of carbamazepine from the gastrointestinal

             tract is slow and erratic but almost complete. Oral

             absorption is more rapid on a full stomach and slower from

             tablets than from solution.

    

             Peak plasma concentrations usually occur within 4 to 12 hours

             of oral aministration.  However, they may be delayed up to 

             24 hours after overdose.

 

        6.2  Distribution by route of exposure

 

             Carbamazepine is 76% bound to plasma proteins.  It is

             rapidly and uniformly distributed throughout the body.

    

             Carbamazepine epoxide, the principal active metabolite, is

             50% bound to plasma proteins (Rane et al., 1976).  It is

             probably subject to enterohepatic circulation (Laffey &

             Guzzardi, 1983).

    

             Carbamazepine crosses the blood-brain barrier and the

             placenta, accumulates in fetal tissues, and is distributed

             into breast milk at concentrations about 60% those of

             maternal plasma.  The drug has been detected in cerebrospinal

             fluid in concentrations approximately 15% those of serum.

    

             The volume of distribution is 0.79 to 1.4 L/kg increasing

             after long-term treatment to 0.96 to 2.07 L/kg (Westenberg et

             al., 1978).

 

        6.3  Biological half-life by route of exposure

 

             Carbamazepine induces its own metabolism, so that the

             plasma half-life ranges from 18 to 60 hours following a

             single dose, and from 10 to 35 hours during chronic therapy. 

             The half-life is shorter in children than in adults.

 

        6.4  Metabolism

 

             Carbamazepine can induce its own metabolism.  It is

             metabolized in the liver to an epoxide and several other

             metabolites.  A major metabolic pathway is oxidation by

             microsomal enzymes to form carbamazepine 10, 11 epoxide. This

             is an active compound and is almost completely metabolized to

             an inactive metabolite, trans-10,11-dihydroxy-10,11-

             dihydrocarbamazepine (trans-carbamazepine-diol), and excreted

             in the urine mainly in an unconjugated form.

    

             Carbamazepine is also inactivated by conjugation and

             hydroxylation.

 

        6.5  Elimination by route of exposure

 

             Carbamazepine and its metabolites are excreted in the

             urine.  After oral administration, 72% of the dose is

             excreted in the urine and 28% is eliminated in the faeces. 

             Only about 1 to 3% of the drug is excreted unchanged in the

             urine.

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             7.1.1  Toxicodynamics

 

                    Signs of toxicity appear at plasma

                    concentrations above the upper limit of the

                    therapeutic level (12 mg/L or 50 µmol/L) and are due

                    to the effects on the central nervous system (Salcman

                    & Pippenger, 1975), gastrointestinal irritation

                    (Lehrman & Bauman, 1981), arrhythmogenic properties

                    (Beerman et al., 1975) and its anti-diuretic action

                    (Stevens, 1977).

 

             7.1.2  Pharmacodynamics

 

                    In cats, carbamazepine depresses thalamic

                    potential and bulbar and polysynaptic reflexes. Its

                    capacity to increase discharges of noradrenergic

                    neurones may contribute to its anti-epileptic actions

                    (Rall & Schleifer, 1985). Although the effects of

                    carbamazepine in animals and humans resemble those of

 

                    phenytoin, there are several important differences. 

                    For example, carbamazepine is more effective than

                    phenytoin in reducing stimulus-induced discharges in

                    the amygdala of stimulated rats.

    

                    The mechanisms responsible for these effects are not

                    clearly understood.  Carbamazepine seems to act by

                    reducing polysynaptic responses and blocking

                    post-tetanic potentiation (Drug Facts & Comparisons,

                    1985).

    

                    Its efficacy in neuralgia may result from the

                    reduction of excitatory synaptic transmission in the

                    spinal trigeminal nucleus because it increases the

                    latency of trigeminal neuronal response and decreases

                    the number of neuronal discharges.  Carbamazepine

                    10,11-epoxide, the major metabolite of carbamazepine,

                    also has considerable activity against neuralgia.

    

                    The antidiuretic effects of carbamazepine are a

                    consequence of  reduced plasma concentrations of

                    anti-diuretic hormone.

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             Of 22 adults requiring admission to

                             hospital following carbamazepine overdose,

                             the mean ingestion was 12 g (range 1.6 to 45

                             g).  All survived.  (Seymour, 1993).

 

                    7.2.1.2  Children

 

                             Children appear more likely to

                             suffer seizures and less likely to develop

                             electrocardiographic abnormalities (Bridge &

                             Norton, 1994).

 

             7.2.2  Relevant animal data

 

                    In animals, the lethal concentrations (oral LD50) are:

    

                    Mice:  3750 mg/kg; Rats:  4025 mg/kg

                    (Budavari, 1996.

 

             7.2.3  Relevant in vitro data

 

                    No data available.

 

        7.3  Carcinogenicity

 

             Carbamazepine in doses of 25, 75, and 250 mg was given

             to Sprague-Dawley rats for two years. It caused a 

             dose-related increase in the incidence of hepatocellular 

             tumours in female rats and benign interstitial cell adenomas

             in the testes of males. The significance of these findings

             for humans is not known (PDR, 1988). There have been no 

             reports of tumorigenic effects in humans.

 

        7.4  Teratogenicity

 

             Carbamazepine is classified as category “C”.  That is to

             say, studies in animals have revealed adverse effects on the

             fetus but there are no controlled studies in women.  Minor

             malformations such as those seen with fetal hydantoin

             syndrome have been observed with carbamazepine monotherapy. 

             However, carbamazepine has been recommended as the drug of

             choice in women at risk of pregnancy who require

             anticonvulsant therapy for the first time (Briggs et al.,

             1986).

 

        7.5  Mutagenicity

 

             Bacterial and mammalian mutagenicity studies using

             carbamazepine have shown no evidence of mutagenicity.

 

        7.6  Interactions

 

             Antibacterials

    

             Co-administration of isoniazid or erythromycin can cause

             significant increases in serum carbamazepine concentrations

             and lead to toxicity (Valsalan & Cooper, 1982; Wright et al.,

             1982; Wong et al., 1983; Mitsch, 1989).

    

             Antidepressants

    

             Co-adminstration of fluoxetine or fluvoxamine may result in

             reduced serum carbamazepine concentrations (Pearson, 1990;

             Fritz et al., 1991).  Serotonin syndrome has been reported

             with co-administration of carbamazepine and fluoxetine

             (Brœsen & Kragh-Sœrensen, 1993).  Severe neurotoxicity has

             been associated with co-administration of carbamazepine and

             lithium (Andrus, 1984; Chaudry & Waters, 1983).  

    

             Carbamazepine is chemically related to the tricyclic

             antidepressants and should not be given to patients who are

             sensitive to these drugs.

    

 

             Antiepileptics

    

             Phenytoin lowers serum carbamazepine by induction of

             metabolism (Christiansen & Dam, 1973).  Carbamazepine may in

             turn lower serum phenytoin concentrations (Hansen et al.,

             1971).  Phenobarbitone reduces serum concentrations of

             carbamazepine without loss of seizure control (Cereghino et

             al., 1975).

    

             Benzodiazepines

    

             Long-term carbamazepine therapy may result in enhanced

             metabolism of benzodiazepines due to enzyme induction

             (Dhillon & Richens, 1981; Lai et al., 1978).

    

             Calcium channel blockers

    

             Verapamil and diltiazem can inhibit carbamazepine metabolism

             to such an extent so as to result in clinical neurotoxicity

             (Macphee et al., 1986; Brodie & Macphee, 1986).

 

        7.7  Main adverse effects

 

             The adverse effects that occur most frequently during

             early treatment are dizziness, drowsiness, lightheadedness,

             unsteadiness, ataxia, nystagmus, nausea, and vomiting.  Their

             severity and incidence may be minimised by starting therapy

             with a low dose which is then gradually increased.

    

             The most severe adverse reactions involve the haemopoietic

             system, the skin, and the cardiovascular system.  They

             are:

 

             Haemopoietic system

             Leucocytosis, leucopenia, agranulocytosis, eosinophilia,

             purpura, aplastic anaemia, and thrombocytopenia.  These

             reactions are rare but can be serious.  Early detection of

             haematological toxicity is very important because aplastic

             anaemia and thrombocytopenia can be fatal. 

    

             Skin

    

             Pruritic and erythematous rashes, urticaria, Stevens-Johnson

             syndrome, exfoliative dermatitis, erythema multiforme or

             erythema nodosum, photosensitivity reactions, alterations in

             pigmentation, and aggravation of systemic lupus

             erythematous.

    

             Alopecia, diaphoresis, and toxic epidermal necrolysis may

             also occur.

    

 

             Cardiovascular system

    

             Congestive heart failure, oedema, aggravation of

             hypertension, hypotension, syncope and collapse, primary and

             recurrent thrombophlebitis, aggravation of coronary artery

             disease, arrhythmias and AV block, hyponatraemia and water

             intoxication.

    

             Other

    

             Genitourinary, metabolic, hepatic, and other reactions are

             rare.  They include lymphadenopathy, urinary frequency, acute

             urinary retention, albuminuria, glycosuria, elevated blood

             urea nitrogen level, microscopic deposits in the urine,

             impotence, cholestatic and hepatocellular jaundice, fever and

             chills, myalgia and arthralgia, leg cramps, conjunctivitis,

             and paraesthesiae. 

    

             (Reynolds, 1996)

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

 

             8.1.1  Sampling and specimen collection

 

                    8.1.1.1  Toxicological analyses

 

                    8.1.1.2  Biomedical analyses

 

                    8.1.1.3  Arterial blood gas analysis

 

                    8.1.1.4  Haematological analyses

 

                    8.1.1.5  Other (unspecified) analyses

 

             8.1.2  Storage of laboratory samples and specimens

 

                    8.1.2.1  Toxicological analyses

 

                    8.1.2.2  Biomedical analyses

 

                    8.1.2.3  Arterial blood gas analysis

 

                    8.1.2.4  Haematological analyses

 

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

 

                    8.1.3.1  Toxicological analyses

 

                    8.1.3.2  Biomedical analyses

 

                    8.1.3.3  Arterial blood gas analysis

 

                    8.1.3.4  Haematological analyses

 

                    8.1.3.5  Other (unspecified) analyses

 

        8.2  Toxicological analyses and their interpretation

 

             8.2.1  Tests on toxic ingredient(s) of material

 

                    8.2.1.1  Simple qualitative test(s)

 

                    8.2.1.2  Advanced qualitative confirmation test(s)

 

                    8.2.1.3  Simple quantitative method(s)

 

                    8.2.1.4  Advanced quantitative method(s)

 

             8.2.2  Tests for biological specimens

 

                    8.2.2.1  Simple qualitative test(s)

 

                    8.2.2.2  Advanced qualitative confirmation test(s)

 

                    8.2.2.3  Simple quantitative method(s)

 

                    8.2.2.4  Advanced quantitative method(s)

 

                    8.2.2.5  Other dedicated method(s)

 

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

 

             8.3.1  Biochemical analysis

 

                    8.3.1.1  Blood, plasma or serum

 

                             Plasma carbamazepine concentration. 

                             This should be repeated at regular intervals

                             until it is falling.

    

                             Serum electrolytes.

                             Renal function tests.

 

                    8.3.1.2  Urine

 

                    8.3.1.3  Other fluids

 

             8.3.2  Arterial blood gas analyses

 

                    Arterial blood gases in the ventilated patient

                    or where pulmonary aspiration is suspected.

 

             8.3.3  Haematological analyses

 

             8.3.4  Interpretation of biomedical investigations

 

                    In general the peak plasma carbamazepine

                    concentration correlates well with the clinical

                    severity of the poisoning.  The peak concentration may

                    be delayed up to 30 hours.  A single plasma

                    carbamazepine concentration may not correlate very

                    well with the severity of intoxication.

    

                    Therapeutic plasma levels of carbamazepine are from 4

                    to 10 mg/L.  Acute ingestion of greater than 10 mg/kg

                    can produce a plasma level above this range.

    

                    Ataxia and nystagmus may occur with levels greater

                    than 12 mg/L

    

                    In one series of adult admissions, a peak plasma

                    carbamazepine concentration above 170 mmol/L (40 mg/L)

                    was associate with an increased risk of serious

                    complications such as coma, seizures, respiratory

                    failure and cardiac conduction defects.  In those

                    patients with a peak concentration less than  170

                    mcmol/L, only one was comatose and none had any of the

                    other severe symptoms (Hojer et al., 1993).

    

                    Peak plasma carbamazepine concentrations have been

                    reported as ranging from 13.5 to 57.7 mg/L (57 to 244

                    mmol/L) in symptomatic children (Macnab et al., 1993). 

                    In ten severely poisoning children (coma, convulsions,

                    hypotension and respiratory depression), the mean

                    plasma carbamazepine concentration was 50 mg/L (213

                    mmol/L) with a range of from 333.7 to 80.9 mg/L (143

                    to 343 mmol/L) ( Tibbals, 1992).

 

        8.4  Other biomedical (diagnostic) investigations and their

             interpretation

 

             A chest x-ray in indicated where there is coma or

             convulsions have occurred to look for evidence of pulmonary

             aspiration.

 

        8.5  Overall Interpretation of all toxicological analyses and

             toxicological investigations

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    The first signs of acute intoxication begin 1

                    to 3 hours after an overdose but may be delayed;

                    presenting symptoms usually include disturbances of

                    the central nervous system, and cardiovascular and,

                    less frequently, anticholinergic signs and symptoms.

 

             9.1.2  Inhalation

 

                    Not relevant.

 

             9.1.3  Skin exposure

 

                    Not relevant.

 

             9.1.4  Eye contact

 

                    Not relevant.

 

             9.1.5  Parenteral exposure

 

                    No data available.

 

             9.1.6  Other

 

                    No data available.

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Effects of chronic intoxication include: 

                    dizziness, drowsiness, and disturbances of cerebellar

                    and oculomotor function (ataxia, nystagmus, and

                    diplopia), cardiac arrhythmias, congestive heart

                    failure (rarely), bone marrow failure including

                    aplastic anaemia, cholestatic and hepatocellular

                    jaundice, dermatological reactions, 

                    tubulo-interstitial nephritis, water retention, and

                    hyponatraemia.

 

             9.2.2  Inhalation

 

                    Not relevant.

 

             9.2.3  Skin exposure

 

                    Not relevant.

 

             9.2.4  Eye contact

 

                    Not relevant.

 

             9.2.5  Parenteral exposure

 

                    No data available.

 

             9.2.6  Other

 

                    No data available.

 

        9.3  Course, prognosis, cause of death

 

             Following overdose, peak plasma carbamazepine

             concentrations and clinical effects are usually delayed by 4

             to 8 hours and may be delayed up to 24 hours.  The degree of

             CNS depression is characteristically “cyclical” with sudden

             improvements and deteriorations.

    

             Severe intoxication is characterised by one or more of the

             following features: coma, seizures, hypotension, or cardiac

             conduction defects.

    

             Moderate intoxication is characterized by a depression in the

             level of consciousness not required intubation and without

             other severe effects.

    

             Minor intoxications may be asymptomatic or exhibit the

             following features: minor drowsiness, nystagmus, ataxia or

             dysarthria.

    

             The prognosis for carbamazepine poisoning is usually good

             even for severe cases provided that appropriate supportive

             care is instituted in a timely fashion.  Where death does

             occur, it is not usually a direct result of carbamazepine

             poisoning but secondary to being pulmonary aspiration of

             gastric contents occuring during convulsions (Bates et al.,

             1997).

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    After acute ingestion, sinus tachycardia is

                    relatively common.  Minor ECG abnormalities, including

                    prolongation of the PR, QRS and QT intervals, are less

                    common, do not correlate with serum carbamazepine

                    concentration and rarely result in clinically

                    significant dysrhythmias.  Mild self-limiting

                    hypotension may be observed (Apfelbaum et al., 1995). 

                    Minor ECG abnormalities may also occur in the context

                    of chronic carbamazepine therapy.

 

             9.4.2  Respiratory

 

                    Severe acute intoxication leads to coma with

                    associated respiratory depression.

 

             9.4.3  Neurological

 

                    9.4.3.1  Central Nervous System (CNS)

 

                             The most prominent feature of

                             carbamazepine toxicity is depression in the

                             level of consciousness.  In one series, this

                             was observed in 100% of cases (Seymour,

                             1993).  Fluctuation in the level of

                             consciousness with sudden deterioration or

                             improvement is said to be characteristic and

                             may reflect irregular absorption or

                             enterohepatic circulation of carbamazepine

                             (Durelli et al., 1989)  Other observed

                             neurological features include paradoxical

                             seizures, mydriasis, abnormal muscle tone and

                             tendon reflexes, ataxia, nystagmus and

                             ophthalmoplegia (Seymour 1993).

    

                             Chronic carbamazepine intoxication can result

                             in headaches, diplopia and ataxia.

 

                    9.4.3.2  Peripheral nervous system

 

                             No significant effects.

 

                    9.4.3.3  Autonomic nervous system

 

                             Antimuscarinic effects especially

                             sinus tachycardia are frequently

                             observed.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             No significant effects.

 

             9.4.4  Gastrointestinal

 

                    Nausea and vomiting are common features of

                    acute toxicity.  Acute pancreatitis is described

                    following overdose (Tsao & Wright, 1993). 

    

                    Chronic ingestion can cause dry mouth, gastric

                    distress, abdominal pain, nausea, vomiting, and

                    anorexia.

 

             9.4.5  Hepatic

 

                    Transient hepatic dysfunction is described

                    following acute overdose (Seymour, 1993).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Acute intoxication can cause urinary

                             retention.

 

                    9.4.6.2  Other

 

             9.4.7  Endocrine and reproductive systems

 

                    High concentrations of carbamazepine can

                    stimulate vasopression secretion and lead to

                    hyponatraemia (Syndrome of inappropriate antidiuretic

                    hormone secretion – SIADH) (Gandelman, 1994). 

 

             9.4.8  Dermatological

 

                    No significant effects.

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    No significant effects

 

             9.4.10 Haematological

 

                    No significant effects with acute poisoning.

                    Dose-related leukopenia has been reported as a chronic

                    effect.

 

             9.4.11 Immunological

 

                    No significant effects.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             No significant effects.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             Hyponatraemia

 

                    9.4.12.3 Others

 

                             Hypothermia is reported after acute

                             overdose (Weaver et al., 1988).

 

             9.4.13 Allergic reactions

 

                    No data available.

 

             9.4.14 Other clinical effects

 

                    No data available.

 

             9.4.15 Special risks

 

                    Pregnancy: Carbamazepine is classified as

                    category “C”.  That is to say, studies in animals have

                    revealed adverse effects on the fetus but there are no

                    controlled studies in women.  Minor malformations such

                    as those seen with fetal hydantoin syndrome have been

                    observed with carbamazepine monotherapy.  However,

                    carbamazepine has been recommended as the drug of

                    choice in women at risk of pregnancy who require

                    anticonvulsant therapy for the first time (Briggs et

                    al, 1986).

    

                    Breast-feeding: Carbamazepine’s safety when used

                    during lactation has not been established.  The

                    concentration of carbamazepine in the milk is

                    approximately 60% of maternal plasma concentration. 

                    Either breast-feeding or carbamazepine should be

                    discontinued, depending on the importance of the drug

                    for the woman (Reynolds, 1996).

    

                    Porphyria: A study in rats showed that carbamazepine

                    should be regarded as potentially hazardous in people

                    who have hereditary hepatic porphyria (Reynolds,1989).

 

        9.5  Other

 

             No data available.

 

             9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             The management of carbamazepine toxicity is essentially

             supportive. In severe cases, this may require endotracheal

             intubation and ventilation.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             The major threat to life is from a decreased level of

             consciousness and inadequate ventilation.

    

             The patient should be immediately assessed for adequacy of

             airway, breathing and circulation, and level of

             consciousness. The airway should be secured by endotracheal

             intubation if necessary. Supplemental oxygen should be

             provided. Intravenous access should be established. Vital

             signs, level of consciousness and cardiac rhythm should be

             carefully monitored.

    

             Seizures, hypotension, hyponatraemia, hypothermia should be

             managed according to standard guidelines.

 

        10.3 Decontamination

 

             Administer oral or nasogastric activated charcoal as

             soon as possible once the airway is deemed adequate or

             secured.

 

        10.4 Enhanced elimination

 

             Repeat-dose activated charcoal is the method of choice

             to enhance elimination of carbamazepine. A dose of 25 to 50 g

             of activated charcoal should be adminstered by nasogastric

             tube every 3 to 4 hours until clinical improvement occurs.

             

    

             Although charcoal haemoperfusion has been used to enhance the

             elimination of carbamazepine, repeat-dose actived charcoal

             appears to be at least as effective and is a much less

             invasive therapy (Vale, 1992).  It is important to note that,

             although repeat dose activated charcoal has been should to

             significantly enhance the elimination of carbamazepine, this

             has not been shown to associated with a more rapid clinical

             recovery (Wason et al., 1992)

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    There is no antidote.

 

             10.5.2 Children

 

                    There is no antidote.

 

        10.6 Management discussion

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             A 23-year-old woman with epilepsy developed superficial

             coma, tachycardia, hypothermia, irregular respiration and

             dilated pupils after she ingested 16,000 mg carbamazepine. 

             Gastric lavage was performed.  However, 45 hours after she

             was admitted to hospital, her coma deepened and her

             respiration became more irregular.  Delayed absorption of

             carbamazepine from the gut, with an increase in serum

             carbamazepine concentration, probably accounts for these

             findings.  Following treatment with activated charcoal,

             sodium sulphate, forced diuresis (with sorbitol and

             mannitol), and metoclopramide, she recovered 100 hours after

             hospital admission (De Zeeuw et al., 1979).

    

             A 21-year-old man developed coma, respiratory depression,

             increased central venous pressure, hypotension and nodal

             tachycardia after he ingested 40 000 mg carbamazepine, with

             an unknown amount of lithium citrate.  Gastric lavage was

             successful and he was given IV fluids, diazepam, and

             phenobarbital.  Forty-five hours after ingestion, he

             developed fixed mydriasis and hypotonia.  He was treated with

             corticosteroids, diuretics, and hyperventilation, and 16

             hours later his pupils reacted increasingly to light.  He was

             extubated 24 hours later, and 2 days later he was conscious

             (Wernberg et al., 1982).

    

             A 23-month-old healthy boy (13.5 kg body weight) developed an

             unsteady gait after he ingested 2000 mg carbamazepine (148

             mg/kg) and was admitted to hospital 3 hours later.  His vital

             signs were normal but he was lethargic and ataxic and his

             pupils were moderately dilated.  He was given ipecac syrup

             but when he vomited, his vomitus did not contain pill

             fragments.  He was then given activated charcoal and

             magnesium sulphate.  He went into a deep coma 9 hours

             post-ingestion.  Fifteen hours after ingestion his vital

             signs were: blood pressure, 110/76 mmHg; pulse, 108 bpm;

 

             respiration, 24/minute; and temperature 36.4°C.  He was given

             multiple doses of activated charcoal and sodium sulphate. 

             Twenty-six hours after ingestion he had 3 episodes of

             tonic-clonic generalized seizures that were treated with

             diazepam 5 mg intravenous (IV).  The patient recovered

             completely in a few days, and there were no sequelae six

             months later (Deng et al., 1986).

    

             A 41-year-old woman was given erythromycin stearate (500 mg

             every 6 hours) while she was being treated with carbamazepine

             and phenobarbital (100 mg, 4 times a day).  This combination

             caused carbamazepine toxicity, with inappropriate ADH

             secretion, dizziness, nystagmus, and ataxia.  One week after

             receiving erythromycin, her blood levels increased from 13.3

             mg/L to 28.2 mg/L.  Twenty-four hours after all medication

             was stopped, her carbamazepine levels fell to 5.9 mg/L. 

             Carbamazepine and phenobarbital were then resumed, and her

             carbamazepine levels rose to 10.8 mg/L after 24 hours and to

             11.3 mg/L after three weeks (Carranco et al., 1985).

    

             A 22-year-old healthy male ingested an overdose of

             carbamazepine.  He had an initial period of restlessness and

             aggression.  He then became stuporous and was admitted to

             hospital in a coma.  His vital signs were normal.  Gastric

             lavage was performed and he was given 30 g sodium sulphate

             and a suspension of 50 g activated charcoal.  Haemoperfusion

             was performed for 4 hours, reducing the half-life and

             successfully enhancing the elimination of carbamazepine

             (Groot et al., 1984).

    

             A 45-year-old epileptic woman who had been receiving

             long-term therapy with carbamazepine, valproic acid, and

             phenytoin, ingested a carbamazepine overdose.  When she

             arrived at hospital, she was stuporous and had motor

             restlessness.  Her heart rate was 90 bpm, blood pressure

             140/80 mmHg, and temperature 35.0°C.  Eight hours later she

             was in a coma, her blood pressure was 90/50 mmHg, and her

             temperature 34.3°C.  Gastric lavage was performed and she was

             given activated charcoal and sodium sulphate.  Haemoperfusion

             for 4 hours, slowly decreased the plasma concentration of

             carbamazepine. Her condition steadily improved (Groot et al.,

             1984).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             Therapy with carbamazepine should begin at low doses

             and be increased gradually until the patient responds.

    

 

             Special care should be taken when carbamazepine is

             administered in addition to other anticonvulsant therapy, or

             when the patient requires other medications because drug

             interactions can occur.

 

        12.2 Other

 

             No data available.

 

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        Neurology 38:755-9.

    

        Wernberg M, Peterson TK & Kristensar HK (1982).  Carbamazepine

        poisoning. Ugeskt Laeg l43: 619-620 (in German).

    

        Westenberg HGM, Klein E van der, Oei TT, Zeeuw RA de (1978). 

        Kinetics of carbamazepine and carbamazepine epoxide determined by

        use of plasma and saliva.  Clin Pharmacol Ther 23: 320-328.

    

        Wong YY et al.  (1983)  Effect of erythomycin on carbamazepine

        kinetics.  Clin Pharmacol Ther 33:460-4.

    

        Wright JM et al.  (1982) Isoniazid-induced carbamazepine toxicity

        and vice versa.  N Engl J Med 307:1325-7.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Authors:    Arlinda Borges, J. Bivar Abrantes, J. Marques Penha,

  1. Paiva Parada, M. Teresa Teixeira, Teresa M. Pinto

                    Centro de Informaçao Antivenénos

                    Instituto Nacional de Emergencia Médica

                    Rua Infante D Pedro, 8

                    1700 Lisbon

                    Portugal

    

                    Tel:     7930503

                    Fax:     7937124

                    Telex:   13304 SNALP P

    

        Date:       February 1988

    

        Reviewer:   Dr J. Pronczuk

                    CIAT, 7° piso

                    Hospital de Clinicas

                    Av. Italia s/n

                    Montevideo

                    Uruguay

    

        Date:       July 1988

    

        Peer

        review:     Adelaide, Australia, April 1991

    

        Update:     Dr R. Fernando, June 1993

    

 

        Update/edit: Dr M.O. Rambourg-Schepens & Dr L. Murray

    

        Date:        November 1999

    

 

    

Clobazam

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/Form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination and excretion

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological Analyses and Their Interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple Qualitative Test(s)

         8.2.1.2 Advanced Qualitative Confirmation Test(s)

         8.2.1.3 Simple Quantitative Method(s)

         8.2.1.4 Advanced Quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple Qualitative Test(s)

         8.2.2.2 Advanced Qualitative Confirmation Test(s)

         8.2.2.3 Simple Quantitative Method(s)

         8.2.2.4 Advanced Quantitative Method(s)

         8.2.2.5 Other Dedicated Method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analysis

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other fluids

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    Clobazam

 

    International Programme on Chemical Safety

    Poisons Information Monograph 921

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Benzodiazepines

    (PIM G008).

 

  1. NAME

 

        1.1  Substance

 

             Clobazam

 

        1.2  Group

 

             ATC classification index

 

             Psycholeptics (N05)/  Anxiolytics (N05B)/

             Benzodiazepine derivatives (N05BA)

 

        1.3  Synonyms

 

             H-4723; HR-376; LM-2717

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    22316-47-8

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Central nervous system, causing depression of

             respiration and consciousness.

 

        2.2  Summary of clinical effects

 

             Central nervous system (CNS) depression and coma, or

             paradoxical excitation, but deaths are rare when

             benzodiazepines are taken alone. Deep coma and other

             manifestations of severe CNS depression are rare. Sedation,

             somnolence, diplopia, dysarthria, ataxia and intellectual

 

             impairment are the most common adverse effects of

             benzodiazepines. Overdose in adults frequently involves co-

             ingestion of other CNS depressants, which act synergistically

             to increase toxicity. Elderly and very young children are

             more susceptible to the CNS depressant action. Intravenous

             administration of even therapeutic doses of benzodiazepines

             may produce apnoea and hypotension.

             Dependence may develop with regular use of benzodiazepines,

             even in therapeutic doses for short periods. If

             benzodiazepines are discontinued abruptly after regular use,

             withdrawal symptoms may develop.  The amnesia produced by

             benzodiazepines can have medico-legal consequences.

 

        2.3  Diagnosis

 

             The clinical diagnosis is based upon the history of

             benzodiazepine overdose and the presence of the clinical

             signs of benzodiazepine intoxication.

             Benzodiazepines can be detected or measured in blood and

             urine using standard analytical methods. This information may

             confirm the diagnosis but is not useful in the clinical

             management of the patient.

             A clinical response to flumazenil, a specific benzodiazepine

             antagonist, also confirms the diagnosis of benzodiazepine

             overdose, but administration of this drug is rarely

             justified.

 

        2.4  First aid measures and management principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly involve co-

             ingestion of other CNS depressants and other drugs. Activated

             charcoal normally provides adequate gastrointestinal

             decontamination. Gastric lavage is not routinely indicated.

             Emesis is contraindicated. The use of flumazenil is reserved

             for cases with severe respiratory or cardiovascular

             complications and should not replace the basic management of

             the airway and respiration. The routine use of flumazenil is

             contraindicated because of potential complications, including

             seizures.  Renal and extracorporeal methods of enhanced

             elimination are not effective.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

        3.2  Chemical structure

 

             Chemical Name:

             7-Chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-

             -2,4(3H)-dione

    

 

             Molecular Formula: C16H13ClN2O2

    

             Molecular Weight: 300.7

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White

 

             3.3.2  State/Form

 

                    Solid-crystals

 

             3.3.3  Description

 

                    Very slightly soluble in water; soluble in

                    alcohol and in methyl alcohol. A 1% suspension in

                    water has a pH of 5.5 to 7.5 (Reynolds, 1996).

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

             3.4.2  Storage conditions

 

  1. USES

 

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

        4.2  Therapeutic dosage

             4.2.1  Adults

             4.2.2  Children

        4.3  Contraindications

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

             7.1.1  Toxicodynamics

             7.1.2  Pharmacodynamics

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

        7.7  Main adverse effects

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.2  Urine

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    “Basic analyses”

                    “Dedicated analyses”

                    “Optional analyses”

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and

             toxicological investigations

 

             Sample collection

             For toxicological analyses: whole blood 10 mL; urine 25 mL

             and gastric contents 25 mL.

    

             Biomedical analysis

             Blood gases, serum electrolytes, blood glucose and hepatic

             enzymes when necessary in severe cases.

    

             Toxicological analysis

             Qualitative testing for benzodiazepines is helpful to confirm

             their presence, but quantitative levels are not clinically

             useful. More advanced analyses are not necessary for the

             treatment of the poisoned patient due the lack of correlation

             between blood concentrations and clinical severity (Jatlow et

             al., 1979; MacCormick et al., 1985; Minder, 1989).

    

             TLC and EMIT: These provide data on the presence of

             benzodiazepines, their metabolites and possible associations

             with other drugs.

    

             GC or HPLC: These permit identification and quantification of

             the benzodiazepine which caused the poisoning and its

             metabolites in blood and urine.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    The onset of impairment of consciousness is

                    relatively rapid in benzodiazepine poisoning.  Onset

                    is more rapid following larger doses and with agents

                    of shorter duration of action. The most common and

                    initial symptom is somnolence.  This may progress to

                    coma Grade I or Grade II (see below) following very

                    large ingestions.

    

                    Reed Classification of Coma (Reed et al., 1952)

    

                    Coma Grade I:   Depressed level of consciousness,

                                    response to painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade II:  Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade III: Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes absent. Vital

                                    signs intact

    

                    Coma Grade IV:  Coma grade III plus respiratory and

                                    circulatory collapse

 

             9.1.2  Inhalation

 

                    Not relevant.

 

             9.1.3  Skin exposure

 

                    No data.

 

             9.1.4  Eye contact

 

                    No data.

 

             9.1.5  Parenteral exposure

 

                    Overdose by the intravenous route results in

                    symptoms similar to those associated with ingestion,

                    but they appear immediately after the infusion, and

                    the progression of central nervous system (CNS)

                    depression is more rapid. Acute intentional poisoning

 

                    by this route is uncommon and most cases are

                    iatrogenic. Rapid intravenous infusion may cause

                    hypotension, respiratory depression and

                    apnoea.

 

             9.1.6  Other

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Toxic effects associated with chronic exposure

                    are secondary to the presence of the drug and

                    metabolites and include depressed mental status,

                    ataxia, vertigo, dizziness, fatigue, impaired motor

                    co-ordination, confusion, disorientation and

                    anterograde amnesia. Paradoxical effects of

                    psychomotor excitation, delirium and aggressiveness

                    also occur. These chronic effects are more common in

                    the elderly, children and patients with renal or

                    hepatic disease.

    

                    Administration of therapeutic doses of benzodiazepines

                    for 6 weeks or longer can result in physical

                    dependence, characterized by a withdrawal syndrome

                    when the drug is discontinued. With larger doses, the

                    physical dependence develops more rapidly.

 

             9.2.2  Inhalation

 

                    No data.

 

             9.2.3  Skin exposure

 

                    No data.

 

             9.2.4  Eye contact

 

                    No data.

 

             9.2.5  Parenteral exposure

 

                    The chronic parenteral administration of

                    benzodiazepines may produce thrombophlebitis and

                    tissue irritation, in addition to the usual symptoms

                    (Greenblat & Koch-Weser, 1973).

 

             9.2.6  Other

 

                    No data.

 

        9.3  Course, prognosis, cause of death

 

             Benzodiazepines are relatively safe drugs even in

             overdose. The clinical course is determined by the

             progression of the neurological symptoms. Deep coma or other

             manifestations of severe central nervous system (CNS)

             depression are rare with benzodiazepines alone.  Concomitant

             ingestion of other CNS depressants may result in a more

             severe CNS depression of longer duration.

    

             The therapeutic index of the benzodiazepines is high and the

             mortality rate associated with poisoning due to

             benzodiazepines alone is very low. Complications in severe

             poisoning include respiratory depression and aspiration

             pneumonia. Death is due to respiratory arrest.

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Hypotension, bradycardia and tachycardia have

                    been reported with overdose (Greenblatt et al., 1977;

                    Meredith & Vale 1985). Hypotension is more frequent

                    when benzodiazepines are ingested in association with

                    other drugs (Hojer et al., 1989). Rapid intravenous

                    injection is also associated with hypotension.

 

             9.4.2  Respiratory

 

                    Respiratory depression may occur in

                    benzodiazepine overdose and the severity depends on

                    dose ingested, amount absorbed, type of benzodiazepine

                    and co-ingestants. Respiratory depression requiring

                    ventilatory support has occurred in benzodiazepine

                    overdoses (Sullivan, 1989; Hojer et al.,1989). The

                    dose-response for respiratory depression varies

                    between individuals.  Respiratory depression or

                    respiratory arrest may rarely occur with therapeutic

                    doses. Benzodiazepines may affect the control of

                    ventilation during sleep and may worsen sleep apnoea

                    or other sleep-related breathing disorders, especially

                    in patients with chronic obstructive pulmonary disease

                    or cardiac failure (Guilleminault, 1990).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             CNS depression is less marked than

                             that produced by other CNS depressant agents

                             (Meredith & Vale, 1985). Even in large

                             overdoses, benzodiazepines usually produce

                             only mild symptoms and this distinguishes

 

                             them from other sedative-hypnotic agents.

                             Sedation, somnolence, weakness, diplopia,

                             dysarthria, ataxia and intellectual

                             impairment are the most common neurological

                             effects. The clinical effects of severe

                             poisoning are sleepiness, ataxia and coma

                             Grade I to Grade II (Reed). The presence of

                             more severe coma suggests the possibility of

                             co-ingested drugs. Certain of the newer

                             short-acting benzodiazepines (temazepam,

                             alprazolam and triazolam) have been

                             associated with several fatalities and it is

                             possible that they may have greater acute

                             toxicity (Forrest et al., 1986). The elderly

                             and very young children are more susceptible

                             to the CNS depressant action of

                             benzodiazepines.

                             The benzodiazepines may cause paradoxical CNS

                             effects, including excitement, delirium and

                             hallucinations. Triazolam has been reported

                             to produce delirium, toxic psychosis, memory

                             impairment and transient global amnesia

                             (Shader & Dimascio, 1970; Bixler et al,

                             1991). Flurazepam has been associated with

                             nightmares and hallucinations.

                             There are a few reports of extrapyramidal

                             symptoms and dyskinesias in patients taking

                             benzodiazepines (Kaplan & Murkafsky, 1978;

                             Sandyk, 1986).

                             The muscle relaxation caused by

                             benzodiazepines is of CNS origin and

                             manifests as dysarthria, incoordination and

                             difficulty standing and walking.

 

                    9.4.3.2  Peripheral nervous system

 

                    9.4.3.3  Autonomic nervous system

 

                    9.4.3.4  Skeletal and smooth muscle

 

             9.4.4  Gastrointestinal

 

                    Oral benzodiazepine poisoning will produce

                    minimal effects on the gastrointestinal tract (GI)

                    tract but can occasionally cause nausea or vomiting

                    (Shader & Dimascio, 1970).

 

             9.4.5  Hepatic

 

                    A case of cholestatic jaundice due focal

                    hepatic necrosis was associated with the

                    administration of diazepam (Tedesco & Mills,

                    1982).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Vesical hypotonia and urinary

                             retention has been reported in association

                             with diazepam poisoning (Chadduck et al.,

                             1973).

 

                    9.4.6.2  Other

 

             9.4.7  Endocrine and reproductive systems

 

                    Galactorrhoea with normal serum prolactin

                    concentrations has been noted in 4 women taking

                    benzodiazepines (Kleinberg et al., 1977).

                    Gynaecomastia has been reported in men taking high

                    doses of diazepam (Moerck & Majelung, 1979). Raised

                    serum concentrations of oestrodiol were observed in

                    men taking diazepam 10 to 20 mg daily for 2 weeks

                    (Arguelles & Rosner, 1975).

 

             9.4.8  Dermatological

 

                    Bullae have been reported following overdose

                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz

                    et al., 1990).

                    Allergic skin reactions were attributed to diazepam at

                    a rate of 0.4 per 1000 patients (Brigby,

                    1986).

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Brown opacification of the lens occurred in 2

                    patients who used diazepam for several years (Pau

                    Braune, 1985).

 

             9.4.10 Haematological

 

                    No data.

 

             9.4.11 Immunological

 

                    Allergic reaction as above (see 9.4.8).

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             No direct disturbances have been

                             described.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             No direct disturbances have been

                             described.

 

                    9.4.12.3 Others

 

             9.4.13 Allergic reactions

 

                    Hypersensitivity reactions including

                    anaphylaxis are very rare (Brigby, 1986). Reactions

                    have been attributed to the vehicle used for some

                    parenteral diazepam formulations (Huttel et al.,

                    1980). There is also a report of a type I

                    hypersensitivity reaction to a lipid emulsion of

                    diazepam (Deardon, 1987).

 

             9.4.14 Other clinical effects

 

                    Hypothermia was reported in 15% of cases in

                    one series. (Martin, 1985; Hojer et al.,

                    1989).

 

             9.4.15 Special risks

 

                    Pregnancy

                    Passage of benzodiazepines across the placenta depends

                    on the degree of protein binding in mother and fetus,

                    which is influenced by factors such as stage of

                    pregnancy and plasma concentrations of free fatty

                    acids in mother and fetus (Lee et al., 1982). Adverse

                    effects may persist in the neonate for several days

                    after birth because of immature drug metabolising

                    enzymes. Competition between diazepam and bilirubin

                    for protein binding sites could result in

                    hyperbilirubinemia in the neonate (Notarianni,

                    1990).

                    The abuse of benzodiazepines by pregnant women can

                    cause withdrawal syndrome in the neonate. The

                    administration of benzodiazepines during childbirth

                    can produce hypotonia, hyporeflexia, hypothermia and

                    respiratory depression in the newborn.

                    Benzodiazepines have been used in pregnant patients

                    and early reports associated diazepam and

                    chlordiazepoxide with some fetal malformations, but

                    these were not supported by later studies (Laegreid et

                    al., 1987; McElhatton, 1994).

    

 

                    Breast feeding

                    Benzodiazepines are excreted in breast milk in

                    significant amounts and may result in lethargy and

                    poor feeding in neonates.  Benzodiazepines should be

                    avoided in nursing mothers (Brodie, 1981; Reynolds,

                    1996).

 

        9.5  Other

 

             Dependence and withdrawal

             Benzodiazepines have a significant potential for abuse and

             can cause physical and psychological dependence. Abrupt

             cessation after prolonged use causes a withdrawal syndrome

             (Ashton, 1989). The mechanism of dependence is probably

             related to functional deficiency of GABA activity.

             Withdrawal symptoms include anxiety, insomnia, headache,

             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,

             weakness, perspiration, irritability, hypersensitivity to

             visual and auditory stimuli, palpitations, tachycardia and

             postural hypotension. In severe and rare cases of withdrawal

             from high doses, patients may develop affective disorders or

             motor dysfunction: seizures, psychosis, agitation, confusion,

             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;

             Reynolds, 1996).

             The time of onset of the withdrawal syndrome depends on the

             half-life of the drug and its active metabolites; the

             symptoms occur earlier and may be more severe with short-

             acting benzodiazepines. Others risk factors for withdrawal

             syndrome include prolonged use of the drug, higher dosage and

             abrupt cessation of the drug.

    

             Abuse

             Benzodiazepines, particularly temazepam, have been abused

             both orally and intravenously (Stark et al., 1987; Woods,

             1987; Funderburk et al, 1988)

    

             Criminal uses

             The amnesic effects of benzodiazepines have been used for

             criminal purposes with medicolegal consequences (Ferner,

             1996).

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly include other

             drugs and other CNS depressants. Activated charcoal normally

             provides adequate gastrointestinal decontamination. Gastric

             lavage is not routinely indicated. Emesis is contraindicated.

 

             The use of flumazenil is reserved for cases with severe

             respiratory or cardiovascular complications and should not

             replace the basic management of the airway and respiration.

             Renal and extracorporeal elimination methods are not

             effective.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             The patient should be evaluated to determine adequacy

             of airway, breathing and circulation. Continue clinical

             observation until evidence of toxicity has resolved.

             Intravenous access should be available for administration of

             fluid. Endotracheal intubation, assisted ventilation and

             supplemental oxygen may be required on rare occasions, more

             commonly when benzodiazepines are ingested in large amounts

             or with other CNS depressants.

 

        10.3 Decontamination

 

             Gastric lavage is not routinely indicated following

             benzodiazepine overdose. Emesis is contraindicated because of

             the potential for CNS depression. Activated charcoal can be

             given orally.

 

        10.4 Enhanced elimination

 

             Methods of enhancing elimination are not

             indicated.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    Flumazenil, a specific benzodiazepine

                    antagonist at central GABA-ergic receptors is

                    available. Although it effectively reverses the CNS

                    effects of benzodiazepine overdose, its use in

                    clinical practice is rarely indicated.

                    Use of Flumazenil is specifically contraindicated when

                    there is history of co-ingestion of tricyclic

                    antidepressants or other drugs capable of producing

                    seizures (including aminophylline and cocaine),

                    benzodiazepine dependence, or in patients taking

                    benzodiazepines as an anticonvulsant agent. In such

                    situations, administration of Flumazenil may

                    precipitate seizures (Lopez, 1990; Mordel et al.,

                    1992).

                    Adverse effects associated with Flumazenil include

                    hypertension, tachycardia, anxiety, nausea, vomiting

                    and benzodiazepine withdrawal syndrome.

                    The initial intravenous dose of 0.3 to 1.0 mg may be

                    followed by further doses if necessary. The absence of

                    clinical response to 2 mg of flumazenil within 5 to 10

 

                    minutes indicates that benzodiazepine poisoning is not

                    the major cause of CNS depression or coma.

                    The patient regains consciousness within 15 to 30

                    seconds after injection of flumazenil, but since it is

                    metabolised more rapidly than the benzodiazepines,

                    recurrence of toxicity and CNS depression can occur

                    and the patient should be carefully monitored after

                    initial response to flumazenil therapy.  If toxicity

                    recurs, further bolus doses may be administered or an

                    infusion commenced at a dose of 0.3 to 1.0 mg/hour

                    (Meredith et al., 1993).

 

             10.5.2 Children

 

                    The initial intravenous dose of 0.1 mg should

                    be repeated each minute until the child is awake.

                    Continuous intravenous infusion should be administered

                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,

                    1993).

 

        10.6 Management discussion

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. Flumazenil is the specific

             antagonist of the effects of benzodiazepines, but the routine

             use for the treatment of benzodiazepine overdosage is not

             recommended. The use of Flumazenil should only be considered

             where severe CNS depression is observed. This situation

             rarely occurs, except in cases of mixed ingestion. The

             administration of flumazenil may improve respiratory and

             cardiovascular function enough to decrease the need for

             intubation and mechanical ventilation, but should never

             replace basic management principles.

             Flumazenil is an imidazobenzodiazepine and has been shown to

             reverse the sedative, anti-convulsant and muscle-relaxant

             effects of benzodiazepines. In controlled clinical trials,

             flumazenil significantly antagonizes benzodiazepine-induced

             coma arising from anaesthesia or acute overdose. However, the

             use of flumazenil has not been shown to reduce mortality or

             sequelae in such cases.

             The administration of flumazenil is more effective in

             reversing the effects of benzodiazepines when they are the

             only drugs producing CNS toxicity. Flumazenil does not

             reverse the CNS depressant effects of non-benzodiazepine

             drugs, including alcohol. The diagnostic use of flumazenil in

             patients presenting with coma of unknown origin can be

             justified by its high therapeutic index and the fact that

             this may limit the use of other diagnostic procedures (CT

             scan, lumbar puncture, etc).

             Flumazenil is a relatively expensive drug and this may also

             influence its use, especially in areas with limited

             resources.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

  1. REFERENCES

 

        Arguelles AE, & Rosner J. (1975) Diazepam and plasma

        testosterone levels. Lancet, ii: 607.

    

        Ashton CH (1989) Drug-induced stupor and coma: some physical signs

        and their pharmacological basis. Adverse drug React Acute

        Poisoning Rev, 8: 1-59.

    

        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD

        (1991) Next-day memory impairment with triazolam use. Lancet, 337:

        827-831.

    

        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:

        3358-63.

    

        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-

        descyclopropylmethyl-prazepam in whole-blood, plasma and milk

        after administration of prazepam to humans. Biopharm Drug Dispos,

        2: 59-68.

    

        Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with

        diazepam. J Urol, 109: 1005-1007.

    

        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J

        Anaesth, 59: 391.

    

        Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell

        Clin Pharm, 15: 487.

    

        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.

    

        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University

        Press, Oxford.

    

        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal

        temazepam overdoses (letter). Lancet, 2: 226.

    

        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,

        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of

        lorazepam and diazepam: an evaluation in “recreational” drug

        users. Drug Alcohol Depend, 22: 215-222.

    

 

        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with

        benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513.

    

        Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J

        Med, 88 (suppl 3A): 25S – 28S.

    

        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990)

        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.

    

        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine

        poisoning: experience of 702 admissions to an intensive care unit

        during a 14-year period. J Intern Med, 226: 117-122.

    

        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-

        mediated reactions to diazepam with Cremophor as solvent. Br J

        Anaesth, 52: 77-9.

    

        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J

        Psychiatry, 134: 477-479.

    

        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms

        associated with low dose benzodiazepine treatment. Am J

        Psychiatry, 135: 1558-1559.

    

        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of

        235 cases. N Eng J Med 296: 589-600.

    

        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in

        children exposed to benzodiazepines in utero. Lancet, 1:108-

        109.

    

        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum

        protein binding of diazepam in maternal and foetal serum during

        pregnancy. Br J Clin Pharmacol, 14: 551-4.

    

        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome

        after a benzodiazepine antagonist. Crit Care Med, 18:1480-

        1481.

    

        Martin SM (1985) The effect of diazepam on body temperature change

        in humans during cold exposure. J Clin Pharmacol, 25: 611-613.

    

        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:

        clinical findings and serum concentrations in two cases. J Clin

        Psychiatr, 46:247-248.

    

        McElhatton PR. (1994) The effects of benzodiazepines use during

        pregnancy and lactation. Reprod Toxicol, 8: 461-75.

    

        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC

        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and

        dantrolene as antidotes, 1st ed. Cambridge University Press,

        Cambridge.

    

 

        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic

        agents. Adverse Drug React Acute Poison Rev, 4: 83-122.

    

        Minder EI (1989) Toxicity in a case of acute and massive overdose

        of chlordiazepoxide and its correlation to blood concentration.

        Clin Toxicol, 27: 117-127.

    

        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam

        abuse.Lancet, i: 1344-5.

    

        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures

        after flumazenil administration in a case of combined

        benzodiazepine and tricyclic antidepressant overdose. Crit Care

        Med, 12: 1733-1734.

    

        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy

        and neonates. Clin Pharnacokinet, 18: 20-36.

    

        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl

        Augenheilkd, 187: 219-20 (in German).

    

        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate

        intoxication. A study of 300 cases based on a physiologic system

        of classification of the severity of intoxication. Ann Intern Med,

        37: 390-396.

    

        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The

        Pharmaceutical Press, London, 699-744.

    

        Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med

        J, 3: 28-29.

    

        Sandyk R (1986) Orofacial diskynesias associated with lorazepam

        therapy. Clin Pharm, 5: 419-21.

    

        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st

  1. Willians & Wilkins, Baltimore.

    

        Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter).

        Lancet, 2:802-803.

    

        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory

        support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-

        452.

    

        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:

        470-2.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author:           Dr Ligia Fruchtengarten

                          Poison Control Centre of Sao Paulo  –  Brazil

                          Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          FAX / Phone:   55  11  2755311

                          E-mail:   [email protected]

    

        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          Centro de Controle de Intoxicaçoes de Sao Paulo

                          Av Francisco de Paula Quintanilha Ribeiro, 860

                          04330 – 020   Sao Paulo  –  SP  –  Brazil.

    

        Date:             July 1997

    

        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,

                          September 1997.

  1. Ferner, L. Murray (Chairperson), M-O.

                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-

                          Nolf, A.Borges.

    

        Review 1998:      Lindsay Murray

                          Queen Elizabeth II Medical Centre

                          Perth, Western Australia.

    

        Editor:           Dr M.Ruse, April 1998

    

 

    

 

INTOX Home Page

Clonazepam

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/Form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination and excretion

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological Analyses and Their Interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple Qualitative Test(s)

         8.2.1.2 Advanced Qualitative Confirmation Test(s)

         8.2.1.3 Simple Quantitative Method(s)

         8.2.1.4 Advanced Quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple Qualitative Test(s)

         8.2.2.2 Advanced Qualitative Confirmation Test(s)

         8.2.2.3 Simple Quantitative Method(s)

         8.2.2.4 Advanced Quantitative Method(s)

         8.2.2.5 Other Dedicated Method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analysis

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other fluids

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    Clonazepam

 

    International Programme on Chemical Safety

    Poisons Information Monograph 326

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Benzodiazepines

    (PIM G008).

 

  1. NAME

 

        1.1  Substance

 

             Clonazepam

 

        1.2  Group

 

             ATC classification index

 

             Psycholeptics (N05)/  Anxiolytics (N05B)/

             Benzodiazepine derivatives (N05BA)

 

        1.3  Synonyms

 

             Clonazepamum; Ro-5-4023

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    1622-61-3

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Central nervous system, causing depression of

             respiration and consciousness.

 

        2.2  Summary of clinical effects

 

             Central nervous system (CNS) depression and coma, or

             paradoxical excitation, but deaths are rare when

             benzodiazepines are taken alone. Deep coma and other

             manifestations of severe CNS depression are rare. Sedation,

             somnolence, diplopia, dysarthria, ataxia and intellectual

 

             impairment are the most common adverse effects of

             benzodiazepines. Overdose in adults frequently involves co-

             ingestion of other CNS depressants, which act synergistically

             to increase toxicity. Elderly and very young children are

             more susceptible to the CNS depressant action. Intravenous

             administration of even therapeutic doses of benzodiazepines

             may produce apnoea and hypotension.

             Dependence may develop with regular use of benzodiazepines,

             even in therapeutic doses for short periods. If

             benzodiazepines are discontinued abruptly after regular use,

             withdrawal symptoms may develop.  The amnesia produced by

             benzodiazepines can have medico-legal consequences.

 

        2.3  Diagnosis

 

             The clinical diagnosis is based upon the history of

             benzodiazepine overdose and the presence of the clinical

             signs of benzodiazepine intoxication.

             Benzodiazepines can be detected or measured in blood and

             urine using standard analytical methods. This information may

             confirm the diagnosis but is not useful in the clinical

             management of the patient.

             A clinical response to flumazenil, a specific benzodiazepine

             antagonist, also confirms the diagnosis of benzodiazepine

             overdose, but administration of this drug is rarely

             justified.

 

        2.4  First aid measures and management principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly involve co-

             ingestion of other CNS depressants and other drugs. Activated

             charcoal normally provides adequate gastrointestinal

             decontamination. Gastric lavage is not routinely indicated.

             Emesis is contraindicated. The use of flumazenil is reserved

             for cases with severe respiratory or cardiovascular

             complications and should not replace the basic management of

             the airway and respiration. The routine use of flumazenil is

             contraindicated because of potential complications, including

             seizures.  Renal and extracorporeal methods of enhanced

             elimination are not effective.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

        3.2  Chemical structure

 

             Chemical Name:

             5-(2-Chlorophenyl)-1,3-dihydro-7-nitro-1,4- -benzodiazepin-2-

             one

    

 

             Molecular Formula: C15H10ClN3O3

    

             Molecular Weight: 315.7

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    Light yellow

 

             3.3.2  State/Form

 

                    Solid-crystals

 

             3.3.3  Description

 

                    Clonazepam has a faint odour. Practically

                    insoluble in water; slightly soluble in alcohol and in

                    methyl alcohol; sparingly soluble in acetone and in

                    chloroform; very slightly to slightly soluble in

                    ether.

                    (Reynolds, 1996).

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

             3.4.2  Storage conditions

 

                    Store in airtight containers. Protect from

                    light (Reynolds, 1996).

 

  1. USES

 

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

        4.2  Therapeutic dosage

             4.2.1  Adults

             4.2.2  Children

        4.3  Contraindications

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

             7.1.1  Toxicodynamics

             7.1.2  Pharmacodynamics

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

        7.7  Main adverse effects

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation  Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

 

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation  Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.2  Urine

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    “Basic analyses”

                    “Dedicated analyses”

                    “Optional analyses”

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and

             their interpretation

 

        8.5  Overall interpretation of all toxicological analyses and

             toxicological investigations

 

             Sample collection

             For toxicological analyses: whole blood 10 mL; urine 25 mL

             and gastric contents 25 mL.

    

             Biomedical analysis

             Blood gases, serum electrolytes, blood glucose and hepatic

             enzymes when necessary in severe cases.

    

             Toxicological analysis

             Qualitative testing for benzodiazepines is helpful to confirm

             their presence, but quantitative levels are not clinically

             useful. More advanced analyses are not necessary for the

             treatment of the poisoned patient due the lack of correlation

             between blood concentrations and clinical severity (Jatlow et

             al., 1979; MacCormick et al., 1985; Minder, 1989).

    

             TLC and EMIT: These provide data on the presence of

             benzodiazepines, their metabolites and possible associations

             with other drugs.

    

 

             GC or HPLC: These permit identification and quantification of

             the benzodiazepine which caused the poisoning and its

             metabolites in blood and urine.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    The onset of impairment of consciousness is

                    relatively rapid in benzodiazepine poisoning.  Onset

                    is more rapid following larger doses and with agents

                    of shorter duration of action. The most common and

                    initial symptom is somnolence.  This may progress to

                    coma Grade I or Grade II (see below) following very

                    large ingestions.

    

                    Reed Classification of Coma (Reed et al., 1952)

    

                    Coma Grade I:   Depressed level of consciousness,

                                    response to  painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade II:  Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade III: Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes absent. Vital

                                    signs intact

    

                    Coma Grade IV:  Coma grade III plus respiratory and

                                    circulatory collapse

 

             9.1.2  Inhalation

 

                    Not relevant.

 

             9.1.3  Skin exposure

 

                    No data.

 

             9.1.4  Eye contact

 

                    No data.

 

             9.1.5  Parenteral exposure

 

                    Overdose by the intravenous route results in

                    symptoms similar to those associated with ingestion,

                    but they appear immediately after the infusion, and

                    the progression of central nervous system (CNS)

                    depression is more rapid. Acute intentional poisoning

                    by this route is uncommon and most cases are

                    iatrogenic. Rapid intravenous infusion may cause

                    hypotension, respiratory depression and

                    apnoea.

 

             9.1.6  Other

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Toxic effects associated with chronic exposure

                    are secondary to the presence of the drug and

                    metabolites and include depressed mental status,

                    ataxia, vertigo, dizziness, fatigue, impaired motor

                    co-ordination, confusion, disorientation and

                    anterograde amnesia. Paradoxical effects of

                    psychomotor excitation, delirium and aggressiveness

                    also occur. These chronic effects are more common in

                    the elderly, children and patients with renal or

                    hepatic disease.

    

                    Administration of therapeutic doses of benzodiazepines

                    for 6 weeks or longer can result in physical

                    dependence, characterized by a withdrawal syndrome

                    when the drug is discontinued. With larger doses, the

                    physical dependence develops more rapidly.

 

             9.2.2  Inhalation

 

                    No data.

 

             9.2.3  Skin exposure

 

                    No data.

 

             9.2.4  Eye contact

 

                    No data.

 

             9.2.5  Parenteral exposure

 

                    The chronic parenteral administration of

                    benzodiazepines may produce thrombophlebitis and

                    tissue irritation, in addition to the usual symptoms

                    (Greenblat & Koch-Weser, 1973).

 

             9.2.6  Other

 

                    No data.

 

        9.3  Course, prognosis, cause of death

 

             Benzodiazepines are relatively safe drugs even in

             overdose. The clinical course is determined by the

             progression of the neurological symptoms. Deep coma or other

             manifestations of severe central nervous system (CNS)

             depression are rare with benzodiazepines alone.  Concomitant

             ingestion of other CNS depressants may result in a more

             severe CNS depression of longer duration.

 

    

             The therapeutic index of the benzodiazepines is high and the

             mortality rate associated with poisoning due to

             benzodiazepines alone is very low. Complications in severe

             poisoning include respiratory depression and aspiration

             pneumonia. Death is due to respiratory arrest.

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Hypotension, bradycardia and tachycardia have

                    been reported with overdose (Greenblatt et al., 1977;

                    Meredith & Vale 1985). Hypotension is more frequent

                    when benzodiazepines are ingested in association with

                    other drugs (Hojer et al., 1989). Rapid intravenous

                    injection is also associated with hypotension.

 

             9.4.2  Respiratory

 

                    Respiratory depression may occur in

                    benzodiazepine overdose and the severity depends on

                    dose ingested, amount absorbed, type of benzodiazepine

                    and co-ingestants. Respiratory depression requiring

                    ventilatory support has occurred in benzodiazepine

                    overdoses (Sullivan, 1989; Hojer et al.,1989). The

                    dose-response for respiratory depression varies

                    between individuals.  Respiratory depression or

                    respiratory arrest may rarely occur with therapeutic

                    doses. Benzodiazepines may affect the control of

                    ventilation during sleep and may worsen sleep apnoea

                    or other sleep-related breathing disorders, especially

                    in patients with chronic obstructive pulmonary disease

                    or cardiac failure (Guilleminault, 1990).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             CNS depression is less marked than

                             that produced by other CNS depressant agents

                             (Meredith & Vale, 1985). Even in large

                             overdoses, benzodiazepines usually produce

                             only mild symptoms and this distinguishes

                             them from other sedative-hypnotic agents.

                             Sedation, somnolence, weakness, diplopia,

                             dysarthria, ataxia and intellectual

                             impairment are the most common neurological

                             effects. The clinical effects of severe

                             poisoning are sleepiness, ataxia and coma

                             Grade I to Grade II (Reed). The presence of

                             more severe coma suggests the possibility of

                             co-ingested drugs. Certain of the newer

                             short-acting benzodiazepines (temazepam,

                             alprazolam and triazolam) have been

                             associated with several fatalities and it is

                             possible that they may have greater acute

                             toxicity (Forrest et al., 1986). The elderly

                             and very young children are more susceptible

                             to the CNS depressant action of

                             benzodiazepines.

                             The benzodiazepines may cause paradoxical CNS

                             effects, including excitement, delirium and

                             hallucinations. Triazolam has been reported

                             to produce delirium, toxic psychosis, memory

                             impairment and transient global amnesia

                             (Shader & Dimascio, 1970; Bixler et al,

                             1991). Flurazepam has been associated with

                             nightmares and hallucinations.

                             There are a few reports of extrapyramidal

                             symptoms and dyskinesias in patients taking

                             benzodiazepines (Kaplan & Murkafsky, 1978;

                             Sandyk, 1986).

                             The muscle relaxation caused by

                             benzodiazepines is of CNS origin and

                             manifests as dysarthria, incoordination and

                             difficulty standing and walking.

 

                    9.4.3.2  Peripheral nervous system

 

                    9.4.3.3  Autonomic nervous system

 

                    9.4.3.4  Skeletal and smooth muscle

 

             9.4.4  Gastrointestinal

 

                    Oral benzodiazepine poisoning will produce

                    minimal effects on the gastrointestinal tract (GI)

                    tract but can occasionally cause nausea or vomiting

                    (Shader & Dimascio, 1970).

 

             9.4.5  Hepatic

 

                    A case of cholestatic jaundice due focal

                    hepatic necrosis was associated with the

                    administration of diazepam (Tedesco & Mills,

                    1982).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Vesical hypotonia and urinary

                             retention has been reported in association

                             with diazepam poisoning (Chadduck et al.,

                             1973).

 

                    9.4.6.2  Other

 

             9.4.7  Endocrine and reproductive systems

 

                    Galactorrhoea with normal serum prolactin

                    concentrations has been noted in 4 women taking

                    benzodiazepines (Kleinberg et al., 1977).

                    Gynaecomastia has been reported in men taking high

                    doses of diazepam (Moerck & Majelung, 1979). Raised

                    serum concentrations of oestrodiol were observed in

                    men taking diazepam 10 to 20 mg daily for 2 weeks

                    (Arguelles & Rosner, 1975).

 

             9.4.8  Dermatological

 

                    Bullae have been reported following overdose

                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz

                    et al., 1990).

                    Allergic skin reactions were attributed to diazepam at

                    a rate of 0.4 per 1000 patients (Brigby,

                    1986).

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Brown opacification of the lens occurred in 2

                    patients who used diazepam for several years (Pau

                    Braune, 1985).

 

             9.4.10 Haematological

 

                    No data.

 

             9.4.11 Immunological

 

                    Allergic reaction as above (see 9.4.8).

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             No direct disturbances have been

                             described.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             No direct disturbances have been described.

 

                    9.4.12.3 Others

 

             9.4.13 Allergic reactions

 

                    Hypersensitivity reactions including

                    anaphylaxis are very rare (Brigby, 1986). Reactions

                    have been attributed to the vehicle used for some

                    parenteral diazepam formulations (Huttel et al.,

                    1980). There is also a report of a type I

                    hypersensitivity reaction to a lipid emulsion of

                    diazepam (Deardon, 1987).

 

             9.4.14 Other clinical effects

 

                    Hypothermia was reported in 15% of cases in

                    one series. (Martin, 1985; Hojer et al.,

                    1989).

 

             9.4.15 Special risks

 

                    Pregnancy

                    Passage of benzodiazepines across the placenta depends

                    on the degree of protein binding in mother and fetus,

                    which is influenced by factors such as stage of

                    pregnancy and plasma concentrations of free fatty

                    acids in mother and fetus (Lee et al., 1982). Adverse

                    effects may persist in the neonate for several days

                    after birth because of immature drug metabolising

                    enzymes. Competition between diazepam and bilirubin

 

                    for protein binding sites could result in hyper-

                    bilirubinemia in the neonate (Notarianni, 1990).

                    The abuse of benzodiazepines by pregnant women can

                    cause withdrawal syndrome in the neonate. The

                    administration of benzodiazepines during childbirth

                    can produce hypotonia, hyporeflexia, hypothermia and

                    respiratory depression in the newborn.

                    Benzodiazepines have been used in pregnant patients

                    and early reports associated diazepam and

                    chlordiazepoxide with some fetal malformations, but

                    these were not supported by later studies (Laegreid et

                    al., 1987; McElhatton, 1994).

    

                    Breast feeding

                    Benzodiazepines are excreted in breast milk in

                    significant amounts and may result in lethargy and

                    poor feeding in neonates.  Benzodiazepines should be

                    avoided in nursing mothers (Brodie, 1981; Reynolds,

                    1996).

 

        9.5  Other

 

             Dependence and withdrawal

             Benzodiazepines have a significant potential for abuse and

             can cause physical and psychological dependence. Abrupt

             cessation after prolonged use causes a withdrawal syndrome

             (Ashton, 1989). The mechanism of dependence is probably

             related to functional deficiency of GABA activity.

             Withdrawal symptoms include anxiety, insomnia, headache,

             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,

             weakness, perspiration, irritability, hypersensitivity to

             visual and auditory stimuli, palpitations, tachycardia and

             postural hypotension. In severe and rare cases of withdrawal

             from high doses, patients may develop affective disorders or

             motor dysfunction: seizures, psychosis, agitation, confusion,

             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;

             Reynolds, 1996).

             The time of onset of the withdrawal syndrome depends on the

             half-life of the drug and its active metabolites; the

             symptoms occur earlier and may be more severe with short-

             acting benzodiazepines. Others risk factors for withdrawal

             syndrome include prolonged use of the drug, higher dosage and

             abrupt cessation of the drug.

             

             Abuse

             Benzodiazepines, particularly temazepam, have been abused

             both orally and intravenously (Stark et al., 1987; Woods,

             1987; Funderburk et al, 1988)

             

             Criminal uses

             The amnesic effects of benzodiazepines have been used for

             criminal purposes with medicolegal consequences (Ferner,

             1996).

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly include other

             drugs and other CNS depressants. Activated charcoal normally

             provides adequate gastrointestinal decontamination. Gastric

             lavage is not routinely indicated. Emesis is contraindicated.

             The use of flumazenil is reserved for cases with severe

             respiratory or cardiovascular complications and should not

             replace the basic management of the airway and respiration.

             Renal and extracorporeal elimination methods are not

             effective.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             The patient should be evaluated to determine adequacy

             of airway, breathing and circulation. Continue clinical

             observation until evidence of toxicity has resolved.

             Intravenous access should be available for administration of

             fluid. Endotracheal intubation, assisted ventilation and

             supplemental oxygen may be required on rare occasions, more

             commonly when benzodiazepines are ingested in large amounts

             or with other CNS depressants.

 

        10.3 Decontamination

 

             Gastric lavage is not routinely indicated following

             benzodiazepine overdose. Emesis is contraindicated because of

             the potential for CNS depression. Activated charcoal can be

             given orally.

 

        10.4 Enhanced elimination

 

             Methods of enhancing elimination are not

             indicated.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    Flumazenil, a specific benzodiazepine

                    antagonist at central GABA-ergic receptors is

                    available. Although it effectively reverses the CNS

                    effects of benzodiazepine overdose, its use in

                    clinical practice is rarely indicated.

                    Use of Flumazenil is specifically contraindicated when

                    there is history of co-ingestion of tricyclic

                    antidepressants or other drugs capable of producing

 

                    seizures (including aminophylline and cocaine),

                    benzodiazepine dependence, or in patients taking

                    benzodiazepines as an anticonvulsant agent. In such

                    situations, administration of Flumazenil may

                    precipitate seizures (Lopez, 1990; Mordel et al.,

                    1992).

                    Adverse effects associated with Flumazenil include

                    hypertension, tachycardia, anxiety, nausea, vomiting

                    and benzodiazepine withdrawal syndrome.

                    The initial intravenous dose of 0.3 to 1.0 mg may be

                    followed by further doses if necessary. The absence of

                    clinical response to 2 mg of flumazenil within 5 to 10

                    minutes indicates that benzodiazepine poisoning is not

                    the major cause of CNS depression or coma.

                    The patient regains consciousness within 15 to 30

                    seconds after injection of flumazenil, but since it is

                    metabolised more rapidly than the benzodiazepines,

                    recurrence of toxicity and CNS depression can occur

                    and the patient should be carefully monitored after

                    initial response to flumazenil therapy.  If toxicity

                    recurs, further bolus doses may be administered or an

                    infusion commenced at a dose of 0.3 to 1.0 mg/hour

                    (Meredith et al., 1993).

 

             10.5.2 Children

 

                    The initial intravenous dose of 0.1 mg should

                    be repeated each minute until the child is awake.

                    Continuous intravenous infusion should be administered

                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,

                    1993).

 

        10.6 Management discussion

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. Flumazenil is the specific

             antagonist of the effects of benzodiazepines, but the routine

             use for the treatment of benzodiazepine overdosage is not

             recommended. The use of Flumazenil should only be considered

             where severe CNS depression is observed. This situation

             rarely occurs, except in cases of mixed ingestion. The

             administration of flumazenil may improve respiratory and

             cardiovascular function enough to decrease the need for

             intubation and mechanical ventilation, but should never

             replace basic management principles.

             Flumazenil is an imidazobenzodiazepine and has been shown to

             reverse the sedative, anti-convulsant and muscle-relaxant

             effects of benzodiazepines. In controlled clinical trials,

             flumazenil significantly antagonizes benzodiazepine-induced

             coma arising from anaesthesia or acute overdose. However, the

             use of flumazenil has not been shown to reduce mortality or

             sequelae in such cases.

 

             The administration of flumazenil is more effective in

             reversing the effects of benzodiazepines when they are the

             only drugs producing CNS toxicity. Flumazenil does not

             reverse the CNS depressant effects of non-benzodiazepine

             drugs, including alcohol. The diagnostic use of flumazenil in

             patients presenting with coma of unknown origin can be

             justified by its high therapeutic index and the fact that

             this may limit the use of other diagnostic procedures (CT

             scan, lumbar puncture, etc).

             Flumazenil is a relatively expensive drug and this may also

             influence its use, especially in areas with limited

             resources.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

  1. REFERENCES

 

        Arguelles AE, & Rosner J. (1975) Diazepam and plasma

        testosterone levels. Lancet, ii: 607.

    

        Ashton CH (1989) Drug-induced stupor and coma: some physical signs

        and their pharmacological basis. Adverse drug React Acute

        Poisoning Rev, 8: 1-59.

    

        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD

        (1991)  Next-day memory impairment with triazolam use.  Lancet,

        337: 827-831.

    

        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:

        3358-63.

    

        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-

        descyclopropylmethyl-prazepam in whole-blood, plasma and milk

        after administration of prazepam to humans. Biopharm Drug Dispos,

        2: 59-68.

    

        Chadduck WM, Loar CR & Denton IC. (1973)  Vesical hypotonicity

        with diazepam. J Urol, 109: 1005-1007.

    

        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J

        Anaesth,  59: 391.

    

        Einarson TR (1981) Oxazepam withdrawal convulsions.  Drug Intell

        Clin Pharm, 15: 487.

    

 

        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.

    

        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University

        Press, Oxford.

    

        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal

        temazepam overdoses (letter).  Lancet, 2: 226.

    

        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,

        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of

        lorazepam and diazepam:  an evaluation in “recreational” drug

        users.  Drug Alcohol Depend, 22: 215-222.

    

        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with

        benzodiazepine derivatives.  Clin Pharm Ther,  21: 497-513.

    

        Guilleminault C. (1990)  Benzodiazepines, bresthing and sleep.  Am

        J Med, 88 (suppl 3A): 25S – 28S.

    

        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) 

        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.

    

        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine

        poisoning: experience of 702 admissions to an intensive care unit

        during a 14-year period.  J Intern Med, 226: 117-122.

    

        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-

        mediated reactions to diazepam with Cremophor as solvent. Br J

        Anaesth,  52:  77-9.

    

        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J

        Psychiatry, 134: 477-479.

    

        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms

        associated with low dose benzodiazepine treatment. Am J

        Psychiatry, 135: 1558-1559.

    

        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of

        235 cases. N Eng J Med  296: 589-600.

    

        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in

        children exposed to benzodiazepines in utero.  Lancet, 1:

        108-109.

    

        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum

        protein binding of diazepam in maternal and foetal serum during

        pregnancy. Br J Clin Pharmacol, 14: 551-4.

    

        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome

        after a benzodiazepine antagonist.  Crit Care Med, 18:

        1480-1481.

    

 

        Martin SM (1985) The effect of diazepam on body temperature change

        in humans during cold exposure. J Clin Pharmacol,   25: 611-613.

    

        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:

        clinical findings and serum concentrations in two cases.  J Clin

        Psychiatr,  46:247-248.

    

        McElhatton PR. (1994) The effects of benzodiazepines use during

        pregnancy and lactation. Reprod Toxicol,  8: 461-75.

    

        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC

        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and

        dantrolene as antidotes, 1st ed. Cambridge University Press,

        Cambridge.

    

        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic

        agents. Adverse Drug React Acute Poison Rev,  4: 83-122.

    

        Minder EI (1989) Toxicity in a case of acute and massive overdose

        of chlordiazepoxide and its correlation to blood concentration. 

        Clin Toxicol,  27: 117-127.

    

        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam

        abuse.Lancet, i: 1344-5.

    

        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures

        after flumazenil administration in a case of combined

        benzodiazepine and tricyclic antidepressant overdose. Crit Care

        Med,  12: 1733-1734.

    

        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy

        and neonates. Clin Pharnacokinet, 18: 20-36.

    

        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl

        Augenheilkd, 187: 219-20 (in German).

    

        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate

        intoxication. A study of 300 cases based on a physiologic system

        of classification of the severity of intoxication. Ann Intern Med,

        37: 390-396.

    

        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The

        Pharmaceutical Press, London, 699-744.

    

        Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med

        J,  3: 28-29.

    

        Sandyk R (1986) Orofacial diskynesias associated with lorazepam

        therapy. Clin Pharm,  5: 419-21.

    

        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st

  1. Willians & Wilkins, Baltimore.

    

 

        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).

        Lancet,  2:802-803.

    

        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory

        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:

        450-452.

    

        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:

        470-2.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author:           Dr Ligia Fruchtengarten

                          Poison Control Centre of Sao Paulo  –  Brazil

                          Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          FAX / Phone:   55  11  2755311

                          E-mail:   [email protected]

    

        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          Centro de Controle de Intoxicaçoes de Sao Paulo

                          Av Francisco de Paula Quintanilha Ribeiro, 860

                          04330 – 020   Sao Paulo  –  SP  –  Brazil.

    

        Date:             July 1997

    

        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,

                          September 1997.

  1. Ferner, L. Murray (Chairperson), M-O.

                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-

                          Nolf, A.Borges.

    

        Review 1998:      Lindsay Murray

                          Queen Elizabeth II Medical Centre

                          Perth, Western Australia.

    

        Editor:           Dr M.Ruse, April 1998

    

 

    

Clorazepate dipotassium

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names, main trade names

   1.6 Main manufacturers, main importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/Form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination and excretion

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological Analyses and Their Interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple Qualitative Test(s)

         8.2.1.2 Advanced Qualitative Confirmation Test(s)

         8.2.1.3 Simple Quantitative Method(s)

         8.2.1.4 Advanced Quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple Qualitative Test(s)

         8.2.2.2 Advanced Qualitative Confirmation Test(s)

         8.2.2.3 Simple Quantitative Method(s)

         8.2.2.4 Advanced Quantitative Method(s)

         8.2.2.5 Other Dedicated Method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analysis

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other fluids

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

   8.6 References

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    Clorazepate dipotassium

 

    International Programme on Chemical Safety

    Poisons Information Monograph 327

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Benzodiazepines

    (PIM G008).

 

  1. NAME

 

        1.1  Substance

 

             Clorazepate dipotassium

 

        1.2  Group

 

             ATC classification index

 

             Psycholeptics (N05)/  Anxiolytics (N05B)/

             Benzodiazepine derivatives (N05BA)

 

        1.3  Synonyms

 

             Abbott-35616; AH-3232; 4306-CB; Clorazepate Dipotassium;

             Dikalii Clorazepas; Dipotassium Clorazepate

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    57109-90-7

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             Central nervous system, causing depression of

             respiration and consciousness.

 

        2.2  Summary of clinical effects

 

             Central nervous system (CNS) depression and coma, or

             paradoxical excitation, but deaths are rare when

             benzodiazepines are taken alone. Deep coma and other

             manifestations of severe CNS depression are rare. Sedation,

 

             somnolence, diplopia, dysarthria, ataxia and intellectual

             impairment are the most common adverse effects of

             benzodiazepines. Overdose in adults frequently involves co-

             ingestion of other CNS depressants, which act synergistically

             to increase toxicity. Elderly and very young children are

             more susceptible to the CNS depressant action. Intravenous

             administration of even therapeutic doses of benzodiazepines

             may produce apnoea and hypotension.

             Dependence may develop with regular use of benzodiazepines,

             even in therapeutic doses for short periods. If

             benzodiazepines are discontinued abruptly after regular use,

             withdrawal symptoms may develop.  The amnesia produced by

             benzodiazepines can have medico-legal consequences.

 

        2.3  Diagnosis

 

             The clinical diagnosis is based upon the history of

             benzodiazepine overdose and the presence of the clinical

             signs of benzodiazepine intoxication.

             Benzodiazepines can be detected or measured in blood and

             urine using standard analytical methods. This information may

             confirm the diagnosis but is not useful in the clinical

             management of the patient.

             A clinical response to flumazenil, a specific benzodiazepine

             antagonist, also confirms the diagnosis of benzodiazepine

             overdose, but administration of this drug is rarely

             justified.

 

        2.4  First aid measures and management principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly involve co-

             ingestion of other CNS depressants and other drugs. Activated

             charcoal normally provides adequate gastrointestinal

             decontamination. Gastric lavage is not routinely indicated.

             Emesis is contraindicated. The use of flumazenil is reserved

             for cases with severe respiratory or cardiovascular

             complications and should not replace the basic management of

             the airway and respiration. The routine use of flumazenil is

             contraindicated because of potential complications, including

             seizures.  Renal and extracorporeal methods of enhanced

             elimination are not effective.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

        3.2  Chemical structure

 

             Chemical Name:

             Potassium 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-

             benzodiazepine-3-carboxylate with potassium hydroxide.

    

 

             Molecular Formula: C16H11ClK2N2O4

    

             Molecular Weight: 408.9

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White or light yellow

 

             3.3.2  State/Form

 

                    Solid-crystals

 

             3.3.3  Description

 

                    The crystals  darken on exposure to light.

                    Solutions in water or in alcohol are unstable and

                    should be used immediately.

                    British Pharmacopoeia solubilities are: freely soluble

                    or very soluble in water; very slightly soluble in

                    alcohol; practically insoluble in dichloromethane.

                    US Pharmacopoeia solubilities are: soluble in water,

                    but may precipitate from solution on standing;

                    slightly soluble in alcohol and in isopropyl alcohol;

                    practically insoluble in acetone, in chloroform, in

                    dichloromethane, and in ether.

                    (Reynolds, 1996).

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

             3.4.2  Storage conditions

 

                    Store under nitrogen in airtight containers.

                    Protect from light.

                    (Reynolds, 1996).

 

  1. USES

 

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

        4.2  Therapeutic dosage

             4.2.1  Adults

             4.2.2  Children

        4.3  Contraindications

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

             7.1.1  Toxicodynamics

             7.1.2  Pharmacodynamics

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

        7.7  Main adverse effects

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation  Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation  Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.2  Urine

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    “Basic analyses”

                    “Dedicated analyses”

                    “Optional analyses”

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and

             toxicological investigations

 

             Sample collection

             For toxicological analyses: whole blood 10 mL; urine 25 mL

             and gastric contents 25 mL.

    

             Biomedical analysis

             Blood gases, serum electrolytes, blood glucose and hepatic

             enzymes when necessary in severe cases.

    

 

             Toxicological analysis

             Qualitative testing for benzodiazepines is helpful to confirm

             their presence, but quantitative levels are not clinically

             useful. More advanced analyses are not necessary for the

             treatment of the poisoned patient due the lack of correlation

             between blood concentrations and clinical severity (Jatlow et

             al., 1979; MacCormick et al., 1985; Minder, 1989).

    

             TLC and EMIT: These provide data on the presence of

             benzodiazepines, their metabolites and possible associations

             with other drugs.

    

             GC or HPLC: These permit identification and quantification of

             the benzodiazepine which caused the poisoning and its

             metabolites in blood and urine.

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    The onset of impairment of consciousness is

                    relatively rapid in benzodiazepine poisoning.  Onset

                    is more rapid following larger doses and with agents

                    of shorter duration of action. The most common and

                    initial symptom is somnolence.  This may progress to

                    coma Grade I or Grade II (see below) following very

                    large ingestions.

    

                    Reed Classification of Coma (Reed et al., 1952)

    

                    Coma Grade I:   Depressed level of consciousness,

                                    response to  painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade II:  Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes and vital signs

                                    intact

    

                    Coma Grade III: Depressed level of consciousness, no

                                    response to painful stimuli

                                    Deep tendon reflexes absent. Vital

                                    signs intact

    

                    Coma Grade IV:  Coma grade III plus respiratory and

                                    circulatory collapse

 

             9.1.2  Inhalation

 

                    Not relevant.

 

             9.1.3  Skin exposure

 

                    No data.

 

             9.1.4  Eye contact

 

                    No data.

 

             9.1.5  Parenteral exposure

 

                    Overdose by the intravenous route results in

                    symptoms similar to those associated with ingestion,

                    but they appear immediately after the infusion, and

                    the progression of central nervous system (CNS)

                    depression is more rapid. Acute intentional poisoning

                    by this route is uncommon and most cases are

                    iatrogenic. Rapid intravenous infusion may cause

                    hypotension, respiratory depression and

                    apnoea.

 

             9.1.6  Other

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Toxic effects associated with chronic exposure

                    are secondary to the presence of the drug and

                    metabolites and include depressed mental status,

                    ataxia, vertigo, dizziness, fatigue, impaired motor

                    co-ordination, confusion, disorientation and

                    anterograde amnesia. Paradoxical effects of

                    psychomotor excitation, delirium and aggressiveness

                    also occur. These chronic effects are more common in

                    the elderly, children and patients with renal or

                    hepatic disease.

    

                    Administration of therapeutic doses of benzodiazepines

                    for 6 weeks or longer can result in physical

                    dependence, characterized by a withdrawal syndrome

                    when the drug is discontinued. With larger doses, the

                    physical dependence develops more rapidly.

 

             9.2.2  Inhalation

 

                    No data.

 

             9.2.3  Skin exposure

 

                    No data.

 

             9.2.4  Eye contact

 

                    No data.

 

             9.2.5  Parenteral exposure

 

                    The chronic parenteral administration of

                    benzodiazepines may produce thrombophlebitis and

                    tissue irritation, in addition to the usual symptoms

                    (Greenblat & Koch-Weser, 1973).

 

             9.2.6  Other

 

                    No data.

 

        9.3  Course, prognosis, cause of death

 

             Benzodiazepines are relatively safe drugs even in

             overdose. The clinical course is determined by the

             progression of the neurological symptoms. Deep coma or other

             manifestations of severe central nervous system (CNS)

             depression are rare with benzodiazepines alone.  Concomitant

             ingestion of other CNS depressants may result in a more

             severe CNS depression of longer duration.

    

             The therapeutic index of the benzodiazepines is high and the

             mortality rate associated with poisoning due to

             benzodiazepines alone is very low. Complications in severe

             poisoning include respiratory depression and aspiration

             pneumonia. Death is due to respiratory arrest.

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Hypotension, bradycardia and tachycardia have

                    been reported with overdose (Greenblatt et al., 1977;

                    Meredith & Vale 1985). Hypotension is more frequent

                    when benzodiazepines are ingested in association with

                    other drugs (Hojer et al., 1989). Rapid intravenous

                    injection is also associated with hypotension.

 

             9.4.2  Respiratory

 

                    Respiratory depression may occur in

                    benzodiazepine overdose and the severity depends on

                    dose ingested, amount absorbed, type of benzodiazepine

                    and co-ingestants. Respiratory depression requiring

                    ventilatory support has occurred in benzodiazepine

                    overdoses (Sullivan, 1989; Hojer et al., 1989). The

                    dose-response for respiratory depression varies

                    between individuals.  Respiratory depression or

                    respiratory arrest may rarely occur with therapeutic

 

                    doses. Benzodiazepines may affect the control of

                    ventilation during sleep and may worsen sleep apnoea

                    or other sleep-related breathing disorders, especially

                    in patients with chronic obstructive pulmonary disease

                    or cardiac failure (Guilleminault, 1990).

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             CNS depression is less marked than

                             that produced by other CNS depressant agents

                             (Meredith & Vale, 1985). Even in large

                             overdoses, benzodiazepines usually produce

                             only mild symptoms and this distinguishes

                             them from other sedative-hypnotic agents.

                             Sedation, somnolence, weakness, diplopia,

                             dysarthria, ataxia and intellectual

                             impairment are the most common neurological

                             effects. The clinical effects of severe

                             poisoning are sleepiness, ataxia and coma

                             Grade I to Grade II (Reed). The presence of

                             more severe coma suggests the possibility of

                             co-ingested drugs. Certain of the newer

                             short-acting benzodiazepines (temazepam,

                             alprazolam and triazolam) have been

                             associated with several fatalities and it is

                             possible that they may have greater acute

                             toxicity (Forrest et al., 1986). The elderly

                             and very young children are more susceptible

                             to the CNS depressant action of

                             benzodiazepines.

                             The benzodiazepines may cause paradoxical CNS

                             effects, including excitement, delirium and

                             hallucinations. Triazolam has been reported

                             to produce delirium, toxic psychosis, memory

                             impairment and transient global amnesia

                             (Shader & Dimascio, 1970; Bixler et al,

                             1991). Flurazepam has been associated with

                             nightmares and hallucinations.

                             There are a few reports of extrapyramidal

                             symptoms and dyskinesias in patients taking

                             benzodiazepines (Kaplan & Murkafsky, 1978;

                             Sandyk, 1986).

                             The muscle relaxation caused by

                             benzodiazepines is of CNS origin and

                             manifests as dysarthria, incoordination and

                             difficulty standing and walking.

 

                    9.4.3.2  Peripheral nervous system

 

                    9.4.3.3  Autonomic nervous system

 

                    9.4.3.4  Skeletal and smooth muscle

 

             9.4.4  Gastrointestinal

 

                    Oral benzodiazepine poisoning will produce

                    minimal effects on the gastrointestinal tract (GI)

                    tract but can occasionally cause nausea or vomiting

                    (Shader & Dimascio, 1970).

 

             9.4.5  Hepatic

 

                    A case of cholestatic jaundice due focal

                    hepatic necrosis was associated with the

                    administration of diazepam (Tedesco & Mills,

                    1982).

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Vesical hypotonia and urinary

                             retention has been reported in association

                             with diazepam poisoning (Chadduck et al.,

                             1973).

 

                    9.4.6.2  Other

 

             9.4.7  Endocrine and reproductive systems

 

                    Galactorrhoea with normal serum prolactin

                    concentrations has been noted in 4 women taking

                    benzodiazepines (Kleinberg et al., 1977).

                    Gynaecomastia has been reported in men taking high

                    doses of diazepam (Moerck & Majelung, 1979). Raised

                    serum concentrations of oestrodiol were observed in

                    men taking diazepam 10 to 20 mg daily for 2 weeks

                    (Arguelles & Rosner, 1975).

 

             9.4.8  Dermatological

 

                    Bullae have been reported following overdose

                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz

                    et al., 1990).

                    Allergic skin reactions were attributed to diazepam at

                    a rate of 0.4 per 1000 patients (Brigby,

                    1986).

 

             9.4.9  Eye, ear, nose, throat: local effects

 

                    Brown opacification of the lens occurred in 2

                    patients who used diazepam for several years (Pau

                    Braune, 1985).

 

             9.4.10 Haematological

 

                    No data.

 

             9.4.11 Immunological

 

                    Allergic reaction as above (see 9.4.8).

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             No direct disturbances have been

                             described.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             No direct disturbances have been

                             described.

 

                    9.4.12.3 Others

 

             9.4.13 Allergic reactions

 

                    Hypersensitivity reactions including

                    anaphylaxis are very rare (Brigby, 1986). Reactions

                    have been attributed to the vehicle used for some

                    parenteral diazepam formulations (Huttel et al.,

                    1980). There is also a report of a type I

                    hypersensitivity reaction to a lipid emulsion of

                    diazepam (Deardon, 1987).

 

             9.4.14 Other clinical effects

 

                    Hypothermia was reported in 15% of cases in

                    one series. (Martin, 1985; Hojer et al.,

                    1989).

 

             9.4.15 Special risks

 

                    Pregnancy

                    Passage of benzodiazepines across the placenta depends

                    on the degree of protein binding in mother and fetus,

                    which is influenced by factors such as stage of

                    pregnancy and plasma concentrations of free fatty

                    acids in mother and fetus (Lee et al., 1982). Adverse

                    effects may persist in the neonate for several days

                    after birth because of immature drug metabolising

                    enzymes. Competition between diazepam and bilirubin

                    for protein binding sites could result in

                    hyperbilirubinemia in the neonate (Notarianni,

                    1990).

 

                    The abuse of benzodiazepines by pregnant women can

                    cause withdrawal syndrome in the neonate. The

                    administration of benzodiazepines during childbirth

                    can produce hypotonia, hyporeflexia, hypothermia and

                    respiratory depression in the newborn.

                    Benzodiazepines have been used in pregnant patients

                    and early reports associated diazepam and

                    chlordiazepoxide with some fetal malformations, but

                    these were not supported by later studies (Laegreid et

                    al., 1987; McElhatton, 1994).

    

                    Breast feeding

                    Benzodiazepines are excreted in breast milk in

                    significant amounts and may result in lethargy and

                    poor feeding in neonates.  Benzodiazepines should be

                    avoided in nursing mothers (Brodie, 1981; Reynolds,

                    1996).

 

        9.5  Other

 

             Dependence and withdrawal

             Benzodiazepines have a significant potential for abuse and

             can cause physical and psychological dependence. Abrupt

             cessation after prolonged use causes a withdrawal syndrome

             (Ashton, 1989). The mechanism of dependence is probably

             related to functional deficiency of GABA activity.

             Withdrawal symptoms include anxiety, insomnia, headache,

             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,

             weakness, perspiration, irritability, hypersensitivity to

             visual and auditory stimuli, palpitations, tachycardia and

             postural hypotension. In severe and rare cases of withdrawal

             from high doses, patients may develop affective disorders or

             motor dysfunction: seizures, psychosis, agitation, confusion,

             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;

             Reynolds, 1996).

             The time of onset of the withdrawal syndrome depends on the

             half-life of the drug and its active metabolites; the

             symptoms occur earlier and may be more severe with short-

             acting benzodiazepines. Others risk factors for withdrawal

             syndrome include prolonged use of the drug, higher dosage and

             abrupt cessation of the drug.

    

             Abuse

             Benzodiazepines, particularly temazepam, have been abused

             both orally and intravenously (Stark et al., 1987; Woods,

             1987; Funderburk et al, 1988)

    

             Criminal uses

             The amnesic effects of benzodiazepines have been used for

             criminal purposes with medicolegal consequences (Ferner,

             1996).

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. It should be remembered that

             benzodiazepine ingestions by adults commonly include other

             drugs and other CNS depressants. Activated charcoal normally

             provides adequate gastrointestinal decontamination. Gastric

             lavage is not routinely indicated. Emesis is contraindicated.

             The use of flumazenil is reserved for cases with severe

             respiratory or cardiovascular complications and should not

             replace the basic management of the airway and respiration.

             Renal and extracorporeal elimination methods are not

             effective.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             The patient should be evaluated to determine adequacy

             of airway, breathing and circulation. Continue clinical

             observation until evidence of toxicity has resolved.

             Intravenous access should be available for administration of

             fluid. Endotracheal intubation, assisted ventilation and

             supplemental oxygen may be required on rare occasions, more

             commonly when benzodiazepines are ingested in large amounts

             or with other CNS depressants.

 

        10.3 Decontamination

 

             Gastric lavage is not routinely indicated following

             benzodiazepine overdose. Emesis is contraindicated because of

             the potential for CNS depression. Activated charcoal can be

             given orally.

 

        10.4 Enhanced elimination

 

             Methods of enhancing elimination are not indicated.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    Flumazenil, a specific benzodiazepine

                    antagonist at central GABA-ergic receptors is

                    available. Although it effectively reverses the CNS

                    effects of benzodiazepine overdose, its use in

                    clinical practice is rarely indicated.

                    Use of Flumazenil is specifically contraindicated when

                    there is history of co-ingestion of tricyclic

                    antidepressants or other drugs capable of producing

                    seizures (including aminophylline and cocaine),

 

                    benzodiazepine dependence, or in patients taking

                    benzodiazepines as an anticonvulsant agent. In such

                    situations, administration of Flumazenil may

                    precipitate seizures (Lopez, 1990; Mordel et al.,

                    1992).

                    Adverse effects associated with Flumazenil include

                    hypertension, tachycardia, anxiety, nausea, vomiting

                    and benzodiazepine withdrawal syndrome.

                    The initial intravenous dose of 0.3 to 1.0 mg may be

                    followed by further doses if necessary. The absence of

                    clinical response to 2 mg of flumazenil within 5 to 10

                    minutes indicates that  benzodiazepine poisoning is

                    not the major cause of  CNS depression or coma.

                    The patient regains consciousness within 15 to 30

                    seconds after injection of flumazenil, but since it is

                    metabolised more rapidly than the benzodiazepines,

                    recurrence of toxicity and CNS depression can occur

                    and the patient should be carefully monitored after

                    initial response to flumazenil therapy.  If toxicity

                    recurs, further bolus doses may be administered or an

                    infusion commenced at a dose of 0.3 to 1.0 mg/hour

                    (Meredith et al., 1993).

 

             10.5.2 Children

 

                    The initial intravenous dose of 0.1 mg should

                    be repeated each minute until the child is awake.

                    Continuous intravenous infusion should be administered

                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,

                    1993).

 

        10.6 Management discussion

 

             Most benzodiazepine poisonings require only clinical

             observation and supportive care. Flumazenil is the specific

             antagonist of the effects of benzodiazepines, but the routine

             use for the treatment of benzodiazepine overdosage is not

             recommended. The use of Flumazenil should only be considered

             where severe CNS depression is observed. This situation

             rarely occurs, except in cases of mixed ingestion. The

             administration of flumazenil may improve respiratory and

             cardiovascular function enough to decrease the need for

             intubation and mechanical ventilation, but should never

             replace basic management principles.

             Flumazenil is an imidazobenzodiazepine and has been shown to

             reverse the sedative, anti-convulsant and muscle-relaxant

             effects of benzodiazepines. In controlled clinical trials,

             flumazenil significantly antagonizes benzodiazepine-induced

             coma arising from anaesthesia or acute overdose. However, the

             use of flumazenil has not been shown to reduce mortality or

             sequelae in such cases.

 

             The administration of flumazenil is more effective in

             reversing the effects of benzodiazepines when they are the

             only drugs producing CNS toxicity. Flumazenil does not

             reverse the CNS depressant effects of non-benzodiazepine

             drugs, including alcohol. The diagnostic use of flumazenil in

             patients presenting with coma of unknown origin can be

             justified by its high therapeutic index and the fact that

             this may limit the use of other diagnostic procedures (CT

             scan, lumbar puncture, etc).

             Flumazenil is a relatively expensive drug and this may also

             influence its use, especially in areas with limited

             resources.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

  1. Additional information

 

        12.1 Specific preventive measures

 

        12.2 Other

 

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        Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med

        J,  3: 28-29.

    

        Sandyk R (1986) Orofacial diskynesias associated with lorazepam

        therapy. Clin Pharm,  5: 419-21.

    

        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st

  1. Willians & Wilkins, Baltimore.

    

 

        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).

        Lancet,  2:802-803.

    

        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory

        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:

        450-452.

    

        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:

        470-2.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author:           Dr Ligia Fruchtengarten

                          Poison Control Centre of Sao Paulo  –  Brazil

                          Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          FAX / Phone:   55  11  2755311

                          E-mail:   [email protected]

    

        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya –

                          Coperpas 12

                          Centro de Controle de Intoxicaçoes de Sao Paulo

                          Av Francisco de Paula Quintanilha Ribeiro, 860

                          04330 – 020   Sao Paulo  –  SP  –  Brazil.

    

        Date:             July 1997

    

        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,

                          September 1997.

  1. Ferner, L. Murray (Chairperson), M-O.

                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-

                          Nolf, A.Borges.

    

        Review 1998:      Lindsay Murray

                          Queen Elizabeth II Medical Centre

                          Perth, Western Australia.

    

        Editor:           Dr M.Ruse, April 1998

    

 

    

Phenytoin

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names/main trade names

   1.6 Main manufacturers and/or importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/Form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination by route of exposure

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biological analyses

         8.1.1.3 Arterial blood gas analyses

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gs analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological Analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological analyses and their interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple qualitative test(s)

         8.2.1.2 Advanced qualitative confirmation test(s)

         8.2.1.3 Simple quantitative method(s)

         8.2.1.4 Advanced quantitative method(s)

      8.2.2 Test(s) for biological specimens

         8.2.2.1 Simple qualitative test(s)

         8.2.2.2 Advanced qualitative confirmation test(s)

         8.2.2.3 Simple quantitative method(s)

         8.2.2.4 Advanced quantitative method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analyses

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other biological specimens

      8.3.2 Arterial blood gas analysis

      8.3.3 Haematological analyses

      8.3.4 Other (unspecified) analyses

      8.3.5 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Summary of the most essential biomedical and toxicological analyses in acute poisoning and their interpretation

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 CNS

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive system

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat, local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from litterature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADRRESS(ES)

 

    Phenytoin

 

    International Programme on Chemical Safety

    Poisons Information Monograph 416

    Pharmaceutical

 

  1. NAME

 

         1.1  Substance

 

               Phenytoin

 

         1.2  Group

 

               (N03) Antiepileptics (N03A B02) Hydantoin derivatives

 

         1.3  Synonyms

 

               diphenylhydantoin; Fenitoina; Phenantoinum; Phenytoinum;

               5,5-Diphenylhydantoin; 5,5-Diphenylimidazoline-2,4-dione

 

         1.4  Identification numbers

 

               1.4.1  CAS number

 

                       57-41-0

 

               1.4.2  Other numbers

 

                       CAS number: phenytoin sodium: 630-93-3

                       ATC codes: N03AB52: phenytoin, combinations

 

         1.5  Main brand names/main trade names

 

               Dantoin, Dilantin, Diphenlyn, Phenyltoin, Divulsan,

               Novo-diphenyl, Phentoin sodium, Denyl sodium, Dilantin

               sodium, Diphentoin, Diphenylan sodium, Kessodanten,

               Elsanutin, Phentoin, Di-Hydan, Phenhydan

 

         1.6  Main manufacturers and/or importers

 

               Carrion, Parke Davis

 

  1. SUMMARY

 

         2.1  Main risks and target organs

 

               The intoxication usually manifests as mild central

               nervous system effects. More severe manifestations may be

               seen following massive overdose but fatalities are extremely

               rare.

 

         2.2  Summary of clinical effects

 

               Onset of symptoms including lateral nystagmus, ataxia,

               and drowsiness occurs within 1 to 2 hours after ingestion and

               may persist for about 4 to 5 days.

               In more severe cases, horizontal nystagmus, coarse tremor and

               inability to walk may be observed.

               In very severe poisoning, conciousness is impaired but coma

               is rarely observed.

 

         2.3  Diagnosis

 

               Diagnosis of phenytoin poisoning is clinical and based

               on history of overdose and/or access to phenytoin and the

               presence of specific clinical features especially nystagmus,

               dysarthria and ataxia. The diagnosis may be confirmed in the

               laboratory by measurement of an elevated serum phenytoin

               level but the levels do not always correlate precisely with

               the clinical severity of the intoxication.

 

         2.4  First aid measures and management principles

 

               Careful supportive management, gut decontamination

               measures and patience for 3 to 5 days almost always result in

               a good clinical outcome.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

         3.1  Origin of the substance

 

               Synthetic.

 

         3.2  Chemical structure

 

               Molecular formula:       phenytoin: C15 H12 N2 O2

                                        phenytoin sodium: C15 H11 N2 Na O2

    

               Molecular weight:        phenytoin: 252.3

                                        phenytoin sodium: 274.3

    

               Structural name(s):      Phenytoin: 5,5-Diphenylhydantoin;

                                        5,5-Diphenylimidazoline-2,4-dione.

 

         3.3  Physical properties

 

               3.3.1  Colour

 

                       White

 

               3.3.2  State/Form

 

                       solid-crystalline

                       solid-powder

 

               3.3.3  Description

 

                       Phenytoin:

                       Very slightly soluble in water, slightly soluble in

                       chloroform and ether, soluble 1 in 70 in alcohol.

                       Melting point: 295-298°C

                       (Reynolds, 1996; Budavari, 1996).

    

                       Phenytoin sodium:

                       Phenytoin sodium (synonyms): Diphenin; Phenytoinum

                       Natricum; Soluble phenytoin

    

                       Slightly hygroscopic; on exposure to air it gradually

                       absorbs carbon dioxide with the liberation of

                       phenytoin.

                       Odourless, tasteless.

                       Soluble in water; the solution is turbid unless pH is

                       adjusted to 11,7

                       Soluble in alcohol

                       Practically insoluble in chloroform, in ether and in

                       methylene chloride.

                       Note on incompatibility: The mixing of phenytoin

                       sodium with other drugs or its addition to infusion

                       solutions is not recommended because precipitation may

                       occur (Reynolds, 1996).

 

         3.4  Other characteristics

 

               3.4.1  Shelf-life of the substance

 

                       5 years at 20°C

 

               3.4.2  Storage conditions

 

                       In airtight containers.

 

  1. USES

 

         4.1  Indications

 

               4.1.1  Indications

 

               4.1.2  Description

 

                       Anticonvulsant

                       Antiarrhythmic.

 

         4.2  Therapeutic dosage

 

               4.2.1  Adults

 

                       Anticonvulsant:

                       The dose should be individualised to optimise control

                       of convulsions.  Measurement of plasma concentrations

                       is useful: 10 to 20 µg / mL (40 to 80 µmol/L) will

                       achieve good control in the majority of cases. A small

                       group of patients may require and will tolerate serum

                       phenytoin concentrations greater than 20 µg/mL (80

                       µmol/L) (Levine & Chang, 1990).

                       The suggested initial dose is 100 mg thrice daily

                       progressively increased at intervals of a few days to

                       a maximum of 600 mg daily.

                       Because it may take a week to establish therapeutic

                       plasma concentrations, an initial loading dose of 12

                       to 15 mg/kg body weight divided into 2 or 3 doses may

                       be given over about 6 hours and then followed by 100

                       mg thrice daily.

                       In the treatment of status epilepticus, a loading dose

                       of 10 to 15 mg/kg body weight of phenytoin sodium may

                       be given as slow intravenous injection (not more than

                       50 mg per minute) (Reynolds, 1996). Cardiac rhythm and

                       blood pressure should be continuously monitored during

                       the infusion.

    

                       Antiarrhythmic:

                       Phenytoin is occasionally used in the treatment of

                       cardiac arrhythmias, particularly those associated

                       with digitalis intoxication; it is of little or no use

                       in cardiac arrhythmias caused by  acute or chronic

                       heart disease.

                       The usual dose is 3.5 to 5  mg/kg body weight

                       administered by slow intravenous injection at a rate

                       of not more than 50 mg per minute. This dose may be

                       repeated once if necessary (Reynolds, 1996). Cardiac

                       rhythm and blood pressure should be continuously

                       monitored during the infusion.

 

               4.2.2  Children

 

                       Anticonvulsant:

                       Suggested initial dose is 5 mg/kg body weight daily in

                       2 or 3 divided  doses. Suggested maintenance dose is 4

                       to 8 mg/kg body weight daily.

                       Status epilepticus: intravenous loading dose of from

                       10 to 20 mg/kg body-weight, at a rate not exceeding 1

                       to 3 mg/kg/mn. (Reynolds, 1996). Cardiac rhythm and

                       blood pressure should be continuously monitored during

                       the infusion.

    

 

                       Antiarrhythmic:

                       As for adults.

 

         4.3  Contraindications

 

               Acute intermittent porphyria, hypersensitivity.

               Intravenous injection in patients with sino-atrial cardiac

               block, second- or third degree atrio-ventricular block, sinus

               bradycardia and Adam-Stokes syndrome. Caution is indicated in

               patients with uremia, hypoalbuminaemia, liver function

               disorders, and viral hepatitis (Informatorium Medicamentorum,

               1995).

 

  1. ROUTES OF EXPOSURE

 

         5.1  Oral

 

               Most common route

 

         5.2  Inhalation

 

               Not applicable

 

         5.3  Dermal

 

               Not applicable

 

         5.4  Eye

 

               Not applicable

 

         5.5  Parenteral

 

               Intravenously in status epilepticus.

 

         5.6  Other

 

               No data

 

  1. KINETICS

 

         6.1  Absorption by route of exposure

 

               Phenytoin is slowly, but almost completely absorbed from

               the gastro-intestinal tract; the rate of absorption is

               variable and its bioavailability can differ markedly with

               different pharmaceutical formulations. Large doses are more

               slowly absorbed. In severe oral poisoning, gastro-intestinal

               absorption may continue up to 60 hours (Wilder et al., 1973).

               Administration of 100 mg orally to normal volunteers produced

               two peaks at 2.5 to 3.5 and 10 to 12 hours (Robinson et al.,

               1975).

 

         6.2  Distribution by route of exposure

 

               Phenytoin is widely distributed throughout the body and

               is extensively (87 to 93%) bound to protein. The apparent

               volume of distribution is about 0.5 to 0.8 L/kg (Gugler et

               al., 1976; Hvidberg & Dam, 1976). Plasma binding is almost

               exclusively to albumin; in individuals with normal plasma

               albumin concentration and in absence of displacing agents,

               phenytoin is about 90% plasma bound.

 

         6.3  Biological half-life by route of exposure

 

               Following oral administration of therapeutic doses,

               phenytoin has a very variable, dose-dependent half-life. The

               range for a therapeutic dose is from 8 to 60 hours with an

               average of from 20 to 30 hours (Robinson et al., 1975;

               Hvidberg & Dam, 1976). In overdose in adults the range is

               from 24 to 230 hours (Holcomb et al., 1972; Gill et al.,

               1978; Albertson et al., 1981).

 

         6.4  Metabolism

 

               Phenytoin is extensively metabolised in the liver to 5-

               (4-hydroxyphenyl)-5 phenyl-hydantoin, which is inactive. This

               para hydroxylation of phenytoin is carried out by cytochrome

               P450 2C9 (Veronese et al., 1991, 1993). This enzyme also

               hydroxylates tolbutamide (Doecke et al., 1991), and warfarin

               (Rettie et al., 1992; Kaminski et al., 1993). This explains

               the interaction with these substances.

               The p-hydroxylated phenytoin is in turn conjugated to its

               glucuronide. Phenytoin hydroxylation is capacity-limited

               because of the saturable enzyme systems in the liver. At

               therapeutic doses, metabolism is nonlinear (first-order

               kinetics), while at toxic doses the metabolism is linear

               (zero-order kinetics) (Ellenhorn & Barceloux, 1988; Reynolds,

               1996).

               The p-hydroxylated phenytoin can be oxidised to 3,4-

               dihydroxyphenyl-phenylhydantoin, the catechol metabolite of

               phenytoin, and further to the 3-O-methylated catechol

               metabolite of phenytoin. These metabolites of phenytoin are

               of possible toxicological interest (Edeki & Brase, 1995).

               Phenytoin is more rapidly metabolised in children. (McEvoy,

               1995)

               The rate of metabolism appears to be subject to genetic

               polymorphism (Reynolds, 1996).

               Phenytoin undergoes entero-hepatic recycling (Reynolds,

               1996).

 

         6.5  Elimination by route of exposure

 

               The total systemic clearance of phenytoin from plasma is

               5.9 mL/minute/kg. (Gilman et al., 1990).

               Phenytoin is mainly excreted in the urine as its hydroxylated

               metabolite (23 to 70%), either free or in conjugated form

               (5%). About 4% is excreted unchanged, in the urine and 5% in

               the faeces. (Parker et al., 1970).

               Small amounts are excreted in the milk.

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

         7.1  Mode of action

 

               7.1.1  Toxicodynamics

 

                       Phenytoin is eliminated mainly through para-

                       hydroxylation by a cytochrome P450 system. The

                       metabolic pathway is subject to saturable kinetics in

                       overdose, allowing accumulation of free phenytoin.

                       Even at therapeutic doses, accumulation of free

                       phenytoin is possible in: hypoalbuminaemia, chronic

                       renal failure, hepatic dysfunction, hereditary

                       insufficient para-hydroxylation (Kutt et al., 1964;

                       Vasko et al., 1980; de Wolff, 1983), and inhibition of

                       phenytoin metabolism by other drugs.

 

               7.1.2  Pharmacodynamics

 

                       Phenytoin binds to specific site on voltage-

                       dependent sodium channels and is thought to exert its

                       anticonvulsant effect by suppressing the sustained

                       repetitive firing of neurons by inhibiting sodium flux

                       through these voltage dependent channels (Francis &

                       Burnham, 1992). Phenytoin stabilises membranes,

                       protecting the sodium pump in the brain and in the

                       heart. It limits the development of maximal convulsive

                       activity and reduces the spread of convulsive activity

                       from a discharging focus without influencing the focus

                       itself. (Reynolds, 1982, 1996)

                       Phenytoin has antiarrhythmic properties similar to

                       those of quinidine or procainamide.  Although

                       phenytoin has minimal effect on the electrical

                       excitability of cardiac muscle, it decreases the force

                       of contraction, depresses pacemaker action and

                       improves atrioventricular conduction. It also prolongs

                       the effective refractory period relative to the action

                       potential duration (Mc Evoy, 1995).

 

         7.2  Toxicity

 

               7.2.1  Human data

 

                       7.2.1.1  Adults

 

                                 Ingestion of 4,5 g has been reported

                                 to produce transient coma. However, 25 g has

                                 been tolerated without serious depression

                                 (Gosselin et al., 1976).

 

                       7.2.1.2  Children

 

                                 Fatal outcome has been reported in a

                                 7-year-old who ingested 2 g (Gosselin et al.,

                                 1976), in a 4 year old child who ingested

                                 forty 50 mg tablets and in a 16 year old girl

                                 who ingested an unknown amount (Laubscher,

                                 1966).

 

               7.2.2  Relevant animal data

 

                       Phenytoin has high acute toxicity:

                       LD50 (oral) mouse: 150 mg/kg

                       LD50 (intravenous) rat: 101 mg/kg

                       LD50 (intravenous) rabbit: 125 mg/kg

                       (Sax & Lewis, 1989; ANDIS, 1994).

 

               7.2.3  Relevant in vitro data

 

                       Not relevant

 

         7.3  Carcinogenicity

 

               Malignancies, including neuroblastoma, in children whose

               mothers were on phenytoin during pregnancy have been reported

               (McEvoy, 1995).

 

         7.4  Teratogenicity

 

               Phenytoin is classed as a teratogen risk factor D

               (Positive evidence of human fetal risk, but the benefits from

               use in pregnant women may be acceptable despite the

               risk).

               The epileptic pregnant woman taking phenytoin, either alone

               or in combination with other anticonvulsants, has a two to

               three times greater risk of delivering a child with

               congenital defects. It is not known if this increased risk is

               due to antiepileptic drugs, the disease itself, genetic

               factors, or a combination of these, although some evidence

               indicates that drugs are the causative factor.

 

               A recognisable pattern of malformations, known as the fetal

               hydantoin syndrome has been described and includes

               craniofacial and limb abnormalities, cleft lip, impaired

               growth, and congenital heart defects. (Briggs, 1994).

 

         7.5  Mutagenicity

 

               No data available.

 

         7.6  Interactions

 

               Drug interactions with phenytoin are numerous. They may

               be classified, according to mechanism, in the following

               way:

    

               Drugs displacing phenytoin plasma protein binding sites

               Azapropazone (Geaney et al., 1983)

               Diazoxide (Roe et al., 1975)

               Heparin (Schulz et al., 1983)

               Ibuprofen (Bachman et al., 1986)

               Phenylbutazone (Lunde et al., 1970)

               Salicylic acid (Lunde et al., 1970; Fraser et al., 1980;

               Paxton, 1980; Leonard et al., 1981)

               Sulfadimethoxine (Hansen et al., 1979)

               Sulfafurazole (Lunde et al., 1970)

               Sulfamethizole (Hansen et al., 1979; Lumholz et al.,

               1975)

               Sulfamethoxydiazine (Hansen et al., 1979)

               Sulfamethoxypyridazine (Hansen et al., 1979)

               Tolbutamide (Wesseling & Mols-Thurkow, 1975)

               Valproic acid (Patsalos & Lascelles, 1977; Monks et al.,

               1978; Dahlqvist et al., 1979; Bruni et al., 1980; Monks &

               Richens, 1980; Perucca et al., 1980; Sanson et al., 1980)

    

               Decreased total and unbound plasma phenytoin concentration

               caused by increased metabolism

               Folic acid (Viukari, 1968; Furlanot et al., 1978; Berg et

               al., 1983)

               Dexamethasone (Wong, 1985)

               Phenobarbital (Cucinell et al., 1965; Kutt et al., 1969;

               Browne et al., 1988a)

               Diazepam (Vajda et al., 1971; Richens & Houghton, 1975)

               Rifampicin (Kay et al., 1985)

               Methadone (Tong et al., 1981)

               Nitrofurantoin (Heipert & Pilz, 1978)

               Oestrogens and progestagens

    

               Increased unbound fraction of phenytoin secondary to reduced

               intrinsic metabolism

               Anticonvulsants:

               Valproic acid (Patsalos & Lascelles, 1977; Wilder et al.,

               1978; Bruni et al., 1980; Sanson et al., 1980; Perucca,

               1984)

 

               Carbamazepine (Hansen et al., 1971; Zielinski et al., 1985;

               Browne et al., 1988b)

               Sulthiame (Hansen et al., 1968; Houghton & Richens, 1974)

               Clobazam (Zifkin et al., 1991)

    

               Antithrombotics:

               Coumarin derivatives (Skovsted et al., 1976; Panegyres &

               Rischbieth, 1991; Abad-Santos et al., 1995)

               Triclodine (Rindone et al., 1996)

    

               Antituberculous drugs:

               Isoniazid and PAS (Kutt et al., 1970; Walubo & Aboo,

               1995)

    

               H2 antagonists:

               Cimetidine (Neuvonen et al., 1981; Levine et al., 1985;

               Sambol et al., 1989)

               Ranitidine (Bramhall & Levine, 1988)

               Omeprazole (Gugler & Jensen, 1985)

    

               Non-steroidal anti-inflammatory agents:

               Azapropazone (Roberts et al., 1981; Geany et al., 1983)

               Phenylbutazone (Andreasen et al., 1973; Neuvonen et al.,

               1979)

               Ibuprofen (Sandyk, 1982)

    

               Antiinfective agents:

               Metronidazole (Jensen & Gugler, 1985; Blyden et al.,

               1988)

               Chloramphenicol (Christensen & Skovsted, 1969; Ballek et al.,

               1973; Cosh et al., 1987)

    

               Antimycotics:

               Miconazole (Rolan et al., 1983)

               Fluconazole (Cadle et al., 1994)

    

               Psychoactive drugs:

               Fluoxetine (Jalil, 1992)

               Risperidone (Sanderson, 1996)

    

               Miscellaneous:

               Amiodarone (Gore et al., 1984; Shackleford & Watson, 1987;

               Ahmad, 1995)

               Allopurinol (Yokochi et al., 1982)

               Disulfiram

 

         7.7  Main adverse effects

 

               Anticonvulsant hypersensitivity syndrome is a

               potentially fatal drug reaction with cutaneous and systemic

               manifestations (incidence 1: 1000 to 1: 10.000). The findings

               are:

    

 

               Fever (90-100%)

               Dermatological (90%): erythema, papulous rash. In some cases

               erythroderma and even a lethal epidermal necrolysis has been

               reported.

               Lymphadenopathy (70%): lymphoma and depressed immunological

               function have been reported.

               Hepatitis (50-60%): hepatitis may develop in severe liver

               failure and death.

               Haematological (50%): leucocytosis with atypical lymphocytes,

               eosinophilia, and agranulocytosis.

               Connective tissues: coarsening of facial features, enlargment

               of the lips, gingival hyperplasia, hypertrichosis, Peyronie’s

               disease.

               (Physician’s Desk Reference, 1995)

 

  1. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

 

         8.1  Material sampling plan

               8.1.1  Sampling and specimen collection

                       8.1.1.1  Toxicological analyses

                       8.1.1.2  Biological analyses

                       8.1.1.3  Arterial blood gas analyses

                       8.1.1.4  Haematological analyses

                       8.1.1.5  Other (unspecified) analyses

               8.1.2  Storage of laboratory samples and specimens

                       8.1.2.1  Toxicological analyses

                       8.1.2.2  Biomedical analyses

                       8.1.2.3  Arterial blood gs analysis

                       8.1.2.4  Haematological analyses

                       8.1.2.5  Other (unspecified) analyses

               8.1.3  Transport of laboratory samples and specimens

                       8.1.3.1  Toxicological analyses

                       8.1.3.2  Biomedical analyses

                       8.1.3.3  Arterial blood gas analysis

                       8.1.3.4  Haematological Analyses

                       8.1.3.5  Other (unspecified) analyses

         8.2  Toxicological analyses and their interpretation

               8.2.1  Tests on toxic ingredient(s) of material

                       8.2.1.1  Simple qualitative test(s)

                       8.2.1.2  Advanced qualitative confirmation test(s)

                       8.2.1.3  Simple quantitative method(s)

                       8.2.1.4  Advanced quantitative method(s)

               8.2.2  Test(s) for biological specimens

                       8.2.2.1  Simple qualitative test(s)

                       8.2.2.2  Advanced qualitative confirmation test(s)

                       8.2.2.3  Simple quantitative method(s)

                       8.2.2.4  Advanced quantitative method(s)

               8.2.3  Interpretation of toxicological analyses

         8.3  Biomedical investigations and their interpretation

               8.3.1  Biochemical analyses

 

                       8.3.1.1  Blood, plasma or serum

                                 “Basic analyses”

                                 “Dedicated analyses”

                                 “Optional analyses”

                       8.3.1.2  Urine

                                 “Basic analyses”

                                 “Dedicated analyses”

                                 “Dedicated analyses”

                                 Optional analyses”

                       8.3.1.3  Other biological specimens

 

               8.3.2  Arterial blood gas analysis

 

                       Decrease of blood pH causes reduced protein

                       binding of phenytoin resulting in higher tissue

                       levels.

 

               8.3.3  Haematological analyses

                       “Basic analyses”

                       “Dedicated analyses”

                       “Optional analyses”

               8.3.4  Other (unspecified) analyses

               8.3.5  Interpretation of biomedical investigations

 

         8.4  Other biomedical (diagnostic) investigations and their

               interpretation

 

         8.5  Summary of the most essential biomedical and toxicological

               analyses in acute poisoning and their interpretation

 

               Interpretation of toxicological tests: total

               phenytoin:

    

               Serum concentration      Signs and Symptoms

               10 – 20 (g/mL)           therapeutic range (Troupin 1984a, b)

    

               20 – 30  (g/mL)          horizontal nystagmus on lateral gaze,

                                        ataxia, and drowsiness (Riker et al.

                                        1978)

    

               30 – 40  (g/mL)          vertical nystagmus, slurred speech

                                        ataxia, lurching gait, coarse tremors

    

               50 – 70 (g/mL)           fatalities recorded (Subik & Robinson

                                        1982)

    

               Interpretation of toxicological tests: free phenytoin

    

               1.5 – 3.5 (g/mL)         minor signs of intoxication (Wilson et

  1. 1979)

    

               > 5 (g/mL)               toxic effects (Booker & Darcey 1973)

 

  1. CLINICAL EFFECTS

 

         9.1  Acute poisoning

 

               9.1.1  Ingestion

 

                       Onset of symptoms and signs, principally

                       involving the central nervous system, occurs within

                       hours of acute overdose (Ellenhorn & Barceloux, 1988;

                       Curtis et al., 1989). These manifestations of toxicity

                       may last many days and, in general, correlate with

                       serum phenytoin concentrations. The earliest

                       manifestations of toxicity following overdose are

                       nystagmus on lateral gaze, ataxia and drowsiness. With

                       more severe intoxication, vertical nystagmus,

                       dysarthria, progressive ataxia to the point of

                       inability to walk, hyperreflexia and impaired level of

                       consciousness are observed. Coma and/or respiratory

                       depression is rarely observed and should prompt

                       consideration of an alternative diagnosis. Paradoxical

                       seizures have been reported in severe phenytoin

                       intoxication but are extremely rare (Stilman & Masdeu,

                       1985).

 

               9.1.2  Inhalation

 

                       Not relevant

 

               9.1.3  Skin exposure

 

                       Not relevant

 

               9.1.4  Eye contact

 

                       Not relevant

 

               9.1.5  Parenteral exposure

 

                       Fatalities have been reported following

                       intravenous administration of phenytoin to elderly

                       patients with cardiac arrhythmias (Gellerman &

                       Martinez, 1967; Unger & Sklaroff, 1967; Zoneraich et

                       al., 1976; Earnest et al., 1983).

                       These complications appear more likely when

                       intravenous phenytoin is administered at a rapid rate

                       (Earnest et al., 1983) and have been attributed to the

                       solvent propylene glycol rather than to the phenytoin

                       itself (Louis et al., 1967; Gross et al., 1979;

                       Randazzo et al., 1995). The risk of hypotension and

                       arrythmia is minimal when intravenous phenytoin is

                       used as an anticonvulsant and administered at the

                       recommended rate. In a series of 164 patients who

                       received intravenous phenytoin loading following

 

                       presentation with acute convulsions, the incidence of

                       hypotension was approximately 5%, and the incidence of

                       apnea and cardiac arrhythmias was 0% (Binder et al.,

                       1996).

 

               9.1.6  Other

 

                       No data available

 

         9.2  Chronic poisoning

 

               9.2.1  Ingestion

 

                       The same as in acute poisoning.

 

               9.2.2  Inhalation

 

                       Not relevant.

 

               9.2.3  Skin exposure

 

                       Not relevant

 

               9.2.4  Eye contact

 

                       Not relevant

 

               9.2.5  Parenteral exposure

 

                       Not relevant

 

               9.2.6  Other

 

                       No data available.

 

         9.3  Course, prognosis, cause of death

 

               Normally the clinical course is one of gradual

               resolution of the signs and symptoms of intoxication leading

               to complete recovery.

               Death is rare after phenytoin overdose. It has been reported

               in association with administration of intravenous phenytoin

               for treatment of cardiac arrhythmias in elderly people

               (Gellerman & Martinez, 1967; Unger & Sklaroff, 1967;

               Zoneraich et al., 1976), and rarely from coma and hypotension

               following oral overdose in children (see section 11 for

               details).

 

         9.4  Systematic description of clinical effects

 

               9.4.1  Cardiovascular

 

                       Intravenous phenytoin has been reported to

                       cause depression of cardiac conduction, ventricular

                       fibrillation and heart block in elderly people treated

                       for cardiac arrhythmias (Gellerman & Martinez, 1967;

                       Unger & Sklaroff, 1967; Zoneraich et al., 1976).

                       Intravenous phenytoin is irritant and may cause

                       phlebitis (Jamerson et al., 1994).

 

               9.4.2  Respiratory

 

                       No data available.

 

               9.4.3  Neurological

 

                       9.4.3.1  CNS

 

                                 Nystagmus, ataxia, dysarthria,

                                 drowsiness, coarse resting tremor, ankle

                                 clonus, brisk deep tendon reflexes. In severe

                                 poisoning, the patient becomes obtund,

                                 confused and disoriented. Coma and

                                 respiratory depression are unusual.

 

                       9.4.3.2  Peripheral nervous system

 

                                 No data available.

 

                       9.4.3.3  Autonomic nervous system

 

                                 No data available

 

                       9.4.3.4  Skeletal and smooth muscle

 

                                 No data available.

 

               9.4.4  Gastrointestinal

 

                       No data available.

 

               9.4.5  Hepatic

 

                       A phenytoin hypersensitivity syndrome occurs

                       and is characterised by hepatitis. Overall mortality

                       rate when liver is involved is between 18% and 40%

                       (Harinasula & Zimmerman 1968; Dhar et al., 1974;

                       Parker & Shearer, 1979; Ting et al., 1982; Smythe &

                       Umstead, 1989; Howard et al., 1991,). The hepatitis is

                       usually anicteric (Pezzimenti & Hahn, 1970). Icterus

                       portends a poorer prognosis (Chaiken et al., 1950;

 

                       Dhar et al., 1974; Parker & Shearer, 1979).

                       Hepatomegaly with or without splenomegaly may be

                       present. The elevated hepatic transaminases, which may

                       be in the thousands of international units, can

                       continue to rise after phenytoin is discontinued (Ting

                       et al., 1982; Howard et al., 1991). Phenytoin-induced

                       chronic hepatitis has been reported (Roy et al.,

                       1993).

 

               9.4.6  Urinary

 

                       9.4.6.1  Renal

 

                                 No data available.

 

                       9.4.6.2  Other

 

                                 No data available.

 

               9.4.7  Endocrine and reproductive system

 

                       Phenytoin can induce hyperglycemia by

                       inhibiting the release of insulin (Belton et al.,

                       1965; Kizer et al., 1970; Levin et al., 1970; Holcomb

                       et al., 1972; Britton & Schwinghammer, 1980; Carter et

                       al., 1981). However, hypoglycemia has been reported in

                       a patient treated with phenytoin for 19 years who

                       ingested 20 g phenytoin together with 225 mg

                       zopiclone. This hypoglycemic episode was attributed to

                       phenytoin and may be due either to an escape from the

                       inhibitory effects of phenytoin on insulin secretion

                       or an increased sensitivity of the tissues to insulin

                       (Manto et al., 1996).

 

               9.4.8  Dermatological

 

                       In the Anticonvulsant Hypersensitivity

                       Syndrome, the cutaneous eruption begins as a patchy

                       macular erythema that evolves into a dusky, pink-

                       red,confluent, papular rash that usually is pruritic.

                       The upper trunk, face, and upper extremities are

                       affected first, with later involvement of the lower

                       extremities. In some cases erythroderma ensues.

                       Patients have periorbital and facial edema (Vittirio &

                       Muglia, 1995).

                       Epidermal necrolysis (even lethal) has been reported

                       (Gately & Lam, 1979; Janinis et al., 1993; Hunt,

                       1995).

 

               9.4.9  Eye, ear, nose, throat, local effects

 

                       No data available.

 

               9.4.10 Haematological

 

                       A number of adverse haematological effects

                       have been reported. These are not observed following

                       acute overdose.

                       The haematological abnormalities reported include

                       leucocytosis with atypical lymphocytes, eosinophilia

                       (Ray-Chaudhuri et al., 1989), leucopenia (Choen &

                       Bovasso, 1973) and agranulocytosis (Tsan et al., 1976;

                       Rawanduzy et al., 1993).

                       The marrow toxicity of anticonvulsants, which may be

                       more likely when used in combination (e.g. primidone),

                       is recognised. There may be three mechanisms of

                       toxicity. Firstly, primidone and phenytoin both cause

                       folate deficiency and a megaloblastic anaemia.

                       Secondly, an immune mechanism with a phenytoin-

                       dependent antigranulocyte antibody may cause

                       leucopenia, which resolves on discontinuing therapy.

                       Finally, phenytoin may cause a direct toxic effect

                       with pancytopenia and agranulocytosis (Laurenson et

                       al., 1994).

                       Subnormal serum-folate concentrations were found in

                       patients with chronic epilepsy treated with phenytoin

                       (Horwitz et al., 1968; Maxwell et al., 1972). It was

                       suggested that folate deficiency resulted from

                       accelerated metabolism of folate consequent upon

                       induction of liver enzymes by

                       anticonvulsants.

 

               9.4.11 Immunological

 

                       It seems likely that an aetiological

                       relationship exists between phenytoin treatment and

                       lymphoma. There is evidence of depressed immunological

                       function in patients given phenytoin (Brandt & Nilson,

                       1976; Rodriguez-Garcia et al., 1991; Ishizaka et al.,

                       1992; Kondo et al., 1994; Abbondazo et al.,

                       1995).

 

               9.4.12 Metabolic

 

                       9.4.12.1 Acid-base disturbances

 

                                 No data available.

 

                       9.4.12.2 Fluid and electrolyte disturbances

 

                                 No data available

 

                       9.4.12.3 Others

 

                                 No data available.

 

               9.4.13 Allergic reactions

 

                       Anticonvulsant hypersensitivity syndrome is a

                       potentially fatal drug reaction with cutaneous and

                       systemic manifestations (incidence one in 1000 to one

                       in 10 000 exposures) to the arene oxide producing

                       anticonvulsants: phenytoin, carbamazepine, and

                       phenobarbital sodium. The features include fever 

                       (90-100%), rash (90%), lympheadenopathy (70%), 

                       periorbital or facial edema (25%), hepatitis (50-60%),

                       haematologic abnormalities (50%), myalgia, arthralgia

                       (21%) and pharyngitis (10%). The reaction may be

                       genetically determined (Vittorio & Muglia,

                       1995).

 

               9.4.14 Other clinical effects

 

                       Not relevant.

 

         9.5  Other

 

               Connective tissues: coarsening of facial features,

               enlargment of the lips, gingival hyperplasia, hypertrichosis,

               Peyronie’s disease (Dahlloef et al., 1991; Hassell & Hefti,

               1991; Bredfeldt, 1992; Natelli, 1992; Thomason et al., 1992;

               Seymour, 1993; Tigaran, 1994; McLoughlin et al., 1995; Perlik

               et al., 1995).

 

         9.6  Summary

 

  1. MANAGEMENT

 

         10.1 General principles

 

               Toxicity is rarely fatal and is treated by the

               institution of general supportive care and the

               discontinuation of phenytoin.

 

         10.2 Life supportive procedures and symptomatic/specific treatment

 

               Make a proper assessment of airway, breathing,

               circulation and neurological status of the patient.

               Maintain a clear airway.

               Administer oxygen if indicated.

               Open and maintain an intravenous route. Administer

               intravenous fluids.

               Monitor vital signs. It is not necessary to monitor the

               cardiac rhythm except in very severe cases.

 

         10.3 Decontamination

 

               Administer activated charcoal following acute overdose

               (not necessary for cases of chronic toxicity).

 

         10.4 Elimination

 

               Forced diuresis, haemodialysis and haemoperfusion are

               all ineffective (Jacobsen et al., 1986).

 

         10.5 Antidote treatment

 

               10.5.1 Adults

 

                       Not applicable.

 

               10.5.2 Children

 

                       Not applicable.

 

         10.6 Management discussion

 

               No data available.

 

  1. ILLUSTRATIVE CASES

 

         11.1 Case reports from litterature

 

               A 70-year old man with chronic lung disease for many

               years and angina pectoris for six months was admitted to the

               hospital because of increasing congestive heart failure

               despite digoxin and diuretic therapy. On admission the

               patient manifested evidence of some left-sided congestive

               heart failure wih tricuspid regurgitation. The ECG revealed

               regular sinus rhythm. The patient responded well to bed rest,

               oxygen, antibiotics, bronchodilators, and expectorants. 

               Maintenance dose of digoxin was continued. Two days after

               admission, he suddenly experienced pulmonary edema and atrial

               flutter with a ventricular response of 150. Phenytoin 250 mg,

               was given intravenously over a period of three minutes. The

               atrial flutter persisted, but with a high degree of atrio-

               ventricular block, followed by asystole three minutes after

               the completion of phenytoin. All attempts at resuscitation

               failed (Unger & Sklaroff, 1967).

    

               A 4 year-old girl was well until midway through the afternoon

               when her parents noted that her behaviour was abnormal. The

               next day, it was learned that she had accidentally ingested

               forty 50-mg tablets of phenytoin which has been prescribed

               for an older sister. The patient was hyperactive and ataxic.

               She appeared to have particular difficulty in keeping her

               head erect. Her pupils were miotic. Shortly thereafter she

               complained of epigastric pain and generalized pruritus. She

               had delusions and was difficult to manage. Her temperature

               was normal. Her condition changed little until that evening

               when she became progressively lethargic and was thereupon

               admitted to the hospital. The ataxia worsened, the patient

               became gradually less responsive, and her pupils were

               alternately miotic and dilated. By the following morning she

 

               was semicomatose. Several times that day and the following

               day, she vomited small mounts of pink material. The patient

               repeatedly opened her eyes and appeared to be afraid and then

               lapsed back into general unresponsiveness. Shortly after, the

               blood pressure became unrecordable. At 80 hours after the

               onset of symptoms there was an irreversible brain damage. A

               blood sample, drawn 24 hours after the onset of symptoms,

               revealed a phenytoin level of 94 mg/L (Laubscher, 1966).

    

               A 15-year-old boy ingested 19,5 g phenytoin sodium (15 g

               verifiable, equivalent to 392 mg/kg body weight)

               approximately four hours before emergency department

               presentation. He demonstrated the following signs: vomiting,

               obtundation responsive only to painful stimuli, reactive to

               light midposition pupils, brisk deep tendon reflexes,

               choreoathetoid movements, and irregular and shallow

               respirations. Treatment included nasotracheal intubation,

               gastric lavage, and activated charcoal. His clinical

               condition improved over the 7 following days, with periods of

               combativeness and agitation requiring the administration of

               diazepam, and responsiveness only to pain, alternately. The

               patient demonstrated no hypotension or cardiac arrhythmia.

               Peak phenytoin plasma level was 100,8 œg/mL. (Mellick et al.,

               1989).

 

  1. ADDITIONAL INFORMATION

 

         12.1 Specific preventive measures

 

               No data available

 

         12.2 Other

 

               No data available

 

  1. REFERENCES

 

         Abad-Santos F, Carcas AJ, Capitan C, Frias J (1995)

         Retroperitoneal haematoma in a patient treated with acenocoumarol,

         phenytoin and paroxetine. Clin Lab Haematol 17: 195-197

    

         Abbondazo SL, Irey NS, Frizzera G (1995) Dilantin-associated

         lymphadenopathy. Spectrum of histopathologic patterns. Am J Surg

         Pathol 19: 675-686

    

         Ahmad S (1995) Amiodarone and phenytoin interaction. J Am Geriat

         Soc 43: 1449-1450

    

         Albertson TE, Fisher CE Jr, Shragg TA (1981) A prolonged severe

         intoxication after ingestion of phenytoin and phenobarbital. West

         J Med 135: 418-422

    

 

         Andreasen PB, Froland A, Skovsted L, Andersen SA, Hauge M (1973)

         Diphenylhydantoin half-life in man and its inhibition by

         phenylbutazone: the role of genetic factors. Acta Medica

         Scandinavica 193: 561-564

    

         Australian National Drug Information Service (ANDIS) (1984)

         Profile on Phenytoin. Canberra, Commonwealth Department of Health

         and Family services, pp 1-21

    

         Bachmann KA, Schwarz JI, Forny RB, Jaurugui L, Sulivan TJ (1986)

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         methadone withdrawal. Ann Intern Med, 94: 349-351

    

         Troupin AS (1984a) The measurement of anticonvulsant agent levels.

         Ann Intern Med, 100: 854-858

    

         Toupin AS (1984b) Phenytoin therapy and toxicities. Ann Intern

         Med, 101: 568

    

         Tsan MF, Mehlman DJ, Green S (1976) Dilantin, agranulocytosis and

         phagocytic marrow histocytes. Ann Intern Med, 84, 710

    

         Unger AH & Sklaroff HJ (1967) Fatalities following intravenous use

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         159-160

    

         Vajda FJE, Prineas RJ, Lovell RRH (1971) Interaction between

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         interaction with clobazam. Neurology 41: 313-314

    

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  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADRRESS(ES)

 

        Author:                 Prof.Dr.A.N.P.van Heijst

                                Baarnseweg 42 A

                                3735 MJ Bosch en Duin

                                The Netherlands

                                Tel. (31) 30 228 7178

                                Fax  (31) 30 225 1368

                                E-mail: [email protected]

                                December 1996.

    

        Reviewer:               MO Rambourg Schepens

                                Centre Anti-Poisons de Champagne Ardenne

                                Centre Hospitalier Universitaire

                                F-51092 Reims Cedex

                                France

                                E-mail: [email protected]

                                August 1997

    

        Peer review:            N Ben Salah, A Borges, J Gregan, M Mathieu

                                Nolf, L Murray (coordinator), MO Rambourg

                                Schepens

                                Rio, September 1997

    

        Finalization/Edition:   L Murray, MO Rambourg Schepens

                                November 1997

    

 

See Also:

        Phenytoin (IARC Summary & Evaluation, Volume 66, 1996)

 

Valproic acid

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Brand names, Trade names

   1.6 Manufacturers, Importers

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/Form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.2.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination and excretion

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

         8.1.1.1 Toxicological analyses

         8.1.1.2 Biomedical analyses

         8.1.1.3 Arterial blood gas analysis

         8.1.1.4 Haematological analyses

         8.1.1.5 Other (unspecified) analyses

      8.1.2 Storage of laboratory samples and specimens

         8.1.2.1 Toxicological analyses

         8.1.2.2 Biomedical analyses

         8.1.2.3 Arterial blood gas analysis

         8.1.2.4 Haematological analyses

         8.1.2.5 Other (unspecified) analyses

      8.1.3 Transport of laboratory samples and specimens

         8.1.3.1 Toxicological analyses

         8.1.3.2 Biomedical analyses

         8.1.3.3 Arterial blood gas analysis

         8.1.3.4 Haematological analyses

         8.1.3.5 Other (unspecified) analyses

   8.2 Toxicological Analyses and Their Interpretation

      8.2.1 Tests on toxic ingredient(s) of material

         8.2.1.1 Simple Qualitative Test(s)

         8.2.1.2 Advanced Qualitative Confirmation Test(s)

         8.2.1.3 Simple Quantitative Method(s)

         8.2.1.4 Advanced Quantitative Method(s)

      8.2.2 Tests for biological specimens

         8.2.2.1 Simple Qualitative Test(s)

         8.2.2.2 Advanced Qualitative Confirmation Test(s)

         8.2.2.3 Simple Quantitative Method(s)

         8.2.2.4 Advanced Quantitative Method(s)

         8.2.2.5 Other Dedicated Method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Biomedical investigations and their interpretation

      8.3.1 Biochemical analysis

         8.3.1.1 Blood, plasma or serum

         8.3.1.2 Urine

         8.3.1.3 Other fluids

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematological analyses

      8.3.4 Interpretation of biomedical investigations

   8.4 Other biomedical (diagnostic) investigations and their interpretation

   8.5 Overall interpretation of all toxicological analyses and toxicological investigations

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Others

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Others

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

    VALPROIC ACID

 

    International Programme on Chemical Safety

    Poisons Information Monograph 551

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Valproic acid

 

        1.2  Group

 

             Antiepileptic (N03)/Fatty acid derivatives (N03AG)

 

        1.3  Synonyms

 

             Abbott-44089;

             2-Propylpentanoic acid;

             2-Propylvaleric acid;

             Di-n-dipropylacetic acid

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    99-66-1

 

             1.4.2  Other numbers

 

                    CAS number:

                    Sodium Valproate      1069-66-5

                    Semisodium Valproate  76584-70-8

                    Valproate Pivoxil     77372-61-3

                    Valpromide            2430-27-5

 

                    RTECS Valproic acid  YV7875000

 

        1.5  Brand names, Trade names

 

             Convulex, Convulexette (Belgium)

    

             Promonta, Mylproin, Valcote (Germany)

    

             Byk, Propymal (Netherlands)

    

             Gerot (Switzerland)

    

             Depakene (Canada, Japan, USA, Philippines)

    

             Depakin (Italy)

    

 

             Depakine (Belgium, France, Netherlands, Spain, Switzerland)

    

             Depamide (France, Italy, Netherlands, Spain)

    

             Deparkine (Denmark, Norway)

    

             Epilim (Australia, South Africa, UK)

    

             Epival (Canada)

    

             Leptilan (Denmark, Germany)

    

             Ergenyl, Leptilen, Orfilept (Sweden)

    

             Logical (Argentina)

    

             Orfiril (Denmark, Germany, Norway, Switzerland)

    

             Vistora (Spain)

 

        1.6  Manufacturers, Importers

 

             Promonta (Germany)

             Sigmatau (Italy)

             Labanz (France, Spain, Switzerland, Germany, South Africa)

             Labanz Sanofi (Netherlands, UK)

             Reckitt and Colman (Australia)

             Geigy (Denmark, Germany)

             Leo Rhodia (Sweden)

             Rhône Poulenc (Switzerland, Denmark)

             Vita (Spain)

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             After oral administration, the drug is rapidly absorbed

             from the gastrointestinal tract and metabolized in the

             liver.

    

             Fatal hepatic failure has been reported in patients on

             valproic acid therapy, especially those on chronic use.

    

             Central nervous system depression and convulsions may

             occur.

    

             The drug crosses the placental barrier and has been found in

             breastmilk.

    

             Pancreatitis has also been reported, usually seen in patients

             receiving normal therapeutic dosage.

 

        2.2  Summary of clinical effects

 

             Reports showed that acute toxicity is rare, and usually

             follows a benign course (Ellenhorn, 1988).

    

             Fatal hepatic failure is usually seen following chronic use

             of valproic acid. 

    

             The most commonly reported adverse effects are anorexia,

             nausea and vomiting.

    

             Gastrointestinal:

    

             Nausea, vomiting, diarrhoea, pancreatitis (usually receiving

             normal therapeutic doses).

    

             Central nervous system:

    

             Drowsiness, possibly apathy and withdrawal, confusion,

             restlessness, hyperactivity. Less frequently, seizures and

             coma may occur.  Asterixis of both hands and feet.  Delayed

             cerebral oedema.

    

             Sedative effects are more pronounced when drug is used

             together with other anti-epileptic agents.

    

             Liver:

    

             Hepatic failure (centrilobular necrosis).

    

             Haematopoietic system:

    

             Thrombocytopenia, abnormal bleeding time and partial

             thromboplastin time with decreased fibrinogen levels and

             prolonged prothrombin time leading to bruising, petechiae,

             haematoma, and epistaxis.

    

             Skin:

    

             Pruritic macular rashes.

    

             Hair:

    

             Transient alopecia.

    

             Metabolic:

    

             Hyperammonaemia, hypocalcaemia, metabolic acidosis.

    

             Endocrine system:

    

             Altered thyroid functions (clinical significance is unknown).

 

        2.3  Diagnosis

 

             Clinical diagnosis is difficult because of multiorgan

             toxicity.

    

             Serum, urine, plasma and breastmilk can be used as samples

             for determining valproic acid and its metabolites using

             either gas chromatography, gas chromatography-mass

             spectrophotometry and high pressure liquid chromatography.

 

        2.4  First aid measures and management principles

 

             Assess airway, breathing, circulation and neurological

             status of the patient.  Maintain a clear airway, aspirate

             secretions.  If respiratory depression is present, intubate

             and ventilate.

    

             Emesis with syrup of ipecac is not advisable since, although

             the patient may be conscious on admission, he/she may rapidly

             deteriorate and become somnolent and stuporous.  Gastric

             lavage should be considered, if the patient is seen within 1

             to 2 hours after ingestion. However, if the patient is

             comatose, convulsing or has lost the gag reflex, endotracheal

             intubation is needed.  This procedure, however, is of limited

             value when the drug was taken in syrup form due to rapid

             absorption of the drug.  The use of activated charcoal may be

             considered after oral overdosage.

    

             Enhancement of elimination either by forced alkaline

             diuresis, haemodialysis or haemoperfusion may be of little

             value, because of its high protein binding.

    

             Supportive therapy is the mainstay in the management of

             valproic acid overdose.

    

             If the patient is stuporous, drowsy or somnolent, but

             otherwise with normal vital signs and baseline liver function

             tests are within normal, then simple observation with

             supportive therapy and good nursing care for 24 to 72 hours

             may be sufficient (Ellenhorn & Barceloux, 1988).

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Valproic acid may be synthesized from 4-heptanol by

             successive conversions to 4-bromoheptane with HBr, to

             4-cyanoheptane with HCN and to 2-propyl pentanoic (valproic)

             acid by alkaline hydrolysis of the 4-cyanoheptane (Gennaro,

             1985).

 

        3.2  Chemical structure

 

             Molecular formula:

    

             Valproic acid          C8H16O2

             Sodium Valproate       C8H15NaO2

             Semisodium Valproate   C16H31NaO4

             Valproate Pivoxil      C14H26O4

             Valpromide             C8H17NO

    

             Molecular weight:

    

             Valproic acid           144.2

             Sodium Valproate        166.2

             Semisodium Valproate     310.4

             Valproate Pivoxil        258.4

             Valpromide               143.2

    

             Chemical names:

    

             Valproic acid

             2-Propylpentanoic acid

             2-Propylvaleric acid

             Di-n-dipropylacetic acid

    

             Sodium Valproate

             Sodium 2-propylvalerate

             Sodium 2-propylpentanoate

    

             Semisodium Valproate

             2-Propylvaleric acid-sodium 2-propylvalerate

             Sodium hydrogen bis(2-propylvalerate)

    

             Valproate Pivoxil 

             Hydroxymethyl 2-propylvalerate pivalate

    

             Valpromide

             Dipropylacetamide

             2-propylvaleramide

    

             (Reynolds, 1989; USP, 1990)

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    Colourless to pale yellow

 

             3.3.2  State/Form

 

                    Liquid-viscous liquid

 

             3.3.3  Description

 

                    It is slightly soluble in water (1.2 mg/mL);

                    fully soluble in acetone, chloroform, ether and methyl

                    alcohol.

    

                    (Ellenhorn & Barceloux, 1988; Reynolds, 1989)

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

                    No data available.

 

             3.4.2  Storage conditions

 

                    Store in airtight containers and protect from

                    light.  Valproic acid capsules should be stored at 15

                    to 30°C and freezing should be avoided. (Reynolds,

                    1989; McEvoy, 1991).

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Antiepileptic preparation

                    Antiepileptic drug

                    Fatty acid derivative; antiepileptic

 

             4.2.2  Description

 

                    Valproic acid is used solely or in combination

                    with other anticonvulsants in the treatment of simple

                    (petit mal) and complex absence seizures.

    

                    Valproate may be effective against myoclonic and

                    atonic seizures in young children and considered by

                    some experts as the agent of choice.

                    (Gilman et al., 1990).

 

        4.2  Therapeutic dosage

 

             4.2.1  Adults

 

                    Oral

    

                    Initial dose of sodium valproate in the UK is 600 mg

                    daily in divided doses, increased every other 3 days

                    by 200 mg daily to a usual range of 1 to 2 g daily (20

 

                    to 30 mg/kg/day); further increase to a maximum of

                    2.5 g daily may be necessary if adequate control has

                    not been achieved.

    

                    In the USA, doses are expressed in terms of valproic

                    acid with an initial dose of 15 mg/kg/day increased at

                    one-week intervals by 5 to 10 mg/kg/day to a maximum

                    of 60 mg/kg/day.

    

                    The dose for valpromide is from 600 mg to 1800 mg

                    daily in divided doses.

    

                    Parenteral

    

                    Sodium valproate may be administered by slow

                    intravenous infusion or injection.  The suggested

                    initial dose is up to 10 mg/kg followed by further

                    doses as necessary, up to a total of 2.5 g/day.

                    (Reynolds, 1993).

 

             4.2.2  Children

 

                    Oral

    

                    A suggested initial dose for children weighing more

                    than 20 kg is 400 mg daily (irrespective of weight) in

                    divided dose, gradually increased until control is

                    achieved, with the usual range of 20 to 30 mg/kg/day;

                    children weighing less than 20 kg may be given a dose

                    of 20 mg/kg/day which may be increased to 40 mg/kg/day

                    in severe cases.  It has been recommended that the

                    dose of 40 mg/kg/day should only be exceeded in

                    patients where plasma concentration, clinical

                    chemistry and haematological parameters are being

                    monitored (Reynolds, 1993).

 

        4.3  Contraindications

 

             Valproic acid should not be used in patients with

             hepatic disease and substantial hepatic dysfunction.

    

             Children younger than 2 years and patients receiving multiple

             anticonvulsant therapy or those with congenital metabolic

             disorder or organic brain disease may be at particular risk

             of hepatotoxicity, thus valproic acid should be used with

             extreme caution; the benefits of seizure control must be

             weighed against the risks.

    

             Hypersensitivity to the drug is also a contraindication.

    

 

             Since the drug crosses the placental barrier and is also

             found in breastmilk, its use in pregnant women is

             contraindicated, however, there is no known effect on nursing

             infants.

    

             (Physician’s Desk Reference, 1990)

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Valproic acid is administered orally either as a tablet,

             a syrup or a capsule.

 

        5.2  Inhalation

 

             No data available.

 

        5.3  Dermal

 

             No data available.

 

        5.4  Eye

 

             No data available.

 

        5.5  Parenteral

 

             May be given as slow intravenous injection or infusion

             in the form of sodium valproate powder 400 mg (provided with

             diluent).

 

        5.6  Other

 

             No data available.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             The drug is well absorbed after oral ingestion. 

    

             The extent of availability (i.e. the percentage of an oral

             dose that reaches the arterial blood in an active form to

             produce pharmacological actions) is estimated at 100% (Gilman

             et al., 1990; Moffat, 1986).

    

             Tablets and syrup are rapidly absorbed from the

             gastrointestinal tract.  Blood concentrations of 50 to 100

             mg/mL may be reached at therapeutic dose levels.  Peak plasma

             levels occur from 15 to 60 minutes after ingestion of the

             syrup, and 1 to 4 hours after a single oral tablet dose. 

 

             After a meal, enteric-coated capsules are absorbed within 1

             to 4.5 hours with peak plasma levels reached at 3 to 7.5

             hours post-ingestion (McEvoy, 1991; Ellenhorn & Barceloux,

             1988).

 

        6.2  Distribution by route of exposure

 

             The apparent volume of distribution is about 0.2 L/kg. 

             The bound drug is restricted to the circulation and rapidly

             exchangeable extracelluar water.  The apparent volume of

             distribution of the free drug in the plasma is 1 L/kg which

             indicates some penetration and binding.

    

             Protein binding at therapeutic concentration is about 90%. 

             At higher blood concentration, protein binding decreases,

             thereby causing changes in the clearance and elimination.

    

             Valproic acid appears to localize in structures with the

             highest levels of gamma-aminobutyric acid degradative

             enzymes.  It is distributed mainly to the serum, liver,

             lungs, spleen, skeletal muscles, kidney and the gut.  The

             concentration of valproic acid detected in the CSF is

             approximately 10% that of the plasma.  Its concentration in

             the saliva is 0.5 to 4%.  It crosses the placental barrier

             and appears in breastmilk (1 to 10%).

    

             (Gilman et al., 1990; Ellenhorn & Barceloux, 1988; McEvoy,

             1991).

 

        6.3  Biological half-life by route of exposure

 

             A half-life of 7 to 15 hours (Gilman et al.,1990,

             estimate 14 hours) is observed in healthy normal individuals.

             It may be longer in elderly patients, patients with cirrhosis

             and neonates, and in epileptics on valproic acid alone.  The

             half-life is the same after a single or multiple doses. When

             other anticonvulsants are used with valproic acid, the mean

             half-life may be reduced.

    

             In children the half-life of valproic acid alone is 10  to 11

             hours; when other medications are added, half-life may be

             reduced to 8 to 9 hours.  Half-lives of up to 30 hours have

             been reported in overdosage.

    

             (Ellenhorn & Barceloux, 1988; McEvoy, 1991)

 

        6.4  Metabolism

 

             Valproic acid is metabolized principally in the liver by

             the beta and omega oxidation.  There is no evidence that it

             can enhance its own metabolism, but metabolism may be

             enhanced by other drugs which induce hepatic microsomal

             enzymes.

    

 

             More than 10 metabolites have been identified in human blood

             and urine, but only 2-propyl 2-pentanoic acid (2-en-VPA) has

             been shown to accumulate in the brain and is 1.3 times more

             potent than its parent compound and it contributes

             significantly to the anti-convulsant effect of chronically

             administered valproic acid.

 

        6.5  Elimination and excretion

 

             The total systemic clearance of the drug from plasma is

             0.11 mL/min/kg. About 1.8% per cent of the administered dose

             is excreted unchanged in the urine of a healthy young adult

             (Gilman et al., 1990).

    

             Valproic acid is eliminated by first order kinetics. Plasma

             clearance after a therapeutic dose is 5 to 10 mL/min and is

             independent of liver blood flow. The free drug is cleared

             much more rapidly about 77 mL/min.  Excretion occurs

             partially in the form of ketone bodies (Ellenhorn &

             Barceloux, 1988).

    

             Metabolites are excreted in the urine as unchanged valproic

             acid 1 to 3%; valproic acid glucuronide 20%; 3-oxovalproic

             acid 3 to 60% and omega oxidation products 2 to 30%. 

             Elimination also occurs by faecal excretion 2 to 3% and in

             expired air.  About 7% of the dose undergoes enterohepatic

             recirculation – results of studies in rats (Ellenhorn &

             Barceloux, 1988; Reynolds, 1989; McEvoy, 1991).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             7.1.1  Toxicodynamics

 

                    No data available.

 

             7.1.2  Pharmacodynamics

 

                    The mechanism of action of valproic acid is

                    unknown.  Effects of the drug may be related, at least

                    in part, to increased brain concentrations of the

                    inhibitory neurotransmitter GABA.  Animal studies have

                    shown that valproic acid inhibits GABA transferase and

                    succinic aldehyde dehydrogenase, enzymes which are

                    important for GABA catabolism.  Results of one study

                    indicate the drug inhibits neuronal activity by

                    increasing potassium conductance.  In animals,

                    valproic acid protects against seizure induced by

                    electrical stimulation, as well as those induced by

                    pentylenetetrazol (McEvoy, 1991).

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             Toxic effects are frequently

                             associated with daily doses of over 1,800 mg

                             per day and blood levels of over 100 mg/mL.

                             Unconsciousness occurs when more than 200

                             mg/kg has been ingested.  Death has been

                             associated with blood levels of 1970 mg/mL

                             and recovery at blood levels at 218 mg/mL. 

                             However, plasma concentration and clinical

                             effects are not correlated sufficiently

                             closely to be of value clinically (Ellenhorn

                             & Barceloux, 1988).

 

                    7.2.1.2  Children

 

                             In a study of 88 paediatric patients

                             receiving sodium valproate monotherapy, side

                             effects were noted in 71 patients and

                             although average doses in these patients were

                             significantly higher than in the 17 patients

                             with no side effects, no difference in plasma

                             concentration was noted.  Behavioural

                             alterations, digestive disorders, and

                             neurological changes were the common side

                             effects observed.  None of the children

                             showed hepatic or pancreatic dysfunction

                             except for 2 cases who had transient increase

                             in their transaminases (Reynolds, 1989).

 

             7.2.2  Relevant animal data

 

                    LD50 oral (rats) (valproic acid) 670

                    mg/kg

    

                    LD50 oral (mice) (sod. valproate) 1700 mg/kg

    

                    (Budavari, 1989)

    

                    In 2-year rat and chronic mouse studies using dosages

                    of 80 to 170 mg/kg/day, an increased incidence of

                    subcutaneous fibrosarcoma occurred in male rats at the

                    higher dosage level and a dose-related trend for an

                    increased incidence of benign pulmonary adenomas was

                    observed in male mice.  The importance of these

                    findings to humans is not known (McEvoy, 1991).

 

             7.2.3  Relevant in vitro data

 

                    No relevant data available.

 

        7.4  Teratogenicity

 

             Safe use of valproic acid during pregnancy has not been

             established.  Adverse foetal effects have been observed in

             reproduction studies in rats and mice.  Although several

             reports suggest an association between the use of valproic

             acid in pregnant epileptic women and an increased incidence

             of birth defects (particularly neural tube defects) in

             children born to these women, a causal relationship remains

             to be established (McEvoy, 1991).

 

        7.5  Mutagenicity

 

             Studies to date have not shown any evidence of mutagenic

             potential for the drug (McEvoy, 1991).

 

        7.6  Interactions

 

             Phenobarbital levels increase when valproic acid is

             given concomitantly, enhancing sedative effects.  Mechanism

             is unknown.  Phenobarbital dose should be reduced.

    

             Carbamazepine serum concentration is increased when valproic

             acid is added to the treatment regimen.  This is largely due

             to an increase in the carbamazepine epoxide level.

    

             Phenobarbital, primidone, phenytoin and carbamazepine may

             produce enzyme inducing effects that can lower the half life

             of valproic acid.

    

             Valproic acid increases the half life of levodopa.

    

             Valproic acid potentiates the CNS depressant effects of

             alcohol.

    

             Administration of clonazepam and valproic acid has been

             reported to produce absence status epilepticus.

    

             Valproic acid inhibits the secondary phase of platelet

             aggregation reflected in an altered bleeding time.  Caution

             is recommended when it is administered with acetylsalicylic

             acid or warfarin.

    

             Cimetidine and ranitidine slightly increase the half life of

             valproic acid when they are added in the treatment regimen. 

             They do not affect volume of distribution or clearance of

             valproic acid.

    

 

             Valproic acid may potentiate the effects of MAO inhibitors

             and other anti-depressant drugs.  Dosage reduction of these

             drugs may be necessary when given with valproic acid.

    

             Serum protein binding of diazepam is competitively inhibited

             by valproic acid.

    

             (Ellenhorn & Barceloux, 1988; Reynolds, 1989; Griffin, 1988).

 

        7.7  Main adverse effects

 

             Gastrointestinal

    

             The most frequent effects of valproic acid are nausea, and

             vomiting.  These adverse effects are usually transient,

             rarely require discontinuation of the drug, and can be

             minimized by administering the drug with meals or by

             gradually increasing the dose. Hypersalivation, anorexia with

             weight loss, increased appetite with weight gain, abdominal

             cramps, diarrhoea and constipation have been reported in

             patients receiving valproic acid.  Acute pancreatitis has

             also been reported (McEvoy, 1991).

    

             These transitory gastrointestinal disturbances are dose-

             related and occurs approximately in 16% of patients treated

             with the drug.

    

             Nervous system

    

             Sedation and drowsiness may occur with valproic acid therapy,

             especially in patients receiving other anticonvulsants.  Some

             patients have reported increased alertness during valproic

             acid therapy.  Rarely paraesthesia, ataxia, headache,

             nystagmus, diplopia spots before the eyes, tremors,

             asterixis, dysarthria, dizziness and incoordination have been

             reported.  Anxiety, confusion, emotional upset, mental

             depression, hallucinations and other behavioural disturbances

             have been reported in a few children receiving valproic acid

             (McEvoy, 1991).

    

             Hepatic

    

             Minor elevation in serum transaminases and lactate

             dehydrogenase occur frequently in patients receiving valproic

             acid.  Occasionally, increases in serum bilirubin

             concentrations and abnormal changes in other hepatic

             functions may reflect potentially serious hepatoxicity

             (McEvoy, 1991).

    

             Prodromal symptoms include anorexia, vomiting followed by

             jaundice, ascites then hepatic encephalopathy eventually by

             death after a few weeks.

    

 

             Metabolic

    

             Hyperammonaemia with or without lethargy or coma may occur in

             patients receiving valproic acid and may occur in the absence

             of abnormal liver function.  Hyperglycaemia has also been

             reported in valproic acid therapy (McEvoy, 1991).

    

             Haematological

    

             Valproic acid inhibits the secondary phase of platelet

             aggregation and may prolong bleeding time.  Thrombocytopenia,

             petechiae, bruising, haematoma, epistaxis, otorrhagia,

             lymphocytosis, leucopenia, eosinophilia, decreased fibrinogen

             levels, anaemia and bone marrow depression have been reported

             (McEvoy, 1991).

    

             Dermatological

    

             Transient alopecia, curliness of the hair, generalized

             pruritus, photosensitivity and erythema multiforme have been

             reported in valproic acid therapy (McEvoy, 1991).

    

             Others

    

             Rare adverse effects include muscular weakness, enuresis and

             fatigue, irregular menses and secondary amenorrhoea.  Altered

             thyroid function has been reported but the clinical

             significance is not known (McEvoy, 1991; Physician’s Desk

             Reference, 1990).

 

  1. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Material sampling plan

 

             8.1.1  Sampling and specimen collection

 

                    8.1.1.1  Toxicological analyses

 

                    8.1.1.2  Biomedical analyses

 

                    8.1.1.3  Arterial blood gas analysis

 

                    8.1.1.4  Haematological analyses

 

                    8.1.1.5  Other (unspecified) analyses

 

             8.1.2  Storage of laboratory samples and specimens

 

                    8.1.2.1  Toxicological analyses

 

                    8.1.2.2  Biomedical analyses

 

                    8.1.2.3  Arterial blood gas analysis

 

                    8.1.2.4  Haematological analyses

 

                    8.1.2.5  Other (unspecified) analyses

 

             8.1.3  Transport of laboratory samples and specimens

 

                    8.1.3.1  Toxicological analyses

 

                    8.1.3.2  Biomedical analyses

 

                    8.1.3.3  Arterial blood gas analysis

 

                    8.1.3.4  Haematological analyses

 

                    8.1.3.5  Other (unspecified) analyses

 

        8.2  Toxicological Analyses and Their Interpretation

 

             8.2.1  Tests on toxic ingredient(s) of material

 

                    8.2.1.1  Simple Qualitative Test(s)

 

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

 

                    8.2.1.3  Simple Quantitative Method(s)

 

                    8.2.1.4  Advanced Quantitative Method(s)

 

             8.2.2  Tests for biological specimens

 

                    8.2.2.1  Simple Qualitative Test(s)

 

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

 

                    8.2.2.3  Simple Quantitative Method(s)

 

                    8.2.2.4  Advanced Quantitative Method(s)

 

                    8.2.2.5  Other Dedicated Method(s)

 

             8.2.3  Interpretation of toxicological analyses

 

        8.3  Biomedical investigations and their interpretation

 

             8.3.1  Biochemical analysis

 

                    8.3.1.1  Blood, plasma or serum

 

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

 

                    8.3.1.2  Urine

 

                             “Basic analyses”

                             “Dedicated analyses”

                             “Optional analyses”

 

                    8.3.1.3  Other fluids

 

             8.3.2  Arterial blood gas analyses

 

             8.3.3  Haematological analyses

 

                    “Basic analyses”

                    “Dedicated analyses”

                    “Optional analyses”

 

             8.3.4  Interpretation of biomedical investigations

 

        8.4  Other biomedical (diagnostic) investigations and their

             interpretation

 

        8.5  Overall interpretation of all toxicological analyses and

             toxicological investigations

 

             Sample collection

    

             Blood collected on EDTA for plasma sample.  Other samples

             used are serum, urine and breastmilk.  Blood samples should

             be collected 1 to 4 hours post-ingestion.

    

             Biomedical analysis

    

             Gas chromatography mass spectrophotometry is a useful and

             accurate method of measuring valproic acid and its

             metabolites.

    

             Toxicological analysis

    

             Measuring blood levels of valproic acid and its metabolites

             is not considered to be of practical assistance in the

             clinical management of valproic acid poisoning since plasma

             concentrations and clinical effects do not correlate closely.

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    Toxic effects are frequently associated with

                    dose levels over 1,800 mg per day and blood levels of

                    >100 mg/mL.  Unconsciousness occurs when 200 mg/kg

                    has been ingested (Ellenhorn & Barceloux, 1988).

 

             9.1.2  Inhalation

 

                     No data available.

 

             9.1.3  Skin exposure

 

                    No data available.

 

             9.1.4  Eye contact

 

                    No data available.

 

             9.1.5  Parenteral exposure

 

                    No data available.

 

             9.1.6  Other

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Hepatoxicity associated with valproic acid use

                    manifests itself in 3 ways:

    

                    Asymptomatic elevation in serum concentration of liver

                    enzymes (fairly common).

    

                    Hyperammonaemia associated with lethargy, vomiting,

                    stupor or coma but generally not accompanied with

                    hepatocellular damage.

    

                    Acute hepatoxicity that may terminate fatally, usually

                    seen in children and adolescents during the first six

                    months of therapy.  Its frequency is 1 in 5,000

                    children.  Hepatic failure has been observed

                    displaying a Reye’s syndrome like illness (Ellenhorn &

                    Barceloux, 1988).

 

             9.2.2  Inhalation

 

                    No data available.

 

             9.2.3  Skin exposure

 

                    No data available.

 

             9.2.4  Eye contact

 

                    No data available.

 

             9.2.5  Parenteral

 

                    No data available.

 

             9.2.6  Other

 

                    No data available.

 

        9.3  Course, prognosis, cause of death

 

             Acute valproic acid poisoning is observed relatively

             infrequently compared to other anticonvulsants.  Reports have

             shown that in most patients the poisoning follows a benign

             course.  Death is rare but if it occurs it results from

             cardio-pulmonary arrest secondary to hepatic failure.

    

             Hepatoxicity following chronic use may be asymptomatic or may

             have a fulminant course (Ellenhorn & Barceloux, 1988).

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Hypotension

 

             9.4.2  Respiratory

 

                    Depression; arrest in fulminant course.

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             Patient is usually drowsy, may be

                             apathetic and withdrawn, stuporous, confused,

                             restless, hyperactive.  Rarely seizures,

                             myoclonic movements, unconsciousness, coma. 

                             No dysarthria, nystagmus or ataxia. 

                             Asterixis.

 

                    9.4.3.2  Peripheral nervous system

 

                             No data available.

 

                    9.4.3.3  Autonomic nervous system

 

                             No data available.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             Muscle weakness.

 

             9.4.4  Gastrointestinal

 

                    Nausea, vomiting, diarrhoea and pancreatitis.

 

             9.4.5  Hepatic

 

                    Centrilobular necrosis, hepatic failure.

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             Nocturnal enuresis.

 

                    9.4.6.2  Others

 

             9.4.7  Endocrine and reproductive systems

 

                    Irregular menses and secondary amenorrhoea.

    

                    Altered thyroid function test (clinical significance

                    is not known).

 

             9.4.8  Dermatological

 

                    Macular pruritic rashes.

 

             9.4.9  Eye, ear, nose, throat

 

                    Pupils may pinpoint and sluggishly reactive to

                    light. 

 

                    Tablets may cause irritating sensation in the throat

                    if accidentally chewed.

 

             9.4.10 Haematological

 

                    Petechiae, bruising, haematoma, epistaxis.

 

             9.4.11 Immunological

 

                    No data available.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             Metabolic acidosis has been

                             reported (Dupuis et al., 1990).

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             Hypocalcaemia (Dupuis et al.,

                             1990).

 

                    9.4.12.3 Others

 

                             Hyperammonaemia with or without

                             lethargy, or coma with or without deranged

                             liver function.

 

             9.4.13 Allergic reactions

 

                    Pruritic rash

 

             9.4.14 Other clinical effects

 

                    No data available.

 

             9.4.15 Special risks

 

                    Pregnancy

    

                    Increased risk of neural tube defects (spina bifida)

                    if used during first trimester.

 

        9.5  Other

 

             No data available.

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Establish the airway and breathing and evaluate

             circulatory status.  If respiration is depressed on

             admission, then perform endotracheal intubation and support

             ventilation using appropriate mechanical device.  Supportive

             treatment is the mainstay in the management of valproic acid

             overdose.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             Supportive treatment is the mainstay of valproate

             overdose.  Maintenance of adequate urine output and

             discontinuation of all anticonvulsive drugs and all hepatic

             enzyme inducers will be sufficient for rapid recovery within

             24 to 72 hours.  Hepatic and pancreatic function should be

             monitored by appropriate biochemical investigations.

    

 

             The drug should be discontinued and seizures should be

             managed by the use of intravenous diazepam (0.1 to 0.3 mg/kg)

             to a maximum of 20 mg in an adult.  This may be repeated in

             10 to 20 minutes if required.

    

             If patients are stuporous, somnolent, or drowsy, but

             otherwise have normal vital signs and liver function tests,

             then simple observation with good nursing care and supportive

             therapy for 24 to 72 hours in a hospital intensive care unit

             may be sufficient.

 

        10.3 Decontamination

 

             Emesis with syrup of ipecac is not ordinarily advisable

             since although the patient may be awake on admission, he/she

             may deteriorate rapidly and become somnolent or stuporous and

             aspiration is possible.

    

             Gastric lavage may be considered.  However, if the patient is

             comatose, convulsing, or has lost the gag reflex,

             endotracheal intubation is needed.  This procedure  may be of

             limited value if the drug was taken in syrup form because of

             the very rapid absorption of the drug.

    

             Activated charcoal (adults, 50 to 100 g; children, 15 to 30

  1. g) may adsorb valproate still in the gut after the overdose. 

             Cathartics are no longer recommended.

 

        10.4 Enhanced elimination

 

             No systematic studies are available to support the

             usefulness of forced alkaline diuresis, haemodialysis,

             peritoneal dialysis, exchange transfusion, or haemoperfusion. 

             The high degree of protein binding, minimal amount of

             unchanged drug excreted through the kidneys, and short

             spontaneous course to recovery with supportive treatment

             alone would tend to preclude the need for such

             measures.

 

        10.5 Antidote treatment

 

             10.5.1 Adults

 

                    No data available.

 

             10.5.2 Children

 

                    No data available.

 

        10.6 Management discussion

 

             The use of naloxone at a dose of 0.01 mg/kg

             intravenously given in patients who are unconscious following

             ingestion of large amount of valproic acid has been reported

             to cause improvement in a 19-month-old male who ingested 2.25

             g of valproic acid (serum level of 185 mg/ml) and presented

             as unconsciousness with poorly reactive pupils three hours

             post-ingestion.  This treatment, however, has yet to be

             confirmed.  Naloxone has been reported to reverse the CNS

             depressant effects of valproic acid overdosage and

             theoretically it could also reverse the anti-epileptic

             effects of valproic acid, therefore naloxone should be used

             with caution (Ellenhorn & Barceloux, 1988; Physician’s Desk

             Reference, 1990).

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Case 1

    

             A 16-year-old epileptic female ingested 30 g of enteric

             coated sodium valproate tablets and 5 hours later appeared

             somnolent, though other physical examination findings appear

             to be within normal.  The serum valproate levels was 689.5

             mg/mL 6 hours after ingestion.  She was treated with gastric

             lavage and activated charcoal and awoke 12 hours post-

             ingestion (Ellenhorn & Barceloux, 1988).

    

             Case 2

    

             A 24-year-old female on 2.2 g/day of sodium valproate was

             stuporous, withdrawn and confused and suffered from visual

             hallucinations with a serum valproic acid level of 113 mg/mL.

             Dose was adjusted to 1.8 g/day and symptoms were resolved

             (Ellenhorn & Barceloux, 1988).

    

             Case 3

    

             A 15-year-old girl ingested an unknown amount of sodium

             valproate, became comatose and died of cardio-respiratory

             arrest at the 20th hour with a plasma level of 1,914 mg/L

             (Ellenhorn & Barceloux, 1988).

    

             Case 4

    

             One adult who ingested 36 g of valproic acid in addition to

             1 g of phenobarbital and 300 mg of phenytoin became deeply

             comatose 4 hours post-ingestion of the drugs.  The patient

             recovered following supporting therapy (McEvoy, 1991).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             Drugs should not be used in patients with hepatic

             disease or significant hepatic dysfunction.  It should not be

             used in pregnant women.  It should be used with caution in

             children below 2 years old, patients with multiple anti-

             epileptic therapy, congenital metabolic disorders, and those

             with organic brain disease.

 

        12.2 Others

 

             No data available.

 

  1. REFERENCES

 

        Budavari S ed. (1989) The Merck index, an encyclopedia of

        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,

        Merck and Co., Inc.

    

        Dupuis RL, Lichtman SIV, & Pollack GM (1990) Acute valproic

        overdose: Clinical course and pharmacokinetic disposition of

        valproic acid and metabolites. Drug Safety, 5(1) 65: 71.

    

        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis

        and treatment of human poisoning. New York, Elsevier Science

        Publishing Co, Inc, p 261-265.

    

        Gennaro AR ed. (1985) Remington’s pharmaceutical sciences 17th ed.

        Easton, Pennsylvania, Mack Publishing Company, p 1082.

    

        Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and 

        Gilman’s the pharmacological basis of therapeutics, 8th ed. New

        York, Pergamon Press, pp 450-453, 1714.

    

        Griffin JP ed.(1988) A Manual of Adverse Drug Interactions, 4th

  1. (1988) Butterworth and Co (Publishers) Ltd, p 173.

    

        McEvoy GK ed. (1991)  American hospital formulary service, drug

        information. Bethesda, MD, American Society of Hospital

        Pharmacists, p 1147.

    

        Moffat AC ed.  (1986) Clarke’s isolation and identification of

        drugs in pharmaceuticals, body fluids, and post-mortem material.

        2nd ed. London, The Pharmaceutical Press, p 1059.

    

        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 29th

  1. London, The Pharmaceutical Press, p 413.

    

        Physician’s Desk Reference (1990) 44th ed. Ordell NJ, Medical

        Economics.

    

 

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th

  1. London, The Pharmaceutical Press. pp 311-313.

    

        United States Pharmacopeia, 22nd rev. The National formulary 17th

  1. (1990)  Rockville MD, United States Pharmacopeial Convention, 

        p 1400.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author: Dr M Mercedes Maat

        National Poisons Control and Information Service

        University of the Philippines

        College of Medicine

        Philippine General Hospital

        Ermita

        Manila 1000

        Philippines

    

        Fax 63-2-50 10 78

    

        Date: December 1991

    

        Reviewer: Dr Tempowski, London Centre

    

        Date: February 1995

    

        Peer review:  Cardiff, United Kingdom, March 1995 (Drs Pronczuk,

        Hartigan-Go, Tempowski, & Ten Ham).

    

        Editor: Dr M. Ruse (October, 1997)

    

 

PHENYTOIN

(Group 2B)

For definition of Groups, see Preamble Evaluation.

 

VOL.: 66 (1996) (p. 175)

 

CAS No.: 57-41-0

Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione

 

CAS No: 630-93-3

Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione, monosodium salt

 

  1. Summary of Data Reported and Evaluation

5.1 Exposure data

 

Phenytoin, often administered as its sodium salt, has been widely used since the 1930s as an anticonvulsant in the treatment of epilepsy and, to a lesser extent and more recently, in the treatment of certain cardiac arrhythmias.

 

5.2 Human carcinogenicity data

 

Many case reports have suggested that there may be a relationship between lymphomas and anticonvulsants, especially phenytoin. In a cohort study in Denmark of epileptic patients exposed to anticonvulsants, including phenytoin, there was an increase in overall cancer risk, attributable to an excess of brain and lung cancer. Nevertheless, brain tumours probably caused the seizure disorder; an evaluation of brain tumour risk over time showed that these tumours were unlikely to be drug-related.

 

Nested case-control studies based on the Danish cohort investigated in detail the influence of several treatments with anticonvulsants on the risk of cancers of the lung, bladder and liver and non-Hodgkin lymphoma. Anticonvulsant treatment with phenytoin was not associated with lung, bladder or liver cancer. There was an elevated risk for non-Hodgkin lymphoma associated with phenytoin use, but this was not significant.

 

Two case-control studies investigated the relationship between multiple myeloma and the use of phenytoin, among many other factors. One found no association between phenytoin use and a risk for multiple myeloma. The other study found a nonsignificantly elevated risk associated with the use of phenytoin. The power of both studies to assess an effect of phenytoin was low.

 

5.3 Animal carcinogenicity data

 

Phenytoin was tested for carcinogenicity by oral administration in three experiments in mice and in two experiments in rats. It was also tested by perinatal/adult exposure in one study in mice and rats and by intraperitoneal administration in one study in mice.

 

In one experiment in three strains of female mice, oral administration of the sodium salt of phenytoin was reported to increase the incidence of lymphomas. Oral administration to female mice in another study decreased the incidence of mammary gland adenocarcinomas, leukaemias and polyps of the endometrium; in a further study, the incidence of hepatocellular tumours was reduced in males. Oral administration to rats did not increase the incidence of tumours in two studies.

 

In the experiment using combinations of adult and perinatal exposure, adult exposure resulted in a dose-dependent increase in the incidence of hepatocellular tumours in female mice. Perinatal treatment followed by adult exposure increased the incidence of hepatocellular tumours in both male and female mice and slightly in male rats. Following intraperitoneal injection of phenytoin into mice, leukaemias and lymphomas were observed.

 

In one experiment in mice, phenytoin increased the incidence of hepatocellular tumours induced by N-nitrosodiethylamine. In a mouse lung adenoma assay, phenytoin decreased the multiplicity of lung adenomas induced by urethane.

 

5.4 Other relevant data

 

Phenytoin is well absorbed in humans. It is eliminated mainly as the glucuronide of the major metabolite, 5-(4′-hydroxyphenyl)-5-phenylhydantoin, which typically accounts for 67-88% of the dose in urine. Several other metabolites are known. The elimination kinetics are non-linear, but an apparent mean half-life of 22 h is a useful guide.

 

5-(4′-Hydroxyphenyl)-5-phenylhydantoin is the main metabolite in all animal species except dogs (5-(3′-hydroxyphenyl)-5-phenylhydantoin) and cats (the N-glucuronide).

 

Acute phenytoin intoxication in humans presents usually with cerebellar-vestibular effects such as nystagmus, ataxia, diplopia, vertigo and dysarthria. Chronic administration of phenytoin at therapeutic doses may rarely induce various adverse health effects such as symptoms associated with impairment of the nervous system described above. Gingival overgrowth, sometimes together with increased thickness of the craniofacial bones as well as folic acid deficiency and development of megaloblastic anaemia, are well established adverse effects of the drug. Phenytoin has also been associated with various forms of cutaneous hypersensitivity reactions, sometimes accompanied by lymphadenopathy and benign lymphoid hyperplasia. In rare cases, the histological architecture of the lymph nodes is lost (pseudolymphoma). Phenytoin may also induce a variety of endocrine effects such as reduction of thyroxine concentrations, hypocalcaemia, osteomalacia and hyperglycaemia.

 

The nervous system appears to be the major target of acute and chronic phenytoin toxicity in experimental animals. In addition, repeated administration of phenytoin induces increased liver and kidney weights, centrilobular hepatic hypertrophy and diverse immunosuppressive effects. Phenytoin may reduce thyroxine concentrations and increase bone thickness in rodents, but gingival hyperplasia has been observed only in cats and monkeys and not in rodents. Phenytoin is an inducer of certain hepatic cytochrome P450 activities in humans and mice. There is evidence for the teratogenicity of phenytoin in humans ingesting 100-800mg per day during the first trimester of gestation. Phenytoin is teratogenic in mice and rats. Animal and a few human studies suggest that neurobehavioural deficits occur at doses which produce no dysmorphic effect.

 

Phenytoin induced mutations in Salmonella typhimurium in the presence of a metabolic activation system in one study. No mutagenic effect was observed in Drosophila or in mammalian cells in vitro in the absence of an exogenous metabolic system. Aneuploidy was induced in one study in primary mouse embryonic fibroblasts in vitro. Cell transformation was induced in Syrian hamster embryo. A single study showed increased clone sizes of murine macrophages in a host-mediated assay. Phenytoin inhibited gap-junctional intercellular communication. In human lymphocytes in vitro, sister chromatid exchanges were induced in one study and chromosomal aberrations were induced in two of five studies. Aneuploidy was observed in human amnion cells but not in lymphocytes. Phenytoin induced micronuclei in three of five studies in rodents in vivo. Aneuploidy, in one of two studies, aberrant sperm morphology and dominant lethal mutations were induced, but not sister chromatid exchange or chromosomal aberrations.

 

In general, studies of human lymphocytes in vivo showed no induction of micronuclei, chromosomal aberrations or aneuploidy but an increase of polyploidy was found in one study and of sister chromatid exchange frequencies in three of seven studies. Neither chromosomal aberrations nor aneuploidy were induced in human bone marrow.

 

The metabolite 5-(4′-hydroxyphenyl)-5-phenylhydantoin was mutagenic in Salmonella typhimurium in the presence of a metabolic activation system; it did not induce micronuclei in mouse bone marrow in vivo.

 

Mechanistic considerations

 

Evidence is available to support the conclusion that phenytoin induces liver tumours in mice by a promoting mechanism. The increase in liver weight, centrilobular hypertrophy and pattern of cytochrome P450 induction are similar to those observed with other non-genotoxic mouse liver tumour promoters such as phenobarbital. In addition, the inhibition of cell-cell communication by phenytoin in vitro supports the role of promotion in mouse carcinogenesis.

 

The metabolic activation of phenytoin to a reactive intermediate has been proposed to account for the teratogenicity and possible genotoxicity of phenytoin. One possible intermediate is an arene oxide, that is hypothesized to result in binding to cellular macromolecules. However, this possibility has not been evaluated definitively, and studies of potential DNA damage in mouse liver or hepatocytes have not been reported. The mechanism of induction of aneuploidy by phenytoin in vitro is unclear, as is its relationship to carcinogenicity in mouse liver.

 

5.5 Evaluation

 

There is inadequate evidence in humans for the carcinogenicity of phenytoin.

 

There is sufficient evidence in experimental animals for the carcinogenicity of phenytoin.

 

Overall evaluation

 

Phenytoin is possibly carcinogenic to humans (Group 2B).

 

For definition of the italicized terms, see Preamble Evaluation

 

Previous evaluation: Suppl. 7 (1987) (p. 319)

 

Synonyms for Phenytoin

 

Aleviatin

Denyl

Difhydan

Dihycon

Di-Hydan

Dihydantoin

Dilabid

Di-Lan

Dilantin

Dilantin-125

Dilantin Infatabs

Dilantin-30 Pediatric

Dintoina

Diphantoin

Diphedan

Diphenylhydantoin

DPH

Diphentyn

Ekko

Enkefal

Epanutin

Epdantoin Simple

Epelin

Epiland

Epinat

Eptoin

Fenantoin

Hidantal

Hydantin

Hydantol

Lehydan

Lepitoin

Novophenytoin

Phenhydan

Phenhydantin

Sodanton

Tacosal

Zentropil

Synonyms for Phenytoin Sodium

 

Soluble phenytoin

Alepsin

Aleviatin

Aleviatin sodium

Antisacer

Citrullamon

Danten

Dantoin

Denyl

Difenin

Difetoin

Difhydan

Dilantin

Di-Len

Dintoina

Diphantoine

Di-Phen

Diphenin

Diphenine

Diphenylan

Diphenylhydantoin sodium

5,5-Diphenylhydantoin sodium

Ditoin

Enkefal

Epanutin

Epdantoin Simple

Epelin

Epilan D

Epilantin

Epsolin

Eptoin

Hidantal

Hydantin

Hydantoinal

Idantoin

Minetoin

Muldis

Neosidantoina

Novodiphenyl

Om-Hydantoïne;

Phenhydan

Pyorédol

SDPH

Sodium diphenylhydantoin

Sodium 5,5-diphenylhydantoin

Sodium diphenylhydantoinate

Sodium 5,5-diphenyl-2,4-imidazolidinedione

Sodium phenytoin

Solantyl

Tacosal

Thilophenyt

Zentropil

Last Updated 05/22/97

See Also:

        Phenytoin (PIM 416)

CBD Offers New Hope for Seizure Relief

Cannabidiol (CBD), a cannabinoid produced by the cannabis plant, is receiving growing attention because it has potential medical benefits for a wide array of conditions, including epilepsy. 

Epidiolex is the first prescription CBD made available. It was approved by the United States Food and Drug Administration (FDA) in June 2018. 

Epidiolex was approved for treating seizures in two forms of epilepsy that are especially difficult to treat. These are Dravet syndrome and Lennox-Gastaut syndrome (LGS). 

Both adults and children over two years old who suffer from one of these rare forms of epilepsy can be prescribed Epidiolex.

LGS and Dravet syndrome are two of the most severe forms of epilepsy. They are treatment-resistant which means that most common epilepsy medications do not work for these conditions. 

CBD is being studied for effectiveness with other kinds of epilepsy, and the introduction of Epidiolex to the market has created much buzz around CBD for seizures.

In this article, we will go over some of the basics about CBD and seizures. If you have any questions about CBD for epilepsy, talk to your doctor. Never make any medical changes without consulting your physician.

What Are CBD and Medical Marijuana?

Medical marijuana (or medical cannabis) is cannabis grown for medical or therapeutic purposes. Cannabis produces an abundance of compounds known as cannabinoids. 

Research shows that the cannabinoids produced by marijuana plants have potential essential health benefits. Cannabinoids can be used for medical purposes because they act on the body’s cells (including the brain). 

Cannabinoids do this through interaction with the body’s endocannabinoid system. The most commonly known and cultivated cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). The latter is known for producing a “high” experience that CBD does not cause.

Medical marijuana is specifically bred for certain cannabinoids, so strains can be bred to have extremely low THC content. This brings many of the benefits of cannabinoids to the body without THC’s “high” effects. 

The distinction between high and low THC strains is often termed marijuana and hemp. However, they are simply varieties of the same cannabis species.

Epidiolex is a CBD-based seizure medication for patients two years or older who have Lennox-Gastaut or Dravet syndrome. 

The FDA recently approved this medication. It is the first medical marijuana product to be approved by the FDA and the first drug for the treatment of seizures from Dravet syndrome. 

Research into the potential uses of CBD and other cannabinoids for people suffering from seizures is ongoing. Medical cannabis has been hotly debated, especially politically, in recent years. 

Many legal difficulties made the use of medical marijuana difficult or even impossible to study until very recently. However, research on medical cannabis oil with neurological conditions, including epilepsy, has been conducted longer.

Lab studies, patient testimonies, and small clinical studies in recent years show CBD may reduce seizures. While the evidence is still growing, it currently indicates many positive potential qualities. 

New studies continue to show evidence that CBD can help patients with epilepsy. Dr. Orrin Devinsky is a professor of neurosurgery, psychiatry, and neurology at NYU School of Medicine. He found that cannabidiol significantly reduced seizures for patients with severe epilepsy. 

LGS could potentially be effectively treated using CBD. LGS is a treatment-resistant type of epilepsy, so this gives hope to many patients.

What Causes Seizures, and How Can CBD Help?

Seizures are caused by erratic electrical brain activity that spreads. They can cause altered states of consciousness and uncontrollable movements. 

Most antiepileptic drugs slow down the electrical brain activity to prevent seizures. Dravet syndrome and LGS are often treated using medications that are less commonly prescribed for other epilepsies. 

Both Dravet syndrome and LGS often need additional antiseizure medications to keep seizures under control.

However, both Dravet syndrome and LGS can be specifically treated using CBD. While it is not yet clear how the process works, CBD can reduce certain kinds of seizures. 

CBD works through the endocannabinoid system located throughout the body. This lets CBD have widespread effects on nerve cells in the brain that could be having impacts on seizures. In order to pinpoint the process further, researchers are currently studying CBD in more depth.

As a developmental disorder, LGS starts during early childhood. LGS causes multiple kinds of seizures, along with physical and cognitive development problems. 

LGS causes seizures that are more difficult to manage than other types. LGS seizures require different medication regimens than most epilepsy patients use.

Dravet syndrome, like LGS, is a developmental disorder that starts during early childhood. Dravet syndrome causes many seizure types, including seizures triggered by high body temperatures. 

People suffering from Dravet syndrome commonly have learning difficulties and behavioral difficulties.

Unfortunately, people with Dravet syndrome or LGS can still have regular seizures even while being treated. 

One of the most important potential uses of CBD is its potential to reduce the severity and seizure frequency for these patients. 

Studies are still being conducted on CBD’s effectiveness. Research already suggests that CBD could reduce symptoms if used with other anti-seizure medications.

In 2019, a review of studies done on Epidiolex indicated that the frequency of sustained seizures was reduced anywhere from 30 to 63 percent. 

The review also showed that patients treated with Epidiolex had seizures that were around half as severe as before. Seizures were accompanied by a less severe postictal state (post-seizure period).

Other studies that use CBD for controlling seizures focus on refractory seizures. Refractory seizures are not as easy to control with typical antiseizure medications. 

It is not yet known whether CBD will benefit these types of seizures or if people with different seizure types will respond well to it. 

Until benefits for other seizure types are established, CBD will not be approved as a treatment option for them by the FDA.

Currently, CBD as a treatment of epilepsy is still controversial since it is derived from medical marijuana. 

Cannabis has been known primarily as a recreational drug. This cultural stigma has slowed clinical research over previous decades. Thankfully, this is changing as cultural attitudes toward cannabis become more favorable. 

The American legal system continues to evolve on cannabis. Currently, CBD is only clinically established to be effective for a select number of medical conditions. 

Nevertheless, emerging evidence shows hopeful signs for CBD’s wide applicability in medicine. Research shows a potential quality-of-life improvement for people with many different conditions.

What Is the Legal Status of Medical Marijuana Products Like CBD?

The 2018 Farm Bill exempted hemp and hemp-derived products (like CBD) from the Controlled Substances Act. 

Before this, hemp products were classified as Schedule I cannabis. That meant they had no recognized medical use and a high potential for abuse. Both characteristics have been shown to be false. 

Pressure has grown from patients, doctors, and patient advocates on the federal government to legalize hemp. There are now no federal restrictions on CBD. 

Hemp can be legally cultivated, products can be legally manufactured, and both can be bought and sold throughout the United States. This does not mean that CBD is appropriate for everyone. 

Still, CBD has finally been recognized as having important medicinal value for many patients.

More than half of the states have laws that allow cannabis to be recommended to patients for specified medical conditions. 

These patients are then able to enter medical dispensaries to buy cannabis products. State medical cannabis programs are unaffected by the Farm Bill. Regulations involving medical cards, registrations, renewals, and recommendations from physicians are still required.

The FDA approved Epidiolex in June 2018. Medical providers can now prescribe Epidiolex for patients suffering from Dravet syndrome or LGS. This places Epidiolex among the numerous approved prescription seizure medications available. 

The DEA rescheduled Epidiolex to Schedule V in late September. The federal government then made provisions so Epidiolex can be brought to market. 

Unlike many state programs, health care providers need no special licenses to prescribe Epidiolex. 

So far, the FDA has approved no other medical formulations of cannabis for seizures or any other conditions.

Before Taking CBD for the First Time

Remember that less is often more with CBD, according to clinical trials. This is especially true when trying to treat epilepsy with cannabis products, like CBD or other cannabinoids. 

In one recent study on Epidiolex, patients actually seemed to perform better with 10 milligrams of the medication than with 20 milligrams. They also experienced fewer adverse events. 

Epidiolex is 99 percent pure CBD. Some doctors believe CBD is better with side effects compared to other available seizure medications. This may be especially true of seizures that are especially difficult to control, such as those with Dravet syndrome and LGS.

Epidiolex is made from a highly refined, pharmaceutical-grade CBD. This distinguishes it from the CBD in states with legal medical marijuana programs or even simply CBD products on store shelves. 

It is not known how well these products could aid people with epilepsy since the FDA does not regulate them. It is also unclear if CBD helps people who have more common forms of epilepsy. 

Caution is advised for anyone attempting to treat their epilepsy with CBD. Patients should consult their doctors before making any dietary, supplemental, or medicinal changes.

How to Take CBD for Seizures

Before using CBD or any cannabis product, consumers should consult with their physicians. This helps doctors alert patients to any potential side effects as well as monitor their symptoms more effectively. 

Obviously, to use Epidiolex, patients would need a prescription from their doctors. However, many CBD products exist as over-the-counter supplements, meaning anyone can consume them so long as it is legal in their state.

Epidiolex is offered to patients in liquid form as an oral solution. The recommended dose of the medication is based on patient weight. 

Ten milligrams for every kilogram each day is the most effective dose and is commonly split into two daily doses. Patients begin by taking a smaller dose of 2.5 milligrams per kilogram. 

After the first week, patients increase their dosage to the target amount. In more extreme cases, Epidiolex can be increased up to 20 milligrams per kilogram daily, but this comes with increased risks of adverse events. 

Like other anti-seizure medications, Epidiolex should be taken at the same scheduled time. Patients should never skip or combine doses.

Patients with Dravet syndrome or LGS can sometimes have difficulty ingesting oral medications. This is because of difficulty swallowing, cognitive issues, or behavioral challenges. 

It can often be difficult to get children to take medications. This leads many parents and doctors to develop personalized strategies to ease the process.

What Are the Side Effects of CBD?

When smoked, cannabis potentially has some of the same risks to lungs and heart health as other types of smoking. 

Although cannabis is a plant, it is broken down by the body’s liver like many other medications. Medication interactions can occur even with medications made from plants or plant oil. 

Certain side effects may be due to the form of CBD taken since oils could potentially cause an upset stomach or diarrhea. This is suggested by the fact that even placebo participants often reported these symptoms.

Certain medication interactions can occur that people with epilepsy should be aware of before using CBD. 

Patients with increased liver enzymes three times the normal rate or more were also taking VPA (valproic acid). VPA is a commonly prescribed seizure treatment. VPA levels were not raised when taken with CBD. 

It is believed that a byproduct or component of VPA may interact with CBD as it breaks down, putting some patients at increased risk of liver problems. 

Patients using Onfi (clobazam) experienced tiredness when using CBD, which may be caused by the drug interacting with CBD.

Most people do not seem to have any serious side effects from CBD or other cannabinoids. However, as with any medicine, supplement, or even dietary change, side effects are possible. 

Thankfully, in the minority of cases where they do occur, the side effects of CBD are generally mild and short-lasting. The potential side effects of prescription Epidiolex include:

  • Fatigue
  • Drowsiness
  • Sleeping Problems
  • Fever
  • Decreased Appetite
  • Diarrhea
  • Rashes
  • Vomiting
  • Rhinitis/Upper Respiratory Tract Infection
  • Lethargy
  • Weakness
  • Status Epilepticus (a long-lasting seizure that needs emergency medical attention)

Studies showed that these side effects were most common in the first two weeks of using Epidiolex. 

Generally, side effects lessened after this initial period. Many studies on Epidiolex involved other antiseizure drugs. Side effects could be from other medications or a mixture of those medications with Epidiolex.

Severe side effects that need immediate attention include jaundice, abdominal pain, and vomiting. Dark-colored urine could be a potential symptom of liver injury. Others are intense mood changes, such as depression, anxiety, or suicidal thoughts and feelings.

By itself, CBD shows no evidence of potential for abuse. CBD also does not produce the psychoactive “high” typically associated with cannabis. 

These qualities mean that consumers do not need to be concerned about anyone abusing CBD products or becoming addicted to it. 

There is great potential for misunderstanding of CBD and its effects. That is because it is a new compound for many people and comes from the same plant that THC derives from.

Research is still being done on whether and how CBD interacts with other antiseizure medications. This will be important since it will allow for more precise and effective use of CBD in treating epilepsy. 

Researchers believe CBD could raise the blood level of Banzel (rufinamide) and Topamax. It may decrease the blood level of Onfi (clobazam). This could have effects on seizure control and potentially cause side effects. 

CBD can potentially elevate liver enzymes when taken alongside other antiseizure medications. This can be a sign of liver injury, and medical attention should be sought immediately. 

Researchers find adding Epidiolex to a regimen can increase the chances of certain side effects. It might also decrease the number of side effects people experience.

Using CBD Without a Prescription

Epidiolex is only available by prescription. However, numerous companies produce over-the-counter CBD products. 

Some consumers have begun to use them as a supplemental seizure control. This trend will likely grow now that CBD has been made federally legal by the 2018 Farm Bill. More states are making CBD and hemp an important part of their economic planning.

The FDA does not regulate over-the-counter CBD or other cannabinoid products. So, they are largely untested unless companies pay for testing themselves voluntarily. 

The FDA warns people to be cautious since products can be mislabeled and overstate their potential benefits. Additionally, these products are not being tested by the government for quality and safety. 

People with epilepsy need to be especially cautious. Products may be mislabeled with dosages and could put consumers at risk of more seizures or other side effects.

One study from 2017 found that 26 percent of CBD products purchased online contained less CBD than companies claimed. 

These sorts of factors make it important to purchase only from transparent, trustworthy companies. Look for companies whose products are proven to be accurately labeled and safely processed