Does CBD Interact With Antibiotics?

Antibiotics are used to prevent or treat specific types of bacterial infections. In some cases, they are prescribed for an infection that keeps coming back or causes an increased risk of complications.

However, antibiotics are not effective against viral infections, such as the common cold or flu (1).

Can CBD Be Taken With Antibiotics?

There is no known interaction between CBD (cannabidiol) and antibiotics. However, there is a potential risk when combining CBD and antibiotics, as both are metabolized (broken down) through the cytochrome P450 enzyme system (2).

Due to how antibiotics are metabolized, the concentrations of these drugs could potentially increase when taken with CBD.

The CYP450 liver enzymes are responsible for breaking down toxic compounds, including over 60% of any over-the-counter or prescription drugs consumed.

Certain substances can affect processing times within this system, making drugs metabolize faster or slower than they would on their own.

Cannabidiol can inhibit the cytochrome P450 system’s ability to metabolize certain drugs, leading to an overall increase in processing times, resulting in potentially higher levels over a longer period of time (3)

Antibiotics use the cytochrome P450 enzyme system and can interact with CBD, as reiterated by authors Eileen Konieczny, RN, and Lauren Wilson, in their book, Healing with CBD (4).

Until studies that specifically look at how CBD interacts with antibiotics are completed, talk with a doctor to make sure there are no CBD drug interactions with other medications currently taken.

CBD Oil As Antibiotic: What the Research Says

CBD oil has been shown to possess antimicrobial properties, making it another tool for fighting infection. 

Although it is not well-understood how CBD oil fights bacteria, studies have confirmed CBD’s antibiotic properties, which are particularly useful in attacking bacteria that have become resistant to traditional antibiotics.

One such study investigated how various cannabinoids, including CBD and tetrahydrocannabinol (THC), affect pathogenic bacteria (5).

In the said study, each cannabinoid was tested against six strains of the antibiotic-resistant superbug, methicillin-resistant Staphylococcus aureus (MRSA). All cannabinoids showed potent activity against a variety of MRSA strains. 

The results of the study indicated that CBD has proven to be effective at fighting one of the most treatment-resistant strains of bacteria the field of medicine has ever seen.

Then, the researchers at the University of Queensland’s Institute for Molecular Bioscience discovered in 2019, through a series of test-tube experiments, that CBD could kill numerous strains of bacteria, including treatment-resistant strains like VRSA, VISA, and MRSA (6).

These strains have developed resistance to other existing Food and Drug Administration (FDA)-approved antibiotics over the years. However, they did not develop any resistance to CBD. 

In one of the experiments, the researchers found that despite exposing the strains to CBD for 20 days, this cannabis compound was able to outmaneuver the entire process of superbug development.

Moreover, CBD was found to be effective at disrupting biofilms, a microscopic conglomeration of bacteria, mucopolysaccharides, and waste products and act as a physical barrier that prevents antibiotics from working against the bacteria growth that leads to difficult-to-treat infections. This breakthrough in microbiology could ultimately lead to the development of new treatments.

Lead author, Mark Blaskovich, stated there was no doubt CBD possessed a unique mechanism that worked against bacteria resistant to other antibiotics. He admitted, however, that he and his team still could not explain how this mechanism works. 

A later study, conducted in August 2019 by scientists from the United Kingdom, has shed light on the workings of that unique mechanism (7).

In the said study, which was published in Frontiers in Cellular and Infection Microbiology, the authors examined the antibacterial effects of CBD and Escherichia Coli bacteria (E. coli)’s membrane vesicles, which the bacteria use to spread and communicate. 

The researchers discovered that the antibiotic’s ability to prevent the release of those membrane vesicles is enhanced by CBD. 

The results suggested that CBD could help fight specific bacteria as a tailored co-application with selected antibiotics.

The researchers concluded that CBD might help increase antibiotic activity and reduce antibiotic resistance when used in tailored co-application.

Conclusion

The results of the studies demonstrating CBD’s antibiotic properties are especially exciting for the CBD community. 

However, it is essential to note that researchers still do not know what made CBD powerful at fighting the infections during the experiments. 

All the research was carried out in a lab, in test tubes and on bacteria cultures, not on humans.

To date, there has been no study that recommends taking CBD with antibiotics. Neither is there a study that suggests CBD can replace antibiotics in the treatment or prevention of some types of bacterial infections. 

Further research needs to be conducted to study the long-term side effects and resistance of CBD as an antibiotic. 

Before taking CBD or any CBD products to treat or prevent any infection, do research and consult with a doctor experienced in cannabis use for advice.


  1. NHS. (2019, May 23). Antibiotics Uses. Retrieved from https://www.nhs.uk/conditions/antibiotics/uses/.
  2. Pharmotech SA. CBD Drug Interactions. Retrieved from https://pharmotech.ch/cbd-drug-interactions/.
  3. Ibid. 
  4. Eileen Konieczny and Lauren Wilson. Healing with CBD: How Cannabidiol Can Transform Your Health without the High (California: Ulysses Press, 2018). P46-47.
  5. Giovanni Appendino, G et al. Antibacterial Cannabinoids from Cannabis sativa: A Structure−Activity Study. Journal of Natural Products 2008 71 (8), 1427-1430. DOI: 10.1021/np8002673.
  6. The University of Queensland. (2019, June 24). Cannabis compound could be powerful new antibiotic. Retrieved from https://imb.uq.edu.au/article/2019/06/cannabis-compound-could-be-powerful-new-antibiotic; CDC. (2010, Nov 24). General Information about VISA/VRSA. Retrieved from https://www.cdc.gov/hai/organisms/visa_vrsa/visa_vrsa.html; CDC. (2019, June 26). Methicillin-resistant Staphylococcus aureus (MRSA). Retrieved from https://www.cdc.gov/mrsa/community/index.html
  7. Kosgodage US, Matewele P, Awamaria B, et al. Cannabidiol Is a Novel Modulator of Bacterial Membrane Vesicles. Front Cell Infect Microbiol. 2019;9:324. Published 2019 Sep 10. DOI:10.3389/fcimb.2019.00324. 

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The following information has been extracted from our CHEMINFO database, which also contains hazard control and regulatory information. [More about…] [Sample Record]

Access the complete CHEMINFO database by contacting CCOHS Client Services.

SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number:  181

CCOHS Chemical Name:        Acetic acid (solutions greater than 10%)

Synonyms:

Ethanoic acid

Ethylic acid

Glacial acetic acid

Methanecarboxylic acid

Acetic acid (non-specific name)

Acide acetique glacial

Chemical Name French:        Acide acétique

Chemical Name Spanish:       Acido acético

Acido acetico

Acido etanoico

CAS Registry Number:  64-19-7

UN/NA Number(s):       2789 2790

RTECS Number(s):       AF1225000

EU EINECS/ELINCS Number: 200-580-7

Chemical Family: Saturated aliphatic carboxylic acid / saturated aliphatic monocarboxylic acid / alkanoic acid / acetic acid

Molecular Formula:       C2-H4-O2

Structural Formula:      CH3-C(=O)-O

SECTION 2. DESCRIPTION

Appearance and Odour:

Pure acetic acid is a clear, colourless liquid above 16 deg C and colourless, icelike crystals below 16 deg C; strong, pungent odour of vinegar. Hygroscopic (absorbs moisture from the air).(17,28,29)

Odour Threshold:

0.037-0.15 ppm (detection) (geometric mean odour threshold: 0.074 ppm).(35)

Warning Properties:

GOOD – The TLV is more than 10 times the odour threshold.

Composition/Purity:

Acetic acid is available as the pure liquid or as solutions in water (6-90%). Virtually pure acetic acid (99.5% or higher) is called glacial acetic acid. Refer to CHEMINFO record 752 for information on acetic acid solutions of 10% and less. Water is the chief impurity in glacial acetic acid. Other impurities include acetaldehyde, acetic anhydride, formic acid, biacetyl, methyl acetate, ethyl acetoacetate, iron and mercury. Acetic acid forms a monohydrate containing about 23% water.(28)

Uses and Occurrences:

Chemical intermediate (e.g. vinyl acetate monomer, cellulose acetate, acetic anhydride, chloroacetic acid, terephthalic acid), used in manufacture of latex emulsion resins, paints, coatings, adhesives, rubber, nylon, fibres, dyes, aspirin and other pharmaceuticals and medicinals, plastics, lacquers, herbicides, solvents, and other chemicals and products; textile dyeing and finishing; laboratory reagent; etching compound; deliming agent, acidifying and neutralizing agent (e.g. oil well acidizer); food additive or flavorant; constituent of photographic fixing baths, bacteriocide, fungicide.(17,28,29)

Occurs widely in the environment. Occurs naturally in plant and animal tissues and is a normal metabolite in both plants and animals. Occurs naturally in many fruit juices and in the stems and woody parts of plants.(17)

SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:

Pure acetic acid is a clear, colourless liquid above 16 deg C and colourless, icelike crystals below 16 deg C. Has a strong, pungent odour of vinegar. Hygroscopic. COMBUSTIBLE LIQUID AND VAPOUR. Vapour is heavier than air and may spread long distances. Distant ignition and flashback are possible. Harmful if inhaled or swallowed. Vapour is irritating to the respiratory tract. May cause lung injury–effects may be delayed. Concentrated solutions are CORROSIVE to eyes and skin. Causes permanent eye damage, including blindness, and skin burns, including tissue death and permanent scarring. May be an aspiration hazard. Swallowing or vomiting of the liquid may result in aspiration into the lungs.

POTENTIAL HEALTH EFFECT

Effects of Short-Term (Acute) Exposure

Inhalation:

Accidental inhalation of high concentrations has produced nose and throat irritation, shortness of breath, cough, wheezing, and reversible lung injury in people exposed occupationally. In one case, symptoms of airways hyperresponsiveness (chest tightness, coughing and shortness of breath) were still present 3 years later.

A maintenance worker inhaled a large cloud of hot glacial acetic acid (99.8%) as it vapourized. Seven days after the incident, he developed progressive exertional shortness of breath. Follow-up showed reversible airways obstruction and interstitial pneumonitis. He had no history of respiratory illness and was a not a smoker.(2) A hospital worker was exposed to an unspecified amount of glacial acetic acid during a spill. Within 15 to 30 minutes, she experienced nose and throat irritation, followed by chest tightness, mild shortness of breath and a slight cough. Over the next several days, she experienced frequent wheezing, worse at night and upon exertion. Chest x-rays and spirometry tests were normal. Despite treatment, mild episodes of airways hyperresponsiveness (chest tightness, coughing and shortness of breath) were still present 3 years later.(5)

Follow-up of 51 employees also exposed in the above incident (5), showed an increased incidence of reactive airways dysfunction in the “high” exposure group (3/14). No conclusions can be drawn from this aspect of the study due to limitations such as potential recall biases, lack of exposure information, and the small number of individuals followed up.

Skin Contact:

The degree of irritation depends on the concentration of acetic acid and the length of exposure. Based on animal evidence, highly concentrated solutions or pure acetic acid can cause corrosive tissue injury with deep burns, tissue death and permanent scarring. Less concentrated solutions can cause mild to severe irritation. Application of 10% acetic acid to the intact or abraded skin of human volunteers in a 4-hour patch test showed slight irritation.(9)

Eye Contact:

Even very dilute solutions of acetic acid have cause severe irritation in animal studies. Concentrated solutions are corrosive and can cause permanent eye damage, including blindness. There are 2 case reports where glacial acetic acid (99.8%) was accidentally used instead of eye drops. In one case, clouding of the cornea, fluid accumulation and inflammation of the iris were observed shortly after the incident. Clouding and loss of sensation of the cornea were observed 2.5 months later. In the second case, fluid accumulation was observed shortly after the incident. Follow-up 2 weeks later showed loss of sensation and permanent clouding of the cornea.(6)

Ingestion:

Intentional ingestion of 100-200 mL of 80-100% acetic acid has caused severe corrosive injury to the gastrointestinal tract and stomach.(15,16) Another report describing kidney injury in 2 people who ingested 80% acetic acid, cannot be evaluated due to the lack of information.(17)

Based on physical properties (viscosity and surface tension), acetic acid may be aspirated (inhaled into the lungs) during ingestion or vomiting. Aspiration of even a small amount of liquid could result in a life-threatening accumulation of fluid in the lungs. Severe lung damage (edema), respiratory failure, cardiac arrest and death may result.

Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

 

There are 2 case reports involving workers exposed to acetic acid during the production of cellulose acetate. One report describes workers exposed to 60 ppm acetic acid daily, with a one-hour exposure to 100-260 ppm. No evidence of injury was reported, other than slight irritation of the air passages, stomach and skin.(7) Another report describes 5 workers who were exposed to 82 and 265 ppm acetic acid during particular work phases for 7-12 years. Chronic bronchitis (asthmatic-like in 3 cases and emphysema in one) was observed.(18) These brief reports involved a very small number of workers and do not indicate if there were any other potential exposures or if there were any personal pre-disposing factors. Therefore, no conclusions can be drawn.

Another report describes a photographer who developed reversible airways obstruction after long-term exposure to acetic and sulfuric acids in a dark room.(3) No conclusions can be drawn due to the concurrent exposure and lack of exposure information.

 

SKIN SENSITIZATION: There is one case report of occupational skin sensitization. A worker occupationally exposed to soldering flux which contained acetic acid, among other ingredients, developed contact dermatitis. No history of allergy was recorded. Patch testing showed a positive result for 2% acetic acid.(19) This single case report does not prove that acetic acid is a skin sensitizer. Two other reports of skin sensitization due to acetic acid cannot be evaluated due to lack of information.(20,21)

 

RESPIRATORY SENSITIZATION: There is one case report of a 58-year old man developing an asthmatic response following occupational exposure to glacial acetic acid (99.8%). The man had a history of childhood asthma, but remained symptom free from age 11-56 until the current exposure commenced. The asthmatic response was confirmed by pulmonary function testing.(4) This single report does not prove that acetic acid is a respiratory sensitizer.

Carcinogenicity:

There is no animal or human information available.

The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.

The American Conference of Governmental Industrial Hygienists (ACGIH) has not assigned a carcinogenicity designation to this chemical.

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:

There is no animal or human information available.

Reproductive Toxicity:

There is no animal or human information available.

Mutagenicity:

There is no human information available. The mutagenicity of acetic acid appears to be an effect of pH on the culture media, rather than mutagenic activity of acetic acid itself. There have been no positive reports of mutagenicity, once the effect of pH on the culture media has been controlled.

Toxicologically Synergistic Materials:

Oral administration of 3% acetic acid to male rats for 8 months has increased the incidence of esophageal cancer caused by N-nitrososarcosin ethyl ester (NSEE).(13) Dermal application of acetic acid to female mice has increased the incidence and rate of development of skin carcinomas caused by 7,12-dimethylbenz[a] anthracene.(14)

Potential for Accumulation:

Acetic acid is absorbed from the gastrointestinal tract and through the lungs. Acetic acid is a normal body component and does not accumulate in the body. It is rapidly metabolized by most tissues and excreted, or used in the production of chemicals required for bodily functions.(17)

 

SECTION 4. FIRST AID MEASURES

 

Inhalation:

Take proper precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment, use the buddy system). Remove source of contamination or move victim to fresh air. If breathing is difficult, oxygen may be beneficial if administered by trained personnel, preferably on a doctor’s advice. DO NOT allow victim to move about unnecessarily. Symptoms of pulmonary edema can be delayed up to 48 hours after exposure. Immediately transport victim to an emergency care facility.

Skin Contact:

Avoid direct contact. Wear chemical protective clothing, if necessary. As quickly as possible flush contaminated area with lukewarm, gently flowing water for at least 20-30 minutes, by the clock. If irritation persists, repeat flushing. DO NOT INTERRUPT FLUSHING. If necessary, keep emergency vehicle waiting. Under running water, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Discard contaminated clothing, shoes and leather goods.

Eye Contact:

Avoid direct contact. Wear chemical protective clothing, if necessary. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for at least 20-30 minutes, by the clock, while holding the eyelid(s) open. Neutral saline solution may be used as soon as it is available. DO NOT INTERRUPT FLUSHING. If necessary, keep emergency vehicle waiting. Take care not to rinse contaminated water into the unaffected eye or onto the face. If irritation persists, repeat flushing. Quickly transport victim to an emergency care facility.

Ingestion:

NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or is convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 240 to 300 mL (8 to 10 oz.) of water to dilute material in the stomach. If milk is available, it may be administered AFTER the water has been given. If vomiting occurs naturally, have victim lean forward to reduce the risk of aspiration. Have victim rinse mouth and repeat administration of water. Quickly transport victim to an emergency care facility.

First Aid Comments:

Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.

Some recommendations in the above sections may be considered medical acts in some jurisdictions. These recommendations should be reviewed with a doctor and appropriate delegation of authority obtained, as required.

All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.

SECTION 5. FIRE FIGHTING MEASURES

Flash Point:

39 deg C (103 deg F) (glacial) (31); 43 deg C (109 deg F) (glacial) (28); 50 deg C (122 deg F) (85%) (33) (closed cup values)

Lower Flammable (Explosive) Limit (LFL/LEL):

4% (28); 5.3-5.4% (32) (glacial)

Upper Flammable (Explosive) Limit (UFL/UEL):

16% (28,32); 19.9% (30) (glacial)

Autoignition (Ignition) Temperature:

463-465 deg C (867-869 deg F) (28,30); 516 deg C (961 deg F) (30) (glacial)

Sensitivity to Mechanical Impact:

Probably not sensitive. Stable material.

Sensitivity to Static Charge:

Information not available. Will not accumulate static discharge. The electrical conductivity of acetic acid (6 x 10(5) pS/m) is high.(33)

Combustion and Thermal Decomposition Products:

Irritant gases, which may include unburned acid and toxic constituents.(30,32)

Fire Hazard Summary:

Combustible liquid. Can form explosive mixtures with air at, or above, 39 deg C. Vapour is heavier than air and may travel a considerable distance to a source of ignition and flash back to a leak or open container. Vapours from warm liquid can accumulate in confined spaces, resulting in a flammability and toxicity hazard. Closed containers may rupture violently when heated. NOTE: The fire properties of acetic acid depend upon the strength of the solution. In concentrated form, its properties approach those of glacial acetic acid.(30)

Extinguishing Media:

Carbon dioxide, dry chemical powder, “alcohol resistant” foam, polymer foam, water spray or fog.(32,34)

 

Fire Fighting Instructions:

Evacuate area and fight fire from a safe distance or protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products.

If possible, isolate materials not yet involved in the fire, and move containers from fire area if this can be done without risk, and protect personnel. Otherwise, fire-exposed containers or tanks should be cooled by application of hose streams. Application should begin as soon as possible and should concentrate on any unwetted portions of the container. If this is not possible, use unmanned monitor nozzles and immediately evacuate the area.

If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours, protect personnel attempting to stop a leak and dilute the spill to a nonflammable mixture. Water spray may be used to flush spills away from ignition sources. Solid streams of water may be ineffective and spread material.

For a massive fire in a large area, use unmanned hose holder or monitor nozzles. If this is not possible, withdraw from fire area and allow fire to burn. Stay away from ends of tanks. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire.

Acetic acid and its decomposition products are hazardous to health. Do not enter without wearing specialized protective equipment suitable for the situation. Firefighter’s normal protective clothing (Bunker Gear) will not provide adequate protection. Chemical resistant clothing (e.g. chemical splash suit) and positive pressure self-contained breathing apparatus (MSHA/NIOSH approved or equivalent) may be necessary.

NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

 

NFPA – Health:    3 – Short exposure could cause serious temporary or residual injury. (Glacial acetic acid)

NFPA – Flammability:    2 – Must be moderately heated or exposed to relatively high ambient temperatures before ignition can occur. (Glacial acetic acid)

NFPA – Instability:        0 – Normally stable, even under fire conditions, and not reactive with water. (Glacial acetic acid)

 

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

 

Molecular Weight:        60.05

Conversion Factor:

1 ppm = 2.45 mg/m3; 1 mg/m3 = 0.408 ppm at 25 deg C (calculated)

Physical State:    Liquid

Melting Point:      FREEZING POINT: 16.6 deg C (61.9 deg F) (100%) (29,32); -7.4 deg C (80.6%); -19.8 deg C (50.6%); -6.3 deg C (18.11%) (29)

Boiling Point:       117.9 deg C (244.2 deg F) (glacial) (28,29,32)

Relative Density (Specific Gravity): 1.05 at 20 deg C (100%) (28,29); 1.08 (80%); 1.06 (50%); 1.03 (20%) at 15 deg C (28,29) (water = 1)

Solubility in Water:      Soluble in all proportions.(32)

Solubility in Other Liquids:     Soluble in all proportions in ethanol, acetone, diethyl ether, glycerol and benzene.(17)

Coefficient of Oil/Water Distribution (Partition Coefficient):  Log P(oct) = -0.31 (17)

pH Value:   2.4 (1M solution in water (approx. 6%)) (17,36)

Acidity:      pKa = 4.76 at 25 deg C (17,29)

Viscosity-Dynamic:       1.22 mPa.s (1.22 centipoises) (100%) at 20 deg C (17,36). 2.39 mPa.s (90 wt.%); 2.72 mPa.s (80%); 2.16 mPa.s (50%); 1.43 mPa.s (20%) at 20 deg C (36)

Surface Tension:  27.57 mN/m (27.57 dynes/cm) (100%) at 20.1 deg C (28,29); 34.3 mN/m (69.9 wt.%); 38.4 mN/m (49.96%); 43.6 mN/m (30.09%) at 30 deg C (36)

Vapour Density:  2.07 (air = 1) (34)

Vapour Pressure: 1.52 kPa (11.4 mm Hg) at 20 deg C (17,34)

Saturation Vapour Concentration:   1.5% (15000 ppm) at 20 deg C (calculated)

Evaporation Rate:        0.97 (n-butyl acetate = 1) (17)

 

SECTION 10. STABILITY AND REACTIVITY

 

Stability:

Normally stable.

Hazardous Polymerization:

Does not occur.

Incompatibility – Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.

 

STRONG OXIDIZING AGENTS (e.g. chromic acid, hydrogen peroxide, nitric acid, perchloric acid, potassium permanganate, sodium peroxide) – react violently, with risk of fire and explosion.(30,31,33,37)

STRONG ALKALIS or CAUSTICS (e.g. sodium or potassium hydroxide), or BASES – may react violently.(30,31)

MOST COMMON METALS (except aluminum) – may give off flammable hydrogen gas.(31,33)

ACETALDEHYDE – polymerization occurs, with evolution of heat.(30,37)

2-AMINOETHANOL, CHLOROSULFONIC ACID, ETHYLENE DIAMINE, ETHYLENEIMINE, OLEUM – mixing in a closed container caused the temperature and pressure to rise.(30)

AMMONIUM NITRATE – may ignite when warmed.(30)

BROMINE PENTAFLUORIDE, CHLORINE TRIFLUORIDE – may react violently, with fire and explosion likely.(30,37)

PHOSPHORUS ISOCYANATE – react violently.(30)

PHOSPHORUS TRICHLORIDE – explosion may occur due to the possible formation of spontaneously flammable phosphine.(30,37)

POTASSIUM tert-BUTOXIDE – ignition occurs after 3 minutes.(30,37)

n-XYLENE – during production of terephthalic acid in which n-xylene is oxidized in the presence of acetic acid, detonating mixtures may be produced.(30)

Hazardous Decomposition Products:

None reported.

Conditions to Avoid:

Temperatures above 39 deg C, open flames, static charge, sparks and other ignition sources.

Corrosivity to Metals:

Acetic acid attacks most common metals, including steel, iron, most stainless steels, copper, bronze and brass, particularly when diluted with water. Depending on conditions, acetic acid (greater than 99%) may be used with or stored and shipped in stainless steel grades 316, 318 and 321, and aluminum. Aluminum slowly corrodes, forming a layer of aluminum acetate that prevents further corrosion. Water increases the corrosion rate, while mercury, present as an impurity, catalyzes the corrosion of aluminum.(28,29,32,38)

Stability and Reactivity Comments:

Attacks many forms of plastics, rubber and coatings. It dissolves synthetic resins and rubber.(32)

 

SECTION 11. TOXICOLOGICAL INFORMATION

 

LC50 (mouse): 2810 ppm (4-hour exposure); cited as 5620 ppm (1-hour exposure) (22)

LD50 (oral, rat): 3530 mg/kg (concentration not specified) (23)

LD50 (dermal, guinea pig): 3300 mg/kg (cited as 3.2 mL/kg) (28% solution) (24, unconfirmed)

Eye Irritation:

There is no specific information on acetic acid solutions greater than 10%. Solutions of 10% and less have produced moderate to very severe eye irritation in rabbits, including corrosive injury.(23,24,25)

Skin Irritation:

Application of 0.01 mL of 100% acetic acid produced strong redness, swelling or slight tissue death in rabbits (graded 5/10).(23) Application of 0.1 mL of glacial acetic acid (99.8%), under cover, produced severe irritation in rabbits (scores of 2.6/4 (intact skin) or 3.2/4 (abraded skin); where 4 is corrosive tissue injury).(8)

Effects of Short-Term (Acute) Exposure:

Inhalation:

Reversible upper respiratory tract irritation and reversible effects on respiratory function have been observed in mice and guinea pigs following inhalation of the vapour. Guinea pigs were exposed for 1 hour to 5, 40, 120 or 570 ppm. Dose-dependent reversible effects on respiratory function (e.g. increased pulmonary flow resistance and decreased compliance) were observed. Concentrations of 120 and 570 ppm also caused a decrease in respiration rate and minute volume and increased resistance to airflow.(1) Mice exposed to concentrations greater than 1000 ppm experienced reversible irritation of the upper respiratory tract.(22)

Ingestion:

Ingestion of 40 or 50% solutions by rabbits has been reported cause slightly caustic or caustic injury to the esophagus, respectively.(26, unconfirmed)

Effects of Long-Term (Chronic) Exposure:

Inhalation:

Continuous exposure to a low concentration (2 ppm) has produced slight changes in the blood and slight changes in liver function in male rats.(27)

Mutagenicity:

The mutagenicity of acetic acid appears to be an effect of pH on the culture media, rather than mutagenic activity of acetic acid itself. There have been no positive reports of mutagenicity, once the effect of pH on the culture media has been controlled.(10,11) One study showed positive results in Eschericheri coli, but the effects of pH were not considered in the evaluation.(12)

 

SECTION 16. OTHER INFORMATION

 

Selected Bibliography:

(1) Amdur, M.O. The respiratory response of guinea pigs to the inhalation of acetic acid vapor. Industrial Hygiene Journal. Vol. 22, no. 1 (February, 1961). p. 1-5

(2) Rajan, K.G., et al. Reversible airways obstruction and interstitial pneumonitis due to acetic acid. British Journal of Industrial Medicine. Vol. 46, no. 1 (January, 1989). p. 67-68

(3) Hodgson, M.J., et al. Respiratory disease in a photographer. American Journal of Industrial Medicine. Vol. 9, no. 4 (April, 1986). p. 349-354

(4) Kivity, S., et al. Late asthmatic response to inhaled glacial acetic acid. Thorax. Vol. 49, no. 7 (July, 1994). p. 727-728

(5) Kern, D.G. Outbreak of the reactive airways dysfunction syndrome after a spill of glacial acetic acid. American Review of Respiratory Disease. Vol. 144, no. 5 (November, 1991). p. 1058-1064

(6) Shafto, C.M. Two cases of acetic acid burns of the cornea. British Journal of Ophthalmology. Vol. 34 (1950). p. 559-562

(7) Vigliani, E.C., et al. Experiences of the Clinica del Lavoro with maximum allowable concentrations of industrial poisons. Archiv fuer Gewerbepathologie und Gewerbehygiene. Vol. 13 (1955). p. 528-535. (English translation: Archives of Industrial Health. Vol. 13 (1956). p. 403)

(8) Campbell, K.I., et al. Dermal irritancy of metal compounds: studies with palladium, platinum, lead and manganese compounds. Archives of Environmental Health. Vol. 30 (April, 1975). p. 168-170

(9) Nixon, G.A., et al. Interspecies comparisons of skin irritancy. Toxicology and Applied Pharmacology. Vol. 31 (1975). p. 481-490

(10) Sipi, P., et al. Sister-chromatid exchanges induced by vinyl esters and respective carboxylic acids in cultured human lymphocytes. Mutation Research. Vol. 279, no. 2 (16 May, 1992). p. 75-82

(11) Morita, T., et al. Evaluation of clastogenicity of formic acid, acetic acid and lactic acid on cultured mammalian cells. Mutation Research. Vol. 240, no. 3 (March, 1990). p. 195-202

(12) Demerec, M., et al. A survey of chemicals for mutagenic action in E. Coli. The American Naturalist. Vol. LXXXV, no. 821 (March-April, 1951). p. 119-136

(13) Alexandrov, V.A., et al. The stimulating effect of acetic acid, alcohol and thermal burn injury on esophagus and forestomach carcinogenesis induced by N-nitrososarcosin ethyl ester in rats. Cancer Letters. Vol. 47 (1989). p. 179-185

(14) Rostein, J.B. et al. Acetic acid, a potent agent of tumor progression in the multistage mouse skin model for chemical carcinogenesis. Cancer Letters. Vol. 42, nos. 1,2 (September/October, 1988). p. 87-90

(15) Jurim, O., et al. Disseminated intravascular coagulopathy caused by acetic acid ingestion. Acta Haematologica. Vol. 89 (1993). p. 204- 205

(16) Hakenbeck, Von H., et al. Vergiftung mit 80%iger Essigsaure. [English summary]. Zeitschrift fur Urologie und Nephrologie. Vol. 77 (1984). p. 311-314

(17) HSDB record for acetic acid. Last revision date: 96/01/18

(18) Parmeggiani, L., et al. On the injuries to health caused by acetic acid in the production of cellulose acetate. [English summary]. Medicina del Lavoro. Vol. 45 no. 5 (1954). p. 319-323

(19) Goh, C.L. Occupational dermatitis from soldering flux among workers in the electronics industry. Contact Dermatitis. Vol. 13. no. 1 (1985). p. 85-90

(20) Weil, A.J., et al. Allergic reactivity to simple aliphatic acids in man. Journal of Investigative Dermatology. Vol. 17 (October, 1951). p. 227-231

(21) Vaneckova, J., et al. Hypersensitivity to rubber surgical gloves in healthcare personnel. Contact Dermatitis. Vol. 31, no. 4 (October, 1994). p. 266-268

(22) Ghiringhelli, L., et al. Pathology due to acetic acid: observations on experimental animals and on men. [English summary]. Medicina del Lavoro. Vol. 48, no. 10 (1957). p. 559-565

(23) Smyth, Jr., H.F., et al. Range-finding toxicity data: list IV. Archives of Industrial Hygiene and Occupational Medicine. Vol. 4 (1951). p. 119-122

(24) Acetic acid. Hygienic Guide Series. American Industrial Hygiene Association, June 1978.

(25) Murphy, J.C., et al. Ocular irritancy responses to various pHs of acids and bases with and without irrigation. Toxicology. Vol. 23 (1982). p. 281-291

(26) v. Muhlendahl, K.E., et al. Local injuries by accidental ingestion of corrosive substances by children. Archives of Toxicology. Vol. 39 (1978). p. 299-314

(27) Takhirov, M.T. Hygienic standards for acetic acid and acetic anhydride in air. Hygiene and Sanitation. Vol. 34, no. 4 (June, 1969). p. 122-125

(28) Wagner, Jr., F.S. Acetic acid. In: Kirk-Othmer encyclopedia of chemical technology. 4th edition. Volume 1. John Wiley and Sons, 1991. p. 121-139

(29) Aguilo, A, et al. Acetic acid. In: Ullmann’s encyclopedia of industrial chemistry. 5th completely revised edition. Volume A 1. VCH Verlagsgesellschaft, 1985. p. 45-64

(30) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 325; NFPA 49; NFPA 491

(31) NIOSH pocket guide to chemical hazards. National Institute of Occupational Safety and Health, June 1994. p. 2-3

(32) Emergency action guide for acetic acid. Association of American Railroads, January, 1988

(33) Chemical safety sheets: working safely with hazardous chemicals. Kluwer Academic Publishers, 1991. p. 3,4

(34) The Sigma-Aldrich library of chemical safety data. Edition II. Volume 1. Sigma-Aldrich Corporation, 1988. p. 13A

(35) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 12, 42

(36) Weast, R.C., ed. Handbook of chemistry and physics. 66th edition. CRC Press, 1985-1986. p. C-47, D-146, D-161, D-221, F-31, F- 63

(37) Urben, P.G., ed. Bretherick’s handbook of reactive chemical hazards. 5th edition. Volume 1. Butterworth-Heinemann Ltd., 1995. p. 319-320

(38) Corrosion data survey: metals section. 6th edition. National Association of Corrosion Engineers, 1985. p. 2-4,5,6 to 3-4,5,6

(39) European Economic Community. Commission Directive 93/72/EEC. September 1, 1993

(40) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002

(41) Occupational Safety and Health Administration (OSHA). Acetic and Formic Acids in Workplace Atmospheres. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc.html>

(42) Occupational Safety and Health Administration (OSHA). Acetic Acid. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc.html>

(43) National Institute for Occupational Safety and Health (NIOSH). Acetic Acid. In: NIOSH Manual of Analytical Methods (NMAM(R)). 4th ed. Edited by M.E. Cassinelli, et al. DHHS (NIOSH) Publication 94-113. Aug. 1994. Available at: <www.cdc.gov/niosh/nmam/nmammenu.html>

Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.

 

Review/Preparation Date: 1996-11-28

 

Revision Indicators:

Ingestion (Health)        1997-05-01

Ingestion (First Aid)     1997-05-01

Emergency Overview    1997-05-01

US transport       2002-12-10

TDG  2003-08-14

Resistance of materials for PPE       2004-04-05

ERPG-1      2004-06-30

ERPG-2      2004-06-30

ERPG-3      2004-06-30

Bibliography        2005-03-10

Passive Sampling Devices      2005-03-10

Sampling/analysis        2005-03-10

Toxicological info 2007-07-09

Relative density   2007-07-09

 

Clofazimine

  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

1.7 Presentation, Formulation

  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 Properties of the substance

3.3.1.1 Colour

3.3.1.2 State/Form

3.3.1.3 Description

3.3.2 Properties of the locally available formulation(s)

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3.4.2 Shelf-life of the locally available formulation(s)

3.4.3 Storage conditions

3.4.4 Bioavailability

3.4.5 Specific properties and composition

  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 ENTRY

5.1 Oral

5.2 Inhalation

5.3 Dermal

5.4 Eye

5.5 Parenteral

5.6 Others

  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

8.1.2 Storage of laboratory samples and specimens

8.1.3 Transport of laboratory samples and specimens

8.2 Toxicological analyses and their interpretation

8.2.1 Tests on active 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 qualitative method(s)

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

8.3.2 Arterial blood gas analyses

8.3.3 Haematologic 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 Relevant laboratory analyses

10.2.1 Sample collection

10.2.2 Biomedical analysis

10.2.3 Toxicological analysis

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific treatment

10.4 Decontamination

10.5 Elimination

10.6 Antidote treatment

10.6.1 Adults

10.6.2 Children

10.7 Management discussion

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

11.2 Internally extracted data on cases

11.3 Internal cases

  1. ADDITIONAL INFORMATION

12.1 Availability of antidotes

12.2 Specific preventive measures

12.3 Other

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

 

  1. NAME

 

1.1 Substance

 

Clofazimine (INN)

 

(WHO, 1992)

 

1.2 Group

 

ATC classification index

 

Antimycobacterials (JO4)/Drugs for treatment of lepra (JO4B)

 

(WHO, 1992)

 

1.3 Synonyms

 

Riminophenazine

B-663

G-30320

 

(Budavari, 1989; Reynolds, 1989).

 

(To be completed by each Centre using local data)

 

1.4 Identification numbers

 

1.4.1 CAS number

 

2030-63-9

 

1.4.2 Other numbers

 

RTECS

 

SG1578000

 

1.5 Brand names, Trade names

 

Lamprene

 

(To be completed by each Centre using local data)

 

1.6 Manufacturers, Importers

 

Ciba-Geigy

 

(To be completed by each Centre using local data)

 

1.7 Presentation, Formulation

 

Capsule containing 50 mg

Capsule containing 100 mg

 

(To be completed by each Centre using local data)

 

  1. SUMMARY

 

2.1 Main risks and target organs

 

Acute poisoning

 

No reports are available on acute toxicity.

 

Chronic poisoning

 

One report mentioned abdominal disposition of clofazamine

crystals and one report of splenic infarction.

 

Target organs

 

CNS; gastrointestinal; ocular effects.

 

2.2 Summary of clinical effects

 

Dermal

 

Pink to brownish-black discolouration of the skin; dryness;

ichthyosis; pruritus; acneform eruptions, skin rashes; and

photosensitivity reactions.

 

Eye

 

Reddish-brown discolouration of the cornea, conjunctiva and

lacrimal fluid.  Occasionally there could be dryness,

itchiness, irritation, burning and watering of the eyes.

 

Gastrointestinal tract

 

Nausea, vomiting, abdominal pain and diarrhoea,

discolouration of faeces.  There was even note of splenic

infarction seen in a patient receiving clofazimine for the

treatment of pyoderma gangrenosum.

 

Nervous system

 

Headache, dizziness, drowsiness, fatigue, and taste disorder.

Some patients became depressed because of skin discolouration.

 

Haematopoietic system

 

Eosinophilia; elevated ESR.

 

Liver

 

Elevated albumin, bilirubin and SGOT.

 

Others

 

Discolouration of the sweat, sputum and urine.

 

(McEvoy, 1990; Reynolds, 1989; PDR, 1990)

 

2.3 Diagnosis

 

By exclusion: If the patient taking clofazimine presents with

symptoms and signs as above in 2.2., it may be caused by

chronic clofazimine poisoning. Other causes that have these

symptoms and signs such as rifampicin toxicity may have to be

excluded.

 

Clofazimine may be measured in biological fluids by Thin-

Layer Chromatographic method (Hauffe et al., 1986), or High

Pressure Liquid Chromatography can also be used (Moffat,

1986). However, these methods are usually of no value in the

diagnosis in the acute stage.

 

2.4 First aid measures and management principles

 

Control for hypokalaemia and its effects on ECG.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

3.1 Origin of the substance

 

Substituted iminophenazine derivative (synthetic)

 

3.2 Chemical structure

 

Structural formula

 

Molecular formula

 

C27H22C12N4

 

Molecular weight

 

473.41

 

Chemical names

 

3-(4-Chloroanilino)-10-(4-chlorophenyl)-2,10-dihydro-2-

phenazin-2-ylideneisopropylamine

 

N,5-Bis(4-Chlorophenyl)-3,5-dihydro-3-[(1-methylethyl)imino]-

2-phenazinamine

 

3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-

(isopropylimino)-phenazine

 

2-(4-Chloroanilino)-3-isopropylimino-5-(4-chlorophenyl)-3,5-

dihydrophenazine

 

2-p-Chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-

isopropyliminophenazine

 

(Budavari, 1989; Reynolds, 1993)

 

3.3 Physical properties

 

3.3.1 Properties of the substance

 

3.3.1.1 Colour

 

Reddish-brown

 

3.3.1.2 State/Form

 

Fine powder

 

3.3.1.3 Description

 

Melting point about 215 °C

Odourless

Readily soluble in benzene, soluble in

chloroform, slightly soluble in methanol and

ethanol, very slightly soluble in ether, poorly

soluble in acetone and ethyl acetate,

practically insoluble in water (Reynolds, 1989;

PDR, 1990).

 

3.3.2 Properties of the locally available formulation(s)

 

To be completed by each Centre using local data.

 

3.4 Other characteristics

 

3.4.1 Shelf-life of the substance

 

Five years (Weber & Kop, 1987).

 

3.4.2 Shelf-life of the locally available formulation(s)

 

To be completed by each Centre using local data.

 

3.4.3 Storage conditions

 

With the storage condition at 23°C, the physical

properties and rate of disintegration of the capsules

remained the same.  If stored at higher temperature,

they became useless and would stick together.  The

capsules should be protected from heat and moisture

(Weber & Kop, 1987).

 

3.4.4 Bioavailability

 

Clofazimine has a variable absorption rate ranging from

45% to 62% after oral administration. Absorption is

 

influenced by particle size. Food increases its

bioavailability.  Its half-life is approximately 70

days.

 

(To be completed by each Centre using local data)

 

3.4.5 Specific properties and composition

 

To be completed by the local centre.

 

  1. USES

 

4.1 Indications

 

4.1.1 Indications

 

As an antileprotic in association with other agents.

 

Has anti-inflammatory properties in erythema nodosum

leprosum reactions.

 

For use in the treatment of Lobo’s disease (a chronic

topical mycosis), Crohn’s disease, Leishmaniasis.

 

It has been used in the treatment of cutaneous

elastolytic lymphoma (von den Driesch P et al.,

1994).

 

Chronic skin ulcers (Buruli ulcer) (Gilman et al.,

1990)

 

4.1.2 Description

 

Not relevant

 

4.2 Therapeutic dosage

 

4.2.1 Adults

 

Clofazimine, 50 to 100 mg daily. WHO recommends a

regimen in which rifampicin 600mg and clofazimine 300

mg are given once monthly, together with Dapsone 100 mg

daily, self-administered (for at least 2 years)

(Reynolds, 1993).

 

The treatment of erythema nodosum leprosum reactions

depends on the severity of symptoms. In general, the

basic antileprosy treatment should be continued. Dosage

of clofazimine above 200 mg daily is not recommended,

and the dosage should be tapered to 100 mg daily as

quickly as possible after the reactive episode is

controlled (PDR, 1990).

 

(Note: Antileprotic regimen is in accordance with the

recommendation of the World Health Organization (WHO).

Depending on the indication, dosage regimen varies.

 

Because adverse effects on the gastrointestinal tract

are dose related, it has been recommended that daily

doses of 300 mg or more should not be administered for

more than three months).

 

4.2.2 Children

 

10-14 years old

 

Clofazimine 200 mg once monthly, supervised; and 50 mg

on alternate days, self-administered (Reynolds, 1993).

 

Note: The dose should be adjusted for children with low

bodyweight as follows:

 

over 35 kg    50 mg daily and 300 mg monthly

20 to 35 kg   50 mg every 2nd day and 200 mg monthly

12 to 20 kg   50 mg every 2nd day and 100 mg monthly

12 kg or less 50 mg twice weekly and 100 mg monthly

 

(Dollery, 1991)

 

(Note: The optimum effective dose has not yet been

established.  The dose recommended above for children

is half the adult dose, adjusted for operational

suitability, since clofazimine is marketed in capsules

of 100 mg and 50 mg).

 

4.3 Contraindications

 

Use of clofazimine should be avoided during pregnancy or

lactation unless absolutely necessary.

 

Administration of the drug should be modified or discontinued

in the presence of liver and kidney function disorder.

 

It should be used with caution together with diuretics to

avoid hypokalaemia.

 

  1. ROUTES OF ENTRY

 

5.1 Oral

 

This is the usual route of administration for therapeutic

use.

 

5.2 Inhalation

 

Not relevant.

 

5.3 Dermal

 

Not relevant.

 

5.4 Eye

 

Not relevant.

 

5.5 Parenteral

 

Not relevant.

 

5.6 Others

 

Not relevant.

 

  1. KINETICS

 

6.1 Absorption by route of exposure

 

Clofazimine has a variable absorption rate ranging from 45 to

62% after oral administration. About 20% of a dose is

absorbed from the gastrointestinal tract when clofazimine is

administered as coarse crystals, but 45 to 70% of a dose may

be absorbed when the drug is administered as capsules

containing a microcrystalline (micronized) suspension of the

drug in an oil-wax base.  Presence of food in the GIT may

increase the rate and extent of absorption of Clofazimine

(McEvoy, 1990).  According to Alford (1989) absorption is

variable with 9 to 74% of an administered dose appearing in

faeces.

 

6.2 Distribution by route of exposure

 

Clofazimine is highly lipophilic and is distributed

principally to fatty tissue and cells of the

reticuloendothelial system; the drug is taken up by

macrophages throughout the body.  It accumulates in high

concentrations in the mesenteric lymph nodes, adipose tissue,

adrenals, liver, lungs, gallbladder, bile, and spleen and in

lower concentrations in the skin, small intestine, lungs,

heart, kidneys, pancreas, muscle, omentum, and bone.

Clofazimine crystals have also been found in bone marrow,

sputum, sebum, and sweat, and in the iris, conjunctiva,

macula, sclera, and cornea.  The drug does not appear to

distribute into the brain or CSF (McEvoy, 1990).  It crosses

the placental barrier and is distributed into breast milk.

 

6.3 Biological half-life by route of exposure

 

At least 70 days after repeated therapeutic dose (AHFS, 1990;

Alford, 1989).

 

Repeated therapeutic doses result with a biological half life

of approximately 70 days with a plasma concentration of

0.4-3_µg/ml (McEvoy, 1990; Alford R, 1989).

 

6.4 Metabolism

 

The metabolic fate of clofazimine has not been fully

elucidated, but the drug appears to accumulate in the body

and to be excreted principally unchanged.  Clofazimine

appears to be partially metabolized and at least 3

metabolites have been found in urine of patients receiving

the drug.  Metabolite I is formed by hydrolytic

dehalogenation of clofazimine, metabolite II presumably is

formed by a hydrolytic deamination reaction followed by

glucuronidation, and metabolite III appears to be a hydrated

clofazimine glucuronide (McEvoy, 1990).

 

6.5 Elimination  by route of exposure

 

Clofazimine is excreted principally in faeces, both as

unabsorbed drug and via biliary elimination. Faecal

elimination of clofazimine exhibits considerable

interindividual variation, and 35% to 74% of a single oral

dose may be excreted unchanged in faeces over the first 72

hours after the dose. Following oral administration of a

single 200 mg or 300 mg dose, elimination of unchanged

clofazimine and its metabolites in urine is negligible during

the first 24 hours. Following multiple doses of the drug,

less than 1% of the daily dose is excreted in urine over a

24-hour period. Small amounts of the drug also are excreted

via sebaceous and sweat glands. (McEvoy, 1990)

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

7.1 Mode of action

 

7.1.1 Toxicodynamics

 

No data available.

 

7.1.2 Pharmacodynamics

 

The precise mechanism of the drug’s antimycobacterial

effect has not been fully elucidated just like its

anti-inflammatory and immunosuppressive effects. The

drug binds preferentially to mycobacterial DNA at base

sequences containing guanine resulting to inhibition of

mycobacterial replication and growth.  The inhibitory

concentration of clofazimine in tissue is between 0.1

and 1_µg/kg (Alford R, 1989).

 

Studies in vivo and in vitro showed that clofazimine

causes a progressive, dose-dependent inhibition of

neutrophil motility and mitogen-induced lymphocyte

transformation.  Clofazimine also increases synthesis

of prostaglandin E2 by the polymorphonuclear leucocytes

in vitro.  However, most of the studies done showed

that clofazimine increases the phagocytic activity and

oxidative metabolism of the polymorphonuclear cells and

 

macrophages in vitro and in vivo (McEvoy, 1990;

Reynolds, 1989,  Alford, 1989).

 

7.2 Toxicity

 

7.2.1 Human data

 

7.2.1.1 Adults

 

Severe abdominal symptoms have necessitated

exploratory laparotomies in some patients on

clofazimine therapy. Rare reports have included

splenic infarction, bowel obstruction, and

gastrointestinal bleeding. Deaths have been

reported, following severe abdominal symptoms.

Autopsies revealed crystalline deposits of

clofazimine in various tissues including the

intestinal mucosa, liver, spleen and mesenteric

lymph nodes (PDR, 1992).

 

To minimise toxicity it is recommended that

daily doses of 300 mg or more should not be

administered for more than three months and

patients on doses greater than 100 mg daily

should be under medical supervision (Reynolds,

1993).

 

7.2.1.2 Children

 

No data available.

 

7.2.2 Relevant animal data

 

Oral LD 50 (rabbits)  3.3 g/kg

 

Oral LD 50 (mice, rats and guinea pigs) >4 g/kg.

 

(McEvoy, 1990; Budavari, 1989).

 

7.2.3 Relevant in vitro data

 

No data available.

 

7.3 Carcinogenicity

 

No data available.

 

7.4 Teratogenicity

 

There is no evidence of teratogenicity.  However, clofazimine

crosses the human placenta.  The skin of infants born to

women who had received the drug during pregnancy was deeply

pigmented at birth. However, no evidence of teratogenicity

was noted.  There are no adequate and well-controlled studies

in pregnant women, but 3 neonatal deaths had been reported in

 

15 pregnancies in patients given clofazimine.  (McEvoy, 1990;

Reynolds, 1989; Farb et al., l982; PDR, 1990).

 

7.5 Mutagenicity

 

The drug was not mutagenic in the Ames microbial mutagen test

with or without metabolic activation (McEvoy, 1990).

However, genotoxic micronuclear testing studies in mice bone

marrow and spermatocytes revealed increase of chromosomal

aberrations.  The mechanism is not well understood but has

been suggested to be secondary to generation of hydroxyl

radicals and their effects on chromosomes (Das & Roy, 1990).

However, there is a significant higher incidence of

micronucleus in bone marrow erythrocytes and regenerated

hepatocytes indicating that clofazamine has a clastogenic

effect.  Clofazamine has been noted to have antimitotic

effects and the proposed mechanism is impairment of DNA

template or antimitochondrial activity (Roy & Das, 1990).

 

7.6 Interactions

 

Several studies done showed that concomitant clofazimine

administration does not affect the pharmacokinetics of

dapsone, but a few patients showed transient increase in the

urinary excretion of dapsone. However, there is some evidence

that the anti-inflammatory effects of clofazimine may be

decreased or nullified by dapsone; since, in vitro studies

showed that there is an opposite effect of both drugs on the

neutrophil motility and lymphocyte transformation.  But there

is no evidence of interference between the two drugs with

regard to their antimycobacterial activity.

 

Clofazimine with rifampicin alone, or in conjunction with

dapsone, results in a delay in time to reach peak serum

rifampicin concentration, decrease in the rate of absorption

of rifampicin, and slight decrease in the area under the

plasma concentration curve (AUC) of the drug.  But, in a

study of lepromatous leprosy patients receiving dapsone 100

mg daily and rifampicin 600 mg daily, concomitant

administration of clofazimine 100 mg daily did not affect

plasma rifampicin concentrations of the AUC, plasma half-life

or urinary elimination of rifampicin.

 

In a study of lepromatous leprosy patients receiving

clofazimine 300 mg daily, concomitant administration of

isoniazid 300 mg daily resulted in increased urinary and

plasma concentrations of clofazimine and decreased

concentration of the drug in the skin (McEvoy, 1990).

 

7.7 Main adverse effects

 

Potentially life-threatening

 

When clofazimine is given in high dosage for months or years,

crystals of the drug are deposited in the lamina propria and

 

submucosa of the small intestine, and in the mesenteric lymph

nodes (Dollery, 1991). The ileal wall may become thickened

with nodular or polypoid changes, and the mucosal pattern

coarsen and eosinophilic enteritis may also occur (Mason et

al., 1977; de Bergeyck, 1980).

 

One patient, who received clofazimine in dosage varying

between 100 mg and 600 mg daily for 6 years for severe ENL,

after 3 years developed severe, progressive loss of weight,

recurring anorexia, nausea, diarrhoea and abdominal pain. She

died 4 months after stopping clofazimine from presumed

electrolyte imbalance (Jopling, 1976; Harvey et al., 1977).

 

Other patients, whose clofazimine dosage was stopped at an

earlier stage, have usually gradually become symptom free,

although clofazimine crystals have been detected in a

mesenteric lymph node 46 months later (Jopling, 1976).  One

patient, who received 300 to 400 mg clofazimine daily for

only 11 months, developed a splenic infarct with evidence of

considerable accumulation of crystals in the spleen with

massive accumulation in a mesenteric lymph node (McDougal et

al., 1980).

 

Dermal

 

Adverse effects are usually dose-related, they include:

 

Pink to brownish-black discolouration of the skin: dryness,

ichthyosis, pruritus, acneform eruptions, skin rashes and

photosensitivity reactions.

 

Ocular

 

Reddish-brown discolouration of the cornea, conjunctiva, and

lacrimal fluid.  Occasionally there could be dryness

itchiness, irritation, burning and watering of the eyes.

 

Gastrointestinal

 

Nausea, vomiting, abdominal pain and diarrhoea,

discolouration of faeces.  There was even note of splenic

infarction in a patient receiving clofazimine for the

treatment of pyoderma gangrenosum. Bowel obstruction and

G.I.S. bleeding in less than 1% of patients.

 

Nervous system

 

Headache, dizziness, drowsiness, fatigue and taste disorder.

Some patients developed depression because of the skin

discolouration.

 

Haematopoietic effects

 

Elevated ESR, eosinophilia.

 

Liver

 

Elevated albumin, bilirubin and SGOT.

 

Other

 

Discolouration of sweat, sputum, urine and breast milk,

hypokalaemia.

 

(McEvoy, 1990; Reynolds, 1989; PDR, 1990).

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

8.1 Material sampling plan

 

8.1.1 Sampling and specimen collection

 

Blood samples are collected in heparinized tubes and

these would be centrifuged.  The plasma must be

separated and transferred into a plastic tube (Hauffe

et al, 1986; Weber and Kop, 1987).

 

8.1.2 Storage of laboratory samples and specimens

 

The samples are to be kept frozen at -20°C until

required for analysis (Hauffe et al, 1986, Weber and

Kop, 1987).

 

8.1.3 Transport of laboratory samples and specimens

 

Samples can be transferred in containers which could

provide a temperature of -20 °C (Hauffe et al., 1986;

Weber and Kop, 1987).

 

8.2 Toxicological analyses and their interpretation

 

8.2.1 Tests on active 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)

 

Photometric determination alone.

 

Photometric determination after TALC-separation

(Weber & Kop, 1987).

 

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)

 

Thin-layer chromatographic method.

 

High pressure liquid chromatography (Moffat,

1986).

 

8.2.2.4 Advanced qualitative method(s)

 

8.3 Biomedical investigations and their interpretation

 

8.3.1 Biochemical analysis

 

8.3.1.1 Blood, plasma or serum

 

Use function test as ALT, AST, albumin,

bilirubin, SGOT.

 

8.3.1.2 Urine

 

8.3.2 Arterial blood gas analyses

 

8.3.3 Haematologic analyses

 

ESR, total eosinophile count, prothrombin time.

 

8.3.4 Interpretation of biomedical investigations

 

8.4 Other biomedical (diagnostic) investigations and their

interpretation

 

ECG.

 

8.5 Overall interpretation of all toxicological analyses and

toxicological investigations

 

In view of the distribution and the lack of information on

therapeutic and/or toxic blood levels, measuring has no

practical relevance in the management of intoxication.

 

8.6 References

 

See Section 13.

 

  1. CLINICAL EFFECTS

 

9.1 Acute poisoning

 

9.1.1 Ingestion

 

No data available.

 

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

 

No data available.

 

9.2 Chronic poisoning

 

9.2.1 Ingestion

 

The only route of administration.  Dose-related adverse

effects are therefore only from oral ingestion of

clofazimine.

 

Adverse reactions are dose-related with daily doses of

300 mg or more, and more than three months of intake.

 

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 exposure

 

No data available.

 

9.2.6 Other

 

No data available.

 

9.3 Course, prognosis, cause of death

 

Adverse effects of clofazimine were generally well tolerated

and no patient stopped treatment because of them. However,

 

there was a report of fatal syndrome of abdominal pain,

malabsorption, intra-abdominal deposition of clofazimine

crystals in one patient.  There was also noted splenic

infarction and tissue accumulation of clofazimine in a

patient receiving clofazimine for the treatment of pyoderma

gangrenosum (Reynolds, 1989).

 

9.4 Systematic description of clinical effects

 

9.4.1 Cardiovascular

 

Arrhythmia secondary to hypokalaemia (PDR, 1990).

 

Its cardiotoxicity has been postulated (Choudhri et

al., 1995).

 

9.4.2 Respiratory

 

Discolouration of the sputum.

 

9.4.3 Neurological

 

9.4.3.1 Central nervous system (CNS)

 

Headache, dizziness, drowsiness, fatigue, taste

disorder, depression.

 

9.4.3.2 Peripheral nervous system

 

Not relevant.

 

9.4.3.3 Autonomic nervous system

 

Not relevant.

 

9.4.3.4 Skeletal and smooth muscle

 

Not relevant.

 

9.4.4 Gastrointestinal

 

Nausea, vomiting, abdominal pain, diarrhoea,

discolouration of the faeces.  There was even note of

splenic infarction seen in a patient receiving

clofazimine for the treatment of pyoderma gangrenosum.

 

9.4.5 Hepatic

 

Elevated albumin, bilirubin, SGOT.

 

9.4.6 Urinary

 

9.4.6.1 Renal

 

Discolouration of urine.

 

9.4.6.2 Other

 

No data available.

 

9.4.7 Endocrine and reproductive systems

 

Urinary-oestrogen excretion, which can be used as an

index of foeto-placental function, was reduced in women

with lepromatous leprosy receiving clofazimine

(Reynolds, 1989).

 

Thyroid: no data available.

 

9.4.8 Dermatological

 

Bilateral pedaloedema developed in five men and one

woman who were treated with clofazimine, rifampicin and

dapsone for multibacillary leprosy. The bilateral

pedaloedema was symmetrical, pitting, nontender and

progressive and developed after about 3 month’s

therapy.  Symptoms developed only in patients receiving

all 3 drugs and not in patients who received only

rifampicin and dapsone. It appears that this oedema is

due to clofazimine (Oommen T, 1990).

 

Pink to brownish-black discolouration of the skin,

dryness, ichthyosis, pruritus, rashes, acneform

eruptions, photosensitivity reactions.

 

9.4.9 Eye, ear, nose, throat: local effects

 

Bull’s eye pigmentary maculopathy and widespread

retinal damage were observed in a 37-year-old man with

AIDS after 8 months therapy with clofazimine 20 mg/day

for disseminated Mycobacterium avium complex infection.

The patient was also receiving isoniazid rifabutin,

ethambutol, ganciclovir, pyrimethamine + sulfadoxine

and prednisone. Clofazimine therapy was withdrawn and

no change was observed after 6 weeks. Long term follow-

up was not possible as the patient died 3 months later.

The authors suggest that all AIDS patients receiving

this drug be closely followed for the development of

macular pigmentary changes (Cunningham, 1990).

 

Reddish-brown discolouration of the cornea conjunctiva,

lacrimal fluid, occasional dryness, itchiness

irritation, burning and watering of the eyes.

 

9.4.10 Haematological

 

Eosinophilia, elevated ESR.

 

9.4.11 Immunological

 

No data available.

 

9.4.12 Metabolic

 

9.4.12.1 Acid-base disturbances

 

No data available.

 

9.4.12.2 Fluid and electrolyte disturbances

 

Hypokalaemia (PDR, 1990).

 

9.4.12.3 Others

 

No data available.

 

9.4.13 Allergic reactions

 

Pruritus, skin rashes.

 

9.4.14 Other clinical effects

 

No data available.

 

9.4.15 Special risks

 

Pregnance

 

It has been found that clofazimine crosses the human

placenta.  The skin of infants born to women who had

received the drug during pregnancy was noted to be

deeply pigmented at birth. However, no evidence of

teratogenicity was noted.  There are no adequate and

well controlled studies in pregnant women, but 3

neonatal deaths had been reported in 15 pregnancies in

patients given clofazimine.  Further evaluation of the

perinatal consequences of clofazimine therapy in

patients with leprosy is needed (McEvoy, 1990;

Reynolds, 1989; PDR, 1990).

 

Urinary oestrogen excretion, which can be used as an

index of foeto-placental function, was reduced in women

with lepromatous leprosy receiving Clofazimine

(Reynolds, 1989).

 

Breastfeeding

 

Clofazimine is excreted in breastmilk.

 

Enzyme deficiencies

 

No data available.

 

9.5 Other

 

No data available.

 

9.6 Summary

 

Not relevant

 

  1. MANAGEMENT

 

10.1 General principles

 

Acute poisoning

 

No data are available.

 

Chronic poisoning

 

Symptomatic therapy.  ECG for detecting hypokalaemia.

 

10.2 Relevant laboratory analyses

 

10.2.1 Sample collection

 

Blood samples for levels of Clofazimine can be

collected in heparinized tubes.  The volume is about

1 ml.  Then the blood sample is to be centrifuges so

that plasma could be separated and transferred into

a plastic tube.  It will be kept frozen at -20°C

until required for analysis with the use of the

thin-layer chromatographic method (Hauffe et al.,

1986).

 

High pressure liquid chromatography and thin-layer

chromatography can be used.

 

10.2.2 Biomedical analysis

 

No data available

 

10.2.3 Toxicological analysis

 

Clofazimine concentration could be analyzed with the

use of blood samples collected in heparinized tubes.

The samples collected are then centrifuged and the

separated plasma is analyzed with the use of thin-

layer chromatographic method or HPLC (Moffat, 1986).

 

10.2.4 Other investigations

 

No data available.

 

10.3 Life supportive procedures and symptomatic/specific

treatment

 

ECG for detecting hypokalaemia.

 

10.4 Decontamination

 

Gastric lavage (preferably with activated charcoal), or

inducing emesis may be useful, if the patient is seen early

after the ingestion.  The use of a cathartic is no longer

recommended.

 

10.5 Elimination

 

No data available.

 

10.6 Antidote treatment

 

10.6.1 Adults

 

No antidote available.

 

10.6.2 Children

 

No antidote available.

 

10.7 Management discussion

 

No data available

 

  1. ILLUSTRATIVE CASES

 

11.1 Case reports from literature

 

A 46 year-old woman experienced weight loss, diarrhoea, and

abdominal pain 10 months after receiving a 6 month course

of clofazimine 300 mg given daily for prurigo nodularis.

Abdominal symptoms were initially relieved by a gluten-free

diet, but returned 22 months after withdrawal of

clofazimine.  Laparotomy showed crystal deposition in the

chorion of intestinal villi and in the mesenteric lymph

nodes (Reynolds, 1989).

 

Splenic infarction and tissue accumulation of clofazimine

in a patient receiving clofazimine for the treatment of

pyoderma gangrenosum (Reynolds, 1989).

 

Although 2 pregnant patients received clofazimine without

any adverse effects to the fetus, 2 neonatal deaths had

been reported in 13 pregnancies in patients given

clofazimine (Farb et al., 1982; Reynolds, 1989).

 

11.2 Internally extracted data on cases

 

No data available.

 

11.3 Internal cases

 

To be completed by each Centre using local data

 

  1. ADDITIONAL INFORMATION

 

12.1 Availability of antidotes

 

To be completed by each Centre using local data

 

12.2 Specific preventive measures

 

Clofazimine should be stored at 23 °C.  It should be

protected from heat and moisture.  If the capsules are

sticking together, then do not use them.  When the

preceding adverse effects are noted, discontinue the use of

the drug.  The drug should not be given to pregnant or

nursing mothers, unless absolutely necessary.  Refrain from

using the drug in patients with liver function

disturbances.  It should be used with caution with

diuretics.  The drug should be used with Dapsone or

Rifampicin in treating leprosy.  At present, it has no

potential of becoming a drug of abuse.

 

12.3 Other

 

No data available.

 

  1. REFERENCES

 

Alford R (1989)  Antimycobacterial agents, principles and

practice of infectious diseases,  3rd ed., pp 358-359.

 

de Bergeyck E, Janssens PG,  & de Muynck A (1980) Radiological

abnormalities of the ileum associated with the use of

clofazamine (Lamprene: B.663) in the treatment of skin

ulceration due to Mycobacterium ulcerans. Leprosy Review, 51:

221-228.

 

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

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

Co., Inc. pp 370-371.

 

Choudhri SH, Harris L, Butany JW, & Keystone JS

(1995)Clofazimine induced cardiotoxicity: a case report. Lepr

Rev 66(1): 63-68.

 

Cunningham CA, Friedberg DN, & Carr RE (1990) Clofazimine-

induced generalized retinal degeneration.  Retina, 10: 131-134.

 

Das RK & Roy B (1990)  Evaluation of genotoxicity of

Clofazamine, an antileprosy drug in mice in vivo. I. Chromosomal

analysis in bone marrow and spermatocytes.  Mutation Research,

241: 161-168.

 

Dollery ed. (1991)  Therapeutic drugs.  Churchill & Livingstone,

Edinburgh.

 

Farb H, West DP, & Pedvis-Leftick A (1982) Clofazimine in

pregnancy complicated by leprosy.  Obstetrics & Gynecology,

59: 122-123.

 

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 1160-1162.

 

Harvey RF Harman RRM, Black C, et al. (1977) Abdominal pain and

malabsorption due to tissue deposition of clofazimine (Lamprene)

crystals. Brit J of Dermatology, 97 (suppl) l5: 19

 

Hauffe et al. (1986) CIBA-Geigy Pharma Research and Development

Pharmacological Chemistry.

 

Jopling WH (1976)  Editorial.  Complications of treatment with

clofazimine (Lamprene: B.663).  Leprosy Review, 47: 1-3.

 

Mason GH, Ellis-Pegler RB, Arthur JF (1977)  Clofazamine and

eosinophilic enteritis.  Leprosy Review, 48: 175-180.

 

McDougal AC, Horsfall WR, Hede JE, Chaplin AJ (1980)  Splenic

infarction and tissue accumulation of crystals associated with

the use of clofazimine (Lamprene: B.663) in the treatment of

pyoderma gangrenosum.  Brit J of Dermatology, 102: 227-230

 

McEvoy GK ed. (1990) American Hospital Formulary Service, Drug

Information. American Society of Hospital Pharmacists. Bethesda,

MD, American Society of Hospital Pharmacists,  pp 442-446.

 

Moffat, AC ed. (1986) Clarke’s Isolation and Identification of

Drugs, 2nd ed. London, The Pharmaceutical Press, pp 476-477.

 

Oommen T (1990) Clofazimine-induced lymphoedema. Leprosy Review,

61: 289.

 

PDR – Physicians’ Desk Reference (1990)  44th ed., Ordell NJ,

Medical Economics, pp 980-981.

 

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

29th ed. London, The Pharmaceutical Press, pp 556-557.

 

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

30th ed. London, The Pharmaceutical Press, pp 151-152.

 

Roy B & Das RK (1990)  Evaluation of genotoxicity of

clofazamine, an antileprosy drug in mice in vivo.  II.

Micronucleus test in bone marrow and hepatocytes.  Mutation

Research, 241: 169-173.

 

von den Driesch, Mielke V, Simon M Jr, Staib G, Tacke J, &

Sterry W (1994) “Granulomatous slack skin” – cutaneous

elastolytic lymphoma. Hautarzt, 45(12): 861-865.

 

Weber & Kop (1987)  CIBA-Geigy Pharma Analytical Development,

Basle. Pharmaceutical Documentation.

 

WHO (1992) Anatomical Therapeutic Chemical (ATC) classification

index. Oslo, WHO Collaborating Centre for Drug Statistics

Methodology, p 61.

 

WHO (1988)  Guide to Leprosy Control, 2nd Edition.  World Health

Organization, Geneva, pp 34-36.

 

WHO (1992) International nonproprietary names (INN) for

pharmaceutical substances. Geneva, World Health Organisation,

p 130.

 

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

ADDRESS(ES)

 

Author        Dr Diana Jacinto Gascon

National Poisons Control and Information Service

UP, College of Medicine – Philippine General

Hospital

Date          January 1992

Updated byauthor   May 1992

 

Peer Review   Newcastle-upon-Tyne, United Kingdom, February 1992

London, United Kingdom, September 1992

 

Dapsone

  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 Properties of the substance

3.3.2 Properties of the locally available formulation

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3.4.2 Shelf-life of the locally available formulation

3.4.3 Storage conditions

3.4.4 Bioavailability

3.4.5 Specific properties and composition

  1. USES

4.1 Indications

4.2 Therapeutic dosage

4.2.1 Adults

4.2.2 Children

4.3 Contraindications

  1. ROUTES OF ENTRY

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

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 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 Relevant laboratory analyses

10.2.1 Sample collection

10.2.2 Biomedical analysis

10.2.3 Toxicological analysis

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific treatment

10.4 Decontamination

10.5 Elimination

10.6 Antidote treatment

10.6.1 Adults

10.6.2 Children

10.7 Management discussion

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

11.2 Internally extracted data on cases

11.3 Internal cases

  1. Additional information

12.1 Availability of antidotes

12.2 Specific preventive measures

12.3 Other

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

PHARMACEUTICALS

  1. NAME

1.1 Substance

Dapsone

1.2 Group

Dihydrofolate reductase inhibitor

1.3 Synonyms

Avlosulfon

Avlosulphone

Croysulfone

DADPS

DDS

Diaphenylsulfone

Diphenasone

Diphone

Disulone

Dumitone

Eporal

Novophone

Sulfona-Mae

Sulphadione

Udolac

1.4 Identification numbers

1.4.1 CAS number

80-08-0

1.4.2 Other numbers

1358F

NCI-CO1718

NSC 6091D

RTECS: BY892500

WR 488

1.5 Brand names, Trade names

Avlosulfon (ICI, Ayerst), DAPS (Sintyal), Dapsone USP (Jacobus

Pharmaceutical), Disulone 100 (Specia), Dubronax (Kela),

Maloprim (Burroughs Wellcome), Sulfona oral (Esteve), Udolac

(ICI).

1.6 Manufacturers, Importers

Disulone (Specia)

  1. SUMMARY

2.1 Main risks and target organs

Methaemoglobinaemia and haemolysis are the main risks of acute

intoxication. Haemolytic anaemia, agranulocytosis, aplastic

anaemia and other blood dyscrasias may occur in chronic

poisoning.

 

Target organs are central and peripheral nervous systems,

blood, liver and skin.

2.2 Summary of clinical effects

Acute poisoning

Methaemoglobinaemia is the principal and constant feature of

dapsone poisoning. Clinical features may include headache,

dizziness, agitation, restlessness, nausea, vomiting,

abdominal pain, bluish-grey cyanosis, tachycardia,

hyperventilation, stupor, convulsions, coma, jaundice, and

intravascular haemolysis.

Chronic poisoning

Haemolytic anaemia and agranulocytosis may occur with the

relatively low doses used for leprosy and malaria, whereas

peripheral neuropathy and hepatitis are only observed with the

higher doses used in the treatment of dermatitis herpetiformis

(Scholer et al., 1984). Deficiency of glucose-6-phosphate

dehydrogenase, and administration in combination with

primaquine are predisposing factors for the occurrence of

haemolytic anaemia.  Concurrent administration of primaquine

also predisposes to agranulocytosis (Chernof 1967; Hutchinson

et al., 1986).

2.3 Diagnosis

Nausea, vomiting, abdominal pain, features of

methaemoglobinaemia (cyanosis, headache, lethargy, syncope

etc), anaemia and jaundice are the features suggesting acute

dapsone poisoning when there is a history of exposure. In

severe cases there may be convulsions and coma.

If methaemoglobinaemia is present the patient’s blood will be

chocolate brown in colour.

Laboratory analysis of blood for methaemoglobin levels is

useful for the diagnosis. Methaemoglobin level correlates well

with symptoms.

Dapsone plasma concentrations are usually higher than 10 mg/l

in patients with methaemoglobinaemia.

Other useful laboratory analyses include blood count,

reticulocytes, haptoglobin, bilirubin, plasma haemoglobin,

sulphaemoglobin, transaminases, arterial blood gases.

Clinical features of chronic dapsone poisoning are haemolytic

anaemia, agranulocytosis, peripheral neuropathy and hepatitis.

2.4 First aid measures and management principles

Patients with acute dapsone poisoning should be admitted to an

intensive care unit.

Monitor respiration, blood pressure and urine output.

Treatment may include:

Gastric lavage or emesis

Repeated oral activated charcoal

Oxygen therapy and antidotes (methylene blue) for

methaemoglobinaemia

Haemodialysis in severe cases.

Dapsone toxicity is due both to the parent drug and its

metabolites. Therefore aggressive therapy may be indicated to

enhance elimination of dapsone and its metabolites when

features of severe poisoning persist despite adequate

supportive, antidotal and charcoal therapy.

  1. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Synthetic

Manufacturing : Reaction of excess sodium sulfide with 1-

chloro-4-nitrobenzene followed by acetylation, oxidation with

hydrogen peroxide, reduction and acidic or basic hydrolysis;

amination of bis(4-chlorophenyl) sulfone.

3.2 Chemical structure

4,4′-Sulfonylbisbenzeneamine; 4,4′-sulfonyldianiline; bis(4-

aminophenyl)sulfone; 4,4′-diaminodiphenyl sulfone.

C12H12N2O2S

3.3 Physical properties

3.3.1 Properties of the substance

Dapsone is a white or slightly yellowish-white,

odourless, crystalline powder with a slightly

bitter taste. Dapsone is practically insoluble

in water (1 in 7000 of water), soluble in

alcohol (1 in 30), methanol and freely soluble

in acetone.  Dapsone is also soluble in diluted

hydrochloric acid (Reynolds & Prasad, 1982).

 

Melting point: 175 – 176° C

also a higher melting form, m.p. 180.5°

3.3.2 Properties of the locally available formulation

To be completed

3.4 Other characteristics

3.4.1 Shelf-life of the substance

To be completed

3.4.2 Shelf-life of the locally available formulation

To be completed

3.4.3 Storage conditions

Protect from light

3.4.4 Bioavailability

To be completed

3.4.5 Specific properties and composition

To be completed

  1. USES

4.1 Indications

Dapsone is the drug of choice for the treatment of

dermatitis herpetiformis.  It is an antibacterial drug used in

the treatment of leprosy.  Dapsone has also been used in malaria

prophylaxis and in the treatment of relapsing polychondritis,

Pneumocystis carinii pneumonia, Kaposi’s sarcoma and various other

dermatoses.  It is also used in veterinary medicine.

Veterinary medicine: in streptococcal mastitis and coccidiosis of

cattle.  Topically in infectious keratitis of cattle and sheep and

otitis externa of dogs.  Used experimentally to suppress

toxoplasmosis in swine.

Former use (non pharmaceutical) : hardening agent for epoxy resins.

4.2 Therapeutic dosage

4.2.1 Adults

Leprosy: 50 to 100 mg per day (6 to 10 mg/kg per week).

Treatment may be continued for several years.

Dermatitis herpetiformis: 100 to 300 mg per day.

4.2.2 Children

Leprosy: 6 to 10 mg/kg per week

4.3 Contraindications

Hypersensitivity to dapsone.  Dapsone should be administered

with caution in patients with renal or hepatic failure and in

patients with glucose-6-phosphate dehydrogenase deficiency.

Dapsone levels are influenced by acetylation rates. Patients

with genetically determined slow acetylation rates, or who are

receiving treatment affecting acetylation, may require an

adjustment in dosage.

  1. ROUTES OF ENTRY

5.1 Oral

This is the only route of exposure.

5.2 Inhalation

No data available.

5.3 Dermal

No data available.

5.4 Eye

No data available.

5.5 Parenteral

No data available.

5.6 Other

No data available.

  1. KINETICS

6.1 Absorption by route of exposure

70 to 80% of a single oral dose of 100 mg is absorbed (Zuidema

et al., 1986) and most is recovered in the urine (Israili et

al., 1973).  The maximum plasma concentration is reached

within 3 – 6 hours.

6.2 Distribution by route of exposure

70 to 80% is bound to plasma proteins (Zuidema et al., 1986).

Dapsone is widely distributed with concentrations in most

organs similar to plasma concentrations.

The apparent volume of distribution is 0.5 to 1 L/kg (Gelber

et al., 1971). Red cell concentrations are higher than those

in plasma (Scholer et al., 1984).  Dapsone crosses the

placenta (Zuidema et al., 1986).

6.3 Biological half-life by route of exposure

Plasma half-lives range between 21 and 30 hours (Gelber et al.,

1971). Zuidema et al (1986) reported a mean elimination half-

life of 30 hours (range: 14 to 83 hours) with a clearance of

about 0.038 L/kg/hr.

 

The following half-lives of dapsone were reported after

overdose:

 

Authors                 Dose ingested  Plasma

(g)         half-life (h)

——————————————————

 

Woodhouse et al., 1983      2.5          29.8

Neuvonen et al., 1983       7           109

70            88

1            33

Berlin et al., 1984        15            24

——————————————————

6.4 Metabolism

The principal metabolite in plasma is mono-N-acetyl dapsone,

which is 97 to 100% bound to plasma proteins and has an

elimination half-life of 30.5 hours. The proportion of this

metabolite in plasma is dependent on the acetylator phenotype.

The dapsone/mono-N-acetyl dapsone ratio is about 1 in slow

acetylators and about 0.2 in rapid acetylators (Gelber et al.,

1971).

 

Another metabolic pathway is the N-oxidation of dapsone to 4-

amino-4′-hydroxamine-diphenylsulphone.  This metabolite may be

responsible for the haematological toxicity in overdose

(Zuidema et al., 1986).

 

The kinetics of the main metabolite, mono-N-acetyl dapsone

(MADDS) after overdose have been reported:

 

Authors                Dapsone ingested    MADDS T1/2 (h)

———————————————————

Woodhouse et al., 1983         2.5           29.9

Neuvonen et al., 1983          7             50.0

10             70.0

1             33.8

———————————————————

6.5 Elimination by route of exposure

After oral exposure the drug is eliminated mainly by kidneys.

 

Kidney:  Urinary excretion is the main route of elimination

and 20% of the drug is excreted unchanged and 80% as

derivatives, namely 20% glucuronide, 1.5% mono-N-acetyl, 1.5%

mono-acetyl glucuronide and 57% sulphamate derivatives

(Scholer et al., 1984).

 

Faeces:  Only minor amounts of dapsone are excreted in faeces

(Zuidema et al., 1986).

 

Bile:  10% of an oral dose was found in the bile (Lang,1979).

 

Breast-milk:  Dapsone is excreted in breast milk (Sanders et

al., 1982; Zuidema et al., 1986).

  1. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

Dapsone produces methaemoglobinaemia by oxidizing the

iron in haemoglobin from its ferrous to its ferric form.

This renders haemoglobin unable to carry oxygen to

tissues. Furthermore, haemolysis and changes in oxygen

affinity may occur, increasing the toxic symptoms more

than would be expected from the methaemoglobin

concentrations alone (Jaeger et al., 1987). The

 

hydroxylated metabolite of dapsone, T-amino-4′-

hydroxamine-diphenylsulphone, is probably responsible

for methaemoglobinaemia and haemolysis (Israili et 1973;

Zuidema et al., 1986).

 

In vitro, this metabolite forms methaemoglobin (Kramer

et al., 1972) and induces haemolysis (Glader 1973). In

vitro, it generates hydrogen peroxide (Weetman et al,

1980) and depletes cellular glutathione (Glader 1973;

Weetman et al., 1980). However, this metabolite has not

been detected in plasma of patients receiving dapsone.

7.1.2 Pharmacodynamics

The mechanism of the bacteriostatic action of dapsone is

probably similar to that of the sulphonamides as both

are inhibited by para-aminobenzoic acid (Lang, 1979).

Dapsone is bacteriostatic against Mycobacterium leprae.

It is also active against Plasmodium spp. In the mouse,

the minimum inhibitory concentration for M. leprae is

less than 10 mcg/l. In man, it has been estimated to be

up to 30 mcg/l. (Reynolds, 1989).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

The toxic dose of dapsone is close to its

therapeutic dose.  Severe poisonings have been

observed after doses of 1 g in adults (Neuvonen

et al., 1983). Recovery without sequelae has

been reported in adults after ingestion of doses

up to 15 g (Berlin et al., 1985).

7.2.1.2 Children

The toxic dose of dapsone is close to its

therapeutic dose.  Severe poisonings have been

observed after doses of 100 mg in children

(Reigart et al., 1982). Sturt (1967) reported a

fatal poisoning in a 16-year-old boy who

developed methaemoglobinaemia, jaundice,

haematuria and coma after ingestion of 1.46 g.

7.2.2 Relevant animal data

Oral rat : LDLo: 1000 mg/kg

Oral rat : TDLo: 20 mg/kg

Oral mouse : LD50: 496 mg/kg  (NIOSH)

7.2.3 Relevant in vitro data

No data available.

7.3 Carcinogenicity

There are no case reports of carcinogenicity in humans. In

experimental animals dapsone has been shown to be carcinogenic

at doses much larger than those used therapeutically (Lang

1979).

7.4 Teratogenicity

No teratogenicity has been reported

7.5 Mutagenicity

No data available

7.6 Interactions

Probenecid increases serum dapsone levels by reducing the

renal elimination of dapsone and its metabolites (Goodwin and

Sparell 1969).

Rifampicin lowers dapsone serum levels 7- to 10-fold by

accelerating plasma clearance.

Folic acid antagonists such as pyrimethamine and primaquine

may increase the likelihood of haematologic reactions.

7.7 Main adverse effects

The following adverse effects after therapeutic doses have

been reported: (Dukes 1976-1984, Drugdex 1990).

Blood – agranulocytosis, haemolytic anaemia,

methaemoglobinaemia, pseudoleukaemia, aplastic anaemia,

mononucleosis with lymphadenopathy

Nervous system –    psychosis, peripheral neuropathy

Kidney – acute renal failure following intravascular

haemolysis, nephrotic syndrome, renal papillary necrosis

Liver – hepatitis and jaundice with increased levels of

transaminases

Skin – exfoliative dermatitis, toxic erythema, erythema

multiforme, urticaria, erythema nodosum

Hypersensitivity reactions – leprotic reactions may occur in

leprosy if the low initial dose is increased too rapidly.

  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

Symptoms may appear from a few minutes to 24 hours

following ingestion. Methaemoglobinaemia is the

principal feature of dapsone poisoning. Clinical

symptoms may include: headache, dizziness, agitation,

restlessness, nausea, vomiting, abdominal pain, bluish-

grey cyanosis, tachycardia, hyperventilation, stupor,

convulsions, coma, jaundice, and intravascular

haemolysis.

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

No data available.

9.2 Chronic poisoning

9.2.1 Ingestion

Haemolytic anaemia and agranulocytosis may occur at the

relatively low doses used for leprosy and malaria,

whereas peripheral neuropathy and hepatitis are only

observed at the higher doses used in the treatment of

dermatitis herpetiformis (Scholer et al., 1984).

Deficiency in glucose-6-phosphate dehydrogenase, and

combination with primaquine are predisposing factors for

the occurrence of haemolytic anaemia, and concurrent

therapy with primaquine may be associated with

agranulocytosis (Chernof, 1967; Hutchinson et al.,

1986).

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 exposure

No data available.

9.2.6 Other

No data available.

9.3 Course, prognosis, cause of death

Methaemoglobinaemia may last for up to 10 days. Haemolysis is

usually delayed but it may persist for 14 days, returning to

normal within 3 to 4 weeks.

With adequate treatment the prognosis is usually good, but a

death has been reported (Sturt 1967).

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Acute

 

Tachycardia and hypotension may be observed and are

secondary to the hypoxaemia following

methaemoglobinaemia (Lambert et al., 1982; Berlin et al.,

1985; Neuvonen et al., 1983).

 

Chronic: No data available.

9.4.2 Respiratory

Acute

 

Tachypnoea and hyperventilation may occur (Lambert et

al., 1982; Berlin et al., 1984).

 

Cyanosis is due to methaemoglobinaemia

 

Chronic: No data available.

9.4.3 Neurological

9.4.3.1 CNS

Headache, dizziness, restlessness, agitation and

confusion are common in moderately severe acute

poisonings.  In severe poisoning, uncoordinated

movements, stupor, convulsions and coma have

been reported (Schvartsman 1979;

Sturt 1967; Woodhouse et al., 1983).  Psychosis

has been reported during therapeutic use (Lang

1979).

9.4.3.2 Peripheral nervous system

Sirsat et al (1987) reported three cases of

motor neuropathy following acute ingestion.

 

Peripheral motor neuropathy may develop in

patients treated for several years at doses of

300 mg/day or greater (Snavely and Hodges 1984).

Slow acetylators are more likely to develop

neuropathy.

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

Acute

 

 

Nausea, vomiting and abdominal pain are usually the

first signs which appear.

 

Chronic: No data available.

9.4.5 Hepatic

Acute

 

Jaundice, elevated bilirubin and moderate increase of

transaminases have been reported (Berlin et al., 1984;

Sturt 1967).

 

Chronic

 

Jaundice and an increase of transaminases may occur

(Scholer 1984; Johnson et al., 1986).

9.4.6 Urinary

9.4.6.1 Renal

Acute: Haematuria has been reported (Sturt

1967).

 

Chronic

 

Acute renal failure secondary to intravascular

haemolysis has been reported after therapeutic

doses in two patients (Chugh et al., 1977).  One

case each of nephrotic syndrome (Hoffbrand 1978)

and renal papillary necrosis have been reported

(Belmont 1967).

9.4.6.2 Other

No data available.

9.4.7 Endocrine and reproductive systems

No data available

9.4.8 Dermatological

Acute

 

Blue-grey cyanosis is due to methaemoglobinaemia

 

Chronic

 

Several dermatological reactions have been observed.

They were: exfoliative dermatitis, toxic erythema,

erythema multiforme, urticaria, and erythema nodosum.

9.4.9 Eye, ear, nose, throat: local effects

No data available.

9.4.10 Haematological

Acute

 

Methaemoglobinaemia is the principal and consistent

feature of dapsone poisoning. Pronounced

methaemoglobinaemia exceeding 50 to 60% is associated

with serious clinical features (Schvartsman 1979);

haemolysis is usually severe in such cases. Cyanosis

and methaemoglobinaemia may persist for 8 to 10 days

following ingestion (Elonen et al., 1979; Lambert et

al., 1982; Neuvonen et al., 1983; Stanfield 1963).

 

 

The following levels of methaemoglobin have been

reported:

 

Authors             Dose ingested  Methaemoglobin (%)

(g)

 

Reigart et al., 1983      0.1                 27

Lambert et al., 1983      3                   41.5

Berlin et al., 1984      15                   48

Neuvonen et al., 1983     7                   62

10                   36

1                   45

Woodhouse et al., 1983    2.5                 22

 

 

Methaemoglobin levels correlate well with symptoms in

most cases (Hall et al., 1986):

 

15-20% clinical cyanosis, patient usually asymptomatic

20-45% headache, lethargy, dizziness, syncope, dyspnoea

45-55% increasing CNS depression

55-70% coma, convulsions, shock

> 70%  high mortality

 

Haemolytic anaemia with Heinz bodies and

teticulocytosis is common in cases with severe

methaemoglobinaemia (Lambert et al., 1982; Berlin et

al., 1984; Neuvonen et al., 1983). Low haptoglobin and

elevated unconjugated bilirubin have been observed

(Lambert et al., 1982). Usually laboratory evidence

indicating haemolysis is apparent after 2 – 3 days and

reaches a maximum in 7 – 14 days after ingestion, the

evidence of haemolysis disappears within 3 – 4 weeks

(Neuvonen et al., 1983).

 

Sulphaemoglobinaemia has been reported in a 22-year-old

man after an acute overdose with 3 g of dapsone.

Sulphaemoglobinaemia was maximal (9%) between days 4

and 8 (Lambert et al., 1982).

 

Chronic

 

Methaemoglobinaemia is also a frequent toxic side

effect during dapsone treatment and has been observed

in patients treated for malaria prophylaxis with 25

mg/day (Willerson et al., 1972). The incidence of

methaemoglobinaemia is even much higher when dapsone is

used in large doses in the treatment of leprosy or

dermatitis herpetiformis (Scholer et al., 1984).

 

Haemolytic anaemia is dose related but may occur with

the relatively low doses used for leprosy and malaria

(Scholer et al., 1984).

 

Agranulocytosis, neutropenia and thrombocytopenia have

 

also been reported (Leoung et al., 1986; Potter et al.,

1989).

 

Deficiency in glucose-6-phosphate dehydrogenase, and

combination with primaquine are predisposing factors

for the occurrence of haemolytic anaemia and concurrent

therapy with primaquine may cause agranulocytosis

(Chernof 1967; Hutchinson et al., 1986).

9.4.11 Immunological

Acute: No data available.

 

Chronic

 

Hypersensitivity reaction may be observed

 

Sulfone syndrome : this is a hypersensitivity reaction

which includes fever, malaise, exfoliative dermatitis,

jaundice with liver necrosis, lymphadenopathy,

methaemoglobinaemia, and anaemia (Allday and Baines,

1951).

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Acute

 

Respiratory alkalosis or metabolic acidosis

with impaired oxygenation has been reported

(Berlin et al., 1984; Reigart et al., 1982).

9.4.12.2 Fluid and electrolyte disturbances

No data available.

9.4.12.3 Others

No data available.

9.4.13 Allergic reactions

Acute:  No data available.

 

Chronic

 

Hypersensitivity reactions may be observed. They

include: exfoliative dermatitis, toxic erythema,

erythema multiforme, urticaria, erythema nodosum.

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

Pregnancy:     Overdose of dapsone during pregnancy has

not been reported. The fetus may be at risk because of

the hypoxemia due to methaemoglobinaemia and

haemolysis.

 

Breast feeding: Two cases of neonatal haemolytic

anaemia presumed to be due to dapsone in breast milk

have been reported (Zuidema et al., 1986).

 

Enzyme deficiencies: Deficiency in glucose-6-phosphate

dehydrogenase is a predisposing factor for the

occurrence of haemolytic anaemia (Chernof, 1967).

9.5 Other

No data available.

 

9.6 Summary

  1. MANAGEMENT

10.1 General principles

Patients with acute dapsone poisoning should be admitted to

an intensive care unit.

 

Monitor respiration, blood pressure and urine output.

 

Treatment may include:

 

Symptomatic measures, especially oxygen therapy

Gastric lavage or emesis. Repeated oral activated charcoal

Antidotes for methaemoglobinaemia: methylene blue

 

Haemodialysis may be considered in severe cases.

 

Given that dapsone toxicity is not only related to the

parent drug but also to its metabolites, aggressive therapy

in order to enhance elimination of dapsone and its

metabolites may be indicated when severe poisoning persists

despite adequate supportive, antidotal and charcoal therapy.

 

Patients may require several days of observation.

10.2 Relevant laboratory analyses

10.2.1 Sample collection

Collect blood and urine for analysis.

10.2.2 Biomedical analysis

The most relevant investigation in dapsone poisoning

is methaemoglobinaemia which correlates well with

symptoms.  The level of methaemoglobin should be

monitored.

 

Other relevant laboratory analyses : blood count,

reticulocytes, haptoglobin, bilirubin, plasma

haemoglobin, sulphaemoglobin, transaminases, arterial

blood gases.

 

Urine analysis

10.2.3 Toxicological analysis

Dapsone plasma concentrations higher than 10 mg/l are

likely to be associated with features of

methaemoglobin-aemia. Therapeutic plasma levels are 1-

3.5 mg/l.

 

Monitoring of dapsone serum concentrations is not

necessary for treatment unless haemodialysis is

contemplated.

 

In acute poisoning, dapsone plasma concentrations of

10-150 mg/l have been reported (Berlin et al., 1985;

Elonen et al., 1979; Neuvonen et al., 1983; Woodhouse

et al., 1983).

 

Table: plasma concentrations of dapsone following

acute overdose

 

 

Authors               Age  Dose ingested  Dapsone

conc

(year) (g)       (mg/ml)

 

Berlin et al., 1984     2          15.0        80.0

Neuvonen et al., 1983  27           7.0        28.0

45          10.0        23.6

21           1.0        17.5

Endre et al., 1983                  4.0        22.3

Elonen et al., 1979  child ?                  150.0

child ?                   73.0

Szajewski et al.,1979  18          10.0        12.0

Linakis et al., 1989                3.5         3.9

Woodhouse et al., 1983 57           2.5        18.8

10.2.4 Other investigations

No data available.

10.3 Life supportive procedures and symptomatic/specific

treatment

Monitor blood pressure, respiration and urine output.

Oxygen therapy is indicated if there are clinical signs of

methaemoglobinaemia.

 

Methylene blue is indicated when methaemoglobinaemia is

present. A dose of 1 to 2 mg/kg intravenously is

administered over a few minutes and may be repeated every 4

hours as needed. Because of the relapsing course of

methaemoglobinaemia due to the long half-life of dapsone,

repeated administration of methylene blue is sometimes

necessary (Berlin et al., 1984, Elonen et al., 1979, Lambert

et al., 1982). Berlin et al, (1984) recommended continuous

administration of methylene blue in order to avoid

overdosage. Monitoring of methaemoglobin is mandatory for

adjustment of the infusion rates: cyanosis is an unreliable

guide especially when anaemia is also present and methylene

blue may cause a bluish-grey discoloration of the skin

(Berlin et al., 1984). Methylene blue therapy should be

continued until the methaemoglobin level is below 10%.

 

Supportive measures include treatment of respiratory failure,

shock, acid-base disturbances, and convulsions.

10.4 Decontamination

Gastric lavage is indicated in recent ingestion, up to 6

hours.

 

Repeated doses (20 g 4 times a day) of oral activated

charcoal are indicated because it enhances the total body

clearance and elimination of dapsone and its principal

metabolite, monoacetyldapsone. In patients receiving

therapeutic dosages of dapsone, the mean serum half-life was

decreased from 20.5 to 10.8 hours by charcoal (Neuvonen et

al., 1983). In three intoxicated patients, activated

charcoal decreased the mean dapsone and monoacetyldapsone

half-lives from 77 to 12.7 hours and from 51 to 13.3 hours,

respectively (Neuvonen et al., 1983). In these patients

charcoal did not prevent the primary absorption of dapsone,

but increased the elimination rates of dapsone and

 

monoacetyldapsone by adsorbing drugs secreted into the

gastrointestinal tract.

10.5 Elimination

Forced diuresis

 

No data indicating the benefit of forced diuresis are

available. However, in one case of poisoning with 15 g of

dapsone, 20% of the amount ingested was excreted in urine

(Berlin et al., 1984).

 

Haemodialysis

 

Haemodialysis removes dapsone from the body. In one patient

who had ingested 7 g dapsone, haemodialysis decreased the

half-life of dapsone from 109 to 10.4 hours and the half-

life of monoacetyldapsone from 50 to 10.9 hours (Neuvonen et

al., 1983). Szajewski et al, (1972) reported  a case of

severe dapsone poisoning in which haemodialysis was

successful with rapid correction of methaemoglobinaemia. In

these 2 patients a subsequent rebound of plasma dapsone

concentrations was observed.

 

Haemoperfusion

 

Endre et al (1983) reported a case of successful treatment

using charcoal haemoperfusion.

 

Plasma exchange

 

Berlin et al (1984) treated a patient with plasma exchange.

Five plasma exchanges were performed on days 3 to 7 with a

total of 15.5 l. plasma exchanged. Only 2% of the amount

ingested was removed by plasma exchange.

 

Exchange transfusion

 

Exchange transfusion has also been suggested (Schvartsman

1979; Stanfield 1963). Because of the low volume which can

be exchanged, this therapy is ineffective for drug removal.

However, it may be indicated when severe intravascular

haemolysis is associated with methaemoglobinaemia (Jaeger et

al., 1987).

10.6 Antidote treatment

10.6.1 Adults

There is no specific antidote.

10.6.2 Children

There is no specific antidote.

10.7 Management discussion

Given that dapsone toxicity is not only related to the

parent drug but also to its metabolites, aggressive therapy

in order to enhance the elimination of dapsone and its

metabolites may be indicated when severe poisoning persists

despite adequate supportive, antidotal and charcoal therapy.

 

After a bolus dose of methylene blue (1 to 2 mg/kg), a

continuous infusion at an initial rate of 0.1 to 0.5 mg/kg

 

has been recommended. The dose of methylene blue should be

titrated against the concentration of methaemoglobin (Dawson

and White, 1989)

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

Lambert et al (1979) reported a case of acute poisoning in a

22 year-old man who had ingested 3 g dapsone and developed

headache, dizziness, nausea, bluish-grey cyanosis and

methaemoglobinaemia (41.5%). Methaemoglobinaemia improved

with methylene blue. Subsequently, significant

sulphaemoglobinaemia (9% from day 4 to day 8) caused

prolonged cyanosis and mild haemolytic anaemia.

 

An 18 month-old child developed methaemoglobinaemia (27%)

after ingestion of 100 mg dapsone. Activated charcoal was

administered orally (10 g every 6 hours). Treatment included

1 mg/kg methylene blue; the methaemoglobin level was 2.3%,

66 hours after ingestion (Reigart et al., 1982).

 

A 57 year-old man was admitted 20 hours after ingestion of

2.5 g dapsone. Examination showed cyanosis with a

methaemoglobinaemia of 22% and an anaemia of 11.5 g/l

haemoglobin. The methaemoglobin level fell to 1% over 7 days

without specific treatment. The kinetics of dapsone and

monoacetyldapsone showed half-lives of 29.7 and 29.9 hours

respectively (Woodhouse et al., 1983).

 

Neuvonen et al (1983) reported 3 cases of dapsone poisoning

in adults with doses of 7, 10 and 1 g, respectively, and

methaemoglobin concentrations of 36 – 62%. The elimination

half-lives were 109, 88 and 33 hours (mean 77) for dapsone

and 50, 70, and 33.8 hours (mean 51) for monoacetyldapsone.

With activated charcoal treatment, the plasma half-life was

12.7 hours for dapsone and 13.3 hours for monoacetyldapsone.

One patient underwent haemodialysis three times. During

haemodialysis, plasma half-lives of dapsone and

monoacetyldapsone decreased from 109 to 10.4 hours and from

50 to 10.9 hours, respectively.

 

Berlin et al (1984) described a 28-year-old man who ingested

15 g dapsone and developed a methaemoglobin level of 50%.

The dapsone concentration rose to a peak of 80 mg/l on the

second day and then decreased with a half-life of 24 hours.

The patient was treated with activated charcoal, forced

diuresis and plasma exchange (5 exchanges on days 3 to 7

with a total of 15.5 l plasma exchanged. Of the amount

ingested, 25% was recovered in urine and only 2% was removed

by plasma exchange.

11.2 Internally extracted data on cases

To be added by the centre.

11.3 Internal cases

To be added by the centre.

  1. Additional information

12.1 Availability of antidotes

No antidote is available.

12.2 Specific preventive measures

 

No data available.

12.3 Other

No data available.

  1. REFERENCES

Belmont A (1967). Dapsone-induced nephrotic syndrome. Journal of

American Medical Association 200:262-263.

 

Berlin G, Brodin B, Hilden JO, Märtensson J (1984). Acute dapsone

intoxication: a case treated with continuous infusion of

methylene blue, forced diuresis and plasma exchange. Clinical

Toxicology 22:537-548.

 

Chernof D (1967). Dapsone-induced haemolysis in G6PD deficiency.

Journal of the American Medical Association 201:122-125.

 

Chugh KS et al (1977). Acute renal failure due to intravascular

haemolysis in the North indian patients. American Journal of

Medical Science 274:139-146.

 

Cooke TJL (1970). Dapsone poisoning. Medical Journal of Australia

23:1158-1159.

 

Davies R (1950). Fatal poisoning with undolac (diaminodiphenyl-

sulphone). Lancet 1:905-906.

 

Dawson AH & Whyte IM (1989). Management of dapsone poisoning

complicated by methaemoglobinaemia. Medical Toxicology and

Adverse Drug Exp. 4: 387 – 392.

 

Dukes MNG (1976-84). Side effects of drugs. Excerpta Medica.

 

Ellenhorn MJ, Barceloux DF (1988). Diagnosis and treatment of

human poisoning. Medical Toxicology, Elsevier, New York, pp. 353-

358

 

Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ (1979). Acute

dapsone intoxication: a case with prolonged symptoms. Clinical

Toxicology 14:79-85.

 

Endre ZH, Charlesworth JA, MacDonald GJ, Woodbridge L (1983).

Successful treatment of acute dapsone intoxication using charcoal

hemoperfusion. Australia and New Zealand Journal of Medicine

13:509-512.

 

Gelber R, Peters JH, Gordon GR, Glazko AJ, Levy L (1971). The

polymorphic acetylation of dapsone in man. Clinical Pharmacology

and Therapeutics 12:225-238.

 

Glader BE (1973). Haemolysis by diphenylsulphones : comparative

effects of DDS and hydroxylamine D. Journal of Laboratory and

Clinical Medicine 81:267:272.

 

Goodwin CS and Sparell G (1969). Inhibition of dapsone excretion

by probenecid. Lancet 2:884-885.

 

Hall AH, Kulig KW, Rumack BH (1986). Drug-and chemical-induced

 

methaemoglobinaemia. Medical Toxicology 1:253-260.

 

Hoffbrand BI (1978). Dapsone and renal papillary necrosis.

British Medical Journal 1:78.

 

Hutchinson DBA, Whiteman PD, Farquhar JAV (1986). Agranulocytosis

associated with Maloprim : review of cases. Human Toxicology

5:221-227.

 

Israili ZH, Cucinel SA, Vaught J, Davis E, Lesser JM et al

(1973). Studies of the metabolism of dapsone in man and

experimental animals : formation of N-hydroxy metabolites.

Journal of Pharmacology and Experimental Therapeutics 187:138-

151.

 

Jaeger A, Sauder P, Kopferschmitt J, Flesch F (1987). Clinical

features and management of poisoning due to antimalarial drugs.

Medical Toxicology 2:242:273.

 

Kramer PA, Glader BE, Li TK (1972). Mechanism of methaemoglobin

formation by diphenylsulphones:effects of 4-amino-4’hydroxy-

aminodiphenylsulphone and other p-substituted derivatives.

Biochemical Pharmacology 21:1265-1274.

 

Lambert M, Sonnet J, Mahieu P, Hassoun A (1982). Delayed

sulfhemoglobinemia after acute dapsone intoxication. Journal of

Toxicology, Clinical Toxicology 19:45-50.

 

Lang PG (1979). Sulfones and sulfonamides in dermatology today.

Journal of American Academy of Dermatology 1:479-492.

 

Lee BL, Medina I, Benowitz NL et al (1989). Dapsone, trimethoprim

and sulfamethoxazole plasma levels during treatment of

pneumocystis pneumonia in patients with acquired immunodeficiency

syndrome (AIDS). Annals of Internal Medicine 110:606-611.

 

Leoung GS, Mills J, Hopewell PC et al (1986). Dapsone-

trimethoprim for pneumocystis carinii pneumonia in the acquired

immunodeficiency syndrome. Annals of Internal Medicine 105: 45-

48.

 

Linakis JG, Shannon M, Woolf A et al (1989). Recurrent

methemoglobinemia after acute dapsone intoxication in a child. J

Emerg Med, 7, 477-480,

 

Manfredi G, de Panfilis G, Zampetti M, Allegra F (1979) Studies

on dapsone induced haemolytic anaemia. British Journal of

Dermatology 100:427.

 

Neuvonen PJ, Elonen E, Haapanen EJ (1983). Acute dapsone

intoxication: clinical findings and effect of oral charcoal and

haemodialysis on dapsone elimination. Acta Medica Scandinavica

214:215-220.

 

Pengelly CD (1963). Dapsone-induced haemolysis. British Medical

Journal 246:660-664.

 

 

Potter MN, Yates P, Slade R et al (1989). Agranulocytosis caused

by dapsone therapy for granuloma annulare. Journal of American

Academic Dermatology 20:87-88.

 

Reigart JR, Harold LT, Lindsey JM (1982). Repetitive doses of

activated charcoal in dapsone poisoning in a child. Journal of

Toxicology, Clinical Toxicology, 19:1061:1066.

 

Reynolds JEF and Prasad AB (eds.) (1982). Martindale, The Extra

Pharmacopoeia, 28th ed. The Pharmaceutical Press, London, pp.

1489-1492.

 

Reynolds JEF ed (1989). Martindale, The Extra Pharmacopoeia, 29th

  1. London, The Pharmaceutical Press.

 

Sanders SW, Zone JJ, Foltz RL et al (1982). Hemolytic anemia

induced by dapsone transmitted through breast milk. Annals of

Internal Medicine 96: 465-466.

 

Scholer HJ, Leimer R, Richle R (1984). Sulphonamides and

sulphones. Handbook of Experimental Pharmacology 68:123-206.

 

Schvartzman S (1979). Sulfone methemoglobinemia. Clinical

Toxicology 15:468.

 

Sirsat AM, Lalitha VS, Pandya SS (1987). Dapsone neuropathy-

report of three cases and pathologic features of a motor nerve.

International Journal of Leprosy 55:23-29.

 

Snavely SR and Hodges GR (1984). The neurotoxicity of

antibacterial agents. Annals of Internal Medicine 101:92-104.

 

Szajewski JM, Dorywalski T, Tomecka Z et al (1972). Przypadek

cieskiego zatrucia preparatem przoeiwtradowym

dwuaminodwufenylsulfonem (DDS). Pol Arch Med Wewn ,49, 181-186.

 

Stanfield JP (1963). A case of acute poisoning with dapsone.

Journal of Tropical Medicine and Hygiene 66:292-295.

 

Sturt J (1967). Too much of a good thing. Papua New Guinea

Medical Journal 10:97.

 

Weetman RM, Boxer LA, Brown MP, Mantich NM, Baehner RL (1980). In

vitro inhibition of granulopoeisis by 4-amino-4’hydroxylamino-

diphenylsulphone. British Journal of Haematology 45:361-370.

 

Willerson D, Rieckmann KH, Kass L, Carson PE, Frischer H et al

(1972). The chemoprophylactic use od fiformyldiamino-

diphenylsulfone (DFD) in falciparum malaria. American Journal of

Tropical Medicine Hygiene 21:138:143.

 

Woodhouse KW, Henderson DB, Charlton B, Peaston RT, Rawlins MD

(1983). Acute dapsone poisoning : clinical features and

pharmacokinetic studies. Human Toxicology 3:507-510.

 

 

Zuidema J, Hilbers-Modderman ESM and Merkus FWHM (1986). Clinical

pharmacokinetics of dapsone. Clinical Pharmacokinetics 11:299-315.

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

ADDRESS(ES)

Author:   J. Higa de Landoni

Jefa Seccion Toxicologia

Hospital de Clinicas “Jose de San Martin”

 

Reviewed and rewritten:

 

Drs A. Jaeger, P. Sauder, J. Kopferschmitt, F. Flesch

Service de Reanimation Medicale

et Centre Anti-poisons

Hospice Civil de Strasbourg

 

Date:          January 1991

Peer Review: Newcastle-upon-Tyne, United Kingdom, January 1991

Review:   IPCS, May 1993

 

See Also:

Dapsone (IARC Summary & Evaluation, Supplement 7, 1987)

Dapsone (IARC Summary & Evaluation, Volume 24, 1980)

 

Ethambutol

  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

1.7 Presentation, Formulation

  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 Properties of the substance

3.3.1.1 Colour

3.3.1.2 State/Form

3.3.1.3 Description

3.3.2 Properties of the locally available formulation(s)

3.4 Other characteristics

3.4.1 Shelf-life of the substance unknown

3.4.2 Shelf-life of the locally available formulation(s)

3.4.3 Storage conditions

3.4.4 Bioavailability

3.4.5 Specific properties and composition

  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 ENTRY

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 Sample

8.1.1 Collection

8.1.2 Storage

8.1.3 Transport

8.2 Toxicological analytical methods

8.2.1 Test for active ingredient

8.2.2 Test for biological analyses

8.3 Other laboratory analyses

8.3.1 Haematological investigations

8.3.2 Biochemical investigations

8.3.2.1 Blood

8.3.2.2 Urine

8.3.3 Arterial blood gas analysis

8.3.4 Other relevant biomedical analyses

8.4 Interpretation

8.5 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 systems

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 Hematological

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 Relevant laboratory analyses

10.2.1 Sample collection

10.2.2 Biomedical analysis

10.2.3 Toxicological analysis

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific treatment

10.4 Decontamination

10.5 Elimination

10.6 Antidote treatment

10.6.1 Adults

10.6.2 Children

10.7 Management discussion

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

11.2 Internally extracted data on cases

11.3 Internal cases

  1. ADDITIONAL INFORMATION

12.1 Availability of antidotes

12.2 Specific preventive measures

12.3 Other

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

 

  1. NAME

 

1.1  Substance

 

Ethambutol               (INN)

 

(WHO, 1992)

 

1.2  Group

 

ATC classification index

 

Antimycobacterials (J04)/

Drugs for treatment of tuberculosis (J04A)/

Other drugs for treatment of tuberculosis (J04AK)

 

(WHO, 1992)

 

1.3  Synonyms

 

CL-40881

 

(Reynolds, 1993)

 

(To be completed by each Centre using local data)

 

1.4  Identification numbers

 

1.4.1                 CAS number

 

Ethambutol                 74-55-5

 

Ethambutol hydrochloride   1070-11-7

 

1.4.2            Other numbers

 

RTECS            EL3640000

 

1.5  Brand names, Trade names

 

Ethambutol (Argentina); Myambutol (Australia, Belgium,

Canada, Denmark, France, Germany, Netherlands, South Africa,

Spain, Sweden, Switzerland, UK, USA)

 

Mynah (UK)

 

Etibi (Canada)

 

Dexambutol (France)

 

EMS-Fasol (Germany)

 

Etambutyl, Etapiam, Miambutol, Mycobutol and Tibutolo (Italy)

 

Afimocil, Anvital, Cidanbutol, Etambin, Farmabutol, Fimbutol,

Inagen and Tisiobutol (Spain).

 

(To be completed by each Centre using local data)

 

1.6  Manufacturers, Importers

 

Northia (Argentina), Lederle (UK, both Myambutol and Mynah).

 

(To be completed by each Centre using local data)

 

1.7  Presentation, Formulation

 

Myambutol is available as powder (50 g per bottle) and

as tablets of 100 and 400 mg; Mynah is available as tablets

containing ethambutol and isoniazid.  Mynah 200, Mynah 250,

Mynah 300 and Mynah 365 contain 200, 250, 300 and 365 mg of

ethambutol hydrochloride respectively, with 100 mg of

isoniazid.

 

(To be completed by each Centre using local data)

 

  1. SUMMARY

 

2.1  Main risks and target organs

 

During chronic treatment ethambutol may produce visual

and neurological disturbances, allergic reactions,

gastrointestinal symptoms, psychiatric symptoms and transient

impairment of liver function.  This last event has a very low

incidence.

 

Increased serum uric acid levels and acute gouty arthritis

have been reported.

 

2.2  Summary of clinical effects

 

Acute overdosage may cause gastrointestinal symptoms,

hallucinations and optic neuritis.  Acute overdosage symptoms

include nausea, abdominal pain, fever, mental confusion,

visual hallucinations, and optic neuropathy (retrobulbar

neuritis) with doses over 10 g.

 

The effects of overdosage are not well established.  During

chronic treatment the following have been reported:

 

Visual disturbances

 

Ethambutol may produce a reduction of visual acuity which

appear to be due to optic neuritis.  Central scotoma and

green-red colour blindness may also occur.

 

Allergic reactions

 

Rash, anaphylactoid reactions, dermatitis, pruritus.

 

Gastrointestinal symptoms

 

Abdominal pain, anorexia, nausea, vomiting.

 

Neurological disturbances and psychiatric symptoms

 

Headache, peripheral neuritis, dizziness, mental confusion,

disorientation, hallucinations.

 

Other side-effects

 

Jaundice, transient impairment of liver function, fever,

increase of serum uric acid levels, joint pain, acute gouty

arthritis,malaise. Ethambutol may diffuse into milk.

 

2.3  Diagnosis

 

Clinical diagnosis is difficult, but the diagnosis of

poisoning with ethambutol should be considered as

differential in patients presenting with hallucinations,

visual disturbances and gastrointestinal symptoms.

 

The following laboratory tests may be performed to detect

side effects:

 

Serum uric acid levels;

 

Liver and renal function tests; and

 

Haematological examinations (neutropenia has been reported in

patients treated with rifampicin, isoniazid and

ethambutol).

 

2.4  First aid measures and management principles

 

In cases of overdosage with ethambutol gastric lavage or

inducing emesis should be considered, if seen 1 to 2 hours

after ingestion. Activated charcoal may be reasonably left in

the stomach after gastric lavage.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

3.1  Origin of the substance

 

Ethambutol is a synthetic oral antibiotic derivative of

ethylenediamine which contains two imine radicals and two

butanol radicals.

 

3.2  Chemical structure

 

CH3CH2CH(CH2OH)NHCH2CH2NHCH(CH2OH)CH2CH3

 

Molecular formula

 

Ethambutol base               C10H24N2O2

 

Ethambutol hydrochloride      C10H24N2O2,2HCl

 

Molecular weight

 

Ethambutol base               204.3

 

Ethambutol hydrochloride      277.2

 

Chemical names

 

(S,S)-N,N’-Ethylenebis(2-aminobutan-1-ol)dihydrochloride

 

2,2′-(1,2-ethanediyldiimino)bis-l-butanol

 

(+)- (R,R)-NN’-Ethylenebis(2-aminobutan-1-ol)dihydrochloride

 

(+)-2,2′-(ethylenediimino)di-1-butanol

 

d-N,N’-bis(1-hydroxymethylpropyl)ethylenediamine

 

(Reynolds, 1982,1993; Budavari, 1989)

 

3.3  Physical properties

 

3.3.1 Properties of the substance

 

3.3.1.1 Colour

 

White

 

3.3.1.2 State/Form

 

Crystalline hygroscopic powder

 

3.3.1.3 Description

 

Odourless or almost odourless

 

Bitter taste

 

Melting point 199 °C to 204 °C

 

Soluble 1 in 1 of water, 1 in 4 of alcohol, 1

in 850 of chloroform, and 1 in 9 of methyl

alcohol; very slightly soluble in ether.

 

A solution in water is dextrorotatory.

 

Solutions are stable when heated at 121 °C for

10 minutes.

 

(Reynolds, 1993; Windholz, 1983)

 

3.3.2 Properties of the locally available formulation(s)

 

(To be completed by each Centre using local data)

 

3.4  Other characteristics

 

3.4.1 Shelf-life of the substance unknown

 

3.4.2 Shelf-life of the locally available formulation(s)

 

To be completed by each Centre using local data.

 

3.4.3 Storage conditions

 

Store in airtight containers between 15 to 30°C.

 

3.4.4 Bioavailability

 

To be completed by each Centre using local data.

 

3.4.5 Specific properties and composition

 

To be completed by each Centre using local data.

 

  1. USES

 

4.1  Indications

 

4.1.1 Indications

 

4.1.2 Description

 

For the treatment of tuberculosis in conjunction

with at least one other antituberculous drug.

 

4.2  Therapeutic dosage

 

4.2.1 Adults

 

Treatment (oral)

 

Initial phase (8 weeks) 25 mg/kg per day as a single

dose in continuous regimens; or 30 to 40 mg/kg three

times weekly in intermittent regimens.

 

Continuation phase: 15 mg/kg daily

 

Prophylaxis (oral)

 

15 mg/kg per day

 

Note:

 

The dose of ethambutol should be reduced or dosage

interval should be adjusted in patients with impaired

renal function.

 

A dose supplement should be given to patients

undergoing haemodialysis or peritoneal dialysis.

 

Ethambutol is usually given with isoniazid, rifampicin

and pyrazinamide in the initial 8 week phase

(Reynolds,1993)

 

4.2.2 Children

 

Ethambutol is not recommended for use in

children under thirteen years of age since safe

conditions for use have not been established (PDR,

1989).  However, children over the age of 6 years have

been given doses similar to those used for adults

(Reynolds, 1989).

 

4.3  Contraindications

 

Ethambutol hydrochloride is contraindicated in patients

who are known to be hypersensitive to this drug.  Renal

impairment, old age and optic neuritis are relative

contraindications (PDR, 1989).

 

  1. ROUTES OF ENTRY

 

5.1  Oral

 

Ethambutol is only available for oral use.  Data about

other  routes of entry are not available.

 

5.2  Inhalation

 

Not relevant

 

5.3  Dermal

 

Not relevant

 

5.4  Eye

 

Not relevant

 

5.5  Parenteral

 

Not relevant

 

5.6  Other

 

Not relevant

 

  1. KINETICS

 

6.1  Absorption by route of exposure

 

Ethambutol hydrochloride, following a single oral dose

of 25 mg/kg of body weight, attains a peak of up to 5 œg/mL

in serum within 4 hours after administration and is less than

1 ug/ml by 24 hours.  When the drug is administered daily for

longer periods of time at this dose, serum levels are

similar.

 

About 80% of an oral dose of ethambutol is absorbed from the

gastro-intestinal tract, and the remainder appears in the

faeces unchanged. Absorption is not significantly impaired by

food.

 

(Reynolds, 1993)

 

6.2  Distribution by route of exposure

 

Ethambutol diffuses readily into red blood cells and

into the cerebrospinal fluid when the meninges are inflamed.

The concentration in erythrocytes at steady state is

approximately twice the plasma concentration.

 

Protein binding is less than 5%; the volume of distribution

is 1.6 L/kg (Gilman et al., 1990)

 

It has been reported to cross the placenta and is excreted in

breast milk (Reynolds, 1989).  The concentration of

ethambutol in one sample of breast milk collected during a 2

hour period after a dose of 15 mg per kg body-weight was 1.4

mcg/mL. Another woman had simultaneous concentrations of 4.62

and 4.60 œg/mL in plasma and milk respectively, but no dose

had been specified (Reynolds, 1989).

 

6.3  Biological half-life by route of exposure

 

The serum half-life in therapeutic doses is 3 hours,

increasing in renal failure, as 80% is excreted renally

(Gilman et al., 1990).

 

In 6 healthy subjects given a single dose of ethambutol 15

mg/kg bodyweight as an aqueous solution and as a commercial

tablet preparation the apparent mean elimination half-life

was 4.78  and 4.06 hours respectively, for plasma

concentration measured up to 12 hours after administration.

It was increased to about 10 hours for 24 to 72 hour

samplings.  The serum levels of ethambutol falls to

undetectable levels by 24 hours after the last dose, except

in some patients with abnormal renal function.

 

6.4  Metabolism

 

The main path of metabolism appears to be an initial

oxidation  of the alcohol to an aldehydic intermediate,

followed by conversion to a dicarboxylic acid (PDR,

1989).

 

6.5  Elimination by route of exposure

 

During the 24-hour period following oral administration

of ethambutol, approximately 50% of the initial dose is

excreted unchanged in the urine, while an additional 8% to

15% appears  in the form of metabolites.  From 20 to 22% of

the initial dose is excreted in the faeces as unchanged drug

(PDR, 1989).

 

No drug accumulation has been reported with consecutive

single daily doses of 25 mg/kg in patients with normal kidney

function, although marked accumulation has been demonstrated

in patients with renal insufficiency (PDR, 1989).

 

The intrinsic total body clearance is 9 mL/min/kg (Gilman et

al., 1990).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

7.1  Mode of action

 

7.1.1 Toxicodynamics

 

The underlying cause of visual alterations

appears to be  a disturbance of metabolism due to

depletion of copper and zinc which serve as prosthetic

groups for many enzymes.  The eye normally contains a

considerable store of zinc, amounting to 0.5% of the

weight of the eyeball.  Much of the zinc is in the

pigmented cells of the outer zone of the retina, where

it serves as a metal prosthetic group for retinol

(alcohol) dehydrogenase.

 

7.1.2 Pharmacodynamics

 

Ethambutol is an oral chemotherapeutic agent

which is specifically effective against actively

growing microorganisms of the genus Mycobacterium,

including M. tuberculosis (PDR,1989). Ethambutol is

bacteriostatic and appears to inhibit the synthesis of

one or more metabolites, thus causing impairment of

cell metabolism, arrest of multiplication, and cell

death.  No cross resistance with other available

antimycobacterial agents has been demonstrated.

Ethambutol has been shown to be effective against

strains of mycobacterium tuberculosis but does not seem

to be active against fungi, viruses, or other bacteria.

Ethambutol is also active against some atypical

mycobacteria including M. kansasii.  Primary resistance

to ethambutol is uncommon in developed countries but

resistant strains of M. tuberculosis are readily

produced if the drug is used alone.

 

7.2  Toxicity

 

7.2.1 Human data

 

7.2.1.1 Adults

 

Adverse effects to ethambutol appear

to be uncommon with doses of 15 mg/kg body-

weight (Reynolds, 1989). Optic neuropathy is

virtually unknown when ethambutol is given in

doses of up to 15 mg/kg body-weight and is rare

at doses of up to 25 mg/kg.  However, a patient

developed rapid progressive deterioration of

vision only 3 days after beginning therapy with

ethambutol 800 mg daily by mouth (about 15

 

 

 

mg/kg body-weight) and this patient remained

blind over one year after the initial reaction

(Karnik et al., 1985).

 

Subclinical impairment of colour discrimination

was reported to be relatively common in 54

patients receiving about 15 mg/kg body-weight

of ethambutol daily as part of antituberculous

chemotherapy when compared with 50 patients

receiving other antituberculous agents

(Reynolds, 1989).

 

Peripheral neuropathy has been reported in 3

tubercular patients who had received ethambutol

13 to 50 mg/kg body-weight, among other drugs.

It has been reported that a patient who took

ethambutol 20 g, rifampicin 9 g and isoniazid

6 g made an uneventful recovery after

haemodialysis and treatment with pyridoxine

(Reynolds, 1989).

 

7.2.1.2 Children

 

No available data.

 

7.2.2 Relevant animal data

 

Toxicological studies in dogs on high prolonged

doses, produced evidence of myocardial damage and

failure, and depigmentation of the tapetum lucidum of

the eyes, the significance of which is not known.

Degenerative changes in the central nervous system,

apparently not dose-related, have also been noted in

dogs receiving ethambutol hydrochloride over a

prolonged period (PDR, 1989).

 

In the rhesus monkey, neurological signs appeared after

treatment with high doses given daily over a period of

several months. These correlated with specific serum

levels of ethambutol hydrochloride and with definite

neuro-anatomical changes in the central nervous system.

Focal interstitial carditis was also noted in monkeys

which received ethambutol hydrochloride in high doses

for a prolonged period (PDR, 1989).

 

7.2.3 Relevant in vitro data

 

Information about in vitro toxicological tests

is not available.

 

7.3  Carcinogenicity

 

No available data.  Tumour inducing effects are not known.

 

7.4  Teratogenicity

 

Although ethambutol may be teratogenic in animals, there

is no evidence of teratogencity in man (Reynolds,

1989).

 

7.5  Mutagenicity

 

No available data

 

7.6  Interactions

 

Results of a crossover study involving 13 tuberculous

patients suggest that concomitant administration of aluminium

hydroxide may delay and reduce absorption of ethambutol in

some patients (Mattila et al., 1978).

 

Untoward effects may be enhanced when ethambutol is combined

with isoniazid or rifampicin (Dukes, 1984).

 

7.7  Main adverse effects

 

Ethambutol may produce decreased visual acuity which

appear to be due to optic neuritis and to be related to dose

and duration of treatment. The effects are generally

reversible when administration of the drug is discontinued

promptly (PDR, 1989).

 

Ethambutol may produce constriction of visual field, central

and peripheral scotoma, and green-red colour blindness which

may be associated with retrobulbar neuritis (Dukes, 1984;

Reynolds, 1989).

 

Renal clearance of urate may be reduced in about 50% of

patients receiving ethambutol and acute gout has been

precipitated in patients with gout or impaired renal function

(Reynolds, 1989).

 

Cholestatic jaundice has been reported (Gulliford et al., 1986).

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

8.1  Sample

 

8.1.1 Collection

 

8.1.2 Storage

 

8.1.3 Transport

 

8.2  Toxicological analytical methods

 

An agar diffusion microbiological assay, based upon

inhibition of Mycobacterium smegmatis (ATCC 607) may be used to

determine concentrations of ethambutol hydrochloride in serum

and urine.  This technique has not been published.

 

8.2.1 Test for active ingredient

 

8.2.2 Test for biological analyses

 

8.3  Other laboratory analyses

 

8.3.1 Haematological investigations

 

Full blood count might be convenient to detect

adverse effects. Leucopenia with neutropenia and

thrombocytopenia have been reported in patients treated

with ethambutol, isoniazid and rifampicin.

 

8.3.2 Biochemical investigations

 

8.3.2.1 Blood

 

The following laboratory test may be

performed to detect side-effects: serum uric

acid levels; liver function tests; serum urea

and creatinine concentrations.

 

8.3.2.2 Urine

 

8.3.3 Arterial blood gas analysis

 

8.3.4 Other relevant biomedical analyses

 

8.4  Interpretation

 

Ethambutol may increase uric acid levels by reducing renal

clearance of urate.  Rarely, it might induce liver or renal

disfunction.

 

8.5  References

 

See Section 13

 

  1. CLINICAL EFFECTS

 

9.1  Acute poisoning

 

9.1.1 Ingestion

 

The acute overdosage symptoms include nausea,

abdominal pain, fever, mental confusion, visual

hallucinations and optical neuropathy with doses above

10 g.

 

According to scarce available information about

ethambutol overdosage in humans, no deaths due to

ethambutol alone have been reported.  One fatal case of

overdose with rifampicin and ethambutol has been

reported (Jack et al., 1978).

 

Ethambutol may induce many other side-effects which

were mentioned as “Main adverse effects” in the item

7.7.  Possible presentation of these signs and symptoms

in an acute overdose with ethambutol is

unknown.

 

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

 

Not relevant.

 

9.1.6 Other

 

Not relevant.

 

9.2  Chronic poisoning

 

9.2.1 Ingestion

 

Signs and symptoms reported in long-term

treatments with ethambutol have been presented in item

7.7.  Other data are not available in our

centre.

 

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

 

Not relevant.

 

9.3  Course, prognosis, cause of death

 

As it has been mentioned, no deaths due to ethambutol

have been reported.  Decrease in visual acuity induced by

ethambutol was reversible when administration of the drug was

discontinued.  In rare cases, recovery may be delayed for up

to one year or more and the effects may possibly be

irreversible in these cases.  Patients should be advised to

report promptly to their physician any change in visual

acuity (PDR,1989). If careful evaluation confirms the

magnitude of visual change and fails to reveal another cause,

ethambutol therapy should be discontinued and the patient

reevaluated at frequent intervals.  Patients developing

visual abnormality during ethambutol therapy may show

subjective visual symptoms before, or simultaneously with,

the demonstration of decreases in visual acuity, and all

patients receiving ethambutol should be questioned

periodically about blurred vision and other subjective eye

symptoms (PDR, 1989).  Recovery of visual acuity generally

occurs over a period of weeks or months after the drug has

been discontinued. Patients have then received ethambutol

again without recurrence of loss of visual acuity (PDR,

1989).

 

9.4  Systematic description of clinical effects

 

9.4.1 Cardiovascular

 

None reported.

 

9.4.2 Respiratory

 

None reported

 

9.4.3 Neurological

 

9.4.3.1 Central nervous system (CNS)

 

Confusion, disorientation,

hallucinations, headache, dizziness,

retrobulbar neuritis with a reduction in visual

acuity, constriction of visual field, central

or peripheral scotoma and green-red colour

blindness have been reported as adverse-effects

of ethambutol therapy. Retinal haemorrhage has

occurred rarely (Reynolds, 1989).

 

Mental confusion, visual hallucination and

optical neuropathy have been reported in cases

of acute overdosage. The incidence and severity

of ocular damage appears to be dose-dependent.

In severe cases even blue- yellow defects

occurred which may result in achromatopsia

(Dukes, 1986).  Visual-evoked potential testing

is reported to be the most reliable method for

early detection of ocular

abnormalities.

 

9.4.3.2 Peripheral nervous systems

 

Peripheral neuritis may precede or

accompany ocular damage.  Changes are more

severe in the sensory than in the motor nervous

system.

 

9.4.3.3 Autonomic nervous system

 

Unknown

 

9.4.3.4 Skeletal and smooth muscle

 

Joint pains can occur with ethambutol

therapy.

 

9.4.4 Gastrointestinal

 

Digestive disturbances may be present both in

acute poisoning or in long-term therapy.  Metallic

taste, nausea, vomiting, anorexia, and abdominal pain

have been reported as adverse-effects to ethambutol

treatment.

 

9.4.5 Hepatic

 

Jaundice and transient liver dysfunction are not

unusual findings during ethambutol treatment.

 

9.4.6 Urinary

 

9.4.6.1 Renal

 

Renal clearance of urate may be

reduced in about 50% of patients receiving

ethambutol.  There are scarce reports about

renal failure and acute diffuse interstitial

nephritis related with ethambutol

therapy.

 

9.4.6.2 Other

 

None reported.

 

9.4.7 Endocrine and reproductive systems

 

Unknown

 

9.4.8 Dermatological

 

Skin rashes and pruritus may occur.

 

9.4.9 Eye, ear, nose, throat: local effects

 

Ocular disturbances as described in

9.4.3.1.

 

9.4.10 Hematological

 

Leucopenia is an unusual finding.

 

9.4.11 Immunological

 

Acute thrombocytopenia, probably due to an

immunological mechanism, has been described in a single

patient (Dukes, 1984). Various exanthemas, Stevens-

Johnson syndrome, “toxic” epidermal necrolysis,

purpura-like vasculitis, acute thrombopenic purpura,

joint pain, drug fever, and leukopenia have been

attributed to hypersensitivity. These reactions may

arise during combined treatment with other

tuberculostatics and it is therefore difficult to

determine which drug is responsible.

 

9.4.12 Metabolic

 

Elevation of serum uric acid levels may occur

during ethambutol treatment (Dukes, 1986) and

precipitation of acute gout has been reported (PDR,

1989).

 

9.4.12.1 Acid-base disturbances

 

Unknown

 

9.4.12.2 Fluid and electrolyte disturbances

 

No data available

 

9.4.12.3 Others

 

No data available

 

9.4.13 Allergic reactions

 

Anaphylactoid reactions

 

9.4.14 Other clinical effects

 

Fever has been reported as an adverse-effect.

It has been attributed to hypersensitivity.

 

9.4.15 Special risks

 

Pregnancy

 

The effects of combination of ethambutol with other

antituberculous drugs on the foetus is not known.

While administration of this drug to pregnant human

patients has produced no detectable effect upon the

foetus, the possible teratogenic potential in women

capable of bearing children should be weighed carefully

against the benefits of therapy.  There are published

reports of five women who received the drug during

pregnancy without apparent adverse effect upon the

foetus (PDR,1989).

 

Breastfeeding

 

Ethambutol may diffuse into milk.

 

Enzyme deficiencies

 

No data available.

 

Alcohol

 

In alcoholics with liver damage, in patients with

intercurrent or previous hepatitis or in diabetics with

retinopathy, monthly controls of the pathological state

are necessary (Dukes, 1984).

 

9.5  Other

 

No data available

 

9.6  Summary

 

Not relevant

 

  1. MANAGEMENT

 

10.1  General principles

 

Consider prevention of absorption by enemas or gastric

lavage, if patient seen within 1 to 2 hours after ingestion.

Otherwise treatment is supportive.

 

10.2  Relevant laboratory analyses

 

10.2.1 Sample collection

 

10.2.2 Biomedical analysis

 

As with any potent drug, assessment of organ

system functions, including renal, hepatic, and

haematopoietic, should be made.

 

10.2.3 Toxicological analysis

 

Ethambutol concentrations may be evaluated both

in blood and urine.

 

10.2.4 Other investigations

 

No data available.

 

10.3  Life supportive procedures and symptomatic/specific

treatment

 

Usual life-supportive and/or symptomatic measures,

depending on clinical presentation of the patient.

 

10.4  Decontamination

 

In case of overdosage, the common methods employed to

limit the absorption of the drug from the gastrointestinal

tract may be utilized. Activated charcoal suspension may be

left in the stomach after gastric lavage.

 

10.5  Elimination

 

Based on the low protein binding (<5%) and volume of

distribution (1.6 L/kg) haemodialysis may theoretically

remove significant amounts of ethambutol. However, the high

intrinsic clearance (9 mL/min/kg) and short half-life (3

hours) indicate that this procedure may only be considered if

renal failure develops. (Jacobsen, personal

communication).

 

10.6  Antidote treatment

 

10.6.1 Adults

 

Antidotes are not available

 

10.6.2 Children

 

Antidotes are not available

 

10.7  Management discussion

 

There are no data about the efficacy of treatment in

cases of ethambutol overdosage.

 

  1. ILLUSTRATIVE CASES

 

11.1  Case reports from literature

 

Neutropenia in a 75-year-old man treated with isoniazid,

ethambutol, and rifampicin.  Neutropenia was induced, on

challenge, by each of the 3 agents (Jenkins et al., 1980).  A

patient who took ethambutol 20 g, rifampicin 9 g, and isoniazid

6 g made an uneventful recovery after haemodialysis and

treatment with pyridoxine (Ducobu et al., 1982).

 

Substitution of ethambutol by isoniazid was considered to be

responsible for thrombocytopenia in a 71 year-old woman who had

been receiving isoniazid and rifampicin for tuberculosis

(Rabinovitz et al., 1982).

 

A patient developed rapid progressive deterioration of vision

only 3 days after beginning therapy with ethambutol 800 mg

daily by mouth (about 15 mg/kg body-weight) as part of

combination chemotherapy for pulmonary tuberculosis.  The

patient remained blind over one year after the initial reaction

(Karnik et al., 1985).

 

Ethambutol might have caused renal failure in 2 patients

(Collier et al., 1976).

 

A report of acute diffuse interstitial nephritis in 3 patients

attributed to antituberculous therapy and especially isoniazid

and/or ethambutol (Stone et al., 1976).

 

Ethambutol was considered to be the cause of jaundice which

developed in a patient also receiving isoniazid and

streptomycin.  Rechallenge was positive for ethambutol or

ethambutol and streptomycin (Gulliford et al., 1986).

 

A report of toxic epidermal necrolysis associated with the use

of ethambutol in one patient (Pegram et al., 1981).

 

Hyperuricaemia has been found in up to 66% of patients

receiving ethambutol (Postlethwaite et al, 1972) and there have

been reports of acute gouty arthritis precipitated by

ethambutol in some patients (Self et al., 1977).

 

An acute overdose of isoniazid (7.l g), rifampicin (15 g) and

ethambutol(20 g) produced seizures with loss of consciousness

and full extension of all four extremities in a 21-year-old

female who had ingested the medication 3.5 hours earlier.

Neurological examination revealed no focal or lateralizing

defects.  Convulsions resisted conventional treatment with

diazepam and phenytoin, but did not recur following

approximately 8.0 g pyridoxine and haemodialysis for 4 hours.

Pancuronium (2 mg intravenously) was also administered under

intubation of the patient.  A severe metabolic acidosis,

 

typical of acute overdosage with isoniazid was treated with

sodium bicarbonate infusion.  The patient’s SGOT and SGPT

peaked on day 3 and declined rapidly thereafter.  She was

released on day 9 with no significant complications.  (Spalding

& Buss, 1986).

 

A fatal case of overdose with both rifampicin and ethambutol

has been reported.  A man was found lying in the street and was

dead on admission to hospital.  He had been receiving

rifampicin and ethambutol. At necropsy, a pink discoloration of

the skin and internal organs was noted.  The dead man’s urine

was bright red.  Blood and urine concentrations of rifampcin

and ethambutol were respectively 182 œg/ml and 3.3 mg/ml and 84

œg/ml and 6.8 œg/ml.  These levels may correlate with acute

overdosage with both drugs. Alcohol concentrations were very

low. Discolouration of skin, mucous membranes, and urine is

typical of rifampicin treatment, since the drug and its

metabolites are deep-red (Jack et al., 1978).

 

11.2  Internally extracted data on cases

 

No data available

 

11.3  Internal cases

 

To be completed by each Centre using local data

 

  1. ADDITIONAL INFORMATION

 

12.1  Availability of antidotes

 

Antidotes are not available.

 

12.2  Specific preventive measures

 

Ethambutol should be given in reduced dosage to patients

with impaired kidney function; it should be used with great

care in patients with visual defects, the elderly, and in

children in whom evaluation of changes in visual acuity may be

difficult; it should not be used in children under at least 6

years and some consider it should not be used in patients with

visual defects; ocular examinations are recommended before

treatment with ethambutol and some consider that regular

examinations are necessary during treatment especially in

children; patients should be advised to report visual

disturbances immediately and ethambutol should be withdrawn if

vision deteriorates; desensitization may be attempted following

hypersensitivity reactions if the use of ethambutol is

considered essential for provision of adequate

chemotherapy.

 

12.3 Other

 

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.  p 587.

 

Collier J, Joekes AM, Philalithis PE, & Thompson FD (1976) Two cases

of ethambutol nephrotoxicity. Br Med J, 2:1105-6.

 

Dictionnaire Vidal (1987) Vidal 1987. Editions du Vidal, Paris.

 

Ducobu J, Dupont P, Laurent M, & Bruart J (1982) Acute

isoniazid/ethambutol/rifampicin overdosage (letter). Lancet,

1: 632.

 

Dukes MNG ed. (1984) Meyler’s Side Effects of Drugs, Volume 10.

Amsterdam, Elsevier.

 

Dukes MNG ed. (1986) Meyler’s Side Effects of Drugs Annual 10.

Amsterdam, Elsevier, p 270.

 

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 1152-1153,1679.

 

 

Gulliford M, Mackay AD, & Prowse K (1986) Cholestatic jaundice

caused by ethambutol. Br Med J, 292: 866.

 

Jack et al (1978)  Fatal Rifampicin-ethambutol overdosage.  Lancet,

2: 1107-8.

 

Jenkins PF, Williams TD, & Campbell IA (1980) Neutropenia with each

standard antituberculosis drug in the same patient. Brit Med J,

280: 1069-70.

 

Karnik AM, Al Shamali MA, & Fenech FF (1985) A case of ocular

toxicity to ethambutol–an idiosyncratic reaction? Postgrad Med J,

61: 8ll-813.

 

Mattila MJ, Linnoila M, Seppala T, & Koskinen R (1978) Effect of

aluminium hydroxide and glycopyrrhonium on the absorption of

ethambutol and alcohol in man.  Brit J Clin Pharmacol,

5: 161-166.

 

Pegram PS Jr, Mountz JD, & O’Bar PR (1981) Ethambutol-induced toxic

epidermal necrolysis. Arch Intern Med, 141: 1677-8.

 

Physician’s Desk Reference (1989) 43rd ed. Ordell NJ, Medical

Economics, p 560.

 

Postlethwaite AE, Bartel AG, & Kelley WN (1972) Hyperuricemia due to

ethambutol. New Engl J Med, 286: 761-762.

 

Rabinovitz M, Pitlik SD, Halevy J, & Rosenfeld JB (1982) Ethambutol-

induced thrombocytopenia.  Chest, 81: 765-6.

 

Reynolds JEF ed. (1982) Martindale, the extra pharmacopoeia, 28th

  1. London, The Pharmaceutical Press, pp 1569-1570.

 

Reynolds JEF ed. (1989) Martindale, 29th ed. The Pharmaceutical

Press, pp 560-563.

 

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

  1. London, The Pharmaceutical Press. pp 164-165

 

Self TH, Fountain FF, Taylor WJ, & Sutliff WD (1977) Acute gouty

arthritis associated with ethambutol. Chest, 71(4): 561-2.

 

Spalding CT & Buss WC (1986) Toxic overdose of isoniazid, rifampicin

and ethambutol. Eur J Clin Pharmcol, 30: 381-382.

 

Stone WJ, Waldron JA, Dixon JH, Primm RK, & Horn RG (1976) Acute

diffuse interstitial nephritis related to chemotherapy of

tuberculosis. Antimicrob Agents Chemother, 10(1): 164-172.

 

WHO (1992) Anatomical Therapeutic Chemical (ATC) classification

index. Oslo, WHO Collaborating Centre for Drug Statistics

Methodology, p 61.

 

WHO (1992) International nonproprietary names (INN) for

pharmaceutical substances. Geneva, World Health Organisation,  p

207.

 

Windholz M ed. (1983)  The Merck index, an encyclopedia of

chemicals, drugs, and biologicals, 10th ed. Rahway, New Jersey,

Merck and Co., Inc, p 539.

 

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

ADDRESS(ES)

 

Co-authors  Dr Julia Higa de Londoni

Professor and Chief

Toxicology Section

Department of Internal Medicine

Hospital de Clínicas José de San Martín

Av Córdoba 2351

1120 Buenos Aires

Argentina

 

Dr Roberto Juan Gabach

Toxicology Section

Department of Internal Medicine

Hospital de Clínicas José de San Martín

Av Córdoba 2351

1120 Buenos Aires

Argentina

 

Date             January 1990

 

Reviewer         Dr R. Ferner Newcastle-upon-Tyne

 

Peer Review      Strasbourg, France, April 1990

 

Ethionamide

  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

1.7 Presentation, Formulation

  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 Properties of the substance

3.3.1.1 Colour

3.3.1.2 State/Form

3.3.1.3 Description

3.3.2 Properties of the locally available formulation(s)

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3.4.2 Shelf-life of the locally available formulation(s)

3.4.3 Storage conditions

3.4.4 Bioavailability

3.4.5 Specific properties and composition

  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 ENTRY

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 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 Advance quantitative method(s)

8.2.2 Test 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 Advance quantitative method(s)

8.2.2.5 Other dedicated method(s)

8.2.3 Interpretation of toxicological analyses

8.3 Interpretation of toxicological analyses

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, and 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 Others

9.6 Summary

  1. MANAGEMENT

10.1 General principles

10.2 Relevant laboratory analyses

10.2.1 Sample collection

10.2.2 Biomedical analysis

10.2.3 Toxicological analysis

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific treatment

10.4 Decontamination

10.5 Elimination

10.6 Antidote treatment

10.6.1 Adults

10.6.2 Children

10.7 Management discussion

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

11.2 Internally extracted data on cases

11.3 Internal cases

  1. ADDITIONAL INFORMATION

12.1 Availability of antidotes

12.2 Specific preventive measures

12.3 Other

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

 

  1. NAME

 

1.1 Substance

 

Ethionamide   (INN)

 

(WHO, 1992)

 

1.2 Group

 

ATC classification index

 

Antimycobacterials (J04)/Drugs for the treatment of

tuberculosis (J04A)/Thiocarbamide derivatives(J04AD).

 

(WHO, 1992)

 

1.3 Synonyms

 

Etionamide

1314-TH

Amidazine

Ethioniamide

 

(Budavari, 1989)

 

(To be completed by each Centre using local data)

 

1.4 Identification numbers

 

1.4.1 CAS number

 

536-33-4

 

1.4.2 Other numbers

 

RTECS

 

NS0350000

 

1.5 Brand names, Trade names

 

Ethatyl (SCS, S. Afr.)

Etiocidan (Cidan, Spain)

Panathide (Propan, S. Afr.)

Regenicide (Gedeon, Richter)

Thioniden (Kaken, Jpn)

Trecator (Belg., Theraplix, Fr)

Trecator-SC (Wyeth, USA)

Trescatyl (May & Baker, S. Afr; May & Baker, UK)

Tubenamide (Meiji. Jpn)

Resitran (Mla. Phil.)

 

(To be completed by each Centre using local data)

 

1.6 Manufacturers, Importers

 

To be completed by each Centre using local data

 

1.7 Presentation, Formulation

 

Tablets 250 mg, in packs of 100  (PDR, 1992)

 

(To be completed by each Centre using local data)

 

  1. SUMMARY

 

2.1 Main risks and target organs

 

Most common adverse reactions are gastrointestinal

disturbances including anorexia, nausea, vomiting, excessive

salivation, a metallic taste, stomatitis and diarrhoea and

hepatitis. Central nervous system effects include dizziness,

drowsiness, headaches, convulsions, peripheral neuropathy,

tremors and paraesthesias.

 

There is no experience in acute overdose of ethionamide. One

of the metabolites resembles isoniazid and one should watch

for similar symptoms.

 

2.2 Summary of clinical effects

 

TOXIC REACTIONS FROM ETHIONAMIDE

 

SITE               REACTIONS

 

Gastrointestinal   Anorexia, vomiting, stomatitis, diarrhoea,

System             excessive salivation, metallic taste,

hepatotoxicity.

 

Central Nervous    Mental depression, anxiety or psychosis,

System             encephalopathy with pellagra-like

symptoms, dizziness, drowsiness, headache,

convulsion, peripheral neuropathy,

tremors, paraesthesias.

 

Eye                Optic neuritis, optic atrophy, diplopia.

 

Nose               Olefactory disturbances

 

Ear                Deafness

 

Endocrine          Hypothyroidism, gynaecomastia, impotence,

menorrhagia, hypoglycaemia

 

Integumentary      Alopecia, acne, severe allergic rashes,

photodermatitis.

 

Haematology        Thrombocytopenia

 

Skeletal system    Rheumatic pains

 

Cardiovascular     Postural hypotension

 

(Reynolds, 1989; Gilman et al., 1990)

 

2.3 Diagnosis

 

Clinical diagnosis is difficult to determine because of the

lack of history of toxic ingestions.

 

Quantitative Analysis

 

Confirmatory tests can be used to document poisoning using

High Pressure Liquid Chromatography on plasma, serum or urine

or a colour reaction on urine; detection limit 10 ng/mL.

 

Qualitative Analysis

 

Presence of sulphoxide derivative of ethionamide gives a

yellow colour in the acid extract.

 

2.4 First aid measures and management principles

 

Whether the presentation of the patient is an overdose or an

adverse drug event, the first principle is to evaluate the

vital functions and provide life-support measures to

stabilize the victim.  Screening and confirmatory tests to

document poisoning in biological fluids should be done. (For

details, see 10.1)

 

Maintain patient airway, adequate breathing and circulation.

Decontaminate with activated charcoal and follow with

cathartic.

 

Although the drug is extensively metabolised by the liver in

toxic doses, excretion may be enhanced with diuretics.

 

There are no known antidotes for ethionamide overdose.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

3.1 Origin of the substance

 

Synthesized from the interaction of 2-ethylisonicotinonitrile

and H2S in the presence of triethanolamine (Budavari, 1989).

 

3.2 Chemical structure

 

Structural formula

Molecular formula

 

C8H10N2S

 

Molecular weight

 

166.2

 

Structural Chemical names

 

2-Ethylpyridine-4-carbothioamide

2-ethyl-4-pyridinecarbothioamide

2-ethylththioisonicotinamide

3-ethylisothionicotinamide

2-ethylisothionicotinamide

2-ethyl-4-thiocarbamoylpyridine

alpha-ethylisonicotinoylthioamide

 

(Reynolds, 1993; Budavari, 1989)

 

3.3 Physical properties

 

3.3.1 Properties of the substance

 

3.3.1.1 Colour

 

Yellow (darkens on exposure to light)

 

3.3.1.2 State/Form

 

Crystal or crystalline powder

 

3.3.1.3 Description

 

Slight sulphide-like odour.

 

Melting range   158°C to 164°C.

 

pH   6.0 to 7.0 in a 1 in 100 slurry in

water.

 

Soluble in 1 in 30 of alcohol.

Very sparingly soluble in water.

Slightly soluble in chloroform (1 in 500)

Slightly soluble in ether (1 in 320).

Soluble in methyl alcohol.

Sparingly soluble in propylene glycol.

 

(Reynolds 1993, Budavari 1989, European

Pharmacopoeia, 1986)

 

3.3.2 Properties of the locally available formulation(s)

 

It is stable at all ordinary temperatures and levels of

humidity.

 

(To be completed by each Centre using local data).

 

3.4 Other characteristics

 

3.4.1 Shelf-life of the substance

 

No data available.

 

3.4.2 Shelf-life of the locally available formulation(s)

 

To be completed by each Centre using local data.

 

3.4.3 Storage conditions

 

Preserve in air-tight containers at less than 40°C,

preferably between 15 to 30°C.

 

3.4.4 Bioavailability

 

To be completed by each Centre using local data.

 

3.4.5 Specific properties and composition

 

To be completed by each Centre using local data

 

  1. USES

 

4.1 Indications

 

4.1.1 Indications

 

For the treatment of pulmonary and extrapulmonary

tuberculosis in conjunction with other antituberculous

agents (when resistance to primary agents has

developed).

 

For the treatment of leprosy, as part of multi-drug

regimens.

 

In the treatment of pulmonary disease in Mycobacterium

kansasii and other atypical mycobacteria.

 

4.1.2 Description

 

Not applicable

 

4.2 Therapeutic dosage

 

4.2.1 Adults

 

Oral

 

Tuberculosis

 

0.5 to 1 g daily in divided doses (PDR, 1992)

 

15 to 20 mg/kg (given as a single daily dose, up to

maximum of 1 g (Reynolds, 1993).

 

Leprosy

 

250 to 375 mg daily (Reynolds, 1989; Gilman et al.,

1990)

 

5 mg/kg (as a single daily dose)(Reynolds, 1993)

 

4.2.2 Children

 

Oral

 

Tuberculosis

 

12 to 15 mg/kg body weight daily to a maximum of 750 mg

daily in divided doses.

 

Some children have received 20 mg/kg daily.

(Reynolds, 1989)

 

15 to 20 mg/kg (given as a single daily dose)

(Reynolds, 1993)

 

Note: Optimum dose for children has not been

established. A report showed the maximum daily dose as

750 mg (Shirkey, 1977).

 

4.3 Contraindications

 

Ethionamide should not be given to pregnant women unless the

benefits outweigh its possible risk.

 

To be used with caution in women of child-bearing age.

 

Severe liver disease.

 

Severe hypersensitivity.

 

Note: Caution is necessary in administering ethionamide to

patients with depression or other psychiatric diseases,

chronic alcoholism, epilepsy, hypothyroidism or diabetes

mellitus.

 

  1. ROUTES OF ENTRY

 

5.1 Oral

 

This is the usual route of administration for therapeutic

use.

 

5.2 Inhalation

 

Unknown.

 

5.3 Dermal

 

Unknown.

 

5.4 Eye

 

Unknown.

 

5.5 Parenteral

 

Ethionamide hydrochloride has been given intravenously, but

there is no commercial preparation.

 

5.6 Other

 

Ethionamide has been administered as rectal suppositories.

 

  1. KINETICS

 

6.1 Absorption by route of exposure

 

Oral

 

Approximately 80% of a gastrointestinal oral dose of

ethionamide is rapidly absorbed from the gastrointestinal

tract.  Following a single 1 g oral dose in adults, peak

plasma concentration of ethionamide averaging 20 ug/mL are

attained within 3 hours and less than 1 ug/mL at 24 hours.

Following a single 250 mg oral dose in adults, peak plasma

concentrations of ethionamide average 1-4 ug/ml (McEvoy,

1990).

 

After oral administration, the bioavailability is circa 100%.

(USPDI, 1993)

 

Rectal

 

Relative bioavailability after rectal administration was

57.3% of that following oral administration.

 

Parenteral

 

No data available.

 

6.2 Distribution by route of exposure

 

Oral

 

It is widely distributed throughout body tissues and fluids.

 

It crosses the placenta and penetrates the meninges,

appearing in the CSF in concentrations equivalent to those in

the serum.

 

(Reynolds, 1989;  Gilman et al., 1990)

 

Protein binding is low (10%) (USPDI, 1993).

 

6.3 Biological half-life by route of exposure

 

Oral

 

Half-life is 2 to 3 hours (Reynolds, 1989).

 

6.4 Metabolism

 

Ethionamide is extensively metabolized, probably in the

liver, to ethionamide sulphoxide, 2-ethylisonicotinic acid

and 2-ethylisonicotinamide. The sulfoxide is the main active

metabolite (Moffat, 1986; McEvoy, 1993).

 

6.5 Elimination by route of exposure

 

Less than 1% of a dose appears in the urine as unchanged

drug, the remainder is excreted in the urine as inactive

metabolites.

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

7.1 Mode of action

 

7.1.1 Toxicodynamics

 

In view of the structural similarity of the metabolite

2-methylisonicotinic acid to isoniazid, it has been

suggested that toxicity is due to pyridoxine deficiency

(Manapat, 1992).

 

7.1.2 Pharmacodynamics

 

Ethionamide inhibits the synthesis of mycolic acids and

stimulates oxidation-reduction reactions. Treated cells

lose acid-fastness, thus the mechanism of action

appears to be similar to that of INH. Specific sites of

action may be different, since strains of

M.tuberculosis that are resistant to high

concentrations of INH are susceptible to ethionamide.

 

Both the drug and the sulphoxide metabolite are active

against M.tuberculosis. 2-ethylisonicotinic acid and 2-

ethylisonicotinamide are not active metabolites.

 

It is bacteriostatic against M. tuberculosis at

therapeutic concentrations, but may be bactericidal at

higher concentrations. The average MIC (Minimum

Inhibitory Concentration) for Mycobacterium

tuberculosis is 0.6 – 2.5 mg/mL (Lorian, 1980). Most

susceptible organisms are inhibited by 10 ug/mL or

less.

 

It is bactericidal against M. leprae and a minimum

inhibiting concentration (MIC) of 0.05 ug/mL has been

reported in mice.

 

Resistance develops rapidly if used alone and there is

complete cross-resistance with prothionamide,

thiacetazone and thiambutosine. (Reynolds, 1989)

 

7.2 Toxicity

 

7.2.1 Human data

 

7.2.1.1 Adults

 

There is no experience with acute overdoses.

Some of the adverse effects are dose-dependent

and would be expected in an overdose situation.

The most serious effects are neuropsychiatric

symptoms and liver necrosis.

 

In clinical use, neuropsychiatric symptoms,

such as headache, sleeping, insomnia,

depression and paraesthesia may occur.

Elevation of liver transaminase enzymes has

been known to develop. (British Tuberculosis

Association, 1968).

 

No special precautions are required due to age,

as doses are adjusted according to patient

response. However, dose should be modified

depending on liver and renal status. (Dollery,

1991)

 

7.2.1.2 Children

 

No data available.

 

7.2.2 Relevant animal data

 

A rat study showed the sublethal neurotoxicity level of

ethionamide to be 1300 mg/kg. The principal signs were

paralysis, loss of screen grip and decreased motor

activity (Manapat et al., 1992).

 

7.2.3 Relevant in vitro data

 

No data available.

 

7.3 Carcinogenicity

 

No data available.

 

7.4 Teratogenicity

 

Teratogenic effects have been reported in rabbits, mice and

 

rats, in which high doses have led to abortions and some

malformations.

Conflicting reports exist in the literature concerning

congenital malformations in children when exposed to the drug

in utero. One observation attributes 7 malformations among 23

children exposed to ethionamide whereas in another study with

70 infants no such relationship to drug treatment during

pregnancy was found. (Dollery, 1991)

 

7.5 Mutagenicity

 

Ethionamide was not found to be mutagenic as shown by Ames

Salmonella and Micronuclei Assay Test (Peters, 1983).

 

7.6 Interactions

 

Ethionamide taken with pyrazinamide may lead to abnormalities

of liver function and the use of these two agents together

should be avoided (Reynolds, 1989).

 

The use of rifampicin with the thiomides (ethionamide or

prothionamide) as part of the regimens recommended by WHO for

the treatment of multibacillary leprosy has been associated

with an unexpectedly high incidence of hepatotoxicity (Pattyn

et al., 1984; Reynolds, 1989).

 

Adverse nervous system effects of ethionamide,

cylcoserine and isoniazid may be additive (McEvoy, 1990).

 

The side effects of other tuberculostatic agents may be

enhanced when ethionamide is administered concomitantly

(Griffin, 1988).

 

Alcohol may contribute to psychotropic reactions in an

ethionamide treated patient. More study is needed to clarify

the clinical significance of this interaction. (Griffin,

1988)

 

7.7 Main adverse effects

 

The most common adverse effects are dose-related, viz:

gastrointestinal disturbances, including anorexia, excessive

salivation, a metallic taste, nausea, vomiting, stomatitis,

diarrhoea and hepatitis.

 

Dizziness, drowsiness, headache, postural hypotension and

asthenia may also occur occasionally.

 

Other side effects reported include acne, allergic reactions

alopecia, convulsions, deafness, dermatitis (including

photodermatitis), visual disturbances, tremors,

gynaecomastia, impotence, menstrual disturbances, olfactory

disorders, peripheral and optic neuropathy, thrombocytopenia

and rheumatic pains.  Mental disturbances, including

depression, anxiety and psychosis have been provoked.  A

 

pellagra-like syndrome with encephalopathy has been reported

rarely.  A tendency towards hypoglycaemia may occur and could

be of significance in patients with diabetes mellitus.

Hypothyroidism has also occurred.  Racial differences in

tolerance may occur, e.g. Chinese and Africans are often more

tolerant of ethionamide than are Europeans (Reynolds, 1989).

 

Note: Many patients cannot tolerate therapeutic doses of

ethionamide and have to discontinue treatment.

 

  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 Biomedical analyses

 

8.1.1.3 Arterial blood gas analysis

 

8.1.1.4 Haematological analyses

 

8.1.1.5 Other (unspecified) analyses

 

Plasma, serum, or urine may be used; however,

blood is preferably collected on the third hour

post-ingestion.

 

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

 

The blood obtained should be frozen at -20 to

-40°.

 

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

 

The blood sample should be transported,

refrigerated and separated within 2 hours of

collection.

 

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)

 

Description

 

Yellow crystal or a yellow crystalline powder,

darkening on exposure to light, with a slight

sulphide-like odour.

 

Identity Tests

 

The assay exhibits an absorbence maximum at 290

+2 nm.

 

Dissolve 1 g of ethionamide tablets in 50 ml of

methanol and filter through a medium porosity

sintered-glass funnel.  Evaporate the filtrate

on a steam bath and the obtained residue melts

between 155 and 164 (USP, 1985).

 

8.2.1.2 Advanced qualitative confirmation test(s)

 

8.2.1.3 Simple quantitative method(s)

 

8.2.1.4 Advance quantitative method(s)

 

8.2.2 Test for biological specimens

 

8.2.2.1 Simple qualitative test(s)

 

Qualitative analysis of urine based on a colour

reaction.

 

8.2.2.2 Advanced qualitative confirmation test(s)

 

8.2.2.3 Simple quantitative method(s)

 

8.2.2.4 Advance quantitative method(s)

 

Quantification analysis using High Pressure

Liquid Chromatography on plasma, serum, or

urine.

 

8.2.2.5 Other dedicated method(s)

 

8.2.3 Interpretation of toxicological analyses

 

Blood levels would peak by the third hour; levels at 6

to 20 ug/ml are considered therapeutic.

 

A yellow urine colour reaction detects the presence of

a sulfoxide derivative.

 

8.3 Interpretation of toxicological analyses

 

8.3.1 Biochemical analysis

 

8.3.1.1 Blood, plasma or serum

 

Liver function tests such as ALT, AST, Alkaline

Phosphatase, Direct and Indirect Bilirubin;

Prothrombin time; Blood Sugar; BUN, Creatinine

 

8.3.1.2 Urine

 

Urinalysis to detect glucose, protein, and

leucocytes; hourly urine output determination.

 

8.3.1.3 Other fluids

 

8.3.2 Arterial blood gas analyses

 

Not relevant.

 

8.3.3 Haematological analyses

 

In severe cases of jaundice or suspected

hepatotoxicity, a full blood count and prothrombin time

must be monitored for coagulopathy.

 

8.3.4 Interpretation of biomedical investigations

 

Transient increase in serum bilirubin, AST (SGOT) and

ALT (SGPT) concentrations have been reported in

patients receiving ethionamide.  Hepatitis (with or

without jaundice) has also been reported.

Hepatotoxicity generally is reversible on

discontinuation of the drug.

 

8.4 Other biomedical (diagnostic) investigations and their

interpretation

 

T3, T4; urinary coproporphyrin, ophthalmoscopy.

 

8.5 Overall Interpretation of all toxicological analyses and

toxicological investigations

 

8.6 References

 

United States Pharmacopeia, The National formulary (1985)

 

21st rev., 16th ed., Rockville MD, United States

Pharmacopeial Convention,,  pp 413.

 

  1. CLINICAL EFFECTS

 

9.1 Acute poisoning

 

9.1.1 Ingestion

 

None reported.

 

9.1.2 Inhalation

 

None reported.

 

9.1.3 Skin exposure

 

Not relevant.

 

9.1.4 Eye contact

 

None reported.

 

9.1.5 Parenteral exposure

 

None reported.

 

9.1.6 Other

 

None reported.

 

9.2 Chronic poisoning

 

9.2.1 Ingestion

 

None reported.

 

9.2.2 Inhalation

 

None reported.

 

9.2.3 Skin Exposure

 

Not relevant.

 

9.2.4 Eye contact

 

None reported.

 

9.2.5 Parenteral exposure

 

None reported.

 

9.2.6 Other

 

9.3 Course, prognosis, cause of death

 

None reported.

 

9.4 Systematic description of clinical effects

 

9.4.1 Cardiovascular

 

None reported.

 

9.4.2 Respiratory

 

None reported.

 

9.4.3 Neurological

 

9.4.3.1 Central nervous system (CNS)

 

May cause encephalopathy with pellagra-like

symptoms; headaches; sleepiness, insomnia,

depression, tremors, convulsions (British

Tuberculosis Assn., 1968)

 

9.4.3.2 Peripheral nervous system

 

Peripheral nerve symptoms consisting of

paraesthesias, motor weakness or sensory

impairment have been observed, following

therapeutic doses (Snavely, 1984).

 

9.4.3.3 Autonomic nervous system

 

None reported.

 

9.4.3.4 Skeletal and smooth muscle

 

None reported.

 

9.4.4 Gastrointestinal

 

Dose-related

 

Anorexia, excessive salivation, metallic taste, nausea,

vomiting, stomatitis, and diarrhoea.

 

9.4.5 Hepatic

 

Although jaundice is rare, hepatitis may occur in about

5% of patients.

 

One study showed a 13% incidence of hepatitis when drug

is combined with rifampicin and dapsone. The

hepatocellular injury is non dose-related, especially

among diabetics.

 

9.4.6 Urinary

 

9.4.6.1 Renal

 

None reported.

 

9.4.6.2 Other

 

9.4.7 Endocrine and reproductive systems

 

Thyroid

 

May cause a disturbance in the synthesis of thyroid

hormone resulting in hypothyroidism.

 

Ethionamide inhibits the trapping of technetium and

organification of iodine at concentration seen

clinically (Drucker 1984).

 

Other

 

Gynaecomastia

Menorrhagia

Impotence

Hypoglycaemia

 

9.4.8 Dermatological

 

Dermatitis (photodermatitis)

Acne

Alopecia

 

9.4.9 Eye, ear, nose, and throat: local effects

 

Local effects

 

None reported.

 

Systemic effects

 

Optic neuritis, optic atrophy, degeneration of the

chiasma, deafness, olefactory disturbances (Holdiness,

1987).

 

9.4.10 Haematological

 

May cause acute porphyria because it has been shown to

be porphyrinogenic in animals.

 

Thrombocytopenia

 

9.4.11 Immunological

 

None reported.

 

9.4.12 Metabolic

 

9.4.12.1 Acid-base disturbances

 

None reported.

 

9.4.12.2 Fluid and Electrolyte disturbances

 

None reported.

 

9.4.12.3 Others

 

Hypoglycaemia when given to diabetic

patients.

 

9.4.13 Allergic reactions

 

Hypersensitivity reactions may occur.

 

9.4.14 Other clinical effects

 

Rheumatic pains.

 

9.4.15 Special risks

 

Pregnancy

 

CNS malformations have been reported (Schardein,

1976).

 

Conflicting reports exist for congenital malformations

of children born to mothers receiving the drug during

pregnancy. Therefore, it is suggested that the drug be

avoided during pregnancy or in women of childbearing

potential unless the benefits outweigh its possible

hazard. (Dollery, 1991)

 

Breast-feeding

 

As far as can be determined there are no data

published indicating the secretion of ethionamide in

breast milk in measurable quantities (Dollery, 1991).

 

Enzyme deficiencies

 

None reported.

 

9.5 Others

 

No data available

 

9.6 Summary

 

Not applicable

 

  1. MANAGEMENT

 

10.1 General  principles

 

Whenever the presentation of the patient is an overdose or

adverse drug event, the first principle is to evaluate the

vital functions and provide life-support measures to

stabilize the victim.

 

Decontamination should be considered to reduce further

absorption, if patient seen early after poisoning.

 

There are no specific antidotes for ethionamide overdose;

however, high dose pyridoxine has been found to inhibit its

neurotoxic effects (Gennaro et al., 1985).

 

Pellagra-like symptoms can be reversed by niacin.

 

10.2 Relevant laboratory analyses

 

Bio-medical tests: (i.e., baseline liver function; platelet

count, blood sugar, prothrombin time).

 

10.2.1 Sample collection

 

Plasma, serum or urine may be used, however, blood

is preferably collected on the third hour post-

ingestion.  Samples obtained should be frozen at

-20 to -40 °C and separated within 2 hours of

collection.

 

10.2.2 Biomedical analysis

 

Blood

 

Liver function tests such as ALT, AST, alkaline

phosphatase, Direct and Indirect Bilirubin;

Prothrombin time; Blood sugar; BUN, Creatinine.

 

Urine

 

Urinalysis to detect glucose, protein, and

leucocytes; hourly urine output determination.

 

10.2.3 Toxicological analysis

 

Blood levels taken on the third hour post-ingestion

whose values are beyond 20 ug/ml are considered

toxic.

 

10.2.4 Other investigations

 

Not relevant

 

10.3 Life supportive procedures and symptomatic/specific

treatment

 

Treatment is mainly supportive.  If patient is in a

critical condition (i.e. cardiorespiratory distress)

maintain a clear airway, aspirate secretions if these are

present in the airway, administer oxygen, perform

endotracheal intubation if indicated, provide artificial

ventilation, if warranted. Maintain a patent intravenous

line to support circulation. Monitor vital signs

(sensorium, blood pressure, heart and respiratory rate)

regularly and correct hypotension with isotonic fluids or

inotropic agents.  Monitor fluids and electrolyte balance

(i.e., input and urine output).

 

If there are cardiac dysrhythmias, antiarrhythmic agents

are best avoided, especially if the “torsades de pointes”

type of arrhythmia is present.

 

If bleeding ensues, correct by doing appropriate component

transfusion only if indicated.

 

Reevaluate other drugs which patient may be taking and

which may interact with ethionamide.

 

10.4 Decontamination

 

Methods to reduce gastrointestinal absorption consist of

inducing emesis or performing gastric lavage.

 

Perform gastric lavage if dose was high and ingestion was

recent. Protect airway if patient is unconscious.

 

Administer activated charcoal (1 mg/kg). (Note: The use of

cathartics is generally no longer recommended).

 

10.5 Elimination

 

No documented information available.

 

10.6 Antidote treatment

 

10.6.1 Adults

 

There are no specific antidotes for ethionamide

overdose. However, high dose pyridoxine may inhibit

its neurotoxic effects (Gennaro et al., 1985)

because of its similarity to isoniazid. This

possible antidotal effect has not been documented.

 

10.6.2 Children

 

There is no specific antidote.  However, high dose

pyridoxine may prevent neurotoxicities.

 

10.7 Management discussion

 

Despite ethionamide’s synthesis in 1956, there is still

paucity of both clinical and experimental data,

specifically in the management of acute poisoning overdose.

 

Drug induced hepatotoxicity was shown to be decreased by

pre-administration of methimazole (MMI)(Ruse, 1991).

 

High dose pyridoxine may prevent neurotoxicities.

 

Pellagra-like symptoms can be reversed by niacin.

 

  1. ILLUSTRATIVE CASES

 

11.1 Case reports from literature

 

Abnormalities of liver function (but no jaundice) occurred

in 12 of 80 patients treated with ethionamide as part of

their antituberculous chemotherapy.  However, 10 of these

patients were also taking pyrazinamide.  The use of these 2

agents together may increase the risk of hepatotoxicity and

should be avoided (Reynolds, 1989).

 

A girl developed acute hepatic necrosis and died after

treatment with ethionamide, isoniazid and aminosalicylic

acid.  It was considered that ethionamide was the most

likely cause (Reynolds, 1989).

 

A report of encephalopathy with pellagra-like symptoms

occurring in association with ethionamide in 2 patients,

and with ethionamide and cycloserine in one patient.

Treatment was with nicotinamide and compound vitamin

preparations (Reynolds, 1989).

 

11.2 Internally extracted data on cases

 

No data available.

 

11.3 Internal cases

 

To be completed by each Centre using local data.

 

  1. ADDITIONAL INFORMATION

 

12.1 Availability of antidotes

 

To be completed by each Centre using local data.

 

12.2 Specific preventive measures

 

Caution is necessary in administration ethionamide to

patients with depression or other psychiatric illnesses,

chronic alcoholism, or epilepsy.

 

As there have been reports of goitre and hypothyroidism

associated with the use of ethionamide it should  be

administered with care to patients requiring treatment for

hypothyroidism.

 

Difficulty may be experienced in controlling diabetes.

The side effects of other tuberculostatic agents may

be increased when ethionamide is used concurrently.

 

Ethionamide is contraindicated in pregnant and lactating

women, in patients with severe liver disease, and those

with severe hypersensitivity to the drug.

 

12.3 Other

 

No data available.

 

  1. REFERENCES

 

British Tuberculosis Association (1968) Comparison of toxicity

of prothionamide and ethionamide: a report from the research

committee of the british tuberculosis association. Tubercule,

49(2): 125-135

 

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

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

Jersey, Merck and Co., Inc.  p 590.

 

Dollery C ed. (1991) Therapeutic Drugs, Volume 1. Edinburgh,

Churchill & Livingstone.

 

Drucker D et al. (1984) Ethionamide-induced goitrous

hypothyroidism. Ann Intern Med, 100(6): 837-9

 

European Pharmacopoeia (1980-1986) 2nd. ed., Maison Neuve,

Council of Europe, p 142.

 

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

  1. Easton, Pennsylvania,  Mack Publishing Company,  p 1216.

 

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 1154-1155

 

Griffin JP, O,Grady J, Well FO,& D’Arcy (1988) A manual of

adverse drug interactions, Butterworth and Co Ltd.

 

Holdiness MR (1984) Clinical pharmacokinetics of antituberculous

drugs. A review. Clin Pharmacokinetics, 9(6): 571-574

 

Lorian V ed. (1980) Antibiotics in laboratory medicine,

Baltimore Press, Williams and Wilkins Company, pp 160-165.

 

McEvoy GK ed. (1990) American hospital formulary service, drug

information, Bethesda, American Society of Hospital Pharmacists,

pp 343-344.

 

McEvoy GK ed. (1993) American hospital formulary service, drug

information, Bethesda, American Society of Hospital Pharmacists,

pp 343-344.

 

Manapat BD et al. (1992) The effectiveness of pyridoxine in

modifying the neurotoxidome of ethionamide overdose in sprague-

dawley rats. Manilla, Pharmacokinetic research paper, UP College

of Medicine-Department of Pharmacology.

 

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, pp 597-598.

 

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

29th ed. London, The Pharmaceutical Press, pp 562-563.

 

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

30th ed. London, The Pharmaceutical Press, p 166.

 

Osol A et al. (1973)  The united states dispensatory, 27th ed. ,

JB Lippincott Company,  p 509.

 

Pattyn SR et al. (1984) Hepatotoxicity of the combination of

rifampicin-ethionamide. Int J Lepr and Other Mycobacterial

Diseases, 1: 1-6

 

Peters JH (1983) Mutagenic activity of antileprosy drugs and

their derivatives. Int J Lepr and Other Mycobacterial Diseases,

51(1): 45-53

 

Physician’s Desk Reference (1992) 46th ed. Ordell NJ, Medical

Economics, p 2527.

 

Ruse MJ (1991) The effect of methimazole on thioamide

bioactivation and toxicity. Toxicol Lett, 58(1): 37-41

 

Schardein JL (1976)  Drugs as teratogens.  CRC Press, Inc,

p 202.

 

Shirkey HC (1984) Pediatric drug handbook , W B  Saunders

Company.

 

Snavely SR et al. (1984) The neurotoxicity of antibacterial

agents. Ann Intern Med, 100(1): 92-104

 

USPDI (1983) Drug Information for the Health Care Professional.

Vol. 1, Rockville MD, United States Pharmacopeial Convention,

pp 396-397.

 

WHO (1992) Anatomical Therapeutic Chemical (ATC) classification

index. Oslo, WHO Collaborating Centre for Drug Statistics

Methodology, p 61.

 

WHO (1992) International nonproprietary names (INN) for

pharmaceutical substances. Geneva, World Health Organisation,

p 208.

 

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

ADDRESS(ES)

 

Author       Dr Perlita Young, M.D.

National Poison Control and Information Service

University of the Philippines

 

Date         January 1992

 

Reviewer     Dr M.C. Alonzo

CIAT 7- piso

Hospital de Clinicas

 

Peer Review  Drs Maramba, Critchley, Caitens, Panganiban,

Ombega, Ten Ham & Ms Kaye. Newcastle-upon-Tyne,

United Kingdom, February 1992.

See Also:

Ethionamide (IARC Summary & Evaluation, Volume 13, 1977)

 

 

 

 

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