1. NAME 1.1 Substance Rifampicin (INN, 1992) 1.2 Group Antimycobacterials (JO4)/Drugs for the treatment of tuberculosis (J04A)/Antibiotics (J04AB). (ATC classification index [WHO] 1992]) 1.3 Synonyms Rifampin Rifaldazine Rifamycin (Merck Index, 1989) 1.4 Identification numbers 1.4.1 CAS number 13292-46-1 1.4.2 Other numbers RTECS VJ7000000 1.5 Brand names, Trade names Rimactan, Rifadin, Rifocine (Argentina) Rifadin, Rimycin (Australia) Rimactan, Rifadine (Belgium) Rofact (Canada) Rimactan (Denmark) Rimactan, Rifadine (France) Eremfat, Rifa, Rifoldine, Rimactan, Rimactane, Rifampin, Rifadin (Germany) Tibirim (India) Archidyn, Rimactan,Rifapiam (Italy) Apectin (Japan) Rimactan, Rifadin (Netherlands) Rimactan (Norway) Abrifam, Dipicin, Famidex, Lederrif, Medifam, Natricin, Ramicin, RAMP, Refam, Resimin, Rifadin, Rifamycin, Rifastat, Rifatrexin,Rimactane, Zyfam, Rimaped (Philippines) Fenampicin, Tregaldin, Rifaprodin, Seamicin, Rifonilo Riforal, Rimactan, Diabacil (Spain) Rifoldine, Rimactan, Chibro-Rifamycine (Switzerland) Rifadin, Rimactane (United Kingdom) Rifadin (USA) (Martindale, 1982, 1989; Phil. Index of Medical Specialties, 1990). (To be completed by each Centre using local data) 1.6 Manufacturers/Importers Merrell(UK) Rifadin Rifinah 150 and Rifinah 300 Ciba Rimactane Rimactazid 150 and Rimactazid 300 Lepetit (Argentina) Rifocina Rifadin Armstrong (Argentina) Rifampicina (To be completed by each Centre using local data) 1.7 Presentation, Formulation Monocomponent products Rifampicin capsules of 150 mg, 300 mg, 450 mg, 600 mg, Rifampicin syrup 100 mg/5 ml. Combination Products Dipicin Isoniazid 150 mg, Rifampicin 300 mg INH IsoRamp. Isoniazid 100 mg Rifampicin 150 mg Isoniazid 150 mg Rifampicin 300 mg Pyrina Isoniazid 150 mg, Rifampicin 150 mg, Pyrazinamide 500 mg Rambutol Isoniazid 200 mg, Ethambutol HCl 400 mg, Rifampicin 300 mg, Pyridoxine 25 mg Ramicin Isoniazid 150 mg, Rifampicin 300 mg Iso Resfaman Isoniazid 150 mg, Rifampicin 300 mg with INH Resimin Isoniazid 200 mg, Rifampicin 300 mg + H Rifater Isoniazid 80 mg, Rifampicin 120 mg, Pyrazinamide 250 mg Rifinah Isoniazid 100 mg, Rifampicin 150 mg Isoniazid 150 mg, Rifampicin 300 mg Isoniazid 300 mg, Rifampicin 450 mg Rifzin Isoniazid 100 mg, Rifampicin 120 mg, Pyrazinamide 250 mg, pyridoxine 7.5 mg Rimactazid Isoniazid 100 mg Rifampicin 150 Isoniazid 200 mg Rifampicin 225 Isoniazid 150 mg Rifampicin 300 Ophthalmic Rifampin 1% ophthalmic ointment. Intravenous infusion Powder for reconstitution, as rifampicin 300 mg, supplied with solvent. (To be completed by each Centre using local data) 2. SUMMARY 2.1 Main risks and target organs The main target organs are the liver and the gastrointestinal system. Risks of concern are toxic hepatitis with elevation of bile and bilirubin concentrations, anaemia, leucopenia, thrombocytopenia, bleeding. 2.2 Summary of clinical effects Some clinical manifestations of overdosage are extension of adverse effects. During therapy, rifampicin is usually well-tolerated, however, adverse side-effects are common in intermittent rifampicin intake. These include febrile reaction, eosinophilia, leucopenia, thrombocytopenia, purpura, haemolysis and shock, hepatotoxicity and nephrotoxicity. Gastrointestinal adverse reactions may be severe leading to pseudomembranous colitis. Neurotoxic effects include confusion, ataxia, blurring of vision, dizziness and peripheral neuritis. A common toxic effect is red skin with orange discolouration of body fluids. Fatalities from adverse reactions have been reported. Rifampicin has shown no significant effects on the human foetus. It diffuses into milk and other body fluids. 2.3 Diagnosis Presence of red skin or orange discolouration of body fluids (e.g. urine) are indicators of the diagnosis. Blood and urine may be used to determine qualitative analysis or quantitative levels. Spare tablets or capsules may be identified using colour reaction tests. 2.4 First aid measures and management principles For acute overdose Stabilize patient by providing basic life support (i.e. airway, breathing and circulation). In the fully conscious patient, consider emesis or gastric lavage if patient seen within 1 or 2 hours after ingestion. Activated charcoal should be given afterwards. The use of a cathartic is no longer recommended. There is no antidote for rifampicin overdosage. Provide adequate hydration to maintain circulation and urine output. For adverse reactions not related to overdosage Withdraw drug and provide symptomatic and supportive therapy promptly. Note the presence of bleeding, jaundice, and renal failure. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Rifampicin is a semisynthetic derivative of rifamycin antibiotics which are produced by the fermentation of a strain of Streptomyces mediterranei, a species which was first isolated in Italy in 1957 from a soil sample collected in France. The fermentation produces rifamycin B. Rifamycin B is transformed by a series of reactions into 3- formylrifamycin SV, which in turn is condensed with 1-amino- 4-methylpiperazine in peroxide-free tetrahydrofuran to give rifampicin. (IARC, 1980) 3.2 Chemical structure Structural formula Molecular formula C₄₃H₅₈N₄O₁₂ Molecular weight 822.96 Chemical names 3-[[(4-methyl-1-piperazinyl)imino]methyl)]rifamycin 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22- heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]2,7- (epoxypentadecal[1,11,13]trienimino)-naphtho[2,1-beta]furan- 1,11(2H)-dione 21-acetate (Merck Index, 1989) 3.3 Physical properties 3.3.1 Properties of the substance 3.3.1.1 Colour Red to orange 3.3.1.2 State/Form Powder 3.3.1.3 Description Odourless. Very slightly soluble in water (1 g in approximately about 762 mL water [pH < 6]), acetone, carbon tetrachloride, alcohol, ether. Freely soluble in chloroform, DMSO; soluble in ethyl acetate and methyl alcohol and tetrahydrofuran. Solubility in aqueous solutions is increased at acidic pH. Melting point 138 to 188 °C Rifampicin has 2 pKa since it is a Zwitterion, pKa 1.7 related to 4-hydroxy and pKa 7.9 related to 3-piperazine nitrogen (Merck Index, 1989). A 1% suspension in water has pH 4.5 to 6.5. 3.3.2 Properties of local available formulation To be completed by each Centre using local data. 3.4 Other characteristics 3.4.1 Shelf-life of the substance As a dry powder it is stable for more than five years at 25°C. As lyophilized preparations for intravenous use it is stable for at least two years before reconstitution (Martindale, 1989). 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 Rifampicin should be protected from air, light and excessive heat and moisture. Store at temperature not exceeding 40 °C (preferably between 15 to 30 °C) in airtight containers in an atmosphere of nitrogen. Protect from light by amber coloured bottles. 3.4.4 Bioavailability To be completed by each Centre using local data. 3.4.5 Specific properties and composition Potency of not less than 900 mg of rifampicin/g (Merck Index, 1989). (To be completed by each Centre using local data) 4. USES 4.1 Indications 4.1.1 Indications The primary indications for rifampicin are for treatment of tuberculosis (pulmonary and extrapulmonary lesions) and for leprosy. It is also useful for elimination of Neisseria meningococci in carriers (but not recommended for active meningococcal infection) and for Gram positive (Staphylococcus aureus and epidermidis, Streptococcus pyogenes, viridans and pneumoniae) and gram negative bacteria (Haemophilus influenzae type B). It has some anti-chlamydial activity and in vitro activity against some viruses (poxvirus and adenovirus) at high doses. (Van Scoy et al, 1987). It has recently been used for brucellosis. 4.1.2 Description Not relevant. 4.2 Therapeutic dosage 4.2.1 Adults Oral Tuberculosis 10 mg/kg bodyweight single daily dose (maximum 600 mg) in combination with other antimycobacterial agents. 15 mg/kg bodyweight (maximum 900 mg) 2 or 3 times weekly in combination with other antimycobacterial agents. Leprosy 600 mg once monthly or once daily in combination with other anti-leprotic drugs. Haemophilus influenzae type B infection 20 mg/kg bodyweight once a day for 4 days. (maximum daily dose 600 mg) Meningococcal carriers 600 mg twice daily for two days. Eye Trachoma (i.e. hyperendemic trachoma or sexually transmitted trachoma-inclusion conjunctivitis) 1% ophthalmic ointment applied three times daily for six weeks. Parenteral Rifampicin has been administered intravenously at 20 mg/kg bodyweight (maximum daily dose 600 mg). (Martindale, 1993) 4.2.2 Children Oral Tuberculosis 10 mg/kg bodyweight single daily dose in combination with other antimycobacterial agents. 15 mg/kg bodyweight 2 or 3 times weekly in combination with other antimycobacterial agents. Generally, for children less than five years of age, the dosage has not been established yet. Clinicians, however, have recommended 10-20 mg/kg bodyweight daily in children and infants with a maximum of 10 mg/kg bodyweight in neonates less than one week of age for tuberculosis treatment. Meningococcal carriers 1 to 12 years 10 mg/kg bodyweight 3 to 12 months 5 mg/kg bodyweight Haemophilus influenzae type B infection Children over 3-months-old 20 mg/kg bodyweight once a day for 4 days. (Martindale, 1993) 4.3 Contraindications Rifampicin is contraindicated in known cases of hypersensitivity to the drug. It may be contraindicated in pregnancy (because of teratogenicity noted in animal studies and since the effects of drugs on fetus has not been established) except in the presence of a disease such as severe tuberculosis. It is contraindicated in alcoholics with severely impaired liver function and with jaundice. 5. ROUTES OF ENTRY 5.1 Oral This is the common route of entry. 5.2 Inhalation Not applicable. 5.3 Dermal Not applicable 5.4 Eye Use for ocular chlamydial infection treatment (Fraunfelder, 1982). 5.5 Parenteral Rifampicin may be given intravenously (Martindale,1989). 5.6 Other No data available. 6. KINETICS 6.1 Absorption by route of exposure Rifampicin is readily absorbed from the gastrointestinal tract (90%). Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose. After a 450 mg oral dose, plasma levels reach 6 to 9 µg/mL while a 600 mg dose on an empty stomach yields 4 to 32 µg/mL (mean 7 µg/mL). Food may reduce and delay absorption (Ellenhorn, 1988; Mandel, 1985). 6.2 Distribution by route of exposure Intravenous rifampicin has the same distribution as in oral route. Eighty nine (+/- 1) per cent of rifampicin in circulation is bound to plasma proteins.(Goodman & Gilman, 1990) It is lipid soluble. It is widely distributed in body tissues and fluids. When the meninges are inflamed, rifampicin enters the cerebrospinal fluid (4.0 µg/mL after a 600 mg oral dose). It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluid, liver, bile, and urine (Van Scoy, 1987). Rifampicin has a high degree of placental transfer with a foetal to maternal serum level ratio of 0.3. It is distributed into breastmilk (Chow & Jesesson, 1985). The apparent volume of distribution (VD) is 0.93 to 1.6 L/kg (Avery, 1976; Drug Information, 1984). 6.3 Biological half-life by route of exposure T1/2 = three hours range (2 to 5 hours). This half-life increases with single high doses or with liver disease. The half-life decreases by 40% during the first two weeks of therapy because of enhanced biliary excretion and induction of its own metabolism. Plasma half-life may decrease after repeated administration. The half-life of rifampicin decreased from 3.5 hours at start of therapy to 2 hours after daily administration for 1 to 2 weeks, and remained constant thereafter (Molavi, 1990). Plasma half- life shortens to 1.8 to 3.1 hours in the presence of anaemia (Avery, 1976). 6.4 Metabolism Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main and active metabolite - deacetylrifampicin. Rifampicin undergoes enterohepatic recirculation but not the deacetylated form. Rifampicin increases its own rate of metabolism. Rifampicin may also be inactivated in other parts of the body. Formylrifampicin is a urinary metabolite that spontaneously forms in the urine. 6.5 Elimination by route of exposure Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and 6 to 30% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Approximately 43 to 60% of oral dose is excreted in the faeces. (Van Scoy 1987; Drug Information, 1990). Intrinsic total body clearance is 3.5 (+/- 1.6) mL/min/kg, reduced in kidney failure (Goodman & Gilman, 1990) Renal clearance is 8.7 mL/min/kg. Rifampicin levels in the plasma are not significantly affected by haemodialysis or peritoneal dialysis. Rifampicin is excreted in breastmilk (1 to 3 µg/ml). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics Rifampicin causes cholestasis at both the sinusoids and canaliculi of the liver because of defect in uptake by hepatocytes and defect in excretion, respectively (Haddad, 1983). Rifampicin may produce liver dysfunction. Hepatitis occurs in 1% or less of patients, and usually in the patient with pre-existing liver disease. Hypersensitivity reactions may occur, usually characterized by a "flu" type syndrome. Nephrotoxicity appears to be related to a hypersensitivity reaction and usually occurs after intermittent or interrupted therapy. It has been suggested that some of the adverse effects associated with rifampicin may be attributed to its metabolite desacetylrifampicin. It is lipid soluble, and thus can reach and kill intracellular, as well as extracellular, Mycobacteria. Rifampicin does not bind to mammalian nuclear RNA polymerase and therefore does not affect the RNA synthesis in human beings. Rifampicin, however, may affect mammalian mitochondrial RNA synthesis at a concentration that is 100 times higher than that which affects bacterial RNA synthesis (Molavi, 1990). 7.1.2 Pharmacodynamics Rifampicin has high activity against mycobacterial organisms, including Mycobacterium tuberculosis and M.leprae. It is also active against Staphylococcus aureus, coagulase-negative staphylocci, Listeria monocytogenes, Neisseria meningitidis, Haemophilus influenzae, Legionella spp., Brucella, some strains of E. coli, Proteus mirabilis, anaerobic cocci, Clostridium spp., and Bacteroides (Molavi, 1990). Rifampicin is also reported to exhibit an immunosuppressive effect which has been seen in some animal experiments, but this may not be clinically significant in humans (Drug Information, 1990). Rifampicin may be bacteriostatic or bactericidal depending on the concentration of drug attained at site of infection. The bactericidal actions are secondary to interfering with the synthesis of nucleic acids by inhibiting bacterial DNA-dependent RNA polymers at the B-subunit thus preventing initiation of RNA transcription, but not chain elongation. (Fahr et al., 1985; Drug Information for Health Care Provider, 1984). 7.2 Toxicity 7.2.1 Human data Patients have survived overdoes of 12 grams (Ellenhorn, 1988; Fahr, 1985). For patients with previously normal liver function, derangements of liver enzymes secondary to rifampicin are mild and nonspecific. In patients with previously deranged liver condition, patients may develop clinical jaundice and a more severe liver damage may ensue. Hypersensitivity reactions which lead to acute renal failure are usually associated with intermittent intake of rifampicin developing antibodies. 7.2.1.1 Adults Eight case data studies of patients aged 14 to 55 who took doses ranging from 9 to 60 grams, developed clinical signs and symptoms of vomiting, lethargy, obtundation, seizures, pruritus, facial oedema, abdominal pain, pink to red discolouration of the skin, red coloured urine. Laboratory findings showed elevated liver transaminases, bilirubin and alkaline phosphatase which may be transient. Three patients out of these 8 cases died (Ellenhorn, 1988). 7.2.1.2 Children In a group of children aged 1 to 4 years given 100 mg/kg bodyweight inadvertently for chemoprophylaxis of H.influenzae type B infections resulted in skin discolouration, periorbital facial oedema, pruritus, vomiting, headaches and diarrhoea. Signs and symptoms developed 0.5 to 4 hours after administration and lasted approximately 28 hours ranging from 1 to 72 hours (Drug Information, 1990). 7.2.2 Relevant animal data LD₅₀ (intraperitoneal) mice 640 mg/kg LD₅₀ (intraperitoneal) rats 550 mg/kg LD₅₀ (intravenous) mice 260 mg/kg LD₅₀ (intravenous) rats 330 mg/kg (Merck Index, 1989) LD₅₀(acute oral) mouse 829.3 mg/kg LD₅₀(acute oral) rats 1303.3 mg/kg LD₅₀(acute oral) rabbits 2120.0 mg/kg (Arzneimittel-Forschung, 1971) 7.2.3 Relevant in vitro data No relevant data available. 7.3 Carcinogenicity One report showed that nasopharyngeal lymphoma may develop after therapy of two years for Pott's disease. This was probably secondary to the immunosuppressive effects of rifampicin (Rate et al., 1979). An increase of hepatomas in female mice has been reported in one strain of mice,following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Because of only limited evidence available for the carcinogenicity of rifampicin in mice and the absence of epidemiological studies, no evaluation of the carcinogenicity of rifampicin to humans could be made (IARC, 1980). 7.4 Teratogenicity Teratogenic effects noted in rodents treated with high doses 100 to 150 mg/kg bodyweight daily in rodents have been reported to cause cleft palate and spina bifida (Drug Information, 1984). Malformation and death have been reported in infants born to mothers exposed to rifampicin, although it was the same frequency as in the general population (Simpson, 1988). Rifampicin is teratogenic for rats and mice (IARC, 1980) 7.5 Mutagenicity The available studies on mutagenicity indicate an absence of mutagenic effect (IARC, 1980). 7.6 Interactions Food lowers peak blood levels because of interference with absorption of rifampicin. Antacids containing aluminium hydroxide reduced the bioavailability of rifampicin. Para-amino salicylic acid granules may delay rifampicin absorption (because of bentonite present as a granule excipient) which leads to an inadequate serum level of rifampicin. These two drugs should be given 8 to 12 hours apart (Van Scoy, 1987). Isoniazid and rifampicin interaction has led to hepatotoxicity. (Note: slow acetylators of isoniazid have accelerated rifampicin clearance). Alcohol intake with rifampicin increases the risk for hepatotoxicity. Rifampicin induces microsomal enzymes of the liver and therefore accelerates metabolism of some drugs, e.g. beta blockers, calciferol, coumadins, cyclosporin, dapsone, diazepam, digitalis, hexobarbitone, ketoconazole, methadone, oral contraceptive pills, oral hypoglycaemic agents, phenytoin, sulphasalazine, theophylline, some anti-arrhythmic drugs such as disopyramide, lorcainide, mexiletine, quinidine, and verapamil. Rifampicin induces liver steroid metabolising enzyme thus lowering the levels of glucocorticoids and mineralocorticoids . Rifampicin lowers chloramphenicol serum levels when the two drugs are used together. When rifampicin and oral contraceptives are used concomitantly, there is decreased effectiveness of oral contraceptives because of the rapid destruction of oestrogen by rifampicin and the latter being a potent inducer of hepatic metabolising enzymes. It was reported that rifampicin may be the cause of some menstrual disorders when used with oral contraceptive pills. When rifampicin and corticosteroids are used, there is a reduction of plasma cortisol half-life and increased urinary excretion of cortisol metabolite. It may be necessary to double or quadruple the dosage of the steroid. When rifampicin and cyclosporin are taken, the serum levels of cycloserine may be lowered. In the therapy of leprosy, rifampicin may induce dapsone metabolism, however, this is of minor significance in the clinical setting (Hastings & Franzblau, 1988). The clinical condition of patients, who are on rifampicin and also taking digoxin for heart failure, may deteriorate because of falling digoxin levels. Hence there may be a need to increase the dosage of digitalis. Another cardiac drug is disopyramide which is used for cardiac dysrhythmias, and when taken with rifampicin, there is a decrease in levels of the antiarrhythmic agent. The clinical importance of this effect has yet to be determined. Patients on methadone maintenance for narcotic detoxification may develop narcotic withdrawal when methadone plasma levels decreased as a consequence of taking rifampicin at the same time. It is also possible that rifampicin alters the distribution of methadone. Rifampicin induces hepatic enzyme metabolism which can decrease metoprolol blood levels, although this may be clinically insignificant. In patients who receive rifampicin and phenytoin together, there is an increase of clearance of phenytoin by twofold, significantly reducing the effects of the anticonvulsant drug. Modification of quinidine dose is necessary when this is used with rifampicin because of the risk of ventricular dysrhythmias. It is recommended that quinidine dosage be always readjusted when one adds or discontinues rifampicin therapy. When verapamil and rifampicin are taken together, rifampicin induces liver enzymes which increases the metabolism of the calcium channel blocker leading to undetectable verapamil levels. Rifampicin can lower the plasma calciferol (Vitamin D) level because of induction of enzyme activity (Griffin, 1988; Bacievicz, 1984). Barbiturates and salicylates decrease the activity of rifampicin (Fraunfelder, 1982). Effects with clofazimine range from no effect to decrease in the rate of absorption of rifampicin, delay in the time it reaches peak plasma concentrations, decrease in plasma rifampicin concentrations. Rifampicin can decrease the therapeutic levels of ketoconazole when given together (Drug Information, 1990). When rifampicin is taken with oral hypoglycaemic agents (e.g.tolbutamide and chlorpropamide), these latter medications had a decrease in elimination half-lives (Baciewicz, 1984). Rifampicin enhances antifungal actions of amphotericin B. Probenecid intake diminishes hepatic uptake of rifampicin (Van Scoy, 1987). 7.7 Main adverse effects Although rifampicin is usually well tolerated, the serious and life-threatening effects of rifampicin at therapeutic doses are severe gastrointestinal side-effects, necessitating withdrawal of drug (e.g. pseudomembranous colitis). Hypersensitivity, shock, shortness of breath, acute haemolytic anaemia and renal failure (nephrotoxicity) have been reported during intermittent therapy. This has been attributed to antibody-mediated immune reactions. The other adverse effects are staining of body fluids, rash, chills and fever, nausea and vomiting, arthralgia, diarrhoea, and peripheral neuritis. Ocular side effects as a consequent to rifampicin use occur in 5 to 15% of patients. Systemic rifampicin has been reported to cause decreased vision, affections of eyelids and conjunctiva, e.g. hyperaemia, erythema, blepharoconjunctivitis, oedema, yellow or red discolouration. Other effects are lacrimation, dyschromatopsia, orange staining of contact lenses, uveitis, subconjunctival/retinal hemorrhages, retrobulbar/optic neuritis. Angioneurotic oedema, urticaria, purpura, Stevens-Johnson syndrome, exfoliative dermatitis or pemphigoid lesions have been reported. Local ophthalmic use of rifampicin has caused irritation of the eyes which manifests transiently as lacrimation, hyperaemia, oedema and ocular pain (Fraunfelder, 1982). 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS 8.1 Methods 8.1.1 Collection No data available. 8.1.2 Storage The pharmaceutical sample should be stored below 40°C (104-F). Store in tight, lightproof container. 8.1.3 Transport No data available. 8.2 Therapeutic and toxic concentrations 8.2.1 Test for active ingredients Identity tests Description: a brick red to red-brown crystalline powder, odourless or almost odourless. Melting behaviour: 193-188°C with strong decomposition. Colour reaction tests for tables Dissolve about 1 mg in 3 ml of water, add 3 drops of copper (II) sulfate (160 mg/li) TS (test solution) and heat to boiling, a violet colour is produced. Dissolve about 1 mg in 2 mg of sulfuric acid (~ 1760 g/l) TS and heat on a water-bath for two minutes; an orange colour is produced which twins gradually to dark red. Dissolve 5 mg in 1.0 ml pyridine R (reagent), add 1.0 ml of sodium hydroxide (~ 80 g/l) TS and five drops of benzenesulfonyl chloride R and shake well; a dark red- violet colour is observed. (Basic Test for Pharmaceutical Substances, WHO Expert Advisory Panel on International Pharmacopoeia, 1988). 8.2.2 Test for biological sample Chemical colour reaction test for urine The basis of this test of antibiotic in the urine is upon the chemical property of rifampicin and its desacetylated metabolite. One test consists of mixing 10 ml of urine with 2 ml chloroform-PR. THe chloroform layer changes colour from yellow to orange according to the quantity of rifampicin in the urine. Another test calls for adding 0.5 ml of a reagent containing 5 mg of phenic nitrate and 10 ml of concentrated nitric acid in 100 ml of distilled water, to 10 ml of urine. If rifampicin is present, a chromogen is released varying from pink to red in colour relative to the concentration of the drug. The presence of other anti- tuberculosis drugs will not interfere with these tests (Arzneimittel-Forschung, 1971). Chemical test for serum A centifuge tube containing 5 ml of liquid to be assayed and 5 ml of butanolbenzene (4:1) solvent and M/15 phosphate buffer pH 7.4 are added. The tube is centrifuged at 2500 r.p.m. for 10 minutes. Extinction of the supernatant liquid is then determined at 340 and 480 mu., using solvent as blank. Standard dilutions of rifampicin are prepared in the same buffer as for the body fluid. The extinctions of these dilutions at 340 and 480 mu are plotted on a graph to give the titration curve, from which the concentrationof the drug in the sample under the curve can be calculated. This method is reliable for antibiotic concentration in the regiona of 0.5 µg/ml (Arzneimittel-Forschung, 1971). 8.3 Other laboratory analyses 8.3.1 Biochemical analyses While patients are on rifampicin therapy, SGOT and SGPT determinations may be indicated monthly, or more frequently. 8.3.2 Arterial blood gases Not necessary. 8.3.3 Haematological investigations Baseline complete blood count (platelets included) and prothrombin time determinations: 8.3.4 Other relevant tests Hepatic biopsy for histologic confirmation of hepatic necrosis (Scheuer, 1974). 8.4 Interpretation Rifampicin can affect normal human physiology such that the following laboratory parameters may be deranged or elevated. Blood urea nitrogen serum creatinine, serum alanine aminotransferase (SGPT), serum aspartate aminotransferase (SGOT), serum alkaline phosphatase, serum bilirubin, and serum uric acid concentrations. Although liver enzyme values may be elevated, they are not always predictive of clinical hepatitis and may return to normal or continued therapy with rifampicin. Rifampicin may interfere with results of certain diagnostic tests such as a positive Coomb's test may be produced; serum B12; sulphobromophthlein (BSP) hepatic uptake and excretion in liver function tests (may be delayed by rifampicin, resulting in BSP retention); urine analysis using colour reaction because of the reddish brown discolouration of urine (Drug Information, 1984). Through the inhibitory of rifampicin on cellular immunity, rifampicin may interfere with cutaneous reactivity to intradermal tuberculosis (Alford, 1990). Rifampicin therapeutic and toxic concentration Therapeutic concentrations The bactericidal concentration for rifampicin against S. Aureus is 3-12 ng/ml while the minimal inhibitory concentration of N. Meningitides is 0.1-0-8 µg/ml (Farr, 1985). Blood levels of 6µg/ml considered therapeutic (Ellenhorn, 1988). Toxic concentrations Blood levels of 55 µg/ml have been reported in an alcoholic patient who took 14-15 grams who subsequently died. A level of 182 µg/ml resulted in death. A level of 204 µg/ml done 5 hours after ingestion of 12 grams did not result in death. A level of 400 µg/ml after 12 hours from ingestion of 12 grams did not result in death. 8.5 References See section 13. 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Acute overdosage by ingestion will give the following clinical effects: Firstly, rifampicin may affect the gastrointestinal system causing nausea, vomiting and abdominal pain. There may be hepatomegaly with impairment of liver function. Secondly, the haemopoietic system may be affected leading to anaemia, and bleeding. The nervous system may be affected by rifampicin overdose manifesting as confusion, lethargy, ataxia, dizziness, blurring of vision, peripheral neuritis. Lastly, rifampicin may cause a red discolouration of the mucous membranes, the skin and all body fluids. Discolouration has been reported to occur within 0.5 to 4 hours post-ingestion. 9.1.2 Inhalation Not known. 9.1.3 Skin exposure Not known. 9.1.4 Eye contact Irritation effects. 9.1.5 Parenteral exposure Not known. 9.1.6 Other No data available. 9.2 Chronic poisoning 9.2.1 Ingestion Chronic poisonings in humans have been associated with intermittent intake of rifampicin. The reactions are gastrointestinal disturbance and include nausea, vomiting, anorexia, constipation, abdominal pain and diarrhoea. Hepatotoxicity and nephrotoxicity may occur. Flu-like symptoms, thrombocytopenia, haemolytic anaemia, leukopenia, eosinophilia and bleeding have been reported. Chronic administration of rifampicin has resulted in hepatic changes particularly in patients with pre-existing liver disease or a history of alcoholism. Animal data with chronic ingestion at dose of 200 mg/kg/day for 6 months in rats, there was slight increase of liver weight, with slight cloudy swelling and/or hydropic degeneration in the liver. No adverse effects noted at 50 to 100 mg/kg/day for 6 months in rats, while in a six months chronic toxicity study in monkeys, there were no adverse effects at 15 to 75 mg/kg/day but at 105 mg/kg/day, emesis, depression, weight loss and elevated alkaline phosphatase were noted (Arzneimittel-Forschung, 1971). 9.2.2 Inhalation Not known. 9.2.3 Skin exposure Not known. 9.2.4 Eye contact Not known. 9.2.5 Parenteral exposure Not known. 9.2.6 Other 9.3 Course, prognosis, cause of death Overdosage of rifampicin produces signs and symptoms which are extensions of adverse reactions, with reddish orange discolouration of skin and body fluids. These appeared within 0.5 to 4 hours after oral administration and lasted for an average of 28 hours (range 1 to 72 hours). Hepatotoxicity may be marked, while effects on the haematopoietic system, acid-base and electrolyte balance are unlikely. Reversal of hepatomegaly and biochemical and transaminase elevation will occur within 72 hours in patients with adequate hepatic function (Drug Information, 1990). 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension and shock. 9.4.2 Respiratory Shortness of breath. 9.4.3 Neurological 9.4.3.1 Central Nervous System (CNS) Rare cases of organic brain syndrome have been reported (i.e. confusion, lethargy, ataxia, dizziness and blurring of vision). 9.4.3.2 Peripheral Nervous System Peripheral neuropathy affecting the limbs, muscle, joints in the form of numbness and pain has been reported 9.4.3.3 Autonomic Nervous System No relevant data available. 9.4.3.4 Skeletal and smooth muscle No relevant data available. 9.4.4 Gastrointestinal Nausea, vomiting, diarrhoea. Pseudomembranous colitis is possibly associated with resistant strains of Clostridium difficile. Pancreatitis is possible, but rare in occurrence. 9.4.5 Hepatic Hepatotoxicity and overt clinical hepatitis (e.g. jaundice). In decompensated liver cirrhosis, rifampicin hepatotoxicity may develop over a period of 4 to 150 days and may lead to death (Di Piazza, 1978). Asymptomatic elevations of serum transaminase enzymes, increase in serum bile acids and bilirubin concentrations can occur. Marked elevation of serum alkaline, phosphatase and bilirubin suggests rifampicin toxicity. Doses of rifampicin below 100 mg/kg show a mild choleretic action in bile secretion, while at high doses (above 100 mg/kg) there is marked cholestatic effect (Haddad, 1983; Scheuer, 1974). 9.4.6 Urinary 9.4.6.1 Renal Intermittent or interrupted therapy with rifampicin is a common denominator for inducing renal failure (i.e. acute haemolysis and shock) as in acute interstitial nephritis and usually preceded by fever and flu-like symptoms. Glycosuria and proteinuria with associated acidifying defects have been noted. This renal failure may be aggravated in the presence of dehydration (Ellenhorn, 1988; Warrington, 1977; Fahr, 1985). 9.4.6.2 Other No data available. 9.4.7 Endocrine and reproductive systems Prolonged use of rifampicin causes a reduction of 25- hydroxycholecalciferol levels without changing 1,25 dihydroxycholecalciferol or parathyroid hormone. Complications of osteomalacia may develop. It also causes increased deiodination and biliary clearance of thyroxine, thus lowering thyroxine serum concentration (Fahr, 1985; Martindale, 1989). 9.4.8 Dermatological Discolouration of skin to glowing red-orange; pruritus at doses five times the therapeutic dose - called "red man syndrome". Chronic daily therapy led to self-limiting rash in up to 5% of cases. Eczematous patches, flaccid bullae and crusted plaques on the skin which are reversible when rifampicin was discontinued (Bolan, 1986). Rarely, exfoliative dermatitis and toxic epidermal necrolysis (Fahr, 1990). 9.4.9 Eye, ear, nose, throat: local effects Ocular effects are primarily adverse side effects such as vision disturbance, eyelid and conjunctival inflammation, angioneurotic oedema, staining of lacrimal fluid, uveitis and subconjunctival/retinal bleeding and pain. No acute or chronic otovestibular toxicity was noted with rifampicin. 9.4.10 Haematological Haemolytic anaemia. Agranulocytosis, haemorrhage, leucopenia, thrombocytopenia. Higher frequency of folic acid deficiency leading to megaloblastic anaemia (because of induction of hepatic microsomal enzymes). (Fahr, 1985; Haddad, 1983). 9.4.11 Immunological Some of the adverse reactions are secondary to immunological mechanisms because of sensitization to intermittent rifampicin intake (e.g. nephritis, anaemia). Other immunological disturbances such as rheumatoid or lupoid syndromes may occur (Remington, 1985). Rifampicin with possible immunosuppressive effects has led to a report of nasopharyngeal carcinoma developing in one case (Rate, 1979). Rifampicin depresses polymorphonuclear cells function leading to immunosuppression and immunologically- mediated thrombocytopenia. Note: The immunosuppressive effects of rifampicin are reversible. 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances No data available. 9.4.12.2 Fluid and electrolyte disturbances Potassium wasting may occur with associated interstitial nephritis and high fractional uric acid excretion and glycosuria (Cheng & Kahn, 1984). 9.4.12.3 Others No data available. 9.4.13 Allergic reactions No relevant data available. 9.4.14 Other clinical effects No relevant data available. 9.4.15 Special risks Pregnancy Malformation, death and haemorrhage (hypoprothrombinemia) have been documented in infants whose mothers were exposed to rifampicin. Rifampicin may be used with caution in pregnant patients with severe tuberculosis, however, the safety has not been well established. Breast feeding Rifampicin is found in breast milk. As only about 0.57% of the usual therapeutic dose for an infant is found there is no need to stop breast feeding, unless the infant is receiving antituberculosis agents. 9.5 Other Rifampicin causes orange-red staining of all body fluids. It has no potential as a substance of abuse. 9.6 Summary Not relevant. 10. MANAGEMENT 10.1 General Principles Symptomatic and supportive care is the basis for treatment of rifampicin overdosage. 10.2 Relevant laboratory analyses 10.2.1 Sample collection See Section 8. 10.2.2 Biomedical analysis Direct and total bilirubin levels, hepatic enzymes, renal function tests. 10.2.3 Toxicological analysis It is possible to measure levels of rifampicin in blood, but this is of no value in the management of poisoning. 10.2.4 Other investigations Not relevant 10.3 Life supportive procedures and symptomatic/specific treatment If the patient is assessed to be 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 indicated, maintain an intravenous line to support circulation. Monitor vital signs (sensorium, blood pressure, heart and respiration rate) regularly and correct hypotension with isotonic fluids or inotropic agents. Monitor fluid and electrolyte balance (i.e. input and urine output). If there are cardiac dysrhytmias, provide appropriate antiarrhythmic agents. If there is an interaction problem between rifampicin and antiarrhythmic drugs, one may have to increase the dose of cardiac medications. If bleeding ensues, correct by doing appropriate component transfusion only if indicated. Re-evaluate other drugs which patient may be taking and which may have been affected with rifampicin interactions. Symptomatic treatment for severe nausea and vomiting caused by rifampicin may be in the form of anti-emetic. Withdraw drug use in all adverse events except for asymptomatic mild liver enzyme elevation which is only transient. 10.4 Decontamination In the fully conscious patient, consider emesis or gastric lavage if patient seen within 1 or 2 hours after ingestion. Activated charcoal should be given afterwards. The use of a cathartic is not generally recommended. Gastric lavage to be performed after proper insertion of orogastric or nasogastric tube and appropriate protection for the airway (i.e. endotracheal intubation). Administration of activated charcoal is by multiple dosing every 2 to 6 hours to block enterohepatic recirculation. If the adverse event involved ocular contact, flush or irrigate eyes with copious amount of water. 10.5 Elimination Due to its high protein binding, forced diuresis or dialysis will not be effective in removal of rifampicin. Due to its relatively low volume of distribution and low intrinsic clearance, haemoperfusion may theoretically remove rifampicin, but this is not documented (Goodman & Gilman, 1990). 10.6 Antidote treatment 10.6.1 Adults There is no antidote. 10.6.2 Children There is no antidote. 10.7 Management discussion There are conflicting suggestions as regards the use of dialysis. It appears that peritoneal dialysis and haemodialysis do not appreciably promote rifampicin elimination (Van Scoy, 1987; Drug Information, 1990). 11. ILLUSTRATIVE CASES 11.1 Case reports from literature Case 1 A 40-year-old man who took 9 g of rifampicin (with 6 g isoniazid and 20 g ethambutol) and presented with orange urine. Discharged after 10 days, following haemodialysis (Ducobu et al., 1982). Case 2 A 14-year-old female overdosed on 12 g of rifampicin. After one hour she experienced pruritus and after 5 hours the skin became orange. She was treated with gastric lavage, activated charcoal, catharsis and forced diuresis, and was discharged after 3 days. (Wong et al., 1984) Case 3 A 28 year-old-male alcoholic died after intentionally overdosing on 14 to 15 g of rifampicin. Skin had orange- yellow discolouration (Plomp et al., 1981) Case 4 A report of lethargy, obtundation, pruritus, facial oedema and orange discolouration of the skin, mucous membranes, sclerae, and urine, following overdose of unknown quantity of rifampicin in a 15-year-old female (Meisel & Brower, 1980). Case 5 Nausea, vomiting, diffuse abdominal pain, intense pruritus and orange discolouration of the skin were seen in a 26- year-old male (with a history of alcohol abuse) who died after ingestion of 60 g of rifampicin (Broadwell et al., 1978). Case 6 A 28-year-old male died after ingesting an unknown quantity of rifampicin and ethambutol. He was found lying in the street and was dead on admission to hospital. At necropsy, bright red urine, a pink discolouration of the skin and internal organs (particularly the oesophagus) were noted. No injury to the mouth or throat was found. The lining of the aorta was also pink. The following concentrations of rifampicin, ethambutol and ethanol were found in blood and urine: Blood Rifampicin 182 mcg/mL (Therapeutic 6 mcg/mL) Ethambutol 84 mcg/mL (Therapeutic 2 to 4 mcg/mL) Ethanol 20 mg/dL Urine Rifampicin 3.3 mg/mL Ethambutol 6.8 mg/mL Ethanol 24 mg/dL (Jack et al., 1978). Case 7 A 55-year-old male with a prior history of overdosage and alcohol abuse recovered after 2 days of treatment following ingestion of 12 g of rifampicin. Toxicity signs were flushing, profuse sweating, bright red skin and hypertension (160/110). Elevated levels of plasma bilirubin, alkaline phosphatase and aspartate aminotransferase were noted (Newton & Forrest, 1975). Case 8 A report of nasopharyngeal lymphoma developed in a 41-year- old man following treatment with isoniazid, ethambutol and rifampicin for two years. It was suggested that this was due to the immunosuppressive effects of rifampicin following long-term therapy (Rate et al., 1979). Case 9 Report of an unsuccessful suicide in a 20-year-old male who recovered after 3 days, following ingestion of 9 g of rifampicin. Prominent symptoms were a transient skin rash, red urine, faeces and saliva. Transient cholestasis and hepatomegaly were noted (Konietsko & Burkhardt, 1971). Case 10 A case of fatal aplastic anaemia or agranulocytosis, probably due to rifampicin, has been reported (Inman, 1977). Case 11 A 75-year-old man treated with isoniazid, ethambutol and rifampicin developed neutropenia which was re-induced, on challenge, by each of the three agents (Jenkins et al., 1980). Case 12 Hepatitis occurred in a child treated with rifampicin and ethambutol. Additional symptoms included polyarthritis and the presence of anti-native DNA antibodies (Grennan & Sutrrock, 1976). Case 13 Rifampicin administered daily to a 60-year-old man was associated with the development of an acute organic brain syndrome in which he became confused, disorientated, agitated, and incoherent and suffered hallucinations and delusions (Pratt, 1979). Case 14 Myopathy in one patient induced by rifampicin was reported (Jenkins & Emerson, 1981). Case 15 Pehphigus foliaceous which developed in a patient receiving isoniazid and rifampicin cleared completely within five weeks on withdrawal of rifampicin, without need for systemic therapy (Lee et al., 1984). 11.2 Internally extracted data on cases No data available. 11.3 Internal cases To be completed by each Centre using local data. 12. ADDITIONAL INFORMATION 12.1 Availability of antidotes No known antidote. 12.2 Specific preventive measures Since an increased risk may exist for individuals with liver disease, benefits must be weighed carefully against the risk of further liver damage; periodic liver function monitoring is advised. The possible teratogenic potential in women of child- bearing age should be carefully weighed against the benefits of therapy. Since rifampicin has been reported to cross the placental barrier and appear in cord blood, neonates of rifampicin- treated mothers should be carefully observed for any evidence of adverse effects. Rifampicin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases. In patients receiving anticoagulants and rifampicin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. Soft contact lenses may be permanently stained, and individuals to be treated should be made aware of these possibilities. In the presence of diminishing creatinine clearance, there is no need to change maintenance dose intervals. When the renal failure is a consequence of rifampicin overdose or its adverse reactions, it should be discontinued (Avery, 1976). For patients with liver dysfunction, use a dose not exceeding 8 mg/kg bodyweight. 12.3 Other No relevant data available. 13. REFERENCES Alford R. (1990) Chapter 32 Antimycobacterial Agents. Principles and Practice of Infectious Diseases, 3rd ed. John Wiley and Sons. American Hospital Formulary Service Drug Information 1989 & 1990. Published by American Society of Hospital Pharmacists. Avery G ed. (1976) Drug Treatment: Principles and Practice of Clinical Pharm & Therap. Adis Press. Baciewicz A & Self T (August 1984) Rifampin Drug Interactions. Arch Intern Med, 144. Barbarash RA (August 1986) Verapamil-Rifampicin Interaction. Drug Intell Clin Pharm, 19(7-8): 559-560. Binda et al. (1971) Arzneimittel-Forschung (Drug Res.) 21. Bolan G et al. (May 1986) Red man syndrome: Inadvertent Administration of an Excessive Dose of Rifampicin to Children in a Day-care Center. Pediatrics, 77: 633-635. Broadwell RO 111, Broadwell SD, Comer PB et al (1978) Suicide by rifampin overdose. JAMA, 240: 2283-2284. Cheng JT & Kahn T (1984) Potassium wasting and other renal tubular defects with Rifampicin Nephrotoxicity. Am J Nephrol, 4: 379-382. Chow AW & Jewesson PJ (1985) Pharmacokinetics & Safety of Antimicrobial Agents during Pregnancy. Rev of Infectious Diseases, 7: 287-313. Di Piazza S et al. (1978) Severe rifampicin-associated liver failure in patients with compensated cirrhosis. The Lancet [letter]: 774. Drug Information for Health Care Providers (1984) USPDI, Vol I. The United States Pharmacopoeia Convention Inc. Ducobu J, Dupont P, Laurent M, et al. (1982) Acute isoniazid/ethambutol/ rifampicin overdosage. Lancet, 1: 632. Ellenhorn MJ & Barceloux DG (1988) Anti-infective Drugs. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Amsterdam, Elsevier. Fahr B & Mandell G. (1985) Chapter 22, Rifampicin: Principles and Practice of Infectious Diseases. 2nd ed., Vol.1: 216-220, and Chapter 24, Rifampicins. Principles and Practice of Infectious Diseases, 3rd ed. Vol.1, John Wiley & Sons, 1990. Fraunfelder FT & Meyer SM (1982) Drug-induced ocular side- effects and drug interactions. 2nd ed. Lea and Febiger. Goldberger M (1988) Antituberculosis Agents. Update on Antibiotic II, The Medical Clinics of North America, 72: No.3: 661-668. WB Saunders Co. Griffin JP et al. (1988) A Manual of Adverse Drug Interactions, 4th ed. Butterworth & Co. Haddad L & Winchester J (1983) Clinical Management of Poisoning and Drug Overdose. WB Saunders Co. Hastings RC & Franzblau SG (1988) Chemotherapy of Leprosy. Annual Rev Pharmacol Toxicol, 28: 231-245. Jack DB, Knepil J, & McLary WDS. (1978) Fatal rifampicin- ethambutol overdosage. Lancet, 2: 1107-1108. Konietsko N & Burkhardt H (1971) Unsuccessful suicide attempt with rifampicin. Pneumonologia, 144: 82-84. Kyriazopoulou V. et al (?) Rifampicin-induced adrenal crisis in Addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 59: 1204-1206. Lee CW et al (1984) Pemphigus Foliaceus induced by Rifampicin. Br J Dermatol, 5: 619-622. Mandel GL & Sande MA (1985) Antimicrobial Agents. Goodman & Gilman's the Pharmacologic Basis of Therapeutics, 7th ed. MacMillan Publish Co. Meisel S & Brower R (1980) Rifampin: a suicidal dose. Ann intern med, 92: 263-263. Newton RW & Forrest ARW (1975) Rifampicin overdosage - The red man syndrome. Scot Med Journ, 20: 55-56. Goodman & Gilman (1990) p1706 Martindale's The Extra Pharmacopoeia, 28th ed. (1982) & 29th ed. (1989). JEF Reynolds ed. London, The Pharmaceutical Press. Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals (1989) 11th ed. Merck & Col. Molavi A (1990) Antimicrobials III: Sulfonamides, Trimethoprim and Anti-Mycobacterial Agents, in Joseph di Palma & John Di Gregorio's Basic Pharmacology in Medicine, 3rd ed. McGraw-Hill Book. Philippine Index of Medical Specialties Coccabo SC (ed.) (1990) 19, No.1, IMS Pacific Ltd. April 1990. Plomp TA, Battista HJ & Unterdorfer H. A case of fatal poisoning by rifampicin. Arch Toxicol 1981, 48: 245-252. Rate R et al. (1979) Annals of Internal Medicine [letter], 90: 276. Remington's Pharmaceutical Sciences (1985) Gennaro A ed, 17th ed, Mack Publishing Co. Scheuer PJ et al (1974) Rifampicin Hepatitis. The Lancet: 421- 425. Simpson M et al (1988) Chapter 15. Bacterial Infections during Pregnancy. Medical Complications during Pregnancy, 3rd ed. WB Saunders Co. Van Scoy R & Wilkowske C (1987) Antituberculosis agents. Mayo Clinic Proceedings. 62: 1129-1136. Warrington R et al. (1977) Insidious Rifampicin-associated renal failure with light-chain proteinuria. Arch Intern Med, 137. Wong P, Bottorff MB, Heritage RW & et al. (1984) Acute rifampin overdose: A pharmacokinetic study and review of the literature. J pediat, 104: 781-783. 14. AUTHOR(S), REVIEWER(S), DATE(S)(INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author Kenneth Hartigan-Go, M.D. Department of Pharmacology UP College of Medicine Manila Philippines Tel 63-2-5218251 Fax 63-2-407168 Date January 1990 Reviewers M. Balali-Mood Poisons Centre Imam Reza Hospital Mashad 91735 Iran Tel 051-93043 Fax 051-92083 J. Magarey Poisons Information Centre Royal Childrens Hospital Melbourne 3052 Australia Tel 03-345 56 78 Peer review Adelaide, Australia, April 1991

    See Also:
       Toxicological Abbreviations
       Rifampicin (IARC Summary & Evaluation, Volume 24, 1980)