Rifampicin + Isoniazid + Pyrazinamide + Ethambutol

CrCl (mL/min)	Dosage
<30	Contraindicated.

Hypersensitivity. History of drug-induced hepatitis; acute liver disease (regardless of origin); porphyria, acute gouty arthritis. Severe renal impairment (CrCl <30 mL/min). Concomitant use with voriconazole and protease inhibitors (except ritonavir when given at full dose or 600 mg bid).

Patient with visual defects, history of gout; diabetes mellitus, convulsive disorder, peripheral or optic neuritis. Chronic alcoholics and undernourished patients. Slow acetylators of isoniazid. Hepatic impairment and moderate renal impairment (CrCl 30-60 mL/min). Elderly. Pregnancy and lactation.

Significant: Severe acute hypersensitivity reactions (e.g. thrombocytopenia, purpura, haemolytic anaemia, dyspnoea, asthma-like attacks, shock, renal failure), visual disturbances, elevated transaminase levels (above the ULN), peripheral neuropathy.
Eye disorders: Reddening of the eyes.
Gastrointestinal disorders: Nausea, abdominal pain, bloatedness, diarrhoea.
General disorders and administration site conditions: Reddish discolouration of body fluids and secretions (e.g. urine, sputum, lacrimal fluid, faeces, saliva, sweat), tiredness, fever.
Metabolism and nutrition disorders: Anorexia, hyperuricaemia.
Musculoskeletal and connective tissue disorders: Mild arthralgia, myalgia.
Nervous system disorders: Drowsiness, headache, dizziness.
Skin and subcutaneous tissue disorders: Flushing, pruritus with or without rash, urticaria, drug exanthema.
Potentially Fatal: Hepatitis.

This drug may cause red-orange discolouration of urine, faeces, saliva, sputum, sweat and tears; this is harmless, do not be alarmed. It may also cause permanent staining of soft contact lenses; remove soft contact lenses during therapy.

Perform culture and susceptibility tests; consult local institutional recommendations before treatment initiation due to antibiotic resistance risks. Monitor full blood count, LFTs, renal function tests, and serum uric acid before and during treatment. Perform ocular examination before starting and during treatment, particularly if high doses are used.

Symptoms: Rifampicin: Nausea, vomiting, abdominal pain, pruritus, headache, lethargy, impaired consciousness; brownish-red or orange discolouration of the skin, urine, sweat, saliva, tears, and faeces; hypotension, sinus tachycardia, ventricular arrhythmias, seizures, cardiac arrest. Isoniazid: Seizures, nausea, vomiting, fever, metabolic acidosis, ketonuria, hyperglycaemia, periorbital myoclonus, dizziness, tinnitus, tremor, hyperreflexia, paraesthesia, hallucinations, impaired consciousness; respiratory depression, apnoea; tachycardia, arrhythmia, hypotension, rhabdomyolysis, hyperkalaemia. Pyrazinamide: Abnormal LFTs and hyperuricaemia. Ethambutol: Loss of appetite, gastrointestinal disturbances, headache, dizziness, fever, confusion, hallucinations. Management: Symptomatic and supportive treatment. Perform gastric lavage. May administer activated charcoal slurry to help absorb any remaining drug in the gastrointestinal tract. Administer antiemetics to control severe nausea and vomiting. Induce active diuresis to help promote drug excretion. Pyridoxine may be used in case of seizures and metabolic acidosis caused by isoniazid. Haemodialysis or haemoperfusion may also be necessary. Correct metabolic acidosis and electrolyte disturbances.

May inactivate oral typhoid vaccine.
Rifampicin: May markedly reduce the plasma concentrations of voriconazole and protease inhibitors. Reduced bioavailability with antacids. May reduce the effectiveness of oral contraceptives. May reduce the plasma concentrations of antifungals (e.g. fluconazole, itraconazole), nevirapine, anticonvulsants (e.g. phenytoin), anticoagulants, antiarrhythmics (e.g. disopyramide, mexiletine, quinidine), chloramphenicol, ciprofloxacin, clarithromycin, barbiturates, antipsychotic agents (e.g. haloperidol, clozapine), diazepam, ciclosporin, Ca channel blockers (e.g. diltiazem, verapamil), β-blockers, dapsone, corticosteroids, cardiac glycosides, narcotic analgesics (e.g. methadone), oral hypoglycaemic agents (e.g. sulfonylureas), TCAs (e.g. nortriptyline), and theophylline. May delay the biliary excretion of contrast media during radiographic examination of the gallbladder. Increased serum concentration with atovaquone. Concomitant use of rifampicin with ketoconazole has led to reduced serum concentrations of both drugs.
Isoniazid: Reduced bioavailability with antacids. May reduce plasma levels with corticosteroids. May inhibit the metabolism of certain drugs such as anticonvulsants (e.g. carbamazepine, phenytoin, primidone), benzodiazepines (e.g. diazepam), theophylline, and warfarin.
Pyrazinamide: May reduce the serum concentration of ciclosporin. May reduce the effectiveness of probenecid on uric acid excretion.
Ethambutol: Reduced bioavailability with antacids.

Rifampicin: May delay and reduce absorption with food.
Isoniazid: Increased risk of hepatotoxicity with alcohol. Reduced rate and extent of absorption with food. Concomitant administration with foods containing tyramine (e.g. cheese, red wine) or histamine (e.g. tuna) may result in headache, palpitations, flushing or hypotension; avoid concomitant intake.

Rifampicin: May inhibit the standard microbiological assay's ability to measure serum folate and vitamin B₁₂.

Description:
Mechanism of Action: Rifampicin, a rifamycin antimycobacterial, binds to the β subunit of DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis and thus blocking RNA transcription.
Isoniazid prevents the synthesis of mycolic acids, the essential components of the bacterial cell wall. It is bactericidal at therapeutic levels against actively growing extracellular and intracellular Mycobacterium tuberculosis.
Pyrazinamide exerts a bactericidal effect on Mycobacterium tuberculosis. Its exact mechanism of action is not known; its activity appears to partly depend on its conversion to pyrazinoic acid (active metabolite), which lowers the intracellular pH to levels toxic to tubercle bacilli.
Ethambutol blocks arabinosyltransferase leading to impaired synthesis of mycobacterial cell wall.
Synonym(s): Rifampicin: Rifampin.
Pharmacokinetics:
Absorption: Rifampicin: Readily absorbed from the gastrointestinal tract. Food may delay and reduce absorption. Time to peak plasma concentration: Approx 2 hours.
Isoniazid: Readily absorbed from the gastrointestinal tract. Reduced rate and extent of absorption with food. Time to peak plasma concentration: 1-2 hours.
Pyrazinamide: Readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 2 hours.
Ethambutol: Absorbed from the gastrointestinal tract (approx 80%). Time to peak plasma concentration: 2-4 hours.
Distribution: Enters breast milk.
Rifampicin: Widely distributed in the body tissues and fluids; increased diffusion in the CSF when meninges are inflamed. Crosses the placenta. Plasma protein binding: Approx 80%.
Isoniazid: Distributed into all body tissues and fluids (including CSF). Crosses the placenta. Plasma protein binding: 10-15%.
Pyrazinamide: Widely distributed in body tissues and fluids; diffuses into the CSF.
Ethambutol: Widely distributed throughout the body (including lungs, kidneys, and erythrocytes); may diffuse into the CSF when meninges are inflamed. Crosses the placenta. Plasma protein binding: 20-30%.
Metabolism: Rifampicin: Rapidly metabolised in the liver into 25-O-deacetylrifampicin (active metabolite). Undergoes enterohepatic recirculation.
Isoniazid: Metabolised in the liver by N-acetyltransferase to acetylisoniazid, which undergoes further hydrolysis to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is then conjugated with glycine to form isonicotinyl glycine, while monoacetylhydrazine is acetylated to form diacetylhydrazine.
Pyrazinamide: Metabolised primarily in the liver via hydrolysis into pyrazinoic acid (major active metabolite), which is subsequently hydroxylated into 5-hydroxypyrazinoic acid (major excretory product).
Ethambutol: Metabolised partially in the liver into aldehyde and dicarboxylic acid derivatives (inactive metabolites).
Excretion: Rifampicin: Via faeces (60-65% as unchanged drug); urine (≤30% as unchanged drug). Elimination half-life: Approx 2-3 hours.
Isoniazid: Via urine (75-95% as unchanged drug and metabolites); faeces and saliva (small amounts). Elimination half-life: 30-100 minutes (fast acetylators); 2-5 hours (slow acetylators).
Pyrazinamide: Via urine (approx 70%; mainly as metabolites, approx 4% as unchanged drug). Elimination half-life: Approx 9-10 hours.
Ethambutol: Via urine (approx 50% as unchanged drug, 8-15% as metabolites); faeces (approx 20% as unchanged drug). Elimination half-life: 2.5-3.6 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 135398735, Rifampin. https://pubchem.ncbi.nlm.nih.gov/compound/Rifampin. Accessed Nov. 26, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3767, Isoniazid. https://pubchem.ncbi.nlm.nih.gov/compound/Isoniazid. Accessed Nov. 26, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 1046, Pyrazinamide. https://pubchem.ncbi.nlm.nih.gov/compound/Pyrazinamide. Accessed Nov. 26, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 14052, Ethambutol. https://pubchem.ncbi.nlm.nih.gov/compound/Ethambutol. Accessed Nov. 26, 2024.

Store below 30°C.

Anti-TB Agents

J04AM06 - rifampicin, pyrazinamide, ethambutol and isoniazid ; Belongs to the class of combination drugs used in the systemic treatment of tuberculosis.

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