Rifampicin + Isoniazid

Oral
Tuberculosis

Max: 8 mg/kg daily.

Should be taken on an empty stomach. Take at least 30 min before or 2 hr after meals.

Hypersensitivity. Patient w/ jaundice. Concomitant use w/ saquinavir/ritonavir combination.

History of DM, psychosis, peripheral neuropathy. Patient w/ HIV infection, porphyria, malnutrition, slow acetylator status, epilepsy and alcohol dependence. Hepatic and severe renal impairment. Elderly. Pregnancy and lactation.

GI symptoms (e.g. anorexia, nausea, vomiting, constipation, diarrhoea), alterations in liver function, peripheral neuritis, optic neuritis, headache, drowsiness, convulsions, vertigo, blood disorders (e.g. leucopenia, haemolytic anaemia, aplastic anaemia, eosinophilia), dry mouth, itching w/ or w/o rash, flushing, urticaria, rash, purpura, pancreatitis, oedema, interstitial pneumonitis, hyperreflexia, hyperglycaemia, adrenal insufficiency, gynaecomastia, menstrual disturbances, difficulty in micturition, muscular weakness, myopathy, SLE-like syndrome, pellagra, exfoliative dermatitis, pemphigus, toxic epidermal necrolysis, pemphigoid reactions, orange-red discolouration of urine, saliva and other body secretions; hearing loss and tinnitus, influenza-like symptoms, resp symptoms, collapse and shock, thrombocytopenic purpura, disseminated intravascular coagulation, acute renal failure. Rarely, psychoses, pemphigoid reaction, erythema multiforme, Lyells syndrome and vasculitis.
Potentially Fatal: Severe/fatal hepatitis (e.g. jaundice).

PO: C

May impair ability to drive or operate machinery. May produce a reddish colouration of the urine, sweat, sputum, and tears. May permanently stain soft contact lenses. Patient should change from oral contraceptives to non-hormonal methods of birth control.

Monitor hepatic enzymes and function, bilirubin, serum creatinine, CBC and platelet count.

Symptoms: Rifampicin: Nausea, vomiting, abdominal pain, pruritus, headache, increasing lethargy, unconsciousness, transient increases in liver enzymes and/or bilirubin; brownish-red or orange colouration of the skin, urine, sweat, saliva and faeces; facial or periorbital oedema, hypotension, sinus tachycardia, ventricular arrhythmias, seizures, cardiac arrest. Isoniazid: Nausea, vomiting, dizziness, slurred speech, blurred vision, visual hallucinations, resp distress, CNS depression, progressing rapidly from stupor to profound coma, along w/ severe, intractable seizures; severe metabolic acidosis, acetonuria, hyperglycaemia. Management: Perform gastric lavage as soon as possible, followed by admin of activated charcoal. Antiemetic drug may be required to control severe nausea and vomiting. Symptomatic and supportive treatment, including airway patency. May admin IV pyridoxine if acute isoniazid overdose is suspected, or anticonvulsant therapy in seizures not controlled by pyridoxine. Na bicarbonate should be given to control metabolic acidosis.

May reduce effectivity of hormonal contraceptives. Reduced absorption w/ antacids. May decrease plasma concentrations of antivirals (e.g. atazanavir, darunavir, fosamprenavir), atovaquone w/ rifampicin. Rifampicin may reduce serum levels of the following drugs: anticonvulsants (e.g., phenytoin), antiarrhythmics (e.g. disopyramide), oral anticoagulants, antifungals (e.g. ketoconazole), barbiturates, β-blockers, Ca channel blockers (e.g. diltiazem), chloramphenicol, clarithromycin, corticosteroids, ciclosporin, cardiac glycosides, clofibrate, dapsone, diazepam, doxycycline, fluoroquinolones (e.g. ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline, TCAs (e.g. amitriptyline, nortriptyline) and zidovudine. Increased risk of hepatotoxicity w/ halothane. Isoniazid may inhibit the metabolism of anticonvulsants (e.g. carbamazepine, phenytoin), benzodiazepines (e.g. diazepam), haloperidol, ketoconazole, theophylline, and warfarin. May enhance the CNS effects of meperidine, cycloserine, and disulfiram w/ isoniazid. Loss of glucose control in patients on oral hypoglycaemics w/ isoniazid.
Potentially Fatal: Concurrent treatment w/ saquinavir/ritonavir combination may result to severe hepatotoxicity.

Absorption may be reduced and delayed w/ food. Increased adverse reaction w/ tyramine-containing foods (e.g. cheese, red wine) and histamine-containing foods (e.g. tuna, other tropical fish). Alcohol may increase the risk of hepatotoxicity.

May inhibit standard microbiological assays for serum folate and vit B12. May impair biliary excretion of contrast media used for visualisation of the gallbladder.

Description:
Mechanism of Action: Rifampicin and isoniazid are active bactericidal anti-TB drugs which are particularly active against the rapidly growing extracellular organisms and also have bactericidal activity intracellularly. Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts w/ bacterial RNA polymerase but does not inhibit the mammalian enzyme. Cross-resistance to rifampicin has only been shown w/ other rifamycins. It has activity against slow- and intermittently-growing M. tuberculosis. Isoniazid acts against actively growing tubercle bacilli.
Pharmacokinetics:
Absorption: Readily absorbed from the GI tract. Food may reduce and delay absorption. Time to peak plasma concentration: 1-2 hr (isoniazid); 2-4 (rifampicin).
Distribution: Rifampicin: Widely distributed in body tissues and fluids. Crosses the placenta and enters breast milk. Plasma protein binding: Approx 80%. Isoniazid: Distributed into all body tissues and fluids, including CSF. Crosses the placenta and enters breast milk.
Metabolism: Rifampicin: Rapidly metabolised hepatically, mainly to active 25-O-deacetylrifampicin. Isoniazid: Hepatic, via acetylation of isoniazid to acetylisoniazid by N-acetyltransferase. Acetylisoniazid is then hydrolysed to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is conjugated w/ glycine to isonicotinyl glycine (isonicotinuric acid) and monoacetylhydrazine is further acetylated to diacetylhydrazine. Some unmetabolised isoniazid is conjugated to hydrazones.
Excretion: Rifampicin: Via urine (up to 30%; approx half of it as unchanged drug) and faeces (approx 60%). Half-life: 2-5 hr. Isoniazid: Via urine (>75% mainly as metabolites) and faeces (small amounts). Plasma half-life: Approx 1-6 hr.

Store below 25°C.

Anti-TB Agents

Buckingham R (ed). Isoniazid. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/07/2014.

Buckingham R (ed). Rifampicin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/07/2014.

Joint Formulary Committee. Rifampicin with Isoniazid. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/07/2014.

Rifamate Capsule (Sanofi-Aventis U.S. LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 01/07/2014.