Rifampicin + Isoniazid + Pyrazinamide


Concise Prescribing Info
Indications/Uses
Pulmonary tuberculosis.
Dosage/Direction for Use
Adult : PO For the initial intensive phase of the short-course treatment: Each tab contains rifampicin (mg)/isoniazid (mg)/pyrazinamide (mg): 120/50/300: <40 kg: 3 tablets/day; 40-49 kg: 4 tablets/day; 50-64 kg: 5 tablets/day; ≥65 kg: 6 tablets/day. Initial phase usually lasts for 2 months with doses given on a daily continuous basis.
Dosage Details
Oral
Pulmonary tuberculosis
Adult: Available preparation:
Rifampicin 120 mg, isoniazid 50 mg, and pyrazinamide 300 mg tablet

For the initial intensive phase of the short-course treatment of pulmonary tuberculosis: <40 kg: 3 tablets daily; 40-49 kg: 4 tablets daily; 50-64 kg: 5 tablets daily; ≥65 kg: 6 tablets daily. Initial phase usually lasts for 2 months with doses given on a daily continuous basis. Once the initial phase is completed, may continue treatment with the combination of rifampicin-isoniazid.
Special Patient Group
Isoniazid, a part of the rifampicin and pyrazinamide combination, is primarily metabolised via acetylation and dehydronisation. Acetylation rate does not significantly alter the effectiveness of isoniazid; however, it is genetically determined. Approx 50% of African Americans and Caucasians are considered as slow inactivators or acetylators, while most of Asians and Eskimos are considered rapid inactivators or acetylators.

According to the FDA-approved label for rifampicin, isoniazid, and pyrazinamide combination, individuals known as slow acetylators or inactivators may have increased blood levels of isoniazid and may be at higher risk for its toxic reactions.
Hepatic Impairment
Severe: Contraindicated.
Administration
Should be taken on an empty stomach. Take 1 hr before or 2 hr after meals. Avoid antacids w/in 1 hr of intake.
Contraindications
Hypersensitivity. History of severe adverse reaction to isoniazid, acute liver disease, jaundice, acute gout. Severe hepatic impairment. Concomitant use with praziquantel, darunavir, atazanavir, fosamprenavir, saquinavir, saquinavir/ritonavir, or tipranavir.
Special Precautions
Patient with diabetes mellitus, chronic gout, risk factors of vitamin K deficiency (e.g. chronic liver disease, poor nutritional status, prolonged use of antibacterials or anticoagulants); epilepsy, history of alcoholism, psychosis, peripheral neuropathy; HIV infection, haemoptysis, porphyria. Renal and mild to moderate hepatic impairment. Pregnancy and lactation. Slow acetylator status.
Adverse Reactions
Significant: Vitamin K-dependent coagulation disorder and bleeding, flu-like syndrome, haematologic effects (e.g. thrombocytopenia, leucopenia, anaemia); hypersensitivity reactions (e.g. fever, rash, urticaria, angioedema), porphyria exacerbation, peripheral neuropathies, hyperuricaemia with acute gouty arthritis; superinfection, including C. difficile-associated diarrhoea and pseudomembranous colitis.
Cardiac disorders: Angina pectoris, chest tightness, palpitations.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, gastrointestinal pain.
General disorders and administration site conditions: Fever, chills, oedema.
Investigations: Increased blood bilirubin, increased AST and ALT.
Metabolism and nutrition disorders: Diabetic coma, anorexia.
Musculoskeletal and connective tissue disorders: Arthralgia, ostealgia.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Anxiety, insomnia.
Respiratory, thoracic and mediastinal disorders: Haemoptysis, pneumothorax, cough.
Skin and subcutaneous tissue disorders: Erythema, erythroderma, exfoliative dermatitis, localised rash, pruritus, diaphoresis.
Potentially Fatal: Hepatotoxicity (e.g. severe hepatitis, isolated jaundice, hyperbilirubinaemia, fulminant liver failure), severe cutaneous adverse reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms syndrome [DRESS]).
Patient Counseling Information
This drug may cause vertigo, visual disorder and psychotic reactions; if affected, do not drive or operate machinery. May produce a discolouration (e.g. red, orange, brown, yellow) of the urine, faeces, saliva, teeth, sweat, and tears. Soft contact lenses may be permanently stained; remove soft contact lenses during therapy.
MonitoringParameters
Perform culture and susceptibility tests; consult local institutional recommendations before treatment initiation due to antibiotic resistance risks. Monitor LFTs at baseline and every 2-4 weeks particularly in patients at risk of hepatitis; CBC and platelet count, serum bilirubin, serum uric acid, and serum creatinine at baseline and periodically thereafter; coagulation test during therapy in patients at risk of vitamin K deficiency. Monitor sputum cultures monthly; chest x-ray after 2-3 months of therapy and at completion. Closely monitor for prodromal signs of hepatitis and skin reactions. Perform ophthalmologic examination periodically (even if visual symptoms do not occur).
Overdosage
Symptoms: Rifampicin: Nausea, vomiting, abdominal pain, headache, pruritus, increasing lethargy, unconsciousness, transient increase in hepatic enzymes and bilirubin; brownish-red or orange discolouration of skin sweat, urine, faeces, saliva or tears; facial or periorbital oedema (children), hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest. Isoniazid: Nausea, vomiting, dizziness, blurring of vision, slurring of speech, and visual hallucinations. Severe: Respiratory distress and CNS depression progressing rapidly from stupor to coma, along with severe, intractable seizures, severe metabolic acidosis, acetonuria and hyperglycaemia. Pyrazinamide: Liver toxicity and hyperuricaemia. Management: Supportive treatment. Perform gastric lavage as soon as possible, followed by instillation of activated charcoal. May give antiemetics if necessary. If acute isoniazid overdose is suspected, consider administration of IV pyridoxine (Vitamin B6). Administer anticonvulsants for uncontrolled seizures. Na bicarbonate may be given for metabolic acidosis.
Drug Interactions
Rifampicin: Decreased plasma concentrations of praziquantel to undetectable levels. May induce the metabolism and decrease the serum concentrations and effects of antiarrhythmics (e.g. disopyramide, quinidine), antiepileptics (e.g. phenytoin), hormone antagonist (e.g. antioestrogens, tamoxifen), antipsychotics (e.g. haloperidol, aripiprazole), anticoagulants (e.g. warfarin), antifungals (e.g. fluconazole, itraconazole), barbiturates, anxiolytics and hypnotics (e.g. diazepam), Ca channel blocker (e.g. diltiazem, nifedipine), antibacterials (e.g. clarithromycin, chloramphenicol), corticosteroids, cardiac glycosides (e.g. digoxin), hormonal contraceptives (e.g. oestrogen, progesterone), antidiabetics (e.g. tolbutamide, sulfonylureas), immunosuppressive agents (e.g. ciclosporin), thyroid hormone (e.g. levothyroxine), analgesics (methadone), selective 5-HT3 receptor antagonist (e.g. ondansetron), TCAs (e.g. amitriptyline), cytotoxics (e.g. imatinib), diuretics (e.g. eplerenone), hepatitis-C antivirals (e.g. sofosbuvir), ACE inhibitors (e.g. enalapril), NSAIDS (e.g. etoricoxib), antiemetics (e.g. aprepitant); morphine, theophylline, quinine, riluzole, losartan, simvastatin, clofibrate, irinotecan, tadalafil. Increased risk of hepatoxicity with halothane, isoniazid. Absorption may be reduced by antacids.
Isoniazid: May increase the risk of distal sensory neuropathy with stavudine. Increased renal clearance with zalcitabine in HIV infected patients. May increase the plasma concentration and elimination half-life with para-aminosalicylic acid. May cause hepatoxicity with general anaesthetics. Absorption may be reduced by antacids. Increased risk of CNS toxicity with ciclosporin. May reduce the plasma concentration of ketoconazole. May increase the plasma levels of theophylline. Inhibits the metabolism of anticonvulsants and benzodiazepines.
Pyrazinamide: May antagonise the effects of probenecid and sulfinpyrazone.
Potentially Fatal: Rifampicin: Increased risk of severe hepatotoxicity with saquinavir/ritonavir combination. May substantially decrease the plasma levels and efficacy of atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir which may result in development of viral resistance. May cause severe coagulation disorders with cefazolin and other cephalosporins containing N-methylthiotetrazole side chain.
Food Interaction
Rifampicin: May reduce and delay absorption with food.
Isoniazid: Reduced rate and extent of absorption with food. Avoid tyramine-containing foods (e.g. cheese, red wine) and histamine-containing foods (e.g. tuna, other tropical fish) as it may cause exaggerated adverse reactions (e.g. headache, sweating, palpitations, flushing, and hypotension). Hepatotoxic effects may be enhanced by alcohol.
Pyrazinamide: May slightly reduce the peak serum levels with high-fat meals.
Lab Interference
Rifampicin: May inhibit the standard assays for serum folate and vitamin B12. Reduced biliary excretion of contrast media used for visualisation of the gallbladder. Cross-reactivity and false-positive urine screening tests for opiates using the Kinetic Interaction of Microparticles in Solution (KIMS) method (e.g. Roche diagnostic systems, Abuscreen online opiates assay); positive direct Coombs’ reaction.
Isoniazid: May cause false-positive urinary glucose with Clinitest®.
Pyrazinamide: May interfere with Acetest® and Ketostix® urine tests to produce pink-brown colour.
Action
Description: Rifampicin, isoniazid and pyrazinamide are all active bactericidal anti-tuberculosis agents.
Rifampicin: Rifampicin binds to the β subunit of DNA-dependent RNA polymerase, thus inhibiting the bacterial RNA synthesis.
Isoniazid: Isoniazid inhibits the synthesis of mycolic acids, the essential components of the bacterial cell wall. It is bactericidal at therapeutic levels against the actively growing extracellular and intracellular Mycobacterium tuberculosis organisms.
Pyrazinamide: Pyrazinamide is converted into pyrazinoic acid in susceptible strains of Mycobacterium which decreases the pH of the environment.
Synonym: Rifampicin: rifampin. Isoniazid: isonicotinic acid hydrazide.
Duration: Rifampicin: ≤24 hours.
Pharmacokinetics:
Absorption: Rifampicin: Readily and well absorbed from the gastrointestinal tract. May reduce and delay absorption with food. Time to peak plasma concentration: 2-4 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 and well absorbed from the gastrointestinal tract. May slightly reduce the peak serum concentration with food, particularly high fat meal. Time to peak plasma concentration: Approx 2 hours.
Distribution: Rifampicin: Widely distributed in the body tissues and fluids; increased diffusion into the CSF with inflamed meninges. Crosses the blood-brain barrier and placenta; enters breast milk. Plasma protein binding: Approx 80%.
Isoniazid: Distributed in all body tissues and fluids, including CSF. Crosses the placenta and enters breast milk. Plasma protein binding: Approx 10-15%.
Pyrazinamide: Widely distributed in the body tissues and fluids, including the liver, lungs, and CSF. Enters breast milk. Plasma protein binding: 50%.
Metabolism: Rifampicin: Rapidly metabolised in the liver mainly to active 25-O-deacetylrifampicin; undergoes enterohepatic recirculation.
Isoniazid: Metabolised in the liver and small intestine via acetylation to acetylisoniazid by N-acetyltransferase; undergoes further hydrolysis to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is then conjugated with glycine into isonicotinyl glycine while monoacetylhydrazine is further acetylated to diacetylhydrazine. Unmetabolised isoniazid is conjugated to hydrazones.
Pyrazinamide: Metabolised mainly in the liver via hydrolysis to major active metabolite pyrazinoic acid; subsequently hydroxylated to 5-hydroxypyrazinoic acid.
Excretion: Rifampicin: Via faeces (60-65%); urine (approx 30% as unchanged drug). Elimination half-life: 3-4 hours.
Isoniazid: Via urine (75-95% as unchanged drug and metabolites); faeces and saliva (small amounts). Elimination half-life: 0.5-1.6 hours (fast acetylators); 2-5 hours (slow acetylators).
Pyrazinamide: Via urine (approx 70% mainly as metabolites, 4% as unchanged drug). Elimination half-life: 9-10 hours.
Chemical Structure

Chemical Structure Image
Rifampicin

Source: National Center for Biotechnology Information. PubChem Database. Rifampicin, CID=135398735, https://pubchem.ncbi.nlm.nih.gov/compound/Rifampicin (accessed on Jan. 22, 2020)


Chemical Structure Image
Isoniazid

Source: National Center for Biotechnology Information. PubChem Database. Isoniazid, CID=3767, https://pubchem.ncbi.nlm.nih.gov/compound/Isoniazid (accessed on Jan. 21, 2020)


Chemical Structure Image
Pyrazinamide

Source: National Center for Biotechnology Information. PubChem Database. Pyrazinamide, CID=1046, https://pubchem.ncbi.nlm.nih.gov/compound/Pyrazinamide (accessed on Jan. 22, 2020)

Storage
Store at 25°C. Protect from excessive humidity.
MIMS Class
ATC Classification
J04AM05 - rifampicin, pyrazinamide and isoniazid ; Belongs to the class of combination drugs used in the systemic treatment of tuberculosis.
References
Annotation of FDA Label for Isoniazid/Pyrazinamide/Rifampin and NAT2. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 23/06/2020.

Anon. Isoniazid. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/06/2020.

Anon. Pyrazinamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/06/2020.

Anon. Rifampin, Isoniazid, and Pyrazinamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/06/2020.

Anon. Rifampin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/06/2020.

Buckingham R (ed). Isoniazid. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/06/2020.

Buckingham R (ed). Pyrazinamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/06/2020.

Buckingham R (ed). Rifampicin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/06/2020.

Joint Formulary Committee. Rifampicin with Isoniazid and Pyrazinamide. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/06/2020.

Rifater Tablet, Sugar Coated (Sanofi-Aventis U.S. LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/06/2020.

Rifater Tablets (Aventis Pharma Limited). MHRA. https://products.mhra.gov.uk/. Accessed 04/06/2020.

Disclaimer: This information is independently developed by MIMS based on Rifampicin + Isoniazid + Pyrazinamide from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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