Rifampicin + Isoniazid + Ethambutol

Hypersensitivity. Optic neuritis, jaundice.

Patient with pre-existing hepatic disease; diabetes, convulsive disorder, history of psychosis; visual defects. Patient at risk of neuropathy or pyridoxine deficiency (e.g. uraemia, HIV infection, malnourishment, alcoholism). Slow acetylators of isoniazid. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.

Significant: Hyperbilirubinaemia, thrombocytopenia, purpura, peripheral neuropathy; optic neuritis resulting in reduced visual acuity or other vision changes; red-orange discolouration of faeces and body fluids (e.g. urine, sweat, saliva, sputum, tears).
Blood and lymphatic system disorders: Anaemia, agranulocytosis, eosinophilia.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, epigastric distress.
General disorders and administration site conditions: Flu-like syndrome, oedema.
Immune system disorders: Hypersensitivity reactions.
Infections and infestations: Pseudomembranous colitis.
Investigations: Transient increase in liver enzymes.
Metabolism and nutrition disorders: Anorexia, pellagra, hyperglycaemia. Rarely, acute gout.
Musculoskeletal and connective tissue disorders: Myopathy, muscular weakness.
Nervous system disorders: Headache, drowsiness, dizziness, ataxia, numbness, convulsions.
Psychiatric disorders: Psychotic reactions.
Renal and urinary disorders: Altered renal function, urinary retention, renal failure.
Reproductive system and breast disorders: Menstrual disturbances, gynaecomastia.
Skin and subcutaneous tissue disorders: Lupus-like syndrome, severe cutaneous adverse reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms).
Potentially Fatal: Hepatitis.

May cause red-orange discolouration of urine, faeces, saliva, sputum, sweat, tears, and other body fluids. 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 liver function, blood counts and serum creatinine concentrations before and during treatment. Perform ocular examination before and during treatment.

Symptoms: Rifampicin: Nausea, vomiting, abdominal pain, pruritus, headache, lethargy, impaired consciousness, periorbital or facial oedema; brownish-red or orange discolouration of the skin, urine, sweat, saliva, tears, and faeces; hypotension, sinus tachycardia, ventricular arrhythmias, seizures, cardiac arrest; liver enlargement (possibly with tenderness), jaundice and rapid increases in total and direct serum bilirubin and hepatic enzymes. Isoniazid: Nausea, vomiting, slurred speech, dizziness, hallucinations; respiratory distress and CNS depression, progressing rapidly from stupor to coma, severe intractable convulsions, metabolic acidosis, hyperglycaemia and acetonuria. 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. Haemodialysis or peritoneal dialysis may also be necessary. Correct metabolic acidosis. Secure airway and establish adequate respiratory exchange immediately during isoniazid overdosage. For isoniazid-induced convulsions, administer initial doses of IV diazepam or lorazepam; in resistant cases, IV pyridoxine equivalent to the estimated amount of isoniazid ingested may also be given.

Rifampicin: May increase the metabolism of certain drugs by inducing microsomal hepatic enzymes (particularly CYP3A) or drug transporter proteins (e.g. P-gp). Reduced absorption with antacids, ketoconazole, or preparations containing bentonite. May reduce the effectiveness of hormonal contraceptives.
Isoniazid: Reduced absorption with Al-containing antacids. Increased risk of hepatotoxicity with rifampicin or other potentially hepatotoxic agents. May inhibit the hepatic metabolism of certain drugs such as antiepileptics (e.g. carbamazepine, ethosuximide, phenytoin), benzodiazepines (e.g. diazepam, triazolam), chlorzoxazone and theophylline. May increase the serum concentrations or toxicity of clofazimine, cycloserine and warfarin.

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 sweating; avoid concomitant intake.

Rifampicin: May inhibit the standard microbiologic 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.
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.
Ethambutol: Absorbed from the gastrointestinal tract (approx 80%). Time to peak plasma concentration: 2-4 hours.
Distribution: Crosses the placenta and enters breast milk.
Rifampicin: Widely distributed in the body tissues and fluids; increased diffusion in the CSF when meninges are inflamed. Plasma protein binding: Approx 80%.
Isoniazid: Distributed into all body tissues and fluids (including CSF). Plasma protein binding: 10-15%.
Ethambutol: Widely distributed throughout the body (including lungs, kidneys, and erythrocytes); may diffuse into the CSF when meninges are inflamed. 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.
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).
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 14052, Ethambutol. https://pubchem.ncbi.nlm.nih.gov/compound/Ethambutol. Accessed Nov. 26, 2024.

Store below 30°C.

Anti-TB Agents

J04AM07 - rifampicin, ethambutol and isoniazid ; Belongs to the class of combination drugs used in the systemic treatment of tuberculosis.

Anon. Ethambutol. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/12/2024.

Anon. Isoniazid. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/12/2024.

Anon. Rifampin. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/12/2024.

Brayfield A, Cadart C (eds). Ethambutol Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/12/2024.

Brayfield A, Cadart C (eds). Isoniazid. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/12/2024.

Brayfield A, Cadart C (eds). Rifampicin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/12/2024.

Ethambutol. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 03/12/2024.

Ethambutol. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 03/12/2024.

Fixcom 2/Fixcom 3/Fixcom 4 (Natrapharm, Inc). MIMS Philippines. http://www.mims.com/philippines. Accessed 03/12/2024.

Isoniazid, INH. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 03/12/2024.

Isoniazid. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 03/12/2024.

Rifampicin [Rifampin]. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 03/12/2024.

Rifampin. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 03/12/2024.