Rifampicin + Isoniazid

Approved Indications:

• Active Tuberculosis (TB):
  Used as part of combination therapy for the treatment of all forms of active pulmonary and extrapulmonary TB, including drug-sensitive Mycobacterium tuberculosis.
• Latent Tuberculosis Infection (LTBI):
  Short-course regimen for latent TB, particularly in patients with recent exposure, immunosuppression, or HIV-positive individuals.

Off-label/Clinically Accepted Uses:

• Prophylaxis of TB:
  In selected contacts of patients with active TB (especially children and immunocompromised adults) when susceptibility is confirmed and multi-drug therapy is not required.

Route: Oral

General Recommendations:
Rifampicin + Isoniazid should always be used in combination with other anti-tubercular drugs to avoid resistance.

Adults:

• Intensive Phase (2 months):
  Rifampicin 10 mg/kg + Isoniazid 5 mg/kg once daily
  Usual fixed dose: Rifampicin 300–450 mg + Isoniazid 150–300 mg once daily

Pediatrics:

• Rifampicin: 10–20 mg/kg/day (maximum 600 mg/day)
• Isoniazid: 10–15 mg/kg/day (maximum 300 mg/day)

Elderly:

• Same as adult dosing with careful monitoring of liver function.

Renal Impairment:

• No dosage adjustment typically required; monitor for accumulation of metabolites.

Hepatic Impairment:

• Mild to moderate: Use with caution; monitor liver enzymes.
• Severe: Contraindicated due to risk of hepatotoxicity.

Administration Notes:

• Administer on an empty stomach (1 hour before or 2 hours after meals) for optimal absorption.
• Continue for a full course (minimum 6 months in total TB treatment).

Rifampicin inhibits DNA-dependent RNA polymerase in mycobacterial cells, blocking RNA synthesis and resulting in bactericidal activity.
Isoniazid inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall, leading to cell death.
Together, they exert a synergistic effect, rapidly reducing the bacterial load in active TB and preventing resistance when used as part of multidrug therapy.

• Absorption: Rapidly absorbed from the gastrointestinal tract. Rifampicin’s absorption is reduced by food.
• Bioavailability: Rifampicin ~70%, Isoniazid ~90%.
• Distribution: Widely distributed in body fluids and tissues, including lungs and cerebrospinal fluid.
• Protein Binding: Rifampicin ~80%, Isoniazid <10%.
• Metabolism:
• Rifampicin: Hepatic (deacetylation); potent inducer of CYP450 enzymes.
• Isoniazid: Hepatic via acetylation (NAT2 enzyme) — genetically influenced (fast vs. slow acetylators).
• Half-life:
• Rifampicin: 2–5 hours
• Isoniazid: 1–4 hours (variable)
• Excretion:
• Rifampicin: Mainly biliary and fecal, some renal.
• Isoniazid: Renal (as metabolites).

• Pregnancy:
• Isoniazid: FDA Pregnancy Category C
• Rifampicin: FDA Pregnancy Category C
• May be used in pregnancy when benefits outweigh risks. Supplement with vitamin B6 (pyridoxine) to reduce risk of neurotoxicity.
• Lactation:
• Both drugs are excreted in breast milk in small amounts. Generally considered compatible with breastfeeding, though infants should be monitored for hepatic function and signs of toxicity.

• Primary Class: Antitubercular Agents
• Subclass: First-line Anti-TB Combination Therapy
• Fixed-Dose Combination (FDC): WHO-recommended

• Hypersensitivity to rifampicin, isoniazid, or any excipients
• Severe hepatic impairment or active liver disease
• History of drug-induced hepatitis from prior TB therapy
• Concomitant use with certain antiretroviral or antifungal agents (e.g., protease inhibitors) due to severe drug interactions
• Acute porphyria (isoniazid-related)

• Hepatotoxicity: Monitor liver function tests before and during therapy, especially in elderly, alcoholics, and patients with pre-existing liver disease.
• Peripheral Neuropathy: Risk increased in malnourished or diabetic patients; supplement with pyridoxine.
• Orange-red discoloration of body fluids (e.g., urine, tears) due to rifampicin — harmless but must warn patients.
• Drug-induced lupus (rare) with isoniazid.
• Immune-mediated reactions: Flu-like symptoms, thrombocytopenia, hemolytic anemia (mainly with intermittent rifampicin).
• Interaction Monitoring: Regularly assess co-administered drugs due to strong CYP450 induction by rifampicin.

Common:

• Hepatic: Elevated liver enzymes, hepatitis
• Neurologic: Headache, dizziness, peripheral neuropathy (isoniazid)
• GI: Nausea, vomiting, abdominal pain
• Hematologic: Mild anemia

Less Common:

• Skin rash, fever, arthralgia
• Orange-red discoloration of urine, sweat, saliva (rifampicin)

Serious/Rare:

• Fulminant hepatitis
• Stevens-Johnson syndrome
• Thrombocytopenia, leukopenia
• Drug-induced lupus
• Anaphylaxis (rare hypersensitivity)

• CYP450 Interactions:
• Rifampicin induces CYP3A4, CYP2C9, CYP2C19, reducing efficacy of:
• Oral contraceptives
• Warfarin
• Protease inhibitors (HIV therapy)
• Azole antifungals
• Avoid rifampicin with protease inhibitors or switch to rifabutin
• Isoniazid inhibits CYP2C9 and CYP2C19, which can increase levels of:
• Phenytoin
• Carbamazepine
• Theophylline
• Alcohol: Increases hepatotoxicity risk
• Antacids: Reduce rifampicin absorption — space by at least 2 hours

• WHO (latest TB guidelines):
• Endorses fixed-dose combination therapy to improve compliance and reduce resistance
• Recommends shorter-course regimens for latent TB using rifampicin + isoniazid for 3 months
• CDC & NICE:
• Emphasize liver monitoring, especially with concurrent hepatotoxic drugs
• Recent safety alerts remind prescribers about severe hepatotoxicity risks and drug interactions in elderly and polypharmacy patients

• Store below 30°C, in a cool, dry place
• Protect from light and moisture
• Keep in original blister pack or container until use
• Do not freeze
• For oral suspension, shake well before use and follow reconstitution instructions carefully (if applicable)