Usage
- This combination drug is prescribed for the treatment of drug-susceptible pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. It is used for the initial, intensive phase of treatment.
- Pharmacological classification: Anti-tuberculosis agents, combination antibiotic.
- Mechanism of Action: This four-drug combination acts synergistically to target different aspects of M. tuberculosis metabolism and reproduction. Isoniazid inhibits cell wall synthesis, rifampicin inhibits RNA polymerase, pyrazinamide disrupts bacterial metabolic processes, and ethambutol inhibits cell wall biosynthesis.
Alternate Names
- This combination is often referred to as RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol), 4-drug FDC, or 4FDC.
- Brand names: Rifater, Voractiv, Myrin-P Forte, Akit-4.
How It Works
- Pharmacodynamics: The combined bactericidal action of the four drugs rapidly reduces the bacterial load, leading to clinical improvement.
- Pharmacokinetics:
- Absorption: All four drugs are absorbed orally, though rifampicin absorption is best on an empty stomach. Food can reduce bioavailability.
- Metabolism: Rifampicin is a potent inducer of CYP450 enzymes, especially CYP3A4 and CYP2C9. Isoniazid inhibits CYP2C19 and CYP3A4. Pyrazinamide is metabolized in the liver. Ethambutol is partially metabolized and largely excreted unchanged.
- Elimination: Rifampicin is primarily excreted in bile and feces; isoniazid is renally excreted; pyrazinamide is renally excreted; and ethambutol is excreted primarily in urine and partially in feces.
- Mode of Action:
- Isoniazid inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall.
- Rifampicin inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis.
- Pyrazinamide disrupts mycobacterial membrane potential and energy production.
- Ethambutol inhibits arabinosyl transferases, disrupting cell wall synthesis.
Dosage
Standard Dosage
Adults:
- Weight-based dosing is recommended:
- 30-35 kg: 150 mg Rifampicin/75 mg Isoniazid/400 mg Pyrazinamide/275 mg Ethambutol (2 tablets Rifater, if using a combination product)
- 36-45 kg: 200 mg Isoniazid, 300 mg Rifampicin, 800 mg Pyrazinamide, 600 mg Ethambutol. This can sometimes be simplified as 3 tablets Rifater, if using a combination product.
- 46-55 kg: 300 mg Isoniazid, 450 mg Rifampicin, 1000-1200 mg Pyrazinamide, 800-1000 mg Ethambutol. This can sometimes be simplified as 4 tablets Rifater, if using a combination product.
- 56-70 kg: 300 mg Isoniazid, 450-600 mg Rifampicin, 1200-1600 mg Pyrazinamide, 1000-1200 mg Ethambutol. This can sometimes be simplified as 5 tablets Rifater, if using a combination product.
- >70 kg: 300 mg Isoniazid, 600 mg Rifampicin, 1600-2000 mg Pyrazinamide, 1200 mg Ethambutol. This can sometimes be simplified as 6 tablets Rifater, if using a combination product.
- Administered orally once daily.
Children:
- Weight-based dosing is essential: Refer to WHO guidelines for detailed weight-band specific dosing using dispersible or liquid formulations. Fixed-dose combination tablets are not suitable for children weighing less than 25 kg as dose adjustments are difficult with these.
- Pediatric Safety Considerations: Monitor closely for adverse reactions, especially hepatotoxicity.
Special Cases:
- Elderly Patients: Assess renal and hepatic function for potential dose adjustments.
- Patients with Renal Impairment: Dose reduction of all components might be necessary, depending on creatinine clearance.
- Patients with Hepatic Dysfunction: Use with caution and monitor closely for hepatotoxicity. Dose reduction may be necessary.
- Patients with Comorbid Conditions: Consider drug interactions and potential exacerbations of pre-existing conditions.
Clinical Use Cases
- The primary use case is the initial phase of drug-susceptible pulmonary tuberculosis treatment. These specific settings (intubation, surgical procedures, etc.) are not relevant for the drug’s clinical use in TB treatment.
Dosage Adjustments
- Dose adjustments are based on renal/hepatic function, drug interactions, and adverse reactions. Therapeutic drug monitoring (TDM) can be helpful in optimizing drug levels.
Side Effects
Common Side Effects:
- Nausea, vomiting, abdominal discomfort
- Loss of appetite, fatigue
- Mild rash, itching
- Arthralgias, myalgias
- Peripheral neuropathy (especially with isoniazid – administer pyridoxine 10 mg/day prophylactically)
- Discoloration of body fluids (reddish-orange) due to rifampicin.
Rare but Serious Side Effects:
- Hepatotoxicity (monitor liver function tests)
- Optic neuritis (ethambutol - perform regular eye exams)
- Thrombocytopenia, purpura, haemolytic anaemia
- Acute kidney injury
- Seizures (isoniazid)
- Gout (pyrazinamide - monitor uric acid levels)
Long-Term Effects:
- Peripheral neuropathy can persist after discontinuation of isoniazid.
- Visual impairment from ethambutol can be permanent if not detected and treated promptly.
Adverse Drug Reactions (ADR):
- Severe hypersensitivity reactions (rash, fever, eosinophilia, angioedema)
- Drug-induced hepatitis
- Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
Contraindications
- Acute liver disease
- Severe renal impairment
- Previous hypersensitivity reaction to any component drug
- Porphyria (use with caution)
- Concurrent use with voriconazole or certain protease inhibitors
Drug Interactions
- Rifampicin is a potent inducer of CYP3A4 and CYP2C9 and interacts with numerous drugs.
- Isoniazid inhibits CYP2C19 and CYP3A4.
- Avoid concomitant use with phenytoin, valproic acid, disulfiram.
- Interactions occur with: anticoagulants, anticonvulsants, antifungals, oral contraceptives, some HIV medications, immunosuppressants.
- Alcohol should be avoided due to increased risk of hepatotoxicity and dizziness.
- Antacids reduce rifampicin absorption.
Pregnancy and Breastfeeding
- Pregnancy: This combination is generally considered safe during pregnancy, though pyrazinamide is sometimes omitted due to limited safety data. Close monitoring is recommended. Pyridoxine supplementation should be considered.
- Breastfeeding: The drugs are excreted in breast milk. Breastfeeding is generally considered safe, though monitoring for infant side effects is advisable. Pyridoxine supplementation should be given to the breastfed infant if the mother is receiving isoniazid.
Drug Profile Summary
- Mechanism of Action: Combined bactericidal action targeting cell wall synthesis, RNA polymerase, and bacterial metabolism.
- Side Effects: Nausea, vomiting, hepatotoxicity, optic neuritis, peripheral neuropathy, rash, fever.
- Contraindications: Acute liver disease, severe renal impairment, hypersensitivity, porphyria, concomitant use with certain drugs.
- Drug Interactions: Numerous, especially due to rifampicin’s enzyme-inducing properties.
- Pregnancy & Breastfeeding: Generally considered safe with monitoring and pyridoxine supplementation; pyrazinamide may be omitted during pregnancy.
- Dosage: Weight-based dosing for both adults and children. Individual components are preferred when the fixed dose combination is not suitable.
- Monitoring Parameters: Liver function tests, visual acuity, complete blood count, uric acid, renal function.
Popular Combinations
- This four-drug combination (RIPE) is itself a popular combination for the treatment of drug-susceptible tuberculosis.
- Pyridoxine is co-administered with isoniazid to prevent peripheral neuropathy.
Precautions
- General Precautions: Baseline liver and renal function tests, vision testing. Monitor for adverse reactions throughout treatment.
- Specific Populations: As described in ‘Special Cases’ under Dosage.
- Lifestyle Considerations: Avoid alcohol. Advise against driving if experiencing dizziness or visual disturbances.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ethambutol + Isoniazid + Pyrazinamide + Rifampicin?
A: Weight-based dosing is crucial. Refer to detailed dosage guidelines provided earlier.
Q2: What are the most common side effects?
A: Nausea, vomiting, loss of appetite, fatigue, mild rash, and discoloration of body fluids (due to rifampicin).
Q3: What are the serious side effects that require monitoring?
A: Hepatotoxicity, optic neuritis, peripheral neuropathy, and hypersensitivity reactions.
Q4: Can this combination be used in pregnant women?
A: Generally yes, but pyrazinamide is sometimes omitted due to limited safety data. Careful monitoring is essential.
Q5: Can this combination be used in breastfeeding women?
A: Yes, it is generally considered safe. Monitor the infant for potential side effects. Supplementation with pyridoxine is recommended for breastfed infants whose mothers are on isoniazid therapy.
Q6: What are the contraindications to using this combination?
A: Acute liver disease, severe renal failure, porphyria, hypersensitivity to any component, and concomitant use with certain drugs like voriconazole or some protease inhibitors.
Q7: What are the key drug interactions to be aware of?
A: Rifampicin is a potent inducer of CYP450 enzymes, leading to interactions with numerous drugs. Isoniazid also has interactions, primarily through CYP inhibition. Always check for potential interactions before co-prescribing medications.
Q8: What monitoring parameters should be followed during treatment?
A: Liver function tests (LFTs), visual acuity (especially with ethambutol), renal function, complete blood count (CBC), and uric acid levels (with pyrazinamide).
Q9: What is the role of pyridoxine in this combination therapy?
A: Pyridoxine (vitamin B6) is co-administered with isoniazid to prevent peripheral neuropathy, a common side effect of isoniazid.
Q10: What should be done if a patient misses a dose?
A: The patient should take the missed dose as soon as they remember, unless it is close to the time for the next dose. Do not double the dose. Consistent dosing is essential for successful treatment.
