Usage
- This fixed-dose combination (FDC) medication is primarily prescribed for the treatment of drug-susceptible pulmonary tuberculosis (TB), specifically during the intensive phase of treatment.
- Pharmacological Classification: Anti-tuberculosis agents, combination drug.
- Mechanism of Action: This combination targets Mycobacterium tuberculosis through multiple pathways, exerting a bactericidal effect. Rifampicin inhibits bacterial RNA polymerase. Isoniazid disrupts mycolic acid synthesis. Pyrazinamide disrupts mycobacterial cell membrane metabolism. Ethambutol inhibits arabinosyl transferases, enzymes involved in cell wall synthesis. Piperine enhances bioavailability of the other drugs, especially rifampicin.
Alternate Names
- Rifampicin + Isoniazid + Pyrazinamide + Ethambutol + Piperine
- Anti-tuberculosis combination therapy (containing Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, and Piperine)
- RIPE + Piperine
How It Works
- Pharmacodynamics: The combination exerts a bactericidal effect against M. tuberculosis by targeting different aspects of bacterial metabolism and cell wall synthesis, leading to bacterial death.
- Pharmacokinetics:
- Absorption: Orally administered; absorption of rifampicin is affected by food. Best taken on an empty stomach.
- Metabolism: Primarily hepatic metabolism for rifampicin, isoniazid, and pyrazinamide. Ethambutol is partially metabolized.
- Elimination: Renal excretion is the major route for all components, except for rifampicin, which is primarily biliary excreted.
- Mode of Action: See “Mechanism of Action” under “Usage.”
Dosage
Standard Dosage
Adults:
- Dosage is based on body weight, aligned with WHO guidelines:
- 30-37 kg: 2 tablets/day as a single dose
- 38-54 kg: 3 tablets/day as a single dose
- 55-70 kg: 4 tablets/day as a single dose
- ≥ 71 kg: 5 tablets/day as a single dose
Intensive phase typically lasts two months, followed by a continuation phase with a different drug regimen.
Children:
- Safety and efficacy not established in children under 13 years old (or weighing less than 20 kg). Alternative formulations and dosing strategies are required for pediatric patients. Refer to WHO guidelines for pediatric dosing of individual components.
Special Cases:
- Elderly Patients: Administer with caution; closely monitor liver and renal function. Dose adjustment may be necessary.
- Patients with Renal Impairment: Individual components require dose adjustments based on creatinine clearance or glomerular filtration rate (GFR).
- Patients with Hepatic Dysfunction: Close monitoring of liver function is essential. Dosage adjustments may be necessary for isoniazid, rifampicin, and pyrazinamide due to hepatic metabolism.
- Patients with Comorbid Conditions: Careful evaluation and potential dose adjustments may be necessary in patients with diabetes, HIV, or other conditions.
Clinical Use Cases
The use of this specific FDC is limited to the treatment of drug-susceptible pulmonary TB. The listed scenarios (intubation, surgical procedures, etc.) are not relevant to the use of this FDC.
Dosage Adjustments
- Dose modifications are necessary based on patient-specific factors, including renal/hepatic dysfunction, metabolic disorders, or genetic polymorphisms affecting drug metabolism. Consider therapeutic drug monitoring for optimization.
Side Effects
Common Side Effects
- Nausea, vomiting
- Loss of appetite
- Abdominal discomfort
- Mild skin rash, itching
- Headache, dizziness
- Flu-like symptoms
- Reddish-orange discoloration of body fluids (urine, sweat, tears) – harmless effect of rifampicin
Rare but Serious Side Effects
- Hepatotoxicity (liver damage) – evidenced by jaundice, dark urine, pale stools
- Optic neuritis (ethambutol) – changes in vision, blurred vision, eye pain
- Peripheral neuropathy (isoniazid) – numbness, tingling, burning in hands and feet
- Thrombocytopenia, purpura, hemolytic anemia (rifampicin)
- Severe hypersensitivity reactions – fever, chills, joint pain, skin rash, difficulty breathing
Long-Term Effects
- Chronic liver disease (with prolonged use of isoniazid, rifampicin, pyrazinamide)
- Persistent peripheral neuropathy
Adverse Drug Reactions (ADR)
ADRs are essentially the same as the rare but serious side effects. Any sign of hepatotoxicity, optic neuritis, peripheral neuropathy, or severe hypersensitivity requires immediate discontinuation of the drug and prompt medical intervention.
Contraindications
- Hypersensitivity to any of the components (rifampicin, isoniazid, pyrazinamide, ethambutol, piperine)
- Severe liver disease (acute or chronic)
- Acute gout
- Concurrent use with voriconazole or HIV protease inhibitors
- Optic neuritis (ethambutol contraindicated unless benefits outweigh risks)
- Porphyria (use rifampicin with caution)
Drug Interactions
- Rifampicin: Induces CYP450 enzymes, decreasing the effectiveness of many drugs, including warfarin, oral contraceptives, some anticonvulsants, antifungals, corticosteroids, and HIV medications.
- Isoniazid: Inhibits metabolism of certain drugs, such as phenytoin. Can enhance the effects of alcohol.
- Pyrazinamide: Can increase serum uric acid levels, interacting with medications for gout.
- Ethambutol: Avoid concomitant use of other drugs that can cause optic neuritis.
- Food Interactions: Avoid alcohol while on this medication. Consult a dietitian for dietary recommendations.
Pregnancy and Breastfeeding
- Pregnancy: While individual components have generally shown a good safety record, caution is advised during pregnancy. Use only if benefits clearly outweigh the risks. Pyridoxine supplementation is recommended with isoniazid.
- Breastfeeding: All components are excreted in breast milk to varying degrees. Monitor infants for potential side effects.
Drug Profile Summary
- Mechanism of Action: Targets M. tuberculosis through multiple pathways inhibiting RNA synthesis, mycolic acid synthesis, cell wall synthesis, and disrupting cell membrane function. Piperine enhances bioavailability.
- Side Effects: Common: Nausea, vomiting, rash, headache. Serious: Hepatotoxicity, optic neuritis, peripheral neuropathy.
- Contraindications: Hypersensitivity, severe liver disease, acute gout, concomitant use with certain drugs, optic neuritis.
- Drug Interactions: Rifampicin induces CYP450; isoniazid inhibits metabolism of some drugs; interactions with anticoagulants, anticonvulsants, antifungals.
- Pregnancy & Breastfeeding: Use with caution; monitor infants.
- Dosage: Weight-based; intensive phase two months, followed by continuation phase.
- Monitoring Parameters: Liver function tests, renal function tests, complete blood count, visual acuity (for ethambutol), uric acid (for pyrazinamide).
Popular Combinations
This FDC already contains the most popular combination for the intensive phase of TB treatment.
Precautions
- General Precautions: Baseline liver and renal function tests, vision testing (ethambutol), and uric acid levels (pyrazinamide). Monitor for adverse events.
- Specific Populations:
- Pregnant Women: Use with caution only if benefits outweigh risks. Supplement with pyridoxine.
- Breastfeeding Mothers: Monitor infants for potential side effects.
- Children & Elderly: Dosage adjustments are necessary.
- Lifestyle Considerations: Avoid alcohol.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ethambutol + Isoniazid + Piperine + Pyrazinamide + Rifampicin?
A: Dosage is weight-based. See “Dosage” section for details. Refer to WHO guidelines for specific recommendations.
Q2: What are the most common side effects?
A: Nausea, vomiting, abdominal discomfort, mild rash, headache, and reddish-orange discoloration of body fluids (harmless, caused by rifampicin).
A: Signs of liver damage (jaundice, dark urine), vision changes (ethambutol), numbness/tingling in extremities (isoniazid), and severe allergic reactions.
Q4: What are the contraindications for this drug?
A: Hypersensitivity to any component, severe liver disease, acute gout, concurrent use of contraindicated medications.
Q5: Can this medication be used during pregnancy and breastfeeding?
A: Use with caution during pregnancy only if benefits clearly outweigh risks. Monitor infants for side effects if breastfeeding. Pyridoxine supplementation is recommended during pregnancy.
Q6: How does rifampicin affect other medications?
A: Rifampicin is a potent CYP450 inducer, decreasing the effectiveness of many drugs metabolized by this enzyme system.
Q7: What monitoring is required during treatment with this FDC?
A: Regular monitoring of liver and renal function, complete blood count, visual acuity with ethambutol, and uric acid levels with pyrazinamide.
Q8: What is the role of piperine in this combination?
A: Piperine enhances the bioavailability of the other drugs, particularly rifampicin.
Q9: What is the duration of treatment with this combination?
A: This FDC is typically used for the first two months (intensive phase) of TB treatment, followed by a continuation phase with a different drug regimen.
Q10: What should be done in case of a missed dose?
A: Take the missed dose as soon as you remember. If it is close to the time for the next dose, skip the missed dose. Do not double the dose. Consult a healthcare professional if multiple doses are missed.
