Isoniazid + Piperine + Rifampicin

Usage

• This fixed-dose combination medication is primarily prescribed for the treatment of all forms of tuberculosis (TB), including drug-susceptible pulmonary and extrapulmonary TB.
• Pharmacological classification: Anti-tuberculosis agents, antibiotic combination.
• Mechanism of action: This combination targets Mycobacterium tuberculosis through multiple pathways. Rifampicin inhibits bacterial RNA polymerase, thus suppressing RNA synthesis. Isoniazid hinders mycolic acid synthesis, a crucial component of the mycobacterial cell wall. Piperine enhances the bioavailability of rifampicin.

Alternate Names

• While Isoniazid, Rifampicin, and Piperine are the established generic names, the combination may be referred to as Rifampicin-Isoniazid-Piperine fixed-dose combination (FDC).
• Brand Names: Risorine

How It Works

• Pharmacodynamics: Rifampicin inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis. Isoniazid inhibits mycolic acid synthesis, disrupting cell wall formation. Piperine acts as a bio-enhancer, increasing rifampicin absorption and potentially its serum concentration. The combination exerts a synergistic bactericidal effect against Mycobacterium tuberculosis.
• Pharmacokinetics:
  • Absorption: Rifampicin is well-absorbed orally, and piperine enhances its bioavailability. Isoniazid is rapidly absorbed orally.
  • Metabolism: Rifampicin undergoes enterohepatic circulation and deacetylation in the liver. Isoniazid is metabolized primarily by acetylation in the liver, exhibiting genetic polymorphism.
  • Elimination: Rifampicin is excreted mainly in bile and feces, with some renal excretion. Isoniazid and its metabolites are eliminated primarily in urine.

Dosage

Standard Dosage

Adults:

• Intensive Phase (First 2 months): This combination is usually part of a four-drug regimen including ethambutol and pyrazinamide. The typical dose is Rifampicin 450mg or 600 mg, Isoniazid 300 mg, and Piperine 10 mg, taken orally once daily on an empty stomach. This combination is not typically used as a standalone treatment during the intensive phase.

Continuation Phase (Next 4 months): Rifampicin 450 mg or 600 mg, Isoniazid 300 mg, and Piperine 10 mg orally once a day on an empty stomach.

Children:

• Dosing in children is determined by body weight and should be guided by pediatric TB treatment guidelines. This combination is not approved for use in children younger than 15 years of age for continuation phase regimens.

Special Cases:

• Elderly Patients: Dosage adjustment based on renal and hepatic function is needed.
• Patients with Renal Impairment: Dose adjustment is needed as rifampicin and isoniazid can accumulate.
• Patients with Hepatic Dysfunction: Close monitoring of liver function and dosage adjustments is essential.

Clinical Use Cases

This specific combination is not typically indicated for the clinical situations listed, as broader TB treatment strategies are employed.

Side Effects

Common Side Effects:

• Discoloration of body fluids (urine, sweat, tears, saliva) to a reddish-orange color
• Nausea, vomiting, loss of appetite
• Abdominal discomfort
• Mild rash, itching
• Joint or muscle pain
• Peripheral neuropathy (numbness, tingling)

Rare but Serious Side Effects:

• Hepatotoxicity (jaundice, dark urine, clay-colored stools)
• Flu-like syndrome
• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Contraindications

• Hypersensitivity to rifamycins, isoniazid, or piperine
• Active liver disease
• Concurrent use with the combination of saquinavir/ritonavir
• History of liver problems caused by isoniazid

Drug Interactions

• Rifampicin is a potent inducer of CYP450 enzymes (CYP3A4, CYP2C9, CYP2C19), significantly reducing the effectiveness of drugs metabolized by these enzymes (e.g., warfarin, oral contraceptives, some antiretrovirals, corticosteroids).
• Isoniazid can inhibit the metabolism of certain drugs (e.g., phenytoin, carbamazepine, disulfiram), potentially leading to toxicity.
• Alcohol should be avoided due to increased risk of hepatotoxicity.
• Foods containing tyramine and histamine should be avoided while taking this combination.

Pregnancy and Breastfeeding

• Consult a specialist. Use only if clearly needed and benefits clearly outweigh risks. Rifampicin and Isoniazid can cross the placenta.
• Excreted into breast milk, monitor infants for potential side effects. Vitamin B6 supplementation is recommended for breastfeeding mothers on isoniazid.

Drug Profile Summary

• Mechanism of Action: Rifampicin inhibits bacterial RNA polymerase, Isoniazid inhibits mycolic acid synthesis. Piperine enhances rifampicin bioavailability.
• Side Effects: Body fluid discoloration, peripheral neuropathy, hepatotoxicity, gastrointestinal upset, rash.
• Contraindications: Liver disease, hypersensitivity.
• Drug Interactions: Numerous, including CYP450 interactions.
• Pregnancy & Breastfeeding: Consult a specialist. Use cautiously. Monitor infants for side effects.
• Dosage: Varies by body weight and phase of treatment. Administer on an empty stomach.
• Monitoring Parameters: Liver function tests, signs of peripheral neuropathy

Popular Combinations

• This combination is typically given with pyrazinamide and ethambutol during the intensive phase of TB treatment.

Precautions

• Baseline liver function tests and monitoring during treatment are essential.
• Monitor for signs and symptoms of peripheral neuropathy.
• Patients should be counseled on potential drug interactions and to report any signs of adverse effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isoniazid + Piperine + Rifampicin in the continuation phase of TB treatment?

A: Rifampicin 450 mg or 600 mg + Isoniazid 300 mg + Piperine 10 mg, taken orally once daily on an empty stomach.

Q2: What is the role of Piperine in this combination?

A: Piperine acts as a bio-enhancer for rifampicin, increasing its absorption and serum levels, potentially allowing for lower rifampicin doses.

Q3: What are the most important drug interactions to consider?

A: Rifampicin induces CYP450 enzymes, affecting numerous drugs. Isoniazid can inhibit the metabolism of some drugs. Consult a comprehensive drug interaction resource.

Q4: What are the key monitoring parameters for patients on this drug?

A: Liver function tests, monitoring for signs of peripheral neuropathy (numbness, tingling), and visual acuity.

Q5: Can this drug be used during pregnancy and breastfeeding?

A: Consult a specialist. Use only if essential and the benefits outweigh the risks. Monitor infants for adverse effects if breastfeeding.

Q6: What are the common side effects patients should be aware of?

A: Reddish-orange discoloration of body fluids, nausea, vomiting, stomach upset, and mild rash.

Q7: What are the contraindications for the use of this medication?

A: Active liver disease, hypersensitivity to the components, and concurrent use with saquinavir/ritonavir.

Q8: Is this FDC used for latent TB infection?

A: No, this combination is not typically used for latent TB infection. Other regimens are preferred.

Q9: What should patients do if they miss a dose?

A: Take the missed dose as soon as possible, but do not double up on doses. Maintaining a regular dosing schedule is important.

Q10: Are there any dietary restrictions while taking this medication?

A: Patients should avoid alcohol and foods rich in tyramine and histamine due to potential interactions.