Isocomb^® (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Manufactured By

M.J. Biopharm Pvt. Ltd. (India)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

J04AM06 (Rifampicin, Pyrazinamide, Ethambutol and Isoniazid)

Dosage Form

Isocomb®

Film-coated tablets: 500 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets dark brown in color, oval, biconvex, with a score, engraved with “MJ” on one side of the score and “RPN” on the other; on the cross-section – reddish-brown with white specks.

Excipients: corn starch, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, sodium starch glycolate, talc, magnesium stearate, Opadry brown 04B56936.

500 pcs. – polymer containers.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Isocomb^® is a five-component drug containing a fixed amount of isoniazid, rifampicin, pyrazinamide, ethambutol, and pyridoxine hydrochloride.

Isoniazid has a bactericidal effect on actively dividing cells of Mycobacterium tuberculosis. Its mechanism of action involves the inhibition of the synthesis of mycolic acids, which are a component of the mycobacterial cell wall. For Mycobacterium tuberculosis, the minimum inhibitory concentration (MIC) is 0.025-0.05 mg/L. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

Rifampicin

The mechanism of action of rifampicin involves the inhibition of DNA-dependent RNA polymerase. In tuberculosis infection, Rifampicin has a bactericidal effect on intracellularly and extracellularly located microorganisms. For Mycobacterium tuberculosis, the MIC for rifampicin is 2 mg/L.

Pyrazinamide

The target of pyrazinamide is the gene for mycobacterial fatty acid synthase 1, involved in the biosynthesis of mycolic acid. It acts on intracellularly located mycobacteria and penetrates well into foci of tuberculosis lesions. It is more effective in an acidic environment.

Pharmacokinetics

Isoniazid

Oral administration of isoniazid together with the drugs included in Isocomb^® does not affect its absorption rate from the gastrointestinal tract (GIT). Isoniazid penetrates into many tissues and fluids, including cerebrospinal fluid (CSF). The time to reach the maximum drug concentration in the blood (C_max) is 2 hours, the maximum concentration value is 6.6 mg/L, the half-life is 5.8 hours. The high C_max level of maximum concentration and half-life (T_1/2) is explained by the slowed excretion of isoniazid under the influence of pyrazinamide. Isoniazid is practically not bound to plasma proteins.

Isoniazid is 80-90% excreted in the urine and 10% in the feces within 24 hours. The main metabolites of isoniazid are N-acetylisoniazid and isonicotinic acid.

Rifampicin

After taking Isocomb^® by healthy adults, the maximum concentration of rifampicin in plasma reaches 16.3 mg/L. When the drug is taken with food, the absorption of rifampicin is reduced by 30%. C_max of rifampicin is reached in 1.5-2 hours, T_1/2 is about 6 hours. Rifampicin included in Isocomb^® binds to plasma proteins 3 times less. About 30% of the drug is excreted in the urine. Rifampicin is metabolized in the liver. The main metabolite is desacetylrifampicin. All metabolites of rifampicin have antimicrobial activity against Mycobacterium tuberculosis (MBT).

Pyrazinamide

After taking Isocomb^®, the C_max of pyrazinamide in plasma reaches 24.1 mg/L after 3 hours. The T_1/2 of the drug averages 17 hours. The main active metabolite of pyrazinamide is pyrazinoic acid. Up to 70% of pyrazinamide metabolites are excreted in the urine and about 4% is the unchanged drug.

Ethambutol

After taking Isocomb^®, the C_max of ethambutol is 6.4-7.6 mg/L. The high C_max of ethambutol is explained by the slowing of its excretion under the influence of isoniazid. C_max of the drug in plasma (60%) is reached after 2 hours.

Ethambutol is excreted in the urine, 70% unchanged and 30% as inactive aldehyde and carboxyl metabolites. On average, 25% of the drug binds to plasma proteins.

Pyridoxine hydrochloride

It is rapidly absorbed throughout the small intestine, with a larger amount absorbed in the jejunum.

It is metabolized in the liver to form pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate). Pyridoxal phosphate is 90% bound to plasma proteins. It penetrates well into all tissues; it accumulates mainly in the liver, and less in muscles and the CNS. It crosses the placenta and is secreted into breast milk. T_1/2 is 15-20 days. It is excreted by the kidneys.

Indications

• Newly diagnosed various forms and localizations of tuberculosis, with or without bacterial excretion (MBT sensitive to the main antituberculosis drugs).

ICD codes

Dosage Regimen

Orally.

Adults and children from 13 years old the drug is dosed at 10 mg/kg of body weight for rifampicin, but not more than 5 tablets. The drug is taken on an empty stomach 30-40 minutes before breakfast. The course of treatment is from 2 to 4 months depending on the nature of the tuberculous process.

For body weight > 80 kg, Isoniazid is additionally prescribed in the evening (total daily dose of isoniazid is 10 mg/kg). According to indications, Isocomb^® is combined with streptomycin (IM at a dose of 15 mg/kg once daily).

Adverse Reactions

Isoniazid

From the CNS and peripheral nervous system: headache, dizziness, rarely – unusual fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, mood changes, depression. In patients with epilepsy, seizures may become more frequent.

From the cardiovascular system: palpitations, angina pectoris, increased blood pressure.

From the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.

Allergic reactions skin rash, itching, hyperthermia, arthralgia.

Other: very rarely – gynecomastia, menorrhagia, tendency to bleeding and hemorrhage.

Rifampicin

From the digestive system nausea, vomiting, diarrhea, decreased appetite, erosive gastritis, pseudomembranous enterocolitis; increased activity of liver transaminases in blood serum, hyperbilirubinemia, hepatitis.

Allergic reactions: urticaria, eosinophilia, angioedema, bronchospasm, arthralgia, fever.

From the CNS: headache, decreased visual acuity, ataxia, disorientation.

From the urinary system: nephronecrosis, interstitial nephritis.

Other: leukopenia, dysmenorrhea, induction of porphyria, myasthenia, hyperuricemia, exacerbation of gout.

With irregular intake or upon resumption of treatment after a break, flu-like syndrome (fever, chills, headache, dizziness, myalgia), skin reactions, hemolytic anemia, thrombocytopenic purpura, acute renal failure are possible.

Pyrazinamide

From the digestive system: nausea, vomiting, diarrhea, metallic taste in the mouth, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow atrophy of the liver): exacerbation of peptic ulcer.

From the CNS: dizziness, headache, sleep disturbances, increased excitability, depression; in some cases – hallucinations, convulsions, confusion.

From the hematopoietic organs and hemostasis system: thrombocytopenia, sideroblastic anemia, vacuolization of erythrocytes, porphyria, hypercoagulation, splenomegaly.

From the musculoskeletal system: arthralgia, myalgia.

From the urinary system: dysuria, interstitial nephritis.

Allergic reactions : skin rash, urticaria.

Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.

Ethambutol

From the nervous system and sensory organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, impaired color perception, mainly of green and red colors, color blindness, scotoma).

From the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function – increased activity of liver transaminases.

Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

Other: hyperuricemia, exacerbation of gout.

Pyridoxine hydrochloride

Allergic reactions, hypersecretion of hydrochloric acid, numbness, feeling of tightness in the extremities – “stocking” and “glove” symptom, rarely – skin rash, skin itching.

Treatment of patients with a multi-component drug reduces the drug load on the patient by 3 times, which helps to improve drug tolerance.

Contraindications

• Hypersensitivity to isoniazid, rifampicin, pyrazinamide, ethambutol, pyridoxine;
• Pregnancy and breastfeeding;
• Children under 13 years of age;
• Liver and gastrointestinal diseases in the acute phase;
• CNS diseases (epilepsy and other diseases with a tendency to convulsive seizures);
• Diseases of the visual organs (inflammation of the optic nerve, cataract, diabetic retinopathy, inflammatory eye diseases);
• Gout;
• Thrombophlebitis.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

The drug is contraindicated in liver diseases.

Pediatric Use

The drug is contraindicated in children under 13 years of age.

Drug Interactions

Taking isoniazid, rifampicin, ethambutol, and especially pyrazinamide in a combined dosage form significantly increases antimicrobial activity against MBT. Rifampicin induces some enzymes of the cytochrome P450 system, accelerating the metabolism of prednisolone, phenytoin, quinidine, oral anticoagulants, hormonal contraceptives, antifungal drugs, cimetidine, cyclosporine A.

Isoniazid reduces the binding of rifampicin to plasma proteins, Pyrazinamide slows down the excretion of rifampicin.

Para-aminosalicylic acid (PAS) impairs the absorption of rifampicin.

Taking rifampicin with lomefloxacin and ofloxacin leads to a decrease in the antimicrobial activity of these combinations against MBT.

Antacids, opioid analgesics reduce the bioavailability of rifampicin.

Isoniazid

MAO inhibitors increase the risk of side effects from the CNS and cardiovascular system.

Pyridoxine, glutamic acid reduce the risk of side effects of isoniazid.

Concomitant use of isoniazid and cycloserine increases the risk of neurotoxic side effects.

Pyrazinamide

Pyrazinamide increases the concentration of isoniazid and rifampicin in the blood serum, slowing their excretion. When taking rifampicin together with pyrazinamide, the risk of hepatotoxic reactions increases.

Ethambutol

Aluminum hydroxide reduces the absorption of ethambutol.

Taking ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic effects of the drug.

Ethambutol enhances the antimicrobial activity of other antituberculosis drugs.

Pyridoxine hydrochloride

Pyridoxine hydrochloride weakens the effect of levodopa when used together. Pyridoxine hydrochloride reduces the risk of toxic effects of antituberculosis drugs on the CNS and peripheral nervous system.

Storage Conditions

List B. In a dry, light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.