Ftizamax^® (Tablets) Instructions for Use

Marketing Authorization Holder

Macleods Pharmaceuticals Ltd. (India)

Manufactured By

Macleods Pharmaceuticals Ltd. (India)

Packaging and Quality Control Release

MACLEODS PHARMACEUTICALS, Ltd. (India)

Or

ADVANCED PHARMA, LLC (Russia)

ATC Code

J04AM05 (Rifampicin, Pyrazinamide and Isoniazid)

Active Substances

Rifampicin (Rec.INN registered by WHO)

Pyrazinamide (Rec.INN registered by WHO)

Isoniazid (Rec.INN registered by WHO)

Dosage Forms

	Ftizamax®	Film-coated tablets, 30 mg+150 mg+60 mg: 84, 100 or 672 pcs.
		Film-coated tablets, 150 mg+375 mg+150 mg: 84, 100 or 672 pcs.

Dosage Form, Packaging, and Composition

Dispersible tablets of an orange-brown color, with dark and light specks, round, flat, with a bevel on both sides, with a faint characteristic odor.

Excipients: microcrystalline cellulose – 25 mg, crospovidone – 15 mg, povidone K30 – 5 mg, shellac – 1 mg, croscarmellose sodium – 7 mg, aspartame – 2 mg, magnesium stearate – 2 mg, strawberry flavor – 3 mg.

28 pcs. – blisters (3) – cardboard packs.
28 pcs. – blisters (24) – cardboard packs.
10 pcs. – strips (10) – cardboard packs.

Dispersible tablets of an orange-brown color, with dark and light specks, biconvex, capsule-shaped, with a bevel on both sides, with a faint characteristic odor.

Excipients: microcrystalline cellulose – 105.5 mg, crospovidone (type A) – 35 mg, povidone K30 – 9.5 mg, shellac – 2 mg, croscarmellose sodium – 15 mg, aspartame – 3.5 mg, magnesium stearate – 10 mg, strawberry flavor – 4.5 mg.

28 pcs. – blisters (3) – cardboard packs.
28 pcs. – blisters (24) – cardboard packs.
10 pcs. – strips (10) – cardboard packs.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Combined antituberculosis agent, active against the population of Mycobacterium tuberculosis at different stages of its development.

Isoniazid has a bactericidal effect on actively dividing cells of Mycobacterium tuberculosis, inhibiting the synthesis of mycolic acids, which are a component of the mycobacterial cell wall. For Mycobacterium tuberculosis, the MIC of isoniazid is 0.05-0.025 mg/l.

Rifampicin is a semisynthetic antibiotic that blocks DNA-dependent RNA polymerase. Isoniazid inhibits the synthesis of mycolic acids in the cell wall of tuberculosis mycobacteria. Rifampicin and Isoniazid are active against rapidly growing extracellular microorganisms and have a bactericidal effect on intracellular pathogens. Rifampicin is active against intermittently growing forms of Mycobacterium tuberculosis. In low concentrations, it acts bactericidally on Mycobacterium tuberculosis, the causative agents of brucellosis, legionellosis, typhus, leprosy, trachoma; in high concentrations – on some gram-negative microorganisms. Resistance develops with monotherapy.

Pyrazinamide acts bactericidally on intracellular mycobacteria, as well as Mycobacterium tuberculosis at different stages of its development, and penetrates well into foci of tuberculosis lesions.

Pharmacokinetics

Isoniazid. It is rapidly and completely absorbed when taken orally; food reduces absorption and bioavailability, the value of which is greatly influenced by the “first-pass” effect through the liver. The value of C_max in blood plasma after a single oral dose of 300 mg is 3-7 µg/ml. Protein binding is insignificant – up to 10%. Volume of distribution – 0.57-0.76 l/kg. It is well distributed throughout the body, penetrating into all tissues and fluids, including cerebrospinal, pleural, and ascitic fluids; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It penetrates the placental barrier and into breast milk. It is metabolized in the liver by acetylation to form inactive products. In the liver, it is acetylated by N-acetyltransferase to form N-acetylisoniazid, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming an active intermediate metabolite through N-hydroxylation by the cytochrome P450 system. It crosses the hematoplacental barrier and is detected in the fetal plasma at concentrations comparable to or exceeding those in the maternal plasma.

Pyrazinamide. It is rapidly and completely absorbed from the gastrointestinal tract, reaching maximum plasma concentration in 1-2 hours. Plasma protein binding is 10-20%. It penetrates well into tissues and organs. It is metabolized in the liver, where an active metabolite, pyrazinoic acid, is first formed, which is then converted into an inactive metabolite, 5-hydroxypyrazinoic acid. T_1/2 is 8-9 hours. It is excreted by the kidneys: unchanged – 3%, in the form of pyrazinoic acid – 33%, in the form of other metabolites – 36%. It is removed by hemodialysis. It is excreted in breast milk in small amounts.

Rifampicin. Absorption is rapid; food intake reduces the absorption of the drug. When taken orally on an empty stomach, 600 mg C_max – 10 µg/ml is reached after 2-3 hours. When taken with food, the absorption of rifampicin is reduced by 30%. Approximately 60-80% of the dose taken binds to plasma proteins. It is quickly distributed to organs and tissues (the highest concentration is in the liver and kidneys), penetrates into bone tissue, the concentration in saliva is 20% of the concentration in plasma. The apparent volume of distribution is 1.6 l/kg in adults and 1.1 l/kg in children. It penetrates the placental barrier and is excreted in breast milk. It is metabolized in the liver to form a pharmacologically active metabolite, 25-O-desacetylrifampicin. After several days of administration, bioavailability decreases and T_1/2 after repeated administration of 600 mg is shortened to 1-2 hours. It is excreted mainly with bile, 80% in the form of a metabolite; by the kidneys – 20%. The amount of rifampicin excreted by the kidneys unchanged depends on the dose taken and is 4-20% of the dose taken.

Indications

Tuberculosis (any location, in the initial period of intensive treatment).

ICD codes

Dosage Regimen

Administer orally. Determine the dosage regimen individually based on the patient’s body weight and age.

For the initial intensive phase of tuberculosis treatment, use the following weight-based dosing for the 150 mg+375 mg+150 mg tablet strength.

For patients weighing 7-12 kg, administer 1 tablet daily.

For patients weighing 13-25 kg, administer 2 tablets daily.

For patients weighing 26-37 kg, administer 3 tablets daily.

For patients weighing 38-54 kg, administer 4 tablets daily.

For patients weighing 55-70 kg, administer 5 tablets daily.

For patients weighing over 70 kg, administer 6 tablets daily.

Take the total daily dose once daily, on an empty stomach, at least 30 minutes before a meal.

Disperse the tablets in a small amount of water immediately before administration. The resulting suspension has a pleasant strawberry taste and odor.

Alternatively, place the tablet on the tongue and swallow with water.

The usual duration of the intensive phase is 2 months. Follow the subsequent continuation phase regimen as directed.

For the 30 mg+150 mg+60 mg tablet strength, adjust the total number of tablets to achieve the equivalent daily dose of each active ingredient based on body weight.

Do not use in children with a body weight of less than 7 kg.

Adverse Reactions

From the nervous system headache, dizziness, rarely – excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of the extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, mood changes, decreased visual acuity, depression, ataxia, disorientation. 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, diarrhea, decreased appetite, erosive gastritis, pseudomembranous colitis; increased activity of hepatic transaminases in blood serum, hyperbilirubinemia, hepatitis.

From the urinary system nephronecrosis, interstitial nephritis, dysuria.

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

From the musculoskeletal system arthralgia, myalgia.

Allergic reactions skin rash, itching, hyperthermia, arthralgia, urticaria, eosinophilia, angioedema, bronchospasm, fever.

Other very rarely – gynecomastia, menorrhagia, tendency to bleeding and hemorrhage, leukopenia, dysmenorrhea, induction of porphyria, myasthenia, hyperuricemia, exacerbation of gout, photosensitivity.

Contraindications

Hypersensitivity to the active substances of the combination; pregnancy and lactation; children with body weight less than 7 kg; diseases of the central nervous system (epilepsy); jaundice; acute liver diseases of various origins; pulmonary-heart failure stage II-III; hyperuricemia; gout; purpura; chronic renal failure; phenylketonuria; thrombophlebitis; porphyria; children’s age (under 12 years).

With caution

Alcoholism, peripheral neuropathy, HIV infection; decompensated diseases of the cardiovascular system; hypothyroidism; old age; electrolyte imbalance; diabetes mellitus with oral administration of hypolipidemic agents.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use is contraindicated in acute liver diseases of various origins.

Use in Renal Impairment

Use is contraindicated in chronic renal failure.

Pediatric Use

Use is contraindicated in children with body weight less than 7 kg.

Geriatric Use

With caution: in elderly persons.

Special Precautions

Before starting treatment and every 2-4 weeks, ALT and AST activity is determined.

If the activity of hepatic transaminases increases, the drug is discontinued. Treatment is resumed after the indicators normalize.

Combination with vitamin B₆ is possible.

Pyrazinamide worsens the course of gout and diabetes mellitus; control of kidney function and uric acid is necessary. In case of persistent hyperuricemia and exacerbation of gouty arthritis, treatment is discontinued.

During treatment, microbiological methods for determining the concentration of folic acid and vitamin B₁₂ in blood serum should not be used.

During treatment, the bromsulfalein test should not be used (false-positive results).

With long-term use, liver function, kidney function, peripheral blood picture should be monitored and an ophthalmological examination should be performed. Consumption of ethanol is prohibited.

During treatment, additional intake of vitamin D is recommended to prevent disorders of calcium and phosphorus metabolism.

Rifampicin stains the skin, sputum, sweat, feces, tear fluid, urine, and soft contact lenses orange-red.

Drug Interactions

Antacids, opioids, anticholinergic drugs and ketoconazole reduce the bioavailability of rifampicin.

Preparations of PAS containing bentonite (aluminum hydrosilicate) are prescribed 4 hours after taking rifampicin. Rifampicin reduces the activity of oral anticoagulants, oral hypoglycemic agents, hormonal contraceptives, digitalis preparations, antiarrhythmics (disopyramide, pirmenol, quinidine, mexiletine, tocainide), corticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, beta-blockers, calcium channel blockers, enalapril, cimetidine. Rifampicin induces liver enzyme systems and accelerates metabolism.

Antacids reduce the absorption of isoniazid.

Isoniazid increases the concentration of phenytoin in the blood, reduces the effectiveness of oral combined contraceptives, glipizide, tolbutamide, theophylline, tolazamide, thiamine; enhances the side effects of phenytoin; suppresses the excretion of triazolam; reduces the zinc content in the blood and increases its excretion.

Rifampicin increases the excretion rate of bromsulfalein.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.