Mac-Pas Plus (Granules) Instructions for Use

ATC Code

J04AC51 (Isoniazid in combination with other drugs)

Active Substances

Isoniazid (Rec.INN registered by WHO)

Aminosalicylate sodium (USP United States Pharmacopeia)

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Combined antituberculosis drug.

Aminosalicylic acid acts bacteriostatically. It competitively suppresses folate synthesis in the bacterial cell. It has a weak effect on the pathogen located intracellularly. Under the influence of gastric juice, aminosalicylic acid is rapidly converted into an inactive metabolite.

Isoniazid acts bactericidally on the process of Mycobacterium tuberculosis cell division in vivo and in vitro. The primary mechanism involves inhibition of the synthesis of long-chain mycolic acids, which are a component of the mycobacterial cell wall. A concentration of isoniazid of at least 600 mg/ml is required to inhibit gram-positive and gram-negative bacteria, while the minimum concentration for inhibiting Mycobacterium tuberculosis is 0.05-0.025 mg/ml. Resistance to isoniazid occurs spontaneously and represents a growth rate of mutant bacilli equal to 1×10⁶ bacteria per generation.

Pharmacokinetics

Aminosalicylic acid

It is characterized by high absorption; it moderately penetrates into the cerebrospinal fluid (only with inflammation of the meninges). It easily passes other histohematic barriers and is distributed in tissues. Protein binding is 50-60%. After a single dose of 4 g, the plasma concentration of the drug is 20 mg/ml (can vary from 9 to 35 mg/ml). The average time to reach C_max in plasma is 6 h (varies from 1.5 to 24 h). A plasma drug concentration of 2 mg/ml is maintained for 7.9 h (variability from 5 to 9 h), and 1 mg/ml – on average, for 8.8 h (variability from 6 to 11.5 h). It is metabolized; half of the dose is determined in the urine as an acetylated derivative. T_1/2 is 30 min. Total clearance depends on both the rate of metabolism and renal excretion. 80% of aminosalicylic acid is excreted by the kidneys, with 50% or more excreted in acetylated form.

Isoniazid

Isoniazid is rapidly and completely absorbed after oral administration; food reduces absorption and bioavailability. The bioavailability indicator is greatly influenced by the “first-pass” effect through the liver. Time to reach C_max in blood plasma is 1-2 h. C_max in blood after a single oral dose of 300 mg is 3-7 µg/ml. Protein binding is insignificant – up to 10%. V_d is 0.57-0.76 l/kg. It is well distributed throughout the body, penetrating into all tissues and fluids, including cerebrospinal, pleural, and ascitic; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It penetrates the placental barrier and into breast milk.

It undergoes metabolism 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 through the formation by the cytochrome P450 mixed oxidase system during N-hydroxylation of an active intermediate metabolite. The rate of acetylation is genetically determined; in people with slow acetylation, there is little N-acetyltransferase. It is an inhibitor of CYP2C9 and CYP2E1 isoenzymes in the liver.

T_1/2 for fast acetylators is 0.5-1.6 h; for slow acetylators – 2-5 h. In renal failure, T_1/2 can increase to 6.7 h. T_1/2 for children aged 1.5 to 15 years is 2.3-4.9 h, and for newborns – 7.8-19.8 h (which is explained by the imperfection of acetylation processes in newborns). Although the T_1/2 indicator varies significantly depending on the individual intensity of acetylation processes, the average T_1/2 is 3 h (oral administration of 600 mg) and 5.1 h (900 mg). With repeated administration, T_1/2 shortens to 2-3 h. It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites – N-acetylisoniazid and isonicotinic acid. In this case, in fast acetylators, the content of N-acetylisoniazid is 93%, while in slow acetylators it is no more than 63%. Small amounts are excreted in feces. The drug is removed from the blood during hemodialysis; hemodialysis performed for 5 hours can remove up to 73% of the drug from the blood.

Indications

Tuberculosis of various forms and localizations with multiple drug resistance, acutely progressive, widespread pulmonary tuberculosis.

ICD codes

Dosage Regimen

Administer the granules orally, after meals, with a full glass of water. Divide the total daily dose into two to three equal administrations.

Calculate the daily dose based on the patient’s body weight and the aminosalicylic acid component. The standard dosage is 10 mg of aminosalicylic acid per kg of body weight per day.

For a patient weighing 60 kg, the total daily dose is 600 mg of aminosalicylic acid. Administer this as 200 mg three times daily or 300 mg twice daily, according to the prescribed regimen.

Adhere strictly to the prescribed dosing schedule to maintain consistent therapeutic blood levels. Do not exceed the recommended daily dose.

Monitor patients for signs of gastrointestinal intolerance; splitting the dose may improve tolerability. Treatment duration is determined by the treating physician based on clinical response and disease form.

Regularly assess hepatic and renal function before and during therapy. Adjust the regimen with caution in patients over 60 years of age or with a body weight under 50 kg.

Adverse Reactions

Adverse reactions are possible as a result of the action of individual components included in the drug.

Aminosalicylic acid

From the digestive system decreased appetite, nausea, vomiting, flatulence, abdominal pain, diarrhea or constipation, hepatomegaly, increased activity of hepatic transaminases, hyperbilirubinemia, partially expressed malabsorption syndrome; rarely – drug-induced hepatitis.

From the urinary system proteinuria, hematuria, crystalluria.

From the hematopoietic system rarely – thrombocytopenia, leukopenia (up to agranulocytosis), B₁₂-deficiency megaloblastic anemia.

Allergic reactions fever, dermatitis (urticaria, purpura, enanthema), eosinophilia, arthralgia, bronchospasm.

With long-term use in high doses or when the dose is exceeded – hypothyroidism, goiter, myxedema.

Isoniazid

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, 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.

Contraindications

Gastric and duodenal ulcer, enterocolitis (in the acute phase); kidney disease (chronic renal failure); liver disease (hepatic failure, hepatitis, liver cirrhosis); amyloidosis of internal organs; myxedema (exacerbation); epilepsy; poliomyelitis (including history); decompensated chronic heart failure (including against the background of heart disease); thrombophlebitis; hypocoagulation; psoriasis; children under 3 years of age or with body weight less than 30 kg (for granules); children and adolescents under 18 years of age; lactation period; hypersensitivity to any component of the drug.

With caution the drug is used for concomitant gastrointestinal diseases, amyloidosis, decompensated diseases of the cardiovascular system, hypothyroidism, patients over 60 years of age and with body weight less than 50 kg, patients with a history of seizures and alcoholism.

Use in Pregnancy and Lactation

Use of the drug during pregnancy is possible if the expected benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in liver diseases (hepatic failure, hepatitis, liver cirrhosis).

Use in Renal Impairment

Contraindicated in kidney diseases (chronic renal failure).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age; in children under 3 years of age or with body weight less than 30 kg (for granules).

Geriatric Use

The drug should be prescribed with caution to patients over 60 years of age and with body weight less than 50 kg.

Special Precautions

Liver and kidney function impairment may occur due to drug administration.

Careful monitoring of patients throughout the course of treatment is necessary.

Laboratory parameters (ALT, AST, serum bilirubin concentration) may transiently increase without clinical manifestations.

If signs of toxic hepatitis appear, the drug should be discontinued.

Decreased renal function against the background of tuberculous intoxication or specific lesions is not a contraindication for prescription. The development of proteinuria and hematuria requires temporary withdrawal of the drug.

Due to different rates of metabolism, before using isoniazid, it is advisable to determine the rate of its inactivation (by the dynamics of its content in blood and urine). In case of rapid inactivation, Isoniazid is used in higher doses.

If there is a risk of developing peripheral neuritis (patients over 65 years of age, patients with diabetes mellitus, pregnant women, patients with chronic renal failure in remission, patients with alcoholism, with malnutrition, concomitant anticonvulsant therapy), the administration of 10-25 mg/day of pyridoxine is recommended.

During treatment, consumption of cheese (especially Swiss or Cheshire), fish (especially tuna, sardines) should be avoided, since when consumed simultaneously with isoniazid, reactions (skin hyperemia, itching, sensation of heat or cold, palpitations, increased sweating, chills, headache, dizziness) may occur, associated with suppression of MAO and diamine oxidase activity and leading to impaired metabolism of tyramine and histamine contained in fish and cheese.

It should be borne in mind that Isoniazid can cause hyperglycemia with secondary glucosuria; tests with copper ion reduction may be false positive, but the drug does not affect enzymatic glucose tests.

Drug Interactions

Aminosalicylic acid

Aminosalicylic acid is compatible with other antituberculosis drugs.

Concomitant use with rifampicin is not recommended, because aminosalicylic acid reduces its concentration. If concomitant therapy with rifampicin is necessary, the drugs should be taken separately: rifampicin before breakfast, Aminosalicylate sodium after dinner and at night.

Impairs the absorption of erythromycin and lincomycin.

Impairs the absorption of cyanocobalamin (vitamin B₁₂) (risk of anemia). Absorption of vitamin B₁₂ when taking 5 g of aminosalicylic acid is impaired by 55%, which leads to significant changes in erythrocytes. Thus, when treating patients with aminosalicylic acid for more than 1 month, therapy with vitamin B₁₂ is necessary.

Isoniazid

When combined with paracetamol, hepatotoxicity and nephrotoxicity increase; Isoniazid induces the cytochrome P450 system, resulting in increased metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism.

Reduces metabolic transformations and increases the concentration in the blood of alfentanil.

Cycloserine and disulfiram enhance adverse effects from the central nervous system.

Increases the hepatotoxicity of rifampicin.

Combination with pyridoxine reduces the risk of developing peripheral neuritis and adverse reactions from the central nervous system.

Caution should be exercised when combining with potentially neuro-, hepato-, and nephrotoxic drugs due to the risk of increased side effects.

Enhances the effect of coumarin and indandione derivatives, benzodiazepines, carbamazepine, theophylline, as it reduces their metabolism by activating the cytochrome P450 system.

Corticosteroids accelerate metabolism in the liver and reduce the active concentration of isoniazid in the blood.

Suppresses the metabolism of phenytoin, leading to an increase in its concentration in the blood and an increase in toxic effects (adjustment of the phenytoin dosage regimen may be required, especially in patients with slow acetylation of isoniazid).

Antacids (especially those containing aluminum) slow down absorption and reduce the concentration of isoniazid in the blood (antacids should be taken no earlier than 1 hour after taking isoniazid).

When used concomitantly with enflurane, Isoniazid may increase the formation of an inorganic fluoride metabolite that has a nephrotoxic effect.

Reduces the concentration of ketoconazole in the blood.

Isoniazid is an antagonist of the hypoglycemic effect of insulin, it increases blood glucose levels. This is explained by the significant absorption of isoniazid by the intestinal walls.

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.