Myzer (Capsules) Instructions for Use

Marketing Authorization Holder

Panacea Biotec Pharma, Ltd. (India)

ATC Code

J04AB01 (Cycloserine)

Active Substance

Cycloserine (Rec.INN registered by WHO)

Dosage Form

Myzer

Capsules 250 mg: 40 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 1, with a red cap and a white body; the capsule contents are an almost white or white with a yellowish tint granular powder.

Excipients: macrogol 6000 – 140 mg, purified talc – 10 mg.

Composition of the gelatin capsule[gelatin (capsule cap 83.432%/capsule body 83.16%), purified water (capsule cap 14.3%/capsule body 14.3%), colorant azorubine (capsule cap 0.112%), colorant ponceau 4R (capsule cap 0.384%), colorant sunset yellow FCF (capsule cap 0.072%), titanium dioxide (capsule cap 1.4%/capsule body 2.24%), povidone (capsule cap 0.1%/capsule body 0.1%), bronopol (capsule cap 0.1%/capsule body 0.1%), sodium lauryl sulfate (capsule cap 0.1%/capsule body 0.1%)] – 76 mg.

10 pcs. – high-density polyethylene bottles (4) – cardboard packs.
10 pcs. – high-density polyethylene bottles (10) – cardboard packs.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Antibiotic

Pharmacological Action

Antituberculosis drug. Cycloserine is a broad-spectrum bactericidal antibiotic. Cycloserine inhibits the synthesis of the cell wall of susceptible strains of gram-positive and gram-negative bacteria and Mycobacterium tuberculosis.

Active against gram-negative microorganisms, at a concentration of 10-100 mg/l – Rickettsia spp., Treponema spp., the minimum inhibitory concentration against Mycobacterium tuberculosis is 3-25 mg/l in liquid and 10-20 mg/l or more – on solid nutrient medium. Drug resistance develops slowly.

Pharmacokinetics

Cycloserine is rapidly absorbed from the gastrointestinal tract after oral administration, producing detectable plasma concentration levels within one hour, absorption 70-90%. It practically does not bind to plasma proteins. Time to reach C_max in blood is 3-4 hours; proportionally to the administered dose of 0.25, 0.5 and 1.0 g, C_max is 6, 24 and 30 µg/l, respectively. After taking 250 mg every 12 hours, C_max is 25-30 µg/ml. It is freely distributed throughout body fluids and tissues.

Cycloserine penetrates the blood-brain barrier, levels in the cerebrospinal fluid are approximately the same as in plasma. In patients with tuberculosis, Cycloserine is found in sputum, as well as in pleural and ascitic fluids, in bile, amniotic fluid and fetal blood, in breast milk, lung tissue and lymphoid tissue.

Cycloserine is excreted in the urine, where it is detected 30 minutes after taking the dose. About 66% of the dose is found unchanged in the urine within 24 hours. Another 10% is excreted over the next 48 hours. Negligible amounts are excreted in feces. About 35% is metabolized, but the metabolites have not been identified to date. T_1/2 of cycloserine ranges from 8 to 12 hours.

Cycloserine crosses the placenta. The abdominal and pleural cavities contain 50-100% of the drug concentration in the blood serum. In chronic renal failure, accumulation phenomena may occur after 2-3 days.

Indications

• Treatment of active pulmonary tuberculosis;
• Treatment of extrapulmonary tuberculosis (including kidney diseases) provided that the microorganisms are sensitive to this drug and after unsuccessful adequate treatment with primary drugs (streptomycin, isoniazid, rifampicin and ethambutol);

Like all antituberculosis drugs, Cycloserine should be used in combination with other chemotherapeutic agents, and not as monotherapy.

• Also used for atypical bacterial infections (including those caused by Mycobacterium avium);
• May be effective for the treatment of acute urinary tract infections caused by susceptible strains of gram-positive and gram-negative bacteria, especially Klebsiella/Enterobacter species and Escherichia coli;
• Treatment of urinary tract infections caused by bacteria, excluding mycobacteria.

Cycloserine should be used to treat these infections only after all conventional treatments have been exhausted and when the sensitivity of the microorganisms to this drug has been determined.

ICD codes

Dosage Regimen

Cycloserine is administered orally, immediately before meals (in case of irritation of the gastrointestinal mucosa – after meals).

Adults. The usual dose is from 500 mg to 1 g/day. The initial dose for adults is most often 250 mg 2 times /day with a 12-hour interval during the first two weeks. Periodically (after several doses, the drug level in the blood is monitored). The daily dose should not exceed 1 g.

Children. The usual initial dose is from 10 mg/kg body weight/day, after which it is adjusted depending on the drug level in the blood and the therapeutic effect. The daily dose for children is 0.01-0.02 g/kg body weight (not higher than 0.75 g/day).

Elderly. Prescribed the same as for adults, but the dose is reduced in case of impaired renal function. For patients over 60 years of age, as well as with a body weight of less than 50 kg – 0.25 g 2 times/day.

Adverse Reactions

From the central nervous system associated with high doses of the drug, i.e., more than 500 mg per day: convulsions, drowsiness, insomnia, nightmares, stupor, headache, tremor, dysarthria, dizziness, confusion and disorientation accompanied by memory loss, anxiety, peripheral neuritis, psychoses, possibly with suicide attempts, personality changes, euphoria, depression, increased irritability, aggressiveness, paresis, hyperreflexia, paresthesia, major and minor clonic convulsive seizures and coma.

From the digestive system nausea, heartburn, diarrhea.

Other fever, increased cough.

Other established side effects include: allergic reactions, itching, megaloblastic anemia and increased serum aminotransferases, especially in elderly patients with pre-existing liver disease. Sudden development of congestive heart failure is possible in patients taking 1 to 1.5 g of cycloserine/day.

Contraindications

• Organic diseases of the central nervous system;
• Epilepsy, epileptic seizures (including history);
• Depression;
• Severe states of agitation or psychoses;
• Heart failure;
• Severe renal failure;
• Alcohol abuse (including history);
• Pregnancy;
• Lactation period;
• Hypersensitivity to cycloserine.

Use with caution when prescribing Cycloserine in childhood.

Use in Pregnancy and Lactation

It has not been established whether Cycloserine causes fetal damage when administered to pregnant women or whether it affects reproductive capacity. Cycloserine should be prescribed to pregnant women only in cases of extreme necessity.

Concentrations in breast milk approach those found in maternal serum. The decision to discontinue breastfeeding or to stop treatment with the drug should be made taking into account the importance of the drug treatment for the mother.

Use in Renal Impairment

Contraindicated

• Severe renal failure.

When treating patients with reduced renal function taking a daily dose of more than 500 mg and who presumably show signs and symptoms of poisoning, the drug level in the blood should be monitored at least once a week. The dose should be adjusted to maintain the drug level in the blood below 30 mg/ml.

Pediatric Use

Prescribed with caution in childhood.

The usual initial dose is from 10 mg/kg body weight/day, after which it is adjusted depending on the drug level in the blood and the therapeutic effect. The daily dose for children is 0.01-0.02 g/kg body weight (not higher than 0.75 g/day).

Geriatric Use

Prescribed the same as for adults, but the dose is reduced in case of impaired renal function. For patients over 60 years of age, as well as with a body weight of less than 50 kg – 0.25 g 2 times/day.

Special Precautions

Cycloserine treatment should be discontinued or the dose should be reduced if the patient develops allergic dermatitis or symptoms of central nervous system intoxication, such as convulsions, psychoses, drowsiness, depression, confusion, hyperreflexia, headache, tremor, dizziness, paresis or dysarthria.

Neurotoxic effect is usually observed at drug blood levels above 30 mg/ml (which may be the result of overdose or impaired creatinine clearance). The risk of developing convulsive syndrome increases in patients with chronic alcoholism. When taking the drug, hematological parameters, renal excretory function, drug blood levels and liver function status should be monitored.

Before starting treatment with cycloserine, it is necessary to isolate microorganism cultures and determine the sensitivity of strains to this drug. In case of tuberculosis infection, it is necessary to determine the sensitivity of the strain to other antituberculosis drugs.

When treating patients with reduced renal function taking a daily dose of more than 500 mg and who presumably show signs and symptoms of poisoning, the drug level in the blood should be monitored at least once a week. The dose should be adjusted to maintain the drug level in the blood below 30 mg/ml.

Anticonvulsant or sedative drugs may be effective in preventing neurotoxic reactions.

Patients receiving more than 500 mg of cycloserine per day should be under direct supervision due to the possible development of such symptoms. The value of pyridoxine in preventing neurotoxic reactions has not been established.

In rare cases, the use of cycloserine and other antituberculosis drugs can cause the development of vitamin B₁₂ and/or folic acid deficiency, megaloblastic and sideroblastic anemias. If anemia occurs during treatment, appropriate examination and treatment of the patient should be carried out. The toxic effect of cycloserine can be prevented or reduced by prescribing glutamic acid 0.5 g 3-4 times/day (before meals) during treatment, and daily intramuscular injection of ATP sodium salt (1 ml of 1% solution), pyridoxine 200-300 mg/day.

Mental stress of patients should be limited and possible overheating factors should be excluded (staying in the sun without a head covering, hot showers).

Due to the rapid development of resistance during cycloserine monotherapy, its combination with other antituberculosis drugs is recommended.

Effect on ability to drive vehicles and operate machinery

Not established.

Overdose

Symptoms acute poisoning can be observed if an adult patient has taken more than 1 g orally. Overdose phenomena can be observed at a cycloserine plasma concentration of 25-30 mg/ml (intake of high doses, if more than 500 mg of cycloserine is administered daily, impaired creatinine clearance). Toxic effects usually occur from the central nervous system. They may include headache, dizziness, semi-consciousness, confusion, increased irritability, paresthesia, dysarthria and psychoses. When high doses are consumed, paresis, convulsions and coma may be observed. Ethanol may increase the risk of epileptic seizures.

Treatment symptomatic and supportive treatment is recommended. Antiepileptic agents. For the prevention of neurotoxic effects, anticonvulsants and sedatives. Activated charcoal may be more effective in reducing drug absorption than inducing vomiting and gastric lavage. In adults, neurotoxic effects can be treated and prevented by administering 200-300 mg of pyridoxine/day. Hemodialysis removes Cycloserine from the blood, but does not exclude the development of life-threatening poisoning.

Drug Interactions

Cycloserine increases the rate of pyridoxine excretion by the kidneys (may cause the development of anemia and peripheral neuritis, an increase in the dose of pyridoxine is required).

Concomitant administration of ethionamide potentiates neurotoxic side effects.

Alcohol and Cycloserine are incompatible, especially when treating with high doses of cycloserine. Alcohol increases the likelihood and danger of epileptic seizures.

Patients receiving Cycloserine and isoniazid should be monitored, as these drugs have a combined toxic effect on the central nervous system. Dose adjustment may be required.

Ethionamide increases the risk of side effects from the central nervous system, especially convulsive syndrome.

Storage Conditions

Store the drug in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Do not use after the date indicated 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.