Cyclomicin Plus (Tablets) Instructions for Use

ATC Code

J04AB01 (Cycloserine)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Cycloserine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Antibiotic

Pharmacological Action

A combined drug.

Cycloserine is a broad-spectrum bactericidal antibiotic that disrupts cell wall synthesis by acting as a competitive antagonist of D-alanine and inhibits the enzymes responsible for cell wall synthesis. It is active against gram-negative microorganisms at a concentration of 10-100 mg/L (Rickettsia spp., Treponema spp). The minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis is 3-25 mg/L in liquid and 10-20 mg/L or more in solid nutrient medium. Drug resistance develops slowly (after 6 months of treatment, it occurs in 20-60% of cases).

Pyridoxine, which is part of the drug, reduces the severity of cycloserine’s adverse reactions from the central nervous system.

Pharmacokinetics

Cycloserine is rapidly absorbed from the gastrointestinal tract. Absorption after oral administration is 70-90%. It practically does not bind to plasma proteins. The time to reach maximum concentration (T_max) is 3-4 hours. After taking 250 mg every 12 hours, the maximum concentration (C_max) is 25-30 µg/ml. It penetrates well into body fluids and tissues. It penetrates into lymphoid tissue, lung tissues, pleural and ascitic fluids, sputum, bile, and breast milk. The abdominal and pleural cavities contain 50-100% of the drug concentration in the blood serum. It crosses the placental barrier and the blood-brain barrier (the concentration in the cerebrospinal fluid corresponds to the concentration in plasma and is detected in the amniotic fluid and fetal blood). About 35% of the administered dose is metabolized. It is excreted mainly by the kidneys unchanged by glomerular filtration (50% is detected in the urine within 12 hours, 65-70% within 24-72 hours), small amounts are excreted through the intestines. The half-life of cycloserine (T_1/2) with normal renal function is about 10 hours. In chronic renal failure, accumulation phenomena may occur after 2-3 days.

Pyridoxine 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, accumulating mainly in the liver, and less in muscles and the central nervous system. It crosses the placenta and is secreted into breast milk. It is excreted by the kidneys. The half-life of pyridoxine (T_1/2) is 15-20 days.

Indications

• As part of combination therapy after unsuccessful adequate treatment with primary drugs in case of microorganism sensitivity to cycloserine;
• Active pulmonary tuberculosis, extrapulmonary tuberculosis (including kidney damage), chronic forms of tuberculosis;
• Combination of tuberculosis with acute urinary tract infections caused by sensitive strains of gram-positive and gram-negative bacteria, especially Klebsiella spp., Enterobacter spp., Escherichia coli, when primary drugs are ineffective;
• Atypical mycobacterial infections (including those caused by Mycobacterium avium).

ICD codes

Dosage Regimen

Tablets

Orally, immediately before meals (in case of gastrointestinal mucosal irritation – after meals).

Adults are prescribed 12.5 mg/kg of body weight or 500-750 mg/day (of cycloserine) in 2-3 doses (the initial dose of cycloserine is 250 mg every 12 hours during the first week, then, if necessary, taking into account tolerance, the dose is carefully increased to 250 mg every 6-8 hours under the control of the cycloserine level in the blood). The maximum single dose of cycloserine for adults is 250 mg; the maximum daily dose is 1 g. Patients over 60 years of age, as well as those weighing less than 50 kg are prescribed 250 mg (of cycloserine) 2 times a day.

In children, the initial dose of cycloserine is 10-20 mg/kg of body weight per day, the maximum daily dose is 750 mg.

Adverse Reactions

During treatment, adverse events may occur, mainly due to the effect of cycloserine on the nervous system. These phenomena usually disappear when the dose is reduced or the drug is discontinued.

From the central and peripheral nervous system convulsions, drowsiness, headache, tremor, dysarthria, dizziness, confusion and disorientation accompanied by memory loss, psychoses (including with suicide attempts), irritability, aggressiveness, peripheral paresis, hyperreflexia, paresthesia, major and minor clonic convulsive seizures, coma.

From the digestive system nausea, heartburn, diarrhea, increased activity of “hepatic” aminotransferases in the serum.

From the cardiovascular system and hematopoietic system sideroblastic and megaloblastic anemia, when used at a dose of 1 g/day, exacerbation of chronic heart failure.

Other cyanocobalamin and folic acid deficiency, allergic reactions (skin rash, itching, fever, increased cough).

If any of the side effects listed in the instructions worsen or any other side effects not listed in the instructions are noticed, you should immediately inform your doctor.

Contraindications

• Hypersensitivity to the components of the drug;
• Organic diseases of the central nervous system;
• Epilepsy;
• Depression;
• Severe state of agitation;
• Psychosis;
• Chronic renal failure (creatinine clearance less than 50 ml/min);
• Acute and chronic heart failure;
• Alcoholism;
• Drug addiction;
• Pregnancy;
• Lactation period;
• Children under 3 years of age.

With caution

• Impaired renal function (risk of drug accumulation phenomena);
• Childhood.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy.

It penetrates into breast milk; if it is necessary to use the drug, breastfeeding should be discontinued during treatment.

Use in Renal Impairment

Contraindicated in chronic renal failure (creatinine clearance less than 50 ml/min). Use with caution in case of impaired renal function (risk of drug accumulation phenomena).

Pediatric Use

Contraindicated in children under 3 years of age. Use with caution in children over 3 years of age.

Special Precautions

With monotherapy, rapid development of mycobacterial resistance to cycloserine is possible, so the drug should be used only in combination with other antituberculosis drugs in the absence of effect from treatment with first-line drugs such as streptomycin, isoniazid, rifampicin, ethambutol. Before starting treatment, it is necessary to isolate the microorganism culture and determine the sensitivity of the strain to cycloserine and other antituberculosis drugs. Alcohol consumption is not allowed during treatment.

To identify signs of the drug’s toxic effect on the central nervous system, careful monitoring of patients receiving Cycloserine at a dose of more than 500 mg/day is necessary. The drug should be taken under the control of the cycloserine level in the blood (the cycloserine concentration should not exceed 30 mg/ml; at a higher concentration, manifestations of toxicity are likely). During treatment, hematological parameters, renal and liver function should also be monitored. In patients with reduced renal function, urinalysis should be monitored weekly. To prevent neurotoxic effects (including convulsions, agitation, tremor) during treatment, it is possible to prescribe anticonvulsant and sedative drugs, benzodiazepine drugs (diazepam) and nootropic drugs (piracetam). The toxic effect of cycloserine can also be prevented or reduced by prescribing glutamic acid 0.5 g 3-4 times a day (before meals) and daily intramuscular injection of the sodium salt of ATP (1 ml of a 1% solution).

To reduce adverse reactions, mental stress of patients should be limited and possible overheating factors (staying in the sun with an uncovered head, hot shower) should be excluded.

It should be taken into account that the presence of pyridoxine in the drug may distort the results when determining urobilinogen using Ehrlich’s reagent.

In case of development of allergic dermatitis or symptoms of central nervous system damage (convulsions, psychosis, drowsiness, confusion, hyperreflexia, headache, dizziness, tremor, peripheral paresis, dysarthria) during treatment, the drug should be discontinued. During treatment, the electroencephalogram (EEG) should be monitored. In some cases, the use of cycloserine and other antituberculosis drugs can lead to the development of cyanocobalamin and folic acid deficiency, megaloblastic anemia.

Effect on the ability to drive vehicles and mechanisms

Considering possible side effects, caution should be exercised when taking the drug while driving vehicles and for people whose profession requires increased concentration and speed of psychomotor reactions.

Overdose

Overdose is observed when the plasma concentration of cycloserine is 25-30 mg/ml (taking high doses, impaired renal clearance). Acute poisoning can occur when taking more than 1 g per day orally. Symptoms of chronic intoxication occur with long-term use of cycloserine at a dose of more than 500 mg per day.

Symptoms headache, dizziness, increased irritability, paresthesia, dysarthria, paresis, convulsions, psychosis, confusion or loss of consciousness (coma).

Treatment symptomatic (activated charcoal, anticonvulsant and sedative drugs). Hemodialysis is effective. To prevent neurotoxic effects, pyridoxine is administered at the rate of 200-300 mg/day. All measures are carried out against the background of drug withdrawal.

Drug Interactions

Cycloserine increases the rate of pyridoxine excretion by the kidneys. It reduces resistance to isoniazid, streptomycin and para-aminosalicylic acid (PAS). Isoniazid enhances the toxic effect of the drug on the central nervous system (increases the frequency of dizziness, drowsiness; dose adjustment of both drugs may be required).

Ethionamide enhances the neurotoxic effect of cycloserine (simultaneous use of ethionamide increases the risk of side effects from the central nervous system, especially convulsive syndrome).

Pyridoxine reduces the intensity of cycloserine’s adverse reactions from the nervous system. It enhances the effect of diuretics and weakens the activity of levodopa.

Isoniazid, penicillamine, Cycloserine and estrogen-containing oral contraceptives weaken the effect of pyridoxine.

Ethanol increases the risk of seizures, especially in persons suffering from chronic alcoholism.

Storage Conditions

In a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

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.