Coxerin^® Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Macleods Pharmaceuticals Ltd. (India)

ATC Code

J04AB01 (Cycloserine)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Cycloserine (Rec.INN registered by WHO)

Dosage Form

Coxerin® Plus

Film-coated tablets, 250 mg+25 mg: 100 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – non-cell contour packs (10) – cardboard packs.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Antibiotic

Pharmacological Action

Combined medicinal product.

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

Pyridoxine 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. 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. In the abdominal and pleural cavities, it contains 50-100% of the serum concentration. It crosses the placental barrier and the blood-brain barrier (concentration in the cerebrospinal fluid corresponds to the concentration in plasma, 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 by the intestines. T_1/2 of cycloserine 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 binds to plasma proteins by 90%. It penetrates well into all tissues, accumulates mainly in the liver, and less in muscles and the central nervous system. It crosses the placental barrier and is excreted in breast milk. It is excreted by the kidneys. T_1/2 of pyridoxine is 15-20 days.

Indications

In combination with other antituberculosis drugs: active pulmonary tuberculosis; extrapulmonary tuberculosis (including kidney damage) in case of microorganism sensitivity to the drug and after unsuccessful adequate treatment with primary drugs (rifampicin, isoniazid, streptomycin, ethambutol); combination of tuberculosis with acute urinary tract infections caused by susceptible 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

Determine the dosage based on patient weight, age, and renal function. Monitor serum cycloserine concentrations regularly, maintaining levels below 30 µg/mL to minimize toxicity risk.

For adult patients, administer 12.5 mg/kg of body weight per day. Divide this total daily dose into two or three equally spaced administrations.

Initiate therapy in adults at 250 mg every 12 hours. Adjust the dose upward based on clinical response and serum drug levels, while carefully monitoring for adverse effects.

For patients over 60 years of age and for adults weighing less than 50 kg, the typical dosage is 250 mg twice daily. Exercise increased caution in these populations due to a higher risk of neurotoxicity.

For pediatric patients, the initial dose is 10 mg/kg/day. Administer this daily dose in one or two divided doses. The drug is contraindicated in children under 3 years of age or weighing less than 25 kg.

In all patients with impaired renal function, dosage reduction is mandatory. The drug is contraindicated if creatinine clearance is below 50 mL/min. For patients with a creatinine clearance above this threshold, adjust the dose and frequency based on specific renal function and serum level monitoring.

Administer the total daily dose for more than 1 gram (1000 mg) only under strict medical supervision and with intensive monitoring for central nervous system toxicity.

Adverse Reactions

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

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

From the cardiovascular system and hematopoietic system sideroblastic and megaloblastic anemia, when used in 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).

Contraindications

Hypersensitivity to the components of the drug; organic diseases of the central nervous system; epilepsy; depression; pronounced 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 and/or weighing less than 25 kg.

With caution

Chronic renal failure with creatinine clearance more than 25 ml/min; children from 3 to 18 years old.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Liver function should be monitored during treatment.

Use in Renal Impairment

Contraindicated in chronic renal failure (creatinine clearance less than 50 ml/min).

With caution in case of renal function impairment (risk of drug accumulation phenomena).

Pediatric Use

Contraindicated in children under 3 years of age.

With caution in children over 3 years of age.

Special Precautions

With monotherapy, rapid development of mycobacterial resistance to cycloserine is possible, therefore 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, determine the sensitivity of the strain to cycloserine and other antituberculosis drugs. Alcohol consumption is not allowed during treatment.

To detect signs of the drug’s toxic effect on the central nervous system, careful monitoring of patients receiving Cycloserine in a dose exceeding 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 seizures, agitation, tremor) during treatment, it is possible to prescribe anticonvulsants and sedatives, benzodiazepine drugs (diazepam) and nootropic drugs (piracetam). Preventing or reducing the toxic effect of cycloserine can also be achieved 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 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 (seizures, psychosis, drowsiness, confusion, hyperreflexia, headache, dizziness, tremor, peripheral paresis, dysarthria) during treatment, the drug should be discontinued. EEG should be monitored during treatment. In some cases, the use of cycloserine and other antituberculosis drugs may lead to the development of cyanocobalamin and folic acid deficiency, megaloblastic anemia.

Effect on ability to drive vehicles and mechanisms.

Caution should be exercised while working for drivers of vehicles and people whose profession requires increased concentration and speed of psychomotor reactions.

Drug Interactions

Cycloserine increases the rate of pyridoxine excretion by the kidneys. Reduces resistance to isoniazid, streptomycin and 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 administration of ethionamide increases the risk of adverse effects from the central nervous system, especially convulsive syndrome).

Pyridoxine reduces the intensity of cycloserine’s adverse reactions from the nervous system. Enhances the effect of diuretics, 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

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.