Coxerin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT COXERIN

Composition:

Active substance: cycloserine;

1 capsule contains 250 mg of cycloserine;

Excipients: magnesium oxide light, magnesium oxide heavy, talc;

hard gelatin capsule (capsule shell) contains: yellow sunset FCF (E 110), carmoisine (E 122), brilliant blue (E 133), titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsule No. 1 of dark burgundy color containing a powder from white to light yellow in color.

Pharmacotherapeutic group.

Agents acting on mycobacteria. Antibiotics. ATC code J04A B01.

Pharmacological properties.

Pharmacodynamics.

Cycloserine exerts bacteriostatic and bactericidal effects depending on the concentration of the drug at the site of inflammation and the sensitivity of microorganisms. The mechanism of action involves inhibition of cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and Mycobacterium tuberculosis. Cycloserine should be used in combination with other antituberculosis drugs.

Pharmacokinetics.

After oral administration, cycloserine is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 hour. It freely distributes into tissues and body fluids. It penetrates the blood-brain barrier; the concentration achieved in cerebrospinal fluid is close to that in plasma. In patients with tuberculosis, cycloserine is detectable in sputum and also reaches pleural and ascitic fluid, bile, amniotic fluid, fetal blood, breast milk, lung tissue, and lymphoid tissue.

It is excreted by the kidneys and can be detected in urine within 30 minutes after administration. Approximately 66% of cycloserine is excreted unchanged in urine within 24 hours. Another 10% is excreted over the following 48 hours. A negligible amount is eliminated in feces.

Approximately 35% of cycloserine undergoes metabolism, but metabolites have not been identified.

The elimination half-life of the drug is 8–12 hours.

Clinical characteristics.

Indications.

Active form of pulmonary and extrapulmonary tuberculosis as part of combination therapy, provided microbial sensitivity to cycloserine and after ineffective treatment with primary drugs (used only as a second-line agent).

Acute urinary tract infections caused by susceptible microorganisms, only when conventional therapy has proven ineffective and microbial sensitivity to this drug has been established.

Contraindications.

Hypersensitivity to cycloserine or to any of the other components of the drug. Organic diseases of the central nervous system, depression, psychiatric disorders, pronounced agitation or psychosis, epilepsy, predisposition to seizures, history of psychiatric disorders, severe renal insufficiency (creatinine clearance less than 250 ml/min), cardiac insufficiency, alcoholism.

Interaction with other medicinal products and other types of interactions.

Concomitant use of ethionamide potentiates the neurotoxic effects of cycloserine. Alcohol and cycloserine are incompatible, especially during administration of high doses of the drug (alcohol increases the risk of epileptic seizures).

Patients receiving cycloserine and isoniazid should be under medical supervision, since this combination may enhance the toxic effect on the central nervous system, and dose adjustment may become necessary.

Special precautions for use.

Treatment with Cocserin should be discontinued or the dosage reduced if allergic dermatitis or symptoms of nervous system involvement occur, such as convulsions, psychosis, drowsiness, depression, confusion, hyperreflexia, headache, tremor, dizziness, paresis, or dysarthria.

The therapeutic index of cycloserine is low. During treatment of patients with impaired renal function who are receiving a daily dose of cycloserine exceeding 500 mg and who develop symptoms of overdose, cycloserine blood levels should be monitored at least once weekly. The dose should be adjusted so that the maintenance level of the drug in the blood remains below 30 mg/L.

In patients with moderate to severe renal impairment, the dose of cycloserine should be reduced.

Patients receiving more than 500 mg of cycloserine per day should be under medical supervision due to the risk of developing symptoms of overdose.

Toxicity may occur if the drug concentration in the blood exceeds 30 mg/L, which may result from overdose or impaired drug clearance.

During treatment with the drug, hematological parameters, renal excretory function, blood drug levels, and liver function should be monitored.

Prior to initiating therapy, a culture of microorganisms should be isolated and the strain's susceptibility to the drug determined. In cases of tuberculosis infection, the strain's susceptibility to other antituberculosis agents should also be determined.

Anticonvulsant and sedative drugs may be effective in preventing symptoms of central nervous system involvement, such as convulsions, agitation, and tremor.

To prevent adverse neurotoxic effects, psychotropic drugs of the benzodiazepine class may be prescribed: diazepam (5 mg) or phenazepam (1 mg) at bedtime; nootropic agents: piracetam (800 mg twice daily), pyridoxine, and glutamic acid (1 g three times daily).

In some cases, the use of cycloserine and other antituberculosis drugs may lead to deficiency of vitamin B12 or folic acid, resulting in megaloblastic and sideroblastic anemia. If anemia develops during antituberculosis therapy, appropriate treatment should be administered.

Contains azo dyes – tartrazine (E 110) and carmoisine (E 122), which may cause allergic reactions.

Cycloserine reduces blood glucose levels both in healthy volunteers and in patients with diabetes mellitus. Cycloserine may exacerbate porphyria; therefore, the drug is not recommended for use in patients with porphyria.

Use during pregnancy or breastfeeding.

Cycloserine should be used during pregnancy only if absolutely necessary, when no alternative treatment options are available and the potential benefit to the mother outweighs the risk to the fetus.

If use of the drug is necessary, breastfeeding should be discontinued for the duration of treatment.

Ability to affect reaction rate when driving or operating machinery.

During treatment, patients should refrain from driving vehicles and engaging in other potentially hazardous activities requiring high concentration and rapid psychomotor reactions.

Method of Administration and Dosage

The drug is taken orally, regardless of food intake; however, to minimize gastrointestinal adverse effects, it is preferable to take it during meals.

Adults. The usual dose is 500 to 1000 mg daily, divided into several doses. The initial dose for adults is typically 250 mg twice daily with a 12-hour interval for 2 weeks. The daily dose should not exceed 1 g.

Children aged 5 years and older. The usual dose is 10 mg/kg body weight daily, divided into two doses. The dose should then be adjusted based on plasma drug concentration and therapeutic response. The desired peak plasma concentration is 15–40 µg/mL. The daily dose should not exceed 750 mg.

Elderly patients. For patients aged 60 years and older, as well as those with body weight less than 50 kg, the recommended dose is 250 mg of cycloserine twice daily.

Duration of treatment depends on the course of the disease, laboratory and radiological findings, and cycloserine tolerability.

Children.

There is insufficient experience with the use of cycloserine in children. Therefore, the drug should be prescribed to children aged 5 years and older only under strict medical supervision, with special caution, and only when absolutely necessary.

Overdose.

Acute poisoning may occur if an adult patient ingests more than 1 g of the drug. Chronic toxicity is dose-dependent and may develop when more than 500 mg of the drug is administered daily. In patients with impaired renal function, see sections "Contraindications" and "Special Warnings and Precautions".

In patients receiving more than 1 g of cycloserine daily, the most serious adverse effects—cardiac arrhythmia and sudden onset of chronic congestive heart failure (rare)—may occur.

Toxic effects typically manifest in the central nervous system: headache, dizziness, confusion, increased irritability, paresthesia, dysarthria, and psychosis. With high-dose intake, peripheral paresis, seizures, and coma may occur. Ethanol increases the risk of epileptic seizures.

Treatment. Symptomatic and supportive therapy is recommended. Activated charcoal is more effective in reducing drug absorption than gastric lavage. In case of neurotoxic effects, 200–300 mg of pyridoxine daily should be administered. Cycloserine is removed from blood during hemodialysis; however, the development of potentially life-threatening toxic effects cannot be excluded.

Adverse Reactions

Most adverse effects are related to disturbances of central nervous system function or increased sensitivity to the drug.

Nervous system disorders (with doses exceeding 500 mg daily): headache, dizziness, paresthesia, paresis, hyperreflexia, tremor, peripheral neuritis, ataxia, epileptiform seizures, major and minor clonic convulsions, coma.

Psychiatric disorders: anxiety, feeling of anxiety, increased irritability, nervousness, aggression, irritability, sleep disturbances, somnolence, memory impairment, disorientation, psychosis, depression, possible suicidal attempts, paranoia, personality changes, fear sensations, speech disturbances, dysarthria, tinnitus, psychomotor agitation, hallucinations, confusion, loss of consciousness.

Adverse reactions affecting the nervous system mostly occur during the first two weeks of treatment and predominantly in patients receiving 500 mg of cycloserine daily.

Gastrointestinal disorders: vomiting, nausea, dry mouth, loss of appetite, abdominal pain.

Hepatobiliary disorders: increased blood transaminase levels, hepatitis, especially in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders: skin rashes, pruritus, petechial-papular eruptions, photosensitivity.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia.

Immune system disorders: hypersensitivity reactions/allergic reactions.

Other: megaloblastic anemia, folic acid and vitamin B12-deficiency anemia, sideroblastic anemia, increased body temperature, hypoglycemia, exacerbation of porphyria.

Cases of cardiac arrhythmias and sudden onset of chronic heart failure have been reported in patients receiving cycloserine at doses of 1 to 1.5 g daily.

Shelf life

In strips: 2 years.

In blisters: 3 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

10 capsules per strip. 10 strips per cardboard box.

10 capsules per blister. 9 or 10 blisters per cardboard box.

Prescription category
Prescription only.

Manufacturer

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and place of business

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.