Helposerin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HELPOCERIN (HELPOCERIN)

Composition:

Active substance: cycloserine;

1 capsule contains 250 mg of cycloserine;

Excipients: magnesium stearate;

Capsule shell contains: gelatin, yellow FCF (E 110), erythrosine (E 127), titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of white/orange color, containing powder ranging from white to light pink.

Pharmacotherapeutic group.

Agents for treatment of tuberculosis. ATC code J04A B01.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics

After oral administration, cycloserine is rapidly absorbed from the gastrointestinal tract. The measurable plasma concentration is achieved within 1 hour. It freely distributes into tissues and body fluids. Cycloserine 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 fluids, bile, amniotic fluid, fetal blood, breast milk, lung tissue, and lymphoid tissue.

The drug 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 subsequent 48 hours. A negligible amount of the drug is eliminated in feces.

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

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

Clinical characteristics.

Indications.

Active pulmonary tuberculosis, extrapulmonary forms of tuberculosis (including renal involvement) provided sensitivity to cycloserine, after unsuccessful treatment with primary drugs (rifampicin, isoniazid, streptomycin, ethambutol).

Acute urinary tract infections caused by susceptible strains of gram-positive and gram-negative bacteria, particularly species of Klebsiella, Enterobacter, Escherichia coli. Cycloserine should be used to treat these infections only if conventional therapeutic agents have failed and microbial susceptibility to the drug has been demonstrated.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

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

Special precautions.

Treatment with cycloserine should be discontinued or the dosage reduced if allergic reactions or symptoms of nervous system involvement occur. Toxicity may occur if the drug concentration in the blood exceeds 30 mg/L, which may result from overdose or impaired drug clearance. The therapeutic index of this drug is low.

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

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

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

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

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

To prevent adverse neurotoxic effects, benzodiazepine psychotropic agents are prescribed: diazepam (5 mg) or fenazepam (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 vitamin B\12\ or folic acid deficiency, megaloblastic or sideroblastic anemia. If anemia develops during antituberculosis therapy, the patient should be examined and treated accordingly.

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

Use during pregnancy or breastfeeding.

The drug concentration in fetal blood is close to that in the plasma of the pregnant woman. Studies in two generations of rats showed no teratogenic effect in newborns. It has not been established whether cycloserine causes fetal harm when administered to pregnant women or whether it affects reproductive function. Cycloserine may be administered to pregnant women only if clearly needed.

The concentration of cycloserine in breast milk is close to that in the plasma of the nursing mother. The physician must decide whether to discontinue breastfeeding or to discontinue the drug.

Ability to affect reaction rate while driving or operating machinery.

During treatment with this drug, patients should refrain from driving vehicles or operating complex machinery.

Method of Administration and Dosage

Administer orally.

Adults: The usual dose is 500 mg to 1000 mg daily in divided doses. The initial dose for adults is usually 250 mg twice daily at 12-hour intervals 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 in divided doses, which should then be adjusted according to plasma drug concentration and therapeutic response. The desired peak plasma concentration is 15–40 mcg/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.

The duration of treatment depends on the course of the disease, laboratory and radiological findings, and the patient's tolerance to cycloserine.

Children:

There is insufficient experience with the use of cycloserine in children. The drug may be used only under strict medical supervision and with special caution in children aged 5 years and older, 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, refer to the sections "Contraindications" and "Special Warnings and Precautions for Use". In patients receiving more than 1 g of cycloserine daily, the most serious adverse effects of the drug—cardiac arrhythmias and sudden onset of chronic congestive heart failure (rare)—may occur.

Toxic effects usually manifest in the central nervous system: headache, dizziness, confusion, increased irritability, paresthesias, 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 treatment is recommended. Activated charcoal is more effective in reducing drug absorption than gastric lavage. In case of neurotoxic effects, administration of 200–300 mg of pyridoxine daily is required. Cycloserine is removed from the blood during hemodialysis; however, the development of potentially life-threatening toxic effects cannot be ruled out.

Adverse Reactions

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

Central nervous system: (in cases of doses exceeding 500 mg/day): headache, dizziness, paresthesia, paresis, hyperreflexia, tremor, peripheral neuritis, ataxia, major and minor clonic seizures, convulsions, coma.

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

Nervous system adverse reactions usually occur during the first two weeks of treatment and primarily affect patients receiving 500 mg of cycloserine per day.

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

Hepatobiliary system and biliary tract: increased blood transaminase levels, hepatitis, particularly in patients with pre-existing liver disease.

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

Musculoskeletal and connective tissue: arthralgia, myalgia.

Immune system: 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 1 to 1.5 g of cycloserine per day.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging.

10 capsules in a blister; 5 blisters in a carton.

50 capsules in a polyethylene or glass bottle; 1 polyethylene or glass bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Help S.A.

Manufacturer's address and location of business operations.

Pedini Ioanninon, Ioannina, 45500, Greece / Pedini Ioanninon, Ioannina, 45500, Greece