Cycloserine
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYCLOSERINE (CYCLOSERINE)
Composition:
Active substance: cycloserine;
1 capsule contains 125 mg or 250 mg of cycloserine;
Excipients: magnesium oxide light, magnesium oxide heavy, talc;
composition of 125 mg strength capsule: titanium dioxide (E 171), gelatin, iron oxide red (E 172), iron oxide black (E 172), iron oxide yellow (E 172);
composition of 250 mg strength capsule: titanium dioxide (E 171), gelatin, indigocarmine (E 132).
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
125 mg strength: hard gelatin capsules, cylindrical in shape, with an opaque white body and an opaque brown cap, filled with powder ranging from white to pale yellow;
250 mg strength: hard gelatin capsules, cylindrical in shape, with an opaque white body and an opaque blue cap, filled with powder ranging from white to pale yellow.
Pharmacotherapeutic group.
Antimicrobial agents for systemic use. Agents acting on mycobacteria. Antituberculosis agents. Antibiotics. Cycloserine.
ATC code J04A B01.
Pharmacological Properties
Pharmacodynamics
Cycloserine exerts bacteriostatic and bactericidal effects depending on the concentration of the drug at the site of infection and the susceptibility 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. The measurable plasma concentration is achieved within 1 hour. It freely distributes into tissues and body fluids. It penetrates across 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 it also reaches pleural and ascitic fluids, 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 subsequent 48 hours. A negligible amount is excreted in feces.
Approximately 35% of cycloserine is metabolized, but the 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: the drug is used as part of combination therapy, provided the microorganisms are sensitive to cycloserine and after ineffective treatment with primary medicinal agents (used only as a second-line drug).
Acute urinary tract infections caused by sensitive microorganisms: the drug is used only when conventional therapy has proven ineffective and when sensitivity of microorganisms to cycloserine has been established.
Contraindications.
Hypersensitivity to cycloserine or to other components of the drug. Organic diseases of the central nervous system, depression, psychiatric disorders, marked agitation or psychosis, epilepsy, tendency to seizures, history of psychiatric disorders, severe renal insufficiency, 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 taking cycloserine and isoniazid should be under medical supervision, as enhanced toxic effects on the central nervous system (dizziness, drowsiness) may occur; dose adjustment may also be necessary.
Special precautions.
Treatment with cycloserine should be discontinued or the dose reduced if allergic dermatitis or symptoms of nervous system involvement occur, such as seizures, psychosis, drowsiness, depression, confusion, hyperreflexia, headache, tremor, dizziness, paresis, or dysarthria.
Cycloserine has a narrow therapeutic index. During treatment of patients with impaired renal function who are receiving a daily dose of cycloserine exceeding 500 mg and who develop signs of overdose, the blood concentration of cycloserine should be monitored at least once a week. The dose should be adjusted to maintain a steady-state serum level below 30 mg/L.
In patients with moderate to severe renal insufficiency, 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 blood exceeds 30 mg/L, which may result from overdose or impaired drug clearance.
During treatment, hematological parameters, renal excretory function, drug blood levels, and liver function should be monitored.
Prior to initiating therapy, the causative microorganism should be cultured and its susceptibility to the drug determined. In cases of tuberculosis infection, susceptibility to other antituberculosis agents should also be assessed.
Anticonvulsant and sedative drugs may be effective in preventing symptoms of central nervous system involvement, such as seizures, agitation, and tremor.
To prevent adverse neurotoxic effects, psychotropic benzodiazepine drugs 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 deficiency of vitamin B12 or folic acid, resulting in megaloblastic or sideroblastic anemia. If anemia develops during antituberculosis therapy, appropriate treatment should be administered.
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 use in patients with porphyria.
Use during pregnancy or breastfeeding.
Cycloserine should be used during pregnancy only when no alternative treatment options are available and when the potential benefit to the mother outweighs the potential risk to the fetus.
If use of the drug is necessary, breastfeeding should be discontinued for the duration of treatment.
Ability to affect reaction speed when driving or operating machinery.
During treatment with this medicinal product, patients should refrain from driving vehicles or engaging in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions.
Method of administration and dosage.
The drug is administered orally. Cycloserine can be taken independently of food intake, but to prevent gastrointestinal adverse effects, it is better to take it during meals.
Adults. The usual dose is from 500 mg to 1000 mg per day in several divided doses. The initial dose for adults is most often 250 mg twice daily at 12-hour intervals for 2 weeks. The daily dose should not exceed 1 g.
Table 1.
| Body weight range for patients aged 14 years and older |
Daily dose depending on body weight |
Standard upper limit of daily dose |
|||||
| Body weight |
30–35 kg |
36–45 kg |
46–55 kg |
56–70 kg |
> 70 kg |
10–15 mg/kg |
1 g |
| Capsules (number of capsules) |
2 |
2 |
3 |
3 |
3 |
||
Children:
The usual dose is 10–20 mg/kg body weight per day. The daily dose should not exceed 1000 mg. If possible, therapeutic drug monitoring may be helpful. The desired peak plasma concentration is 15–40 μg/mL.
Table 2.
| Body weight range for patients up to 14 years of age |
Daily dose according to body weight |
Standard upper limit of daily dose |
|||||||
| Body weight |
5–6 kg |
7–9 kg |
10–15 kg |
16–23 kg |
24–30 kg |
31–34 kg |
> 34 kg |
15–20 mg/kg |
1 g |
| 125 mg capsules* (number of capsules) |
1 |
1 |
2 |
3 |
4 |
See Table 1 |
See Table 1 |
||
| Capsules 250 mg* (number of capsules) |
4–5 ml* |
5–6 ml* |
7–10 ml* |
2 |
2 |
2 |
See Table 1 |
*It is recommended to avoid using solid dosage forms in patients with low body weight. Instead, the contents of one 250 mg capsule should be dissolved in 10 mL of water (administer the volume of the resulting solution as specified in the table). This method of administration may facilitate dosing, but bioavailability has not been clearly defined.
Elderly patients. For patients aged 60 years and older, as well as for patients with body weight below 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 if 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 if more than 500 mg of the drug is administered daily. In case of necessity to use the drug in patients with impaired renal function, see sections "Contraindications" and "Special precautions".
Toxic effects usually manifest in the central nervous system: headache, dizziness, confusion, increased irritability, paresthesia, dysarthria, psychosis. With high-dose intake, peripheral paresis, seizures, and coma may occur. Ethanol increases the risk of epileptic seizures.
In patients receiving more than 1 g of cycloserine per day, the most serious adverse effect of the drug—cardiac arrhythmia and sudden onset of chronic congestive heart failure (rare)—may develop.
Cycloserine is removed from the blood during hemodialysis, but the development of a potentially life-threatening toxic effect cannot be excluded.
Treatment: symptomatic and supportive therapy is recommended. Activated charcoal is more effective than gastric lavage in reducing drug absorption. In case of neurotoxic effects, 200–300 mg of pyridoxine should be administered daily. Cycloserine is removed from the blood during hemodialysis.
Side effects.
Nervous system disorders: headache, dizziness, paresthesia, paresis, hyperreflexia, tremor, peripheral neuritis, ataxia, major and minor clonic seizures, convulsions, coma, epileptiform seizures (when doses exceeding 500 mg per day are administered).
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.
Adverse reactions affecting the nervous system mostly occur during the first two weeks and primarily in patients receiving 500 mg of cycloserine daily.
Gastrointestinal disorders: vomiting, nausea, dry mouth, loss of appetite, abdominal pain.
Hepatobiliary disorders: elevated 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, folate and vitamin B12 deficiency anemia, sideroblastic anemia, increased body temperature, hypoglycemia, porphyria exacerbation.
Sudden onset of chronic heart failure has been reported in patients receiving 1 to 1.5 g of cycloserine daily.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
For 125 mg dosage:
10 capsules in a blister; 3 blisters in a cardboard box.
For 250 mg dosage:
10 capsules in a blister; 3 blisters in a cardboard box.
60 capsules in a container. 1 container in a cardboard box.
Prescription category. Prescription only.
Manufacturer.
JSC "Tekhnolog".
Manufacturer's address and location of manufacturing activities.
8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.