MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS
(information for health care professionals)
Trade name: Cycloserine.
International nonproprietary name: Cycloserine.
Description: White hard gelatin capsules No. 0.
Content of the capsule: white, almost white, or yellowish powder. Stake- of tablet-shaped compactions of the capsule content crumbling when pressing them with a glass rod are admissible.
Composition: each capsule contains:
- Active substance: cycloserine 250 mg.
- Excipients: calcium stearate, lactose monohydrate.
Hard gelatin capsule composition: gelatin, titanium dioxide.
Pharmaceutical form: 250 mg capsules.
Pharmaco-therapeutic group: Antibacterial , reserve-line anti-tuberculous agent.
ATC Code: J04AB01.
Cycloserine possesses a broad-spectrum antibacterial activity suppressing Gram-positive as well as Gram-negative bacteria including Escherichia coli and Staphylococcus aureus; in 10 to 100 mg/l concentration, also Rickettsia spp. and Treponema spp. Depending on the focal concentration and microorganism sensitivity, this drug has either a bacteriostatic or bactericidal effect. The most valuable property of Cycloserine is its ability to retard tuberculous mycobacterial growth (anti-tuberculous antibiotic drug). Minimal suppressive concentration towards Mycobacterium tuberculosis is 3-25 mg/l in liquid medium, and 10-20 mg/l and higher in solid growth medium. Cycloserine activity is inferior to streptomycine, tubazide and ftivazide, but it is active against tuberculous mycobacteria resistant to these medicines and para-aminosalicylic acid. M. tuberculosis resistance towards cycloserine develops slowly and rarely: 20% to 30% of resistant strains are isolated after 6 months of treatment. No cross resistance with other anti-tuberculous drugs was demonstrated. Cycloserine is active against Mycobacterium avium.
Mechanism of action: cycloserine inhibits Mycobacterium cell wall synthesis. At the early stage D-alanine molecules are joined together. Being an analog of D-alanine aminoacid, cycloserine competitively inhibits L-alanine racemase enzyme activity which converts L-alanine to D-alanine, and D-alanyl-D-alanine synthetase including D-alanine into a pentapeptide necessary for peptidoglycane development and bacterial cell wall synthesis.
Cycloserine is rapidly and nearly completely (70% to 90%) absorbed from gastrointestinal tract after oral administration. Detectable concentrations develop after 1 hour. Cycloserine insignificantly binds with plasma proteins (< 20%) and is freely distributed across biological fluids and tissues within the human organism. Cycloserine penetrates through blood-brain and placental barriers. In tuberculosis-infected patients, cycloserine is detected in sputum as well as in pleural and ascitic fluids. It is also detected in fetal blood, breast milk, pulmonary and lymphoid tissues, sputum, and bile. It should be noted that cerebrospinal fluid, pleural and ascitic fluid concentrations are similar to those in blood plasma.
After 250 mg dose intake, peak plasma concentrations being approximately 10 mg/l are achieved in 3-4 hours. In case if 250 mg dose is taken every 12 hours, maximal concentration is 25-30 µg/l. Dose duplication results in two-fold plasma peak concentration thus indicating dose proportionality. Subsequently, drug plasma concentration rapidly falls, with 50% of the drug excreted within 12 hours.
About 60% to 70% of cycloserine oral dose is subjected to renal excretion in an unaltered active form by means of glomerular filtration within 24 hours. Another 10% are excreted within next 48 hours. About 35% of the administered dose is metabolized in the liver; however, metabolites are not identified and are excreted with the urine. Fecal excretion in negligible.
Mean elimination half-life is 10 hours, ranging from 8 to 12 hours. In case of renal impairment, half-life is increased.
Repeated administration may result in accumulation.
Cyclosporine is indicated as a part of complex treatment of:
- Active pulmonary tuberculosis, extrapulmonary tuberculosis (including renal damage) in case of drug sensitivity of microorganisms and after major drug adequate treatment failure, chronic cases of tuberculosis.
- Tuberculosis accompanied by acute urinary tract infections caused by sensitive Gram-positive and Gram-negative bacterial strains, especially Klebsiella spp. and Enterobacter coli, in case if main drug therapy appeared ineffective.
- Atypical mycobacterial infections (including those caused by Mycobacterium avium) and urinary tract infections.
Posology and method of administration
Orally, immediately before meals; in case of gastrointestinal tract mucous tunic irritation - after meals.
Adults: usual daily dose is 500 mg to 1 g. Initial adult dose is mostly 250 mg every 12 hours, 2 times per day for first two weeks. If necessary, the dose may be subsequently increased with caution to 250 mg every 6 – 8 hours considering drug tolerance and with monitoring of drug serum concentrations. Daily dose should not exceed 1 g.
Patients > 60 years old and patients with body weight less than 50 kg should receive a 250 mg dose 2 times per day.
Children > 3 years old: initial cycloserine daily dose is 10 to 20 mg/kg body weight divided into 2 – 3 administrations but not more than 750 mg daily. A greater dose is indicated only in case of acute stage of tuberculous process or in case if lower doses appeared ineffective.
Nervous system disorders. High dose (> 500 mg per day) Cycloserine may cause side effects mostly due to its toxic effect on nervous system: headache, dizziness, insomnia (in contrast, sometimes sleepiness), anxiety, aggressiveness, increased irritability, mental confusion, disorientation accompanied by amnesia, memory impairment, peripheral neuritis, paresis, hyperreflexia, paresthesia, tremor, clonic convulsion attacks. In some cases, more severe symptoms may be observed such as: apprehensiveness, psychastenic state, hallucinatory phenomena, psychosis accompanied by suicide attempts, altered character, epileptiform seizures, semiconscious state or loss of consciousness.
Gastrointestinal tract disorders: nausea, heartburn, diarrhea, especially in elderly patients with pre-existing hepatic diseases.
Cardiovascular system disorders: sudden development of congestive heart failure was observed in patients who took 1 to 1.5 g of this drug per day.
Blood disorders: in isolated cases – megaloblastic and sideroblastic anemia.
Other: allergic reactions, skin rash, pruritus, cyanocobalamin and folic acid deficiency, increased transaminase activity (especially in elderly patients with hepatic diseases); chronic cardiac impairment exacerbation was observed in patients who took 1000 to 1500 mg of this drug per day.
These effects are mostly reversible after dose decrease or discontinuation. The toxic effect of cycloserine may be prevented or reduced by prescribing 0.5 g of glutamic acid 3 – 4 times per day before meals during the treatment. An intramuscular injection of 1 ml sodium adenosine triphosphate 1% solution daily is recommended as well. An intramuscular injection of 1 – 2 ml pyridoxine 5% solution daily may sometimes be effective. If necessary, anticonvulsant, sedative and antidepressant drugs may be administered.
In order to reduce adverse effects, it is necessary to restrict psychic tension of patients and to exclude possible overheating factors (staying under the direct sunlight bare headed, hot showers, etc.) that may provoke complications.
Hypersensitivity to cycloserine and other drug components, central nervous system organic diseases, epilepsy, epileptic attacks (incl. in past medical history), psychiatric disorders (anxiety, psychosis, depression [incl. in past medical history]), chronic cardiac insufficiency, chronic renal impairment (creatinine clearance < 50 ml/min), alcoholism, lactation, children under 3 years old.
The product contains lactose, thus it is not recommended in patients with hereditary lactase deficiency, lactose intolerance and glucose-galactose malabsorption syndrome.
This drug should be used with caution during pregnancy.
Symptoms: Toxic effects mainly include central nervous system-related symptoms: headache, dizziness, irritability, paresthesia, dysarthria, paresis, convulsions, psychosis, mental confusion or loss of consciousness (coma).
Overdose is observed when cycloserine plasma concentration is equal to 25-30 mg/ml and occurs due to high dose intake or impaired renal clearance. Intake of cycloserine daily dose exceeding 1 g may cause acute intoxication. Continuous administration of cycloserine doses exceeding 500 mg/day may result in chronic intoxication symptoms.
Treatment: all measures are taken after cycloserine discontinuation: activated charcoal, supportive treatment, hemodialysis, administration of pyridoxine 200 – 300 mg/day in order to stop possible neurotoxic effect development, anticonvulsant and sedative drugs are used if necessary.
Precautions for use
Prior to cycloserine treatment, pathogen cultures should be isolated to identify microorganism strain sensitivity towards cycloserine. In case of tuberculous infection, strain sensitivity to other anti-tuberculous drugs should be determined as well. Close monitoring of patients receiving more than 500 mg cycloserine per day is required due to the possible development of nervous system disorders.
Cycloserine dose should be discontinued or reduced if a patient develops allergic dermatitis or central nervous system intoxication symptoms, e.g.: convulsions, psychosis, somnolence, mental depression or confusion, hyperreflexia, headache, tremor, dizziness, paresis or dysarthria. Patients with chronic alcoholism are at an increased risk of convulsive syndrome development thus cycloserine is contraindicated in such patients. Anticonvulsant or sedative agents may be effective to prevent neurotoxic reactions, e.g.: convulsions, agitation or tremor.
Hematological parameters, excretory renal function, cycloserine blood concentration and hepatic function should be monitored during the treatment. Cycloserine blood concentrations should not exceed 30 mg/ml.
In patients with decreased renal function taking cycloserine daily dose exceeding 500 mg and possibly demonstrating overdose signs and symptoms, drug blood level should be controlled at least once a week. The dose should be adjusted to maintain drug blood levels lower than 30 mg/l. Such patients should stay under close monitoring due to the possible development of toxicity symptoms. Patients with renal function impairment, especially elderly, should receive lower cycloserine doses. Cycloserine accumulation may develop in patients with normal renal function as well, in this case dose should be decreased.
In some cases cycloserine and other anti-tuberculous drugs may cause cyanocobalamin (vitamin B12) and folic acid deficiency and megaloblastic anemia. In case if anemia has developed during treatment with cycloserine, the patient should undergo examination and receive appropriate treatment.
The toxic effect of cycloserine may be prevented or reduced by prescribing 0.5 g of glutamic acid 3 – 4 times per day before meals during the treatment, and daily intramuscular injections of 1 ml sodium adenosine triphosphate 1% solution, and pyridoxine 200 to 300 mg/day.
It is necessary to restrict psychic tension of the treated patients and to exclude possible overheating factors, e.g.: staying under the direct sunlight bare headed, hot showers.
No alcohol should be consumed during cycloserine treatment.
Effects on ability to drive and use other potentially dangerous machines. Since cycloserine has toxic effects on central nervous system, it is recommended to avoid driving, operating machines and carrying out of other works requiring concentrated attention during the treatment.
Use during pregnancy. It is unknown whether cycloserine may cause fetal injury when used in pregnant women. Cycloserine should be used in pregnant women only if strictly indicated.
Use during lactation. Cycloserine concentrations in breast milk are similar to those detected in mother’s blood serum. A decision to terminate either lactation or treatment should be taken with regard to treatment significance to the mother.
Co-administration of cycloserine and ethionamide potentiates adverse neurotoxic effects.
Concurrent intake of cycloserine and alcohol, especially with high doses of the latter, increases the possibility and risk of epileptic attack development.
Patients concurrently receiving cycloserine and isoniazid should be under constant monitoring to prevent development of central nervous system toxicity symptoms such as dizziness and somnolence because these drugs have a combined toxic effect on central nervous system. Dose adjustment may be necessary.
Co-administration of cycloserine and other anti-tuberculous drugs may result in vitamin B12 and / or folic acid deficiency, megaloblastic anemia, sideroblastic anemia.
Cyclosporine increases renal pyridoxine excretion rate, and thus may cause anemia and peripheral neuritis development. In this case pyridoxine dose should be increased.
Protected from moisture and light, at temperature not exceeding 25°C.
Store out of the reach of children.
Do not use after expiration date indicated on the package.
10 capsules in contour cellular pack No. 10 x 3.
30 Fabriciuss Str., 220007 Minsk, Republic of Belarus
Tel./fax: (+375 17) 220 37 16