Each uncoated sustained release tablet contains: Carbamazepine……………………………………. 400 mg

INDICATIONS

Carbamazepine is used to control secondarily generalized tonic-clonic seizures and partial seizures. It is also used in the treatment of trigeminal neuralgia and has been tried with variable success in glossopharyngeal neuralgia and other severe pain syndromes associated with neurological disorders such as tabes dorsalis and multiple sclerosis. Another use is in the prophylaxis of manic depression (bipolar disorder) unresponsive to lithium.

DOSAGE AND ADMINISTRATION

In the treatment of epilepsy;

The suggested initial oral dose is 100 to 200 mg once or twice daily gradually increased by increments of 100 to 200 mg every 2 weeks to a usual maintenance dose of 800mg to 1.2 g daily in divided doses;

Children: the usual oral dosage based on body-weight is 10 to 20 mg per kg daily in divided doses. Alternatively the dose may be expressed in terms of the age of the child and suggested daily doses are: up to 1 year of age, 100 to 200 mg; 1 to 5 years, 200 to 400 mg; 5 to 10 years, 400 to 600 mg; 10 to 15 years, 600mg to 1 g.

Carbamazepine may be given by the rectal route in doses up to a maximum of 250 mg every 6 hours to patients for whom oral treatment is temporarily not possible. The dosage should be increased by about 25% when changing from an oral formulation to suppositories and it is recommended that the rectal route should not be used for longer than 7 days.

In the treatment of trigeminal neuralgia the initial dose of carbamazepine is 100 mg once or twice daily by mouth increased gradually as necessary; the usual maintenance dose is 400 to 800 mg daily in to 4 divided doses but up to 1.6 g daily may be required. When pain relief has been obtained attempt should be made to reduce and ultimately discontinue the therapy, until another attack occurs.

For the prophylaxis of manic depression, carbamazepine is given in an initial oral dose of 400 mg daily in divided doses, increased gradually as necessary up to a maximum of 1.6 g daily; the usual maintenance dose range is 400 to 600 mg daily.

ADVERSE EFFECTS

Fairly common adverse effects of carbamazepine, particularly in the initial stages of therapy, include dizziness, drowsiness and ataxia.

These effects may be minimized by starting therapy with a low dose.

Drowsiness and disturbances of cerebellar and oculo-motor function (with ataxia, nystagmus and diplopia) are also symptoms of excessive plasma concentrations of carbamazepine and may disappear with continued treatment at reduced dosage. Gastro-intestinal symptoms are reported to be less common and include dry mouth, abdominal pain, nausea and vomiting, anorexia and diarrhea or constipation.

Generalized erythematous rashes may be severe and may necessitate withdrawal of treatment. Photosensitivity reactions, urticaria, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme and the Stevens-Johnson syndrome and systemic lupus erythematosus have also been reported.

Occasional reports of blood disorders include agranulocytosis, aplastic anaemia, eosinophilia, persistent leucopenia, leucocytosis, thrombocytopenia and purpura. Lymphadenopathy splenomegaly, pneumonitis, abnormalities of liver and kidney function and cholestatic jaundice have occurred. Some or all of these symptoms as well as fever and rashes may represent a generalized hypersensitivity reaction to carbamazepine.

Other adverse effects reported include paraesthesia, headache, arrhythmias and heart block, heart failure, hyponatraemia and oedema, impotence, male infertility, gynaecomastia, galactorrhea and dystonias and dyskinesis with asterixis. Rectal administration has resulted in local irritation.

Overdosage may be manifested by many of the adverse effects listed above, especially those on the nervous system and may result in stupor, coma, convulsions, respiratory depression and death. In rare cases, carbamazepine has been reported to exacerbate seizures in patients suffering from mixed-type epilepsy.

Congenital malformations have been reported in infants born to women who received carbamazepine during pregnancy.

TREATMENT OF ADVERSE EFFECTS

In the treatment of carbamazepine overdosage, the stomach should be emptied by lavage; repeated doses of activated charcoal may be given with the aim not only of preventing absorption but also of aiding elimination. Supportive and symptomatic therapy alone may then suffice; haemoperfusion has been suggested for the management of the more severely poisoned patient.

PRECAUTIONS

Carbamezepine should be avoided in patients with atrioventricular conduction abnormalities. It should not be given to patients with a history of blood disorders or of cardiac, hepatic, or renal disease. Patients or their carriers should be told how to recognize signs of blood, liver, and skin toxicity and they should be advised to seek immediate medical attention if the symptoms such as fever, sore throat, rash, mouth ulcers, bruising, or bleeding develop.

Carbamazepine should be withdrawn, if necessary under cover of a suitable alternative antiepileptic, if leucopenia which is severe, progressive, or associated with clinical symptoms develops. Care is required in identifying patients with mixed seizure disorders that include generalized absence or atypical absence seizures. who may be at risk of an increase in generalized seizures if given carbamazepine. It may also exacerbate absence and myoclonic seizures.

Care is required when withdrawing carbamazepine therapy. Since carbamazepine has mild antimuscarinic properties caution should be observed in patients with glaucoma or raised intra-ocular pressure; scattered punctuate lens opacities occur rarely with carbamazepine and it has been suggested that patients should be examined periodically for eye changes.

PHARMACOKINETICS

Carbamazepine is slowly and irregularly absorbed from the gastrointestinal tract. It is extensively metabolized in the liver and one of its primary metabolites, carbamazepine- 10,11 –epoxide is also active.

Carbamazepine is excreted in the urine almost entirely in the form of its metabolites; some is also excreted in faeces Elimination of carbamazepine is reported to be more rapid in children and accumulation of active metabolite may often be higher than in adults.

Carbamazepine is widely distributed throughout the body and is extensively bound (about 75% ) to plasma proteins. It induces its own metabolism so that the plasma half-life may be considerably shorter in children than in adults. Moreover, the metabolism of carbamazepine is readily induced by drugs which induce hepatic microsomal enzymes.

Monitoring of plasma concentrations may be performed as an aid in assessing control and the therapeutic range of total plasma – carbamazepine is usually quoted as being about 4 to 12 μg per mL (16 to 50μmol per liter), although this is subject to considerable variation. It has been suggested by some, but not all investigators, that measurement of free carbamazepine concentrations in plasma may prove more reliable, and measurement of concentrations in saliva or tears, which contain only free carbamazepine has also been performed. Carbamazepine crosses the placental barrier and is distributed into breast milk.