The active ingredient is 5H-dibenzo[b,f]azepine-5-carboxamide. Each coated tablet contains 200mg or 400mg carbamazepine Ph.Eur.

The 200mg tablets are beige-orange, oval, slightly biconvex, coated tablets with a score on each side. One side bears the imprint “H/C”, the other “C/G”. The 400mg tablets are brownish-orange, oval, slightly biconvex coated tablets with a score on each site. One side bears the imprint “ENE/ENE”, the other “C/G”.

Epilepsy - generalised tonic-clonic and partial seizures. Tegretol Retard is indicated in newly diagnosed patients with epilepsy and in those patients who are uncontrolled or unable to tolerate their current anti-convulsant therapy. Note: Carbamazepine is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences. The paroxysmal pain of trigeminal neuralgia. For the prophylaxis of manic-depressive psychoses in patients unresponsive to lithium therapy.

Tegretol Retard is given orally, generally in the same total daily dose as conventional Tegretol dosage forms but usually in two divided doses. In a few patients when changing from other oral dosage forms of Tegretol to Tegretol Retard the total daily dose may need to be increased, particularly when it is used in polytherapy. When starting treatment with Tegretol Retard in monotherapy, 100-200mg once or twice daily is recommended. This may be followed by a slow increase in dosage until the best response is obtained, often 800-1200mg daily. In some instances, 1600mg or even 2000mg daily may be necessary.

Tegretol Retard (either the whole or half divisible tablet as prescribed), should not be chewed but should be swallowed with a little liquid, before, during or between meals. The divisible tablet presentation enables flexibility of dosing to be achieved.

Before deciding to initiate treatment, patients of Han Chinese and Thai origin should whenever possible be screened for HLA-B*1502 as this allele strongly predicts the risk of severe carbamazepine-associated Stevens-Johnson syndrome.

Epilepsy:

Adults: It is advised that with all formulations of Tegretol, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient. It may be helpful to monitor the plasma concentration of carbamazepine to establish the optimum dose (see Pharmacokinetics, Precautions and Interactions).

Elderly: Due to the potential for drug interactions, the dosage of Tegretol should be selected with caution in elderly patients.

Children: It is advised that with all formulations of Tegretol, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient. It may be helpful to monitor the plasma concentration of carbamazepine to establish the optimum dose (see Pharmacokinetics, Precautions and Interactions).

Usual dosage 10-20mg/kg bodyweight daily in several divided doses.

Age up to 5 years: Tegretol Retard Tablets are not recommended

5-10 years: 400-600mg daily

10-15 years: 600-1000mg

Wherever possible, Tegretol Retard should be used as the sole drug anti-epileptic agent but if used in polytherapy, the same incremental dosage pattern is advised.

When Tegretol is added to existing antiepileptic therapy, this should be done gradually while maintaining or, if necessary, adapting the dosage of the other antiepileptic(s) (see 4.5 Interaction with other Medicaments and other forms of Interaction).

Trigeminal neuralgia:

Slowly raise the initial dosage of 200-400mg daily (100mg twice daily in elderly patients) until freedom from pain is achieved (normally at 200mg 3-4 times daily). In the majority of patients a dosage of 200mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, doses of 1600 Tegretol daily may be needed. However, once the pain is in remission, the dosage should be gradually reduced to the lowest possible maintenance level.

For the prophylaxis of manic depressive psychosis in patients unresponsive to lithium therapy:

Initial starting dose of 400mg daily, in divided doses, increasing gradually until symptoms are controlled or a total of 1600mg given in divided doses is reached. The usual dosage range is 400-600mg daily, given in divided doses.

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.

Patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).

The use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs).

Warnings

Agranulocytosis and aplastic anaemia have been associated with Tegretol; however, due to the very low incidence of these conditions, meaningful risk estimates for Tegretol are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.

Decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tegretol. Nonetheless, complete pre-treatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline, and periodically thereafter.

Patients and their relatives should be made aware of early toxic signs and symptoms indicative of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult his physician immediately.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. However, treatment with Tegretol should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Tegretol should also be discontinued if any evidence of significant bone marrow depression appears.

Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.

Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.

Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Tegretol suspended pending the outcome of the evaluation.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for carbamazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome) and Stevens Johnson syndrome (SJS) have been reported very rarely with Tegretol. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tegretol. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell's syndrome/TEN) appear, Tegretol should be withdrawn at once and alternative therapy should be considered.

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.

It is not definitely known whether all individuals of south east-Asian ancestry are at risk due to lack of data.

The allele HLA-B*1502 has been shown not to be associated to SJS in the Caucasian population.

Mild skin reactions e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).

Tegretol may trigger hypersensitivity reactions, including multi-organ hypersensitivity reactions, which can affect the skin, liver (including intrahepatic bile ducts), haematopoietic organs and lymphatic system or other organs, either individually or together in the context of a systemic reaction.

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be withdrawn immediately.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

Tegretol should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, Tegretol may exacerbate seizures. In case of exacerbation of seizures, Tegretol should be discontinued.

An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.

Abrupt withdrawal of Tegretol may precipitate seizures:

If treatment with Tegretol has to be withdrawn abruptly, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).

Tegretol and oestrogen and/or progestogen preparations

Due to hepatic enzyme induction, Tegretol may cause failure of the therapeutic effect of oestrogen and/or progestogen containing products. This may result in failure of contraception, recurrence of symptoms or breakthrough bleeding or spotting.

Patients taking Tegretol and requiring hormonal contraception should receive a preparation containing not less than 50µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.

Although correlations between dosages and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used.

Precautions

Tegretol should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.

Baseline and periodic complete urinalysis and BUN determinations are recommended.

Tegretol has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be warned and advised regarding possible hazards.

The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

Novartis Pharmaceuticals UK Ltd

POM – Prescription Only Medicine