SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Carbamazepine Norton Tablets BP 200mg / Epimaz Tablets / Tenkepine Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Carbamazepine Ph.Eur 200mg For excipients see section 6.1.

3    PHARMACEUTICAL FORM

White FBE tablets coded CBZ 200 and breakline on one side, twin triangle logo on reverse or coded CBZ 200 and breakline on one side, plain on reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Epilepsy, generalised tonic-clonic and partial seizures.

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 psychoss in patient unresponsive to lithium therapy.

4.2 Posology and method of administration

For oral administration

Carbamazepine is given orally, usually in two or three divided doses.

Carbamazepine may be taken during, after or between meals, with a little liquid e.g. a glass of water.

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. (see section 4.4)

Epilepsy

Adults:

It is advised that 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). In most cases the optimum therapeutic plasma level for carbamazepine ranges from 4-12 mcg/ml (17-50mcmoles/l).

Carbamazepine should be taken in a number of divided doses although initially 100 200 mg once or twice a day is recommended. This may be followed by a slow increase until the best response is obtained, often 800 1,200 mg daily. In some instances, 1,600 mg or even 2,000mg daily may be necessary.

Elderly:

Due to the potential for drug interactions, the dosage of carbamazipine should be selected with caution in elderly patients.It is recommended that the initial dose be small and the increments titrated against the patient’s clinical condition.

Children

Use a gradually increasing dosage scheme and adjust to suit the needs of the patient. It may be helpful to monitor the plasma concentration of carbamazepine to establish the optimum dose, (see Pharmacokinetics, Precautions and Interactions).. In most cases the optimum therapeutic plasma level for carbamazepine ranges from 4-12mcg/ml (17-50mcmoles/l).

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

Carbamazepine tablets are not recommended for very young children.

5 - 10 years: 2 3 x 200 mg tablets to be taken in divided doses. 10 - 15 years: 3 5 x 200 mg tablets to be taken in divided doses.

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

When carbamazepine 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 Medicinal Products and other forms of Interaction).

Trigeminal neuralgia:

The individual dosage requirements of carbamazepine vary considerably, depending on the age and weight of the patient. An initial dose of 200-400 mg daily is recommended (100 mg twice daily in the elderly).

The dose may be increased gradually until freedom from pain is achieved (normally at 200mg 3-4 times daily). It has been found that in the majority of patients a dosage of 200 mg three or four times a day is sufficient to maintain a pain free state. In some instances, doses of 1600 mg carbamazepine daily may be needed. However, once the pain is in remission, the dosage should be gradually reduced until the lowest possible maintenance level is achieved. It is suggested that carbamazepine is taken only during acute stage of the condition and not as a prophylactic measure.

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

For patients with manic depressive psychosis who are unresponsive to lithium, an initial starting dose of 400mg, in divided doses is suitable. The dosage can be increased gradually until symptoms are controlled or a total of 1600mg given in divided doses is reached. The maximum dosage given should not exceed 1600mg.

The typical dosage is 400-600mg daily, in divided doses.

4.3 Contraindications

Previous drug sensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants). Known sensitivity to any of the excipients contained in the product formulation.

Carbamazepine should not be used concurrently with monoamine oxidase inhibitors (see section 4.5 Interaction with other medicinal products and other forms of interaction). MAOI treatment should be discontinued for 2 weeks or longer before treatment with carbamazepine begins.

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).

Because carbamazepine depresses AV-conduction, it is inadvisable to administer this drug to patients with atrioventricular conduction abnormalities unless paced.

4.4 Special warnings and precautions for use

WARNINGS

Agranulocytosis and aplastic anaemia have been associated with carbamazepine. The incidence of these is very rare so clinical risk estimates are difficult to obtain, The overall risk in the general untreated population has been estimated at 4.7 person 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 carbamazepine. 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 patients white blood cell or platelet count decreases or is low during treatment, the patient and the complete blood count should be closely monitored (see Section 4.8 Undesirable Effects). Non-progressive or fluctuating asymptomatic leucopenia, which is quite often encountered, does not generally call for withdrawal of carbamazepine. However, treatment with carbamazepine should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat, or in the event of any other evidence of bone marrow depression.

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.

Abnormal liver function tests particularly gamma glutamyl transferase, have been reported during carbamazepine treatment. This is probably due to hepatic enzyme induction. This may also produce moderate increases 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 carbamazepine suspended pending the outcome of the evaluation.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, also known as Lyell's syndrome) have been reported very rarely with the use of carbamazepine. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. Most of the SJS/TEN cases appear in the first few months of treatment however the highest risk for occurrence of SJS or TEN is within the first weeks of treatment. (Adoption to individual drug if such data are available).

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, carbamazepine treatment should be discontinued and alternative therapy should be considered.

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of carbamazepine, carbamazepine must not be re-started in this patient at any time.

There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions (see section 4.2).

HLA-B*1502 allele - in Han Chinese, Thai and other Asian populations HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as 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.

There are some data that suggest an increased risk of serious carbamazepine-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.

The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).

HLA-A*3101 allele - European descent and Japanese populations

There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash (see section 4.8) in people of European descent and the Japanese.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.

There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.

If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.

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).

Carbamazepine 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 (see section 4.8 Undesirable Effects).

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, carbamazepine 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.

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

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

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

Abrupt withdrawal of Carbamazepine may precipitate seizures:

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

Carbamazepine and oestrogen and/or progestogen preparations

Due to hepatic enzyme induction, carbamazepine may reduce the effectiveness of oestrogen and/or progestogen containing products. This may result in failure of contraception, recurrence of symptoms or breakthrough bleeding or spotting.

Patients taking carbamazepine and requiring hormonal contraception should receive a preparation containing not less than 50pg oestrogen or use of some alternative nonhormonal 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 carbamazepine plasma levels may be useful in the following conditions: dramatic increase in seizure frequency, patient compliance, pregnancy, in the treatment of children and adolescents, in suspected absorption disorders, suspected toxicity when one or more drug is being used (see 4.5 Interaction with other Medicaments and other forms of Interaction).

In patients with hepatic disorders and elderly patients, the initial dosage should be small and the increments titrated against the patient’s condition.

Complete blood counts, including platelets and possibly reticulocytes, serum iron and liver function tests should be performed before commencing treatment. Blood counts should then be repeated at weekly intervals during the first month of treatment and subsequently at monthly intervals; liver function tests should also be undertaken periodically. If significant haematological reactions occur, if tests reveal a deterioration in liver function, or if allergic skin reactions, carbamazepine should be withdrawn.

Although no causal relationship has been established there have been reports of impaired male fertility and abnormal spermatogenesis.

There have been reported cases of neonatal seizures and respiratory depression in neonates during maternal carbamazepine use with or without concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal carbemazepine use. These reactions may represent a neonatal withdrawal syndrome.

Note: in keeping with current opinion it is suggested that the level of serum folic acid is observed during anti-convulsant therapy.

Precautions

Carbamazepine should only be prescribed after a critical risk assessment has been performed.

Patients with a history of cardiac, hepatic or renal damage, or who have experienced haematological reactions to other drugs should be monitored carefully or interrupted courses of therapy with carbamazepine. Close monitoring of patients is necessary in patients who have received interrupted courses of carbamazepine.

Baseline and periodic complete urinalysis and BUN determinations are recommended.

Carbamazepine 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.

Lactose warning: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalysing formation of carbamazepine 10, 11- epoxide. Co-administration of inhibitors of CYP 3A4 may result in increased plasma concentrations which could induce adverse reactions. Coadministration of CYP 3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to a potential decrease in carbamazepine serum level and potential decrease in the therapeutic effect.

Similarly, discontinuation of a CYP 3A4 inducer may decrease the rate of metabolism of carbmazepine, leading to an increase in carbmazepine plasma levels.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by induction of their metabolism.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10, 11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10, 11 epoxide plasma concentrations.

Agents that may raise carbamazepine plasma levels.

Certain drugs have been shown to elevate carbamazepine levels including isoniazid, some calcium antagonists (i.e. verapamil, diltiazem), dextropropoxyphene, fluoxetine, fluvoxamine, paroxetine, viloxazine, possibly cimetidine, omeprazole, acetazolamide, danazol, nicotonamide (in adults, only in high dosage), trazodone, nefazodone, vigabatrin, macrolide antibiotics (e.g. erythromycin, clarithromycin),azoles (e.g. itraconazole, ketoconazole, Fluconazole, voriconazole), terfenadine and loratadine, olanzapine, grapefruit juice, protease inhibitors for HIV treatment (e.g. ritonavir).

Since raised plasma levels of carbamazepine may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage should be adjusted accordingly and/or the plasma levels monitored.

Agents that may raise the active metabolite carbamazepine-10, 11-epoxide plasma levels:

Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:

Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Agents that may decrease carbamazepine plasma levels

Plasma levels of carbamazepine may be reduced by combined therapy with other antiepileptic drugs (phenobarbitone, phenytoin, fosphenytoin, primidone), theophylline, aminophylline, isotretinoin, rifampicin, cisplatin, doxorubicin, although the data are partly contradictory and possibly also by clonazepam or valproic acid, oxcarbazepine. Antimalaria drugs such as mefloquine or chloroquine may antagonise anticonvulsant effect. The dose of carbamazepine may have to be adjusted accordingly.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine -10,    11-epoxide; carbamazapeine plasma

concentrations should be monitored.

Serum levels of carbamazepine can be reduced by concomitant use of the herbal remedy St. John Wort (Hypericum perforatum).

Effects of carbamazepine on plasma levels of concomitant agents

Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirement: levothyroxine, clobazam clonazepam, ethosuximide primidone valproic acid, alprazolam, corticosteroids, (e.g. prednislone, dexamethasone); ciclosporin, digoxin, doxycycline dihydropyridine derivatives, e.g. felodipine and isradipine, indinavir, saquinavir, ritonavir haloperidol, imipramine, buprenorphine methadone, paracetamol, tramadol, products containing oestrogens and/or progestogens (alternative contraceptive methods should be considered) see section 4.4 special warnings and precautions for use, gestrinone, tibolone, toremifene, theophylline, oral anticoagulants (warfarin and acenocoumarol), lamotrigine, tiagabine, topiramate, bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptylline, nortriptylline, clomipramine), clozapine, oxcarbazapine, olanzapine, quetiapine, itraconazole, imatinib and risperidone. If oral anticoagulants, e.g. warfarin, are administered in conjunction with carbamazepine the dose of warfarin may need to be increased (approximately doubled) to maintain the INR.

Plasma levels of phenytoin may be raised or lowered by concomitant administration of carbamazepine. Rare increases of plasma mephenytoin levels have been reported.

Combinations to be taken into consideration

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine induced toxicity.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Combined use of carbamazepine with metoclopramide or major tranquillisers, e.g. haloperidol, thioridazine, may also result in an increase in neurological side effects.

Since carbamazepine is structurally related to tricyclic anti-depressants, the use of carbamazepine is not recommended in combination with MAOIs, before administering carbamazepine, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Administration of carbamazepine to patients receiving therapy with some diuretics (hydrochlorothiazide, frusemide) may increase the risk of hyponatraemia.

Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (eg pancuronium); their dosage may need to be raised and patients monitored closely for unexpectedly rapid recovery from neuromuscular blockade.

Alcohol may exacerbate the CNS side-effects of psychoactive drugs including carbamazepine; it is therefore advisable that the patient abstain from alcohol during treatment.

Co-administration of carbamazepine and paracetamol may reduce the bioavailability of paracetamol/acetaminophen.

Caution should be exercised when prescribing carbamazepine together with lamotrigine since this combination may result in increased incidence of CNS/neurotoxic adverse events such as dizziness, diplopia, headache and ataxia. Whilst serum levels of carbamazepine remain unaffected, lamotrigine serum levels are depressed. Carbamazepine dose reduction may ameliorate these symptoms.

4.6 Fertility, pregnancy and lactation

In animals (mice, rats and rabbits) oral administration of carbamazepine during organogenesis led to increased embryo mortality at a daily doses which caused maternal toxicity (above 200mg/kg b.w. daily i.e. 20 times the usual human dosage).In the rat there was also some evidence of abortion at 300mg/kg body weight daily. Near-term rat foetuses showed growth retardation, again at maternally toxic doses. There was no evidence of teratogenic potential in the three species tested but, in one study using mice, carbamazepine (40-240 mg/kg b.w. daily orally) caused defects (mainly dilatation of cerebral ventricles in 4.7% of exposed foetuses as compared with 1.3% in controls).

Pregnant women with epilepsy should be treated with special care.

The incidence of congenital abnormalities in the offspring of women being treated with a combination of anti-convulsants is greater than in those mothers receiving monotherapy. Therefore, in women of child-bearing potential, carbamazepine should be prescribed as monotherapy wherever possible.

In women of child-bearing potential, the need to control seizures in the mother or the problem of initiating carbamazepine treatment during pregnancy should be carefully weighed against possible risks to the foetus. This applies particularly to the first 3 months of pregnancy. The minimum effective dose should be prescribed and monitoring of plasma levels is advisable.

During pregnancy, an effective antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.

Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental and malformation disorders. There is the possibility that carbamazepine like all anti-epileptic drugs increases the risk. However conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. There have been reports of malformations and developmental disorders such as spina bifida and other congential abnormalities e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems have been reported in association with carbamazepine. Patients should be counselled regarding these increased risks of malformations and provided with the opportunity of antenatal screening.

Folic acid deficiency is known to occur in pregnancy. Anti-epileptic drugs have been known to aggravate this deficiency. This may contribute to the increased incidence of birth defects. Folic acid supplementation has therefore been recommended before and during pregnancy.

To prevent bleeding disorders in offspring, vitamin K₁ should be given to the mother during the last weeks of pregnancy as well as to the new born.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal carbamazepine use. These reactions may represent a neonatal withdrawal syndrome.

Use during lactation:

Carbamazepine passes into breast milk in concentrations of about 25-60% of the plasma level. The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking carbamazepine may breast-feed their infants, provided that the infant is observed for possible adverse reactions (e.g. excessive somnolence and allergic skin reactions).

Fertility:

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

4.7 Effects on ability to drive and use machines

The patients reactions, e.g. as a road user may be impaired by dizziness and drowsiness, especially in the early stages of treatment or in connection with dose adjustments. Patients should be warned of the possible hazards when driving or operating machinery.

4.8 Undesirable effects

Particularly at the start of treatment with Carbamazepine or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions.

Provided a gradually increasing dosage scheme is followed, carbamazepine is generally well tolerated but side-effects may occur particularly at the start of treatment. The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and divide the daily dosage into smaller (i.e. 3-4) fractional doses.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (>1/10) common (>1/100, < 1/10); uncommon (>1/1000, < 1/100); rare (>1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Blood and lymphatic system disorders
Very common:	Leucopenia
Common	Thrombocytopenia, eosinophilia.
Rare	Leucocytosis, lymphadenopathy, folic acid deficiency
Very rare	Agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda, reticulocytosis, and possibly haemolytic anaemia.
Immune system disorders
Rare	A delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepatosplenomegaly, abnormal liver function

	tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon).
Very rare	Aseptic meningitis, with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic oedema. (Treatment must be discontinued immediately if such hypersensitivity reactions occur.)
Endocrine disorders
Common	Oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.
Very rare	Blood prolactin increased with or without clinical symptoms such as galactorrhoea, gynaecomastia, abnormal thyroid function tests; decreased l-thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol), leading to osteomalacia /osteoporosis, increased blood cholesterol, including HDL cholesterol and triglycerides.
Psychiatric disorders
Rare	Hallucinations (visual or auditory), depression, anorexia, restlessness, aggression, agitation, confusional state.
Very rare	Activation of psychosis.
Nervous system disorders
Very common	Dizziness, ataxia, drowsiness, fatigue
Common	Headache
Uncommon	Abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus.

Rare	Orofacial dyskinesia, eye movement disturbances, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia and paresis
Very rare	Taste disturbances, neuroleptic malignant syndrome. The causative role of carbamazepine in inducing or contributing to the development of a neuromalignant syndrome, expecially in conjection with neuroleptics, is unclear.
Eye disorders
Common	diplopia, accommodation disorders (e.g. blurred vision)
Very rare	lenticular opacities, conjunctivitis, intraocular pressure increased
Ear and labyrinth disorders
Very Rare	hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.
Cardiac disorders
Rare	Cardiac conduction disorders, hypertension or hypotension.
Very Rare	Bradycardia, arrhythmia, atrioventricular block with syncope, collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thrombo-embolism (e.g. pulmonary embolism).
Respiratory , thoracic and mediastinal disorders
Very rare	Pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia. (If the antiepileptic hypersensitivity syndrome develops, immediate withdrawal of carbamazepine is recommended).
Gastro-intestinal disorders
Very common	Nausea, vomiting.
Common	Dry mouth,
Uncommon	Diarrhoea, constipation.
Rare	Abdominal pain
Very rare	Glossitis, stomatitis, pancreatitis.
Hepatobiliary disorders

Very common	Increased-gamma-GT (due to hepatic enzyme nduction), usually not clinically relevant.
Common	Elevated alkaline phosphatase
Uncommon	Elevated transaminases
Rare	Hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type, vanishing bile duct syndrome, jaundice
Very rare	Granulomatous hepatitis, hepatic failure.
Skin and subcutaneous tissue disorders:
Very common	Dermatitus allergic, urticaria, which may be severe
Uncommon	Exfoliative dermatitis and erythroderma
Rare	Systemic lupus erythematosus, pruritus.
Very rare	Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, (sweating), hair loss, hirsutism Severe cutaneous tissue adverse reactions (SCARS).
Musculoskeletal, connective tissue and bone disorders
Rare	muscle weakness
Very rare	Arthralgia, muscle pain, muscle spasms.
Not known	There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.
Renal and urinary disorders
Very rare	Interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and elevated blood urea/ azotaemia), urinary frequency, urinary retention, sexual disturbances/impotence.
Reproductive System
Very rare	Spermatogenesis abnormal (with decreased sperm count and/or motility).
Investigations

* In some Asian countries also reported as rare. See also section 4.4 Special warnings and precautions for use.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.

There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients, these reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among individuals of Han Chinese, Thai and some other Asian ancestry (see sections 4.2 and 4.4 for further information).

4.9 Overdose

Signs and symptoms:

Presenting symptoms and signs of Carbamazepine overdosage involve the central nervous, cardiovascular and respiratory systems.

Central Nervous System

CNS depression, disorientation, somnolence, agitation, hallucination, coma, blurred vision, slurred speed, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia, convulsions, psychomotor disturbances, myoclonus, hypothermia and mydriasis.

Respiratory System

Respiratory depression and pulmonary oedema.

Cardiovascular System:

Tachycardia, hypotension and at times hypertension, conduction disturbance with widening of the QRS complex, arrhythmia, syncope in association with cardiac arrest.

Gastro-intestinal System

Vomiting, delayed gastric emptying, reduced bowel motility.

Renal function

Retention or urine, oligura or anuria, fliuid retention, water intoxication due to ADH-like effect of carbamazepine.

Laboratory findings

Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatinine phosphokinase.

Treatment:

There is no specific antidote for Carbamazepine.

Management should initially be guided by the patient's clinical condition; admission to hospital. Measurement of the plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose.

Evacuation of the stomach, gastric lavage and administration of activated charcoal. Delay in evacuating the stomach may lead to a delay in the absorption. This may lead to relapse during recovery from intoxication. Cardiac monitoring and correction of electrolyte imbalance along with supportive care in an intensive care unit is advisable.

Special Recommendations:

Hypotension

Administer dopamine or dobutamine i.v.

Disturbance of cardiac rhythm Should be handled on an individual basis.

Convulsions

Administration of a benzodiazepine (e.g. diazepam) or another anti-convulsant e.g. phenobarbitone (with caution because of increased respiratory depression) or paraldehyde.

Hyponatraemia (water intoxication)

Fluid restriction and slow and careful NaCl 0.9% infusion i.v. These measures may be useful in preventing brain damage.

Charcoal haemoperfusion has been recommended. Forced diuresis, haemodialysis and peritoneal dialysis have been reported not to be effective.

Relapse and aggravation of symptomatology on the 2^nd and 3^rd day after overdose, due to delayed absorption, should be anticipated.

5.1 Pharmacodynamic properties

Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent; (ATC Code: N03 AF01).

Dibenzazepine derivative.

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.

The mechanism of action of carbamazepine, has only been partially elucidated. Carbamazepine stabilites hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potential in depolarised neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.

5.2    Pharmacokinetic properties

Absorption:

Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The tablets yield mean peak plasma concentrations of the unchanged substance within 12 hours following single oral doses. After a single oral dose of 400mg carbamazepine the mean peak concentration of unchanged carbamazepine in the plasma is approx. 4.5pg/ml.

The bioavailability of carbamazepine when given orally has shown to be between 85 - 100%. Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of carbamazepine.

Steady-state plasma concentrations of carbamazepine are attained within 1-2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pre-treatment status, dosage, and duration of treatment.

Different preparations of carbamazepine may vary in bioavailability; to avoid reduced effect or risk of breakthrough seizures or excessive side effects, it may be prudent to avoid changing the formulation.

Distribution

Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non -protein bound portion in plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.

Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazapine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

Biotransformation

Carbamazepine is metabolised in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-transdiol derivative and its glucuronide as the main metabolites.

Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of carbamazepine 10, 11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. 9-Hydroxymethyl-10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway.

Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Elimination

The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other enzyme-inducing drugs (e.g. phenytoin, phenobarbitone), half life values averaging 910 hours have been found.

The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

After administration of a single oral dose of 400mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite.

Characteristics in patients

The steady-state plasma concentrations of carbamazepine considered as “therapeutic range” vary considerable inter-individually; for the majority of patients a range between 4-12pg/ml corresponding to 17-50pmol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepiine (in mg/kg) than adults to maintain therapeutic concentrations.

There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.

No data is available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.

5.3 Preclinical safety data

In rats treated with carbamazepine for two years, the incidence of tumours of the liver was found to be increased. There is, however, no evidence to indicate that this observation has any significant bearing on the therapeutic use of the drug. Bacterial and mammalian mutagenicity studies have yielded negative results.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize Starch Lactose Monohydrate Croscarmellose Sodium Polyvidone Magnesium Stearate

6.2 Incompatibilities

None known.

6.3 Shelflife

3 years

6.4    Special precautions for storage

Store in a cool dry place

6.5 Nature and contents of container

Each container consists of a polypropylene tubular container with an open end equipped to accept a polyethylene closure, with a tamper-evident tear strip, and is of the appropriate size to accommodate 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 500 or 1000 tablets, or PVdC coated PVC/Aluminium blisters (60g/m² PVdC on 250pm PVC/20pm Al) in pack sizes of 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 or 120 tablets.

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

T/A IVAX Pharmaceuticals UK Albert Basin Royal Docks London E16 2QJ

8    MARKETING AUTHORISATION NUMBER(S)

PL 00530/0329

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Granted: 19.08.91 / Renewal: 05.11.96

10    DATE OF REVISION OF THE TEXT

06/01/2015