4.1. Therapeutic indications

Epilepsy - generalised tonic-clonic and partial seizures.

Note: Tegretol 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 psychosis in patients unresponsive to lithium therapy.

4.2. Posology and method of administration

Tegretol is given orally, usually in two or three divided doses. Tegretol 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 information on genetic testings and cutaneous reactions in section 4.4).

Epilepsy:

The dose of carbamazepine should be adjusted to the needs of the individual patient to achieve adequate control of seizures. Determination of plasma levels may help in establishing the optimum dosage. In the treatment of epilepsy, the dose of carbamazepine usually requires total plasma-carbamazepine concentrations of about 4 to 12 micrograms/mL (17 to 50 micromoles/litre) (see warnings and precautions).

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.

Tegretol should be taken in a number of divided doses although initially 100-200mg once or twice daily is recommended. This may be followed by a slow increase until the best response is obtained, often 800-1200mg daily. In some instances, 1600mg or even 2000mg daily may be necessary.

Elderly population (65 years or above): Due to the potential for drug interactions, the dosage of Tegretol should be selected with caution in elderly patients.

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

Tegretol tablets are not recommended for very young children.

5-10 years:

400 to 600 mg daily (2-3 x 200mg tablets per day, to be taken in divided doses).

10-15 years:

600 to 1000mg daily (3-5 x 200mg tablets per day, to be taken in several divided doses).

>15 years of age:

800 to 1200mg daily (same as adult dose).

Maximum recommended dose

Up to 6 years of age: 35mg/kg/day

6 to15 years of age: 1000mg/day

>15 years of age: 1200mg/day.

Wherever possible, anti-epileptic agents should be prescribed as the sole 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 medicinal products and other forms of interaction).

Trigeminal neuralgia:

Slowly raise the initial dosage of 200-400mg daily 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 1600mg Tegretol daily may be needed. However, once the pain is in remission, the dosage should be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.

Elderly population (65 years of age or above):

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tegretol should be selected with caution in elderly patients.

Dosage in Trigeminal neuralgia

In elderly patients, an initial dose of 100mg twice daily is recommended. The initial dosage of 100mg twice daily should be slowly raised daily until freedom from pain is achieved (normally at 200mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.

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.

Special populations

Renal impairment / Hepatic impairment

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

4.3. Contraindications

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 contraindicated in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5 Interaction with other medicinal products and other forms of interaction).

4.4. Special warnings and precautions for use

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 the 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 (see Section 4.8 Undesirable Effects). 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. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. 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.

Cutaneous reactions

Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with 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.

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 Stevens-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine (see section 4.2). 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.

Other dermatologic reactions

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).

Hypersensitivity

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been reported with Tegretol. If a patient develops these reactions after treatment with Tegretol, the drug must be discontinued, and an alternative treatment started.

Tegretol may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon) see section 4.8 Undesirable Effects.

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 aromatic antiepileptic drugs (e.g. phenytoin, primidone and phenobarbital).

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.

Dose reduction and withdrawal effects

Abrupt withdrawal of Tegretol may precipitate seizures, therefore carbamazepine withdrawal should be gradual. If treatment with Tegretol has to be withdrawn abruptly in a patient with epilepsy, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug.

Women of childbearing potential

Carbamazepine may cause foetal harm when administered to a pregnant woman. Prenatal exposure to carbamazepine may increase the risks for major congenital malformations and other adverse development outcomes (see Section 4.6).

Carbamazepine should not be used in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.

Women of childbearing potential should be fully informed of the potential risk to the foetus if they take carbamazepine during pregnancy.

Before the initiation of treatment with carbamazepine in a woman of childbearing potential, pregnancy testing should be considered.

Women of childbearing potential should use highly effective contraception during treatment and for at least two weeks after stopping treatment. Due to enzyme induction, carbamazepine may result in a failure of the therapeutic effect of hormonal contraceptives, therefore, women of childbearing potential should be counselled regarding the use of other effective contraceptive methods (see Sections 4.5 and 4.6).

Women of childbearing potential should be counselled regarding the need to consult their physician as soon as they are planning a pregnancy to discuss switching to alternative treatments prior to conception and before contraception is discontinued (see Section 4.6).

Women of childbearing potential should be counselled to contact the doctor immediately if they become pregnant or think they might be pregnant and are taking carbamazepine.

Endocrinological effects

Breakthrough bleeding has been reported in women taking Tegretol while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Tegretol and women of child-bearing potential should be advised to consider using alternative forms of birth control while taking Tegretol.

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.

Monitoring of plasma levels

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 (see 4.5 Interaction with other medicinal products and other forms of interaction).

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.

Hyponatremia

Hyponatremia is known to occur with carbamazepine. In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, medicinal products associated with inappropriate ADH secretion), serum sodium levels should be measured prior to initiating carbamazepine therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. If hyponatraemia is observed, water restriction is an important counter-measurement if clinically indicated.

Hypothyroidism

Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction requiring an increase in dose of thyroid replacement therapy in patients with hypothyroidism. Hence thyroid function monitoring is suggested to adjust the dosage of thyroid replacement therapy.

Anticholinergic effects

Tegretol has shown mild anticholinergic activity; patients with increased intraocular pressure and urinary retention should therefore be closely observed during therapy (see section 4.8).

Psychiatric effects

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

Interactions

Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can induce adverse reactions (increase of carbamazepine or carbamazepine-10,11 epoxide plasma concentrations, respectively). The dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored.

Co-administration of CYP3A4 inducers with carbamazepine may decrease carbamazepine plasma concentrations and its therapeutic effect, while discontinuation of a CYP3A4 inducer may increase carbamazepine plasma concentrations. The dosage of Tegretol may have to be adjusted.

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 co-medications mainly metabolized by CYP3A4 by induction of their metabolism. See section 4.5 Interactions.

Female patients of child-bearing potential should be warned that the concurrent use of Tegretol with hormonal contraceptives may render this type of contraceptive ineffective. Alternative non-hormonal forms of contraception are recommended when using Tegretol (see sections 4.5 Interactions and 4.6 Fertility, pregnancy and lactation).

Falls

Tegretol treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state, sedation (see section 4.8 Undesirable effects) which may lead to falls and, consequently fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete risk assessment of fall should be considered recurrently for patients on long-term Tegretol treatment.

Tegretol Tablets contain sodium

This medicine contains less than 1mmol sodium (23mg) per tablet, that is to say essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine 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 co-medications 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.

Interactions resulting in a contraindication

The use of Tegretol is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before administering Tegretol MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits (see contraindications).

Agents that may raise carbamazepine plasma levels:

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

Analgesics, anti-inflammatory drugs: dextropropoxyphene.

Androgens: danazol.

Antibiotics: macrolide antibiotics (e.g. erythromycin, clarithromycin), ciprofloxacine.

Antidepressants: fluoxetine, fluvoxamine, paroxetine, trazodone.

Antiepileptics: vigabatrin.

Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.

Antipsychotics: olanzapine.

Antituberculosis: isoniazid.

Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: diltiazem, verapamil.

Gastrointestinal drugs: possibly cimetidine, omeprazole.

Other interactions: grapefruit juice, nicotinamide (only in high dosage).

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 Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:

Antiepileptics: Quetiapine, progabide, valproic acid, valnoctamide, valpromide, primidone, brivaracetam.

Agents that may decrease carbamazepine plasma levels:

The dose of Tegretol may have to be adjusted when used concomitantly with the substances described below:

Antiepileptics: oxcarbazepine, phenobarbital, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.

Antineoplastics: cisplatin or doxorubicin.

Antituberculosis: rifampicin.

Bronchodilatators or anti-asthma drugs: theophylline, aminophylline.

Dermatological drugs: isotretinoin.

Other interactions: herbal preparations containing St John's wort (Hypericum perforatum).

Effect of Tegretol 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:

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), tramadol.

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g. warfarin, acenocoumarol, rivaroxaban, dabigatran, apixaban and edoxaban).

Antidepressants: bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant

Antiepileptics: clobazam, clonazepam, ethosuximide, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment. There have been rare reports of an increase in plasma mephenytoin levels.

Antifungals: itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.

Antihelmintics: albendazole.

Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, aripiprazole, paliperidone.

Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).

Anxiolytics: alprazolam.

Bronchodilatators or anti-asthma drugs: theophylline.

Contraceptives: hormonal contraceptives (alternative contraceptive methods should be considered).

Cardiovascular drugs: calcium channel blockers (dihydropyridine group) e.g. felodipine, digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).

Drugs used in erectile dysfunction: tadalafil.

Immunosuppressants: ciclosporin, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Other drug interactions: products containing oestrogens and/or progesterones.

Combinations that require specific 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.

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (e.g. pancuronium). Their dosage should be raised and patients monitored closely for a more rapid recovery from neuromuscular blockade than expected.

Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.

Concomitant use of carbamazepine with direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban and edoxaban) may lead to reduced plasma concentrations of direct acting oral anti-coagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is necessary, closer monitoring of signs and symptoms of thrombosis is recommended.

Interference with serological testing

Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.

Carbamazepine and the 10,11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.

4.6. Fertility, pregnancy and lactation

Pregnancy

Risk related to antiepileptic medicinal products in general

Specialist medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant.

Sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to seizures that could have serious consequences for the woman and the unborn child.

Monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated AEDs.

Risk related to carbamazepine

Carbamazepine crosses the placenta in humans. Epidemiological data from pregnancy registries and cohort studies have shown that children born to mothers with epilepsy treated with carbamazepine during the first trimester of pregnancy are at an increased risk of major congenital malformations. The most common types of major congenital malformations reported in association with carbamazepine include neural tube defects including spina bifida, craniofacial defects including cleft lip/palate, cardiovascular malformations, genitourinary tract defects including hypospadias, skeletal malformations and anomalies involving various body systems. Data derived from a meta-analysis (including registries and cohort studies) has shown that 4.93% of children of epileptic women exposed to carbamazepine monotherapy during first trimester of pregnancy suffer from congenital malformations (95% CI: 3.84-6.16) compared with the background rate on the general population of around 2-3%. Malformations such as neural tube defects (spina bifida), craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, hypoplasia of the fingers, microcephaly and other anomalies involving various body systems, have been reported in the offspring of women who used carbamazepine during pregnancy. Specialised antenatal surveillance for these malformations is recommended.

Data from an epidemiological study suggests an increased risk for infants of being born small for gestational age (potentially associated with fetal growth restriction) in pregnant women receiving antiepileptic drugs (including carbamazepine) during pregnancy compared to unexposed pregnant women with epilepsy.

Neurodevelopmental disorders (such as developmental delay, Autism spectrum disorder, Intellectual disability, ADHD, etc.) have been reported among children born to women with epilepsy treated with carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Studies related to the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are contradictory and a risk cannot be excluded.

Carbamazepine should not be used during pregnancy unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risks of taking carbamazepine during pregnancy.

Evidence suggest that the risk of malformation with carbamazepine may be dose-dependent, i.e. at a dose < 400mg per day, the rates of malformation were lower than with higher doses of carbamazepine. If based on a careful evaluation of the risks and the benefits, no alternative treatment option is suitable, and treatment with carbamazepine is continued, monotherapy and the lowest effective dose of carbamazepine should be used and monitoring of plasma levels is recommended. The plasma concentration could be maintained in the lower side of the therapeutic range 4 to 12 micrograms/mL provided seizure control is maintained.

Some antiepileptic drugs, such as carbamazepine, have been reported to decrease serum folate levels. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women.

Folic acid supplementation is recommended before and during pregnancy. In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.

If a woman is planning to become pregnant, all efforts should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to reassess carbamazepine treatment and consider alternative treatment options.

In the neonate

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol 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 Tegretol use. These reactions may represent a neonatal withdrawal syndrome.

Animal studies have shown reproductive toxicity (see section 5.3).

Breastfeeding:

Risk summary

Carbamazepine passes into the breast milk (about 25-60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Tegretol may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction). There have been some reports of cholestatic hepatitis in neonates exposed to carbamazepine during antenatal and or during breast feeding. Therefore breast-fed infants of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.

Women of childbearing potential

Carbamazepine should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risk of potential harm to the foetus if carbamazepine is taken during pregnancy and therefore the importance of planning any pregnancy. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with carbamazepine.

Women of childbearing potential should use highly effective contraception during treatment and for at least two weeks after stopping treatment. Due to enzyme induction, carbamazepine may result in a failure of the therapeutic effect of hormonal contraceptives (see section 4.5), therefore, women of childbearing potential should be counselled regarding the use of other effective contraceptive methods. At least one effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, involving the patient in the discussion, when choosing the contraception method.

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 patient's ability to react may be impaired by the medical condition resulting in seizures and adverse reactions including dizziness, drowsiness, ataxia, diplopia, impaired accommodation, and blurred vision have been reported with Tegretol, especially at the start of treatment or in connection with dose adjustments. Patients should therefore exercise due caution when driving a vehicle or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

Particularly at the start of treatment with Tegretol, 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.

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.

Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports

Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Blood and lymphatic system disorders

Very common:

Common:

Rare:

Very rare:

Not known:

leucopenia.

thrombocytopenia, eosinophilia.

leucocytosis, lymphadenopathy.

agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia.

bone marrow depression.

Immune system disorders

Rare:

Very rare:

Not known**:

a delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, 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).

anaphylactic reaction, oedema angioedema, hypogammaglobulinaemia.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Infections and infestations

Not known**:

reactivation of Human herpes virus 6 infection.

Endocrine disorders

Common:

Very rare:

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.

galactorrhoea, gynaecomastia.

Metabolism and nutrition disorders

Rare:

Very rare:

Not known:

folate deficiency, decreased appetite.

porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda).

hyperammonaemia.

Psychiatric disorders

Rare:

Very rare:

hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state.

activation of psychosis.

Nervous system disorders

Very common:

Common:

Uncommon:

Rare:

Very rare:

Not known**:

ataxia, dizziness, somnolence.

diplopia, headache.

abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics), nystagmus.

dyskinesia, eye movementdisorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis.

neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

sedation, memory impairment.

Eye disorders

Common:

Very rare:

accommodation disorders (e.g. blurred vision)

lenticular opacities, conjunctivitis.

Ear and labyrinth disorders

Very rare:

hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

Cardiac disorders

Rare:

Very rare:

cardiac conduction disorders.

arrhythmia, atrioventricular block with syncope, bradycardia, cardiac failure congestive, coronary artery disease aggravated.

Vascular disorders

Rare:

Very Rare:

hypertension or hypotension.

circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis.

Respiratory, thoracic and mediastinal disorders

Very rare:

pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia.

Gastro-intestinal disorders

Very common:

Common:

Uncommon:

Rare:

Very rare:

Not known**:

vomiting, nausea.

dry mouth, with suppositories rectal irritation may occur.

diarrhoea, constipation.

abdominal pain.

Pancreatitis, glossitis, stomatitis.

colitis.

Hepatobiliary disorders

Rare:

Very rare:

hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice.

hepatic failure, granulomatous liver disease.

Skin and subcutaneous tissue disorders:

Very common:

Uncommon:

Rare:

Very rare:

Not known**:

urticaria, which may be severe dermatitus allergic.

dermatitis exfoliative.

systemic lupus erythematosus, pruritus.

Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, erythema nodosum, pigmentation disorder, purpura, acne, hyperhydrosis, alopecia, hirsutism.

Acute Generalized Exanthematous Pustulosis (AGEP)**, lichenoid keratosis, onychomadesis, Fixed drug eruption, generalised bullous fixed drug eruption.

Musculoskeletal, connective tissue and bone disorders

Rare:

Very rare:

Not known**:

muscular weakness.

bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms.

fracture.

Renal and urinary disorders

Very rare:

tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/ azotaemia), urinary retention, urinary frequency.

Reproductive System

Very rare:

sexual disturbances/erecticle dysfunction spermatogenesis abnormal (with decreased sperm count and/or motility).

General disorders and administration site conditions

Very common:

fatigue.

Investigations

Very common:

Common:

Uncommon:

Very rare:

Not known**:

gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant.

blood alkaline phosphatase increased.

transaminases increased.

intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased,

bone density decreased.

Injury, poisoning and procedural complications

Not known**:

Fall (associated with Tegetol treatment induced ataxia, dizziness, somnolence, hypotension, confusional state, sedation) (see section 4.4 warning and precautions).

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

**Additional adverse drug reactions from spontaneous reports (frequency 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.

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

The presenting signs and symptoms of overdosage involve the central nervous, cardiovascular, respiratory systems and the adverse drug reactions mentioned under section 4.8.

Central nervous system: CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.

Respiratory system: Respiratory depression, pulmonary oedema.

Cardiovascular system: Tachycardia, hypotension and at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.

Gastro-intestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.

Musculoskeletal system: There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.

Renal function: Retention of urine, oliguria, or anuria; fluid retention, water intoxication due to ADH-like effect of carbamazepine.

Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.

Management

There is no specific antidote.

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 result in delayed absorption, leading to relapse during recovery from intoxication. Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.

Special recommendations:

Charcoal haemoperfusion has been recommended. Hemodialysis is the effective treatment modality in the management of the carbamazepine overdose.

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