Summary of medicine characteristics - TEGRETOL 400 MG TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Tegretol® 400 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is 5H-dibenzo[b,f]azepine-5-carboxamide.
Each tablet contains 400 mg carbamazepine Ph.Eur.
3 PHARMACEUTICAL FORM
The tablets are white, flat, rod-shaped tablets with bevelled edges. One side bears the imprint „CG/CG“, the other „LR/LR“ and both sides are scored.
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 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 × 200mg tablets per day, to be taken in
divided doses).
10–15 years: 600 to 1000mg daily (3–5 × 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
6–15 years of age: 1000mg/day
>15 years of age: 1200mg/day.
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 Tegretol is added to existing antiepileptic therapy, this should be done gradually while maintaining or, if necessary, adapting the dosage of the other antiepileptic(s) (see 4.5 Interaction with other Medicaments and other forms of Interaction).
Trigeminal neuralgia:
Slowly raise the initial dosage of 200–400mg daily 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 or above):
Dosage in Trigeminal neuralgia
Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tegretol should be selected with caution in elderly patients.
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
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 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.
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.
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).
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.
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.
Carbamazepine may be associated with foetal harm when administered to a pregnant woman (see section 4.6 Fertility, pregnancy and lactation). Tegretol should be used during pregnancy only if the potential benefit justifies the potential risks.
Adequate counselling should be made available to all pregnant women and women of childbearing potential, regarding the risks associated with pregnancy due to potential teratogenic risk to the fetus (see section 4.6 Fertility, pregnancy and lactation).
Women of childbearing potential should use effective contraception unaffected by enzyme inducing drugs, during treatment with Tegretol and for a period of 28 days after discontinuation of treatment (see section 4.6 Fertility, pregnancy and lactation).
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 50^g 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 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).
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 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.
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.
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.
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 comedications 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).
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.
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 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.
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).
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.
Antihistamines: loratadine.
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).
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:
Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
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).
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.
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.
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 summary
Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental disorders, including malformations. Developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects such as clept lip/palate, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with the use of Tegretol. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening. Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth was 3.0% (95% CI 2.1 to 4.2%) among mothers exposed to carbamazepine monotherapy in the first trimester and 1.1% (95% CI 0.35 to 2.5%) among pregnant women not taking any antiepileptic drug (relative risk 2.7, 95% CI 1.1 to 7.0).
Clinical considerations
Taking these data into consideration:
– Pregnant women with epilepsy should be treated with special care.
– If women receiving Tegretol become pregnant or plan to become pregnant, or if the need of initiating treatment with Tegretol arises during pregnancy, the drug's expected benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
– In women of child-bearing potential Tegretol should, wherever possible, be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy. The risk of malformations following exposure to carbamazepine as polytherapy may vary depending on the specific drugs used and may be higher in polytherapy combinations that include valproate.
– Minimum effective doses should be given 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. There is evidence to 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.
– Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
– During pregnancy, an effective antiepileptic treatment should not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been 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.
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.
Females and males of reproductive potential
Contraception
Due to enzyme induction, Tegretol may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of childbearing potential should use effective contraception during treatment with Tegretol and for a period of 28 days after discontinuation of treatment. According to national recommendations (FSRH Clinical Guidance: Drug Interactions with Hormonal Contraception), women taking carbamazepine should preferably change to a contraceptive method unaffected by enzyme inducing drugs (i.e. copper IUDs and the levonorgestrel-releasing IUD or depot progestogen-only injections).
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: | 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). |
| Very rare: | anaphylactic reaction, oedema angioedema, hypogammaglobulinaemia. |
| Not known: | 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: | folate deficiency, decreased appetite. porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda). |
| 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. |
| 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: | 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 |
| Not known: | 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
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.
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.
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.
5 PHARMACOLOGICAL PROPERTIES
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, the active substance of Tegretol, has only been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodiumdependent action potentials 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 conventional tablets yield mean peak plasma concentrations of the unchanged substance within 12 hours (chewable tablets 6 hours; syrup 2 hours) following single oral doses. With respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms. After a single oral dose of 400mg carbamazepine (tablets) the mean peak concentration of unchanged carbamazepine in the plasma is approx. 4.5^ig/mi.
The bioavailability of Tegretol in various oral formulations has been shown to lie between 85–100%.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tegretol.
Steady-state plasma concentrations of carbamazepine are attained within about 1–2 weeks, depending individually upon auto-induction by carbamazepine and heteroinduction 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 carbamazepine, 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-Hydroxy-methyl-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 9–10 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 considerably inter-individually; for the majority of patients a range between 4–12^ig/mi corresponding to 17–50^mol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.
Special populations
Paediatric populations
Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults to maintain therapeutic concentrations.
Elderly population (65 years or above)
There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
Patients with hepatic or renal impairment
No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, local tolerance, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of carbamazepine in humans.
Carcinogenicity
In rats treated with carbamazepine for two years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence to date that these observations are of any relevance to the therapeutic use of carbamazepine in humans.
Reproductive toxicity
Animal data
The cumulative evidence from various animal studies in mice, rats and rabbits indicates that carbamazepine has no or only minor teratogenic potential at doses relevant to man. However, the animal studies were insufficient to rule out a teratogenic effect of carbamazepine. In a reproduction study in rats, nursing offspring demonstrated a reduced weight gain at a maternal dosage level of 192 mg/kg/day.
Fertility
In chronic toxicity studies dose related testicular atrophy and aspermatogenesis occurred in rats receiving carbamazepine. The safety margin for this effect is not known.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Each uncoated tablet contains silica, colloidal anhydrous, cellulose, microcrystalline, carmellose sodium, low substituted and magnesium stearate.
6.2 Incompatibilities
None known.
6.3 Shelf Life
24 months
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Tegretol 400mg come in PVC/PE/PVdC blister packs of 56 tablets.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
Novartis Pharmaceuticals UK Limited,
2nd Floor, The WestWorks Building, White City Place,
195 Wood Lane,
London, W12 7FQ
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00101/0463
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
4th July 1997 / 8th Dec 2008