Carbamazepine Tablets USP 400mg Taj Pharma

1. Name of the medicinal product

Carbamazepine Tablets USP 100mg Taj Pharma
Carbamazepine Tablets USP 200mg Taj Pharma
Carbamazepine Tablets USP 300mg Taj Pharma
Carbamazepine Tablets USP 400mg Taj Pharma

2. Qualitative and quantitative composition

a) Carbamazepine Tablets USP 100mg Taj Pharma
Each uncoated tablet contains:
Carbamazepine USP 100mg
Colours: Red Oxide of Iron and Titanium Dioxide.

b) Carbamazepine Tablets USP 200mg Taj Pharma
Each uncoated tablet contains:
Carbamazepine USP 200mg
Colours: Red Oxide of Iron and Titanium Dioxide.

c) Carbamazepine Tablets USP 300mg Taj Pharma
Each uncoated tablet contains:
Carbamazepine USP 300mg
Colours: Red Oxide of Iron and Titanium Dioxide.

d) Carbamazepine Tablets USP 400mg Taj Pharma
Each uncoated tablet contains:
Carbamazepine USP 400mg
Colours: Red Oxide of Iron and Titanium Dioxide.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Uncoated Tablet

Red Oxide of Iron and Titanium Dioxide.

4. Clinical particulars

4.1 Therapeutic indications

Epilepsy – Generalised tonic – clonic and partial seizures.

Note: Carbamazepine is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences. The paroxysmal pain of trigeminal neuralgia. For the prophylaxis of manic-depressive psychosis in patients unresponsive to lithium therapy.

4.2 Posology and method of administration

Posology

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:

It is advised that a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient to achieve adequate control of seizures. If possible a sole anti-epileptic agent should be used but if polytherapy is necessary, the same incremental dosage pattern should be followed.

If adding carbamazepine to existing antiepileptic treatment, the dose should be increased gradually, and if needed, the dose of the existing antiepileptics adjusted (see section 4.5).

Monitoring of the plasma level of carbamazepine will ensure that the optimum dose is prescribed. 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:

Carbamazepine should be taken in a number of divided doses. Initially: 100 – 200mg once or twice a day, followed by a slow increase until the best response is obtained, often 800 – 1200mg daily in divided doses. In some cases, 1600mg or even 2000mg daily in divided doses may be necessary.

Elderly:

In elderly patients there is an increased potential for drug interactions. Therefore, the dose of carbamazepine should be selected with caution in this group of patients.

Paediatric population and adolescents:

It is advised that a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient. It may be helpful to monitor the plasma concentration of carbamazepine to establish the optimum dose (see sections 4.4. and 5.2).

Usual dosage 10 – 20mg/kg body weight daily in several divided doses.

For children less than 5 years old it is inappropriate to prescribe carbamazepine tablets, another formulation should be used.

5-10 years: 400 to 600mg daily (2 – 3 x 200mg tablets per day, to be taken in several 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 recommendation dose

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

6-15 years of age: 1000mg/day

>15 years of age: 1200mg/day

Trigeminal neuralgia:

Slowly raise the initial dosage of 200-400mg daily (100mg twice daily in elderly patients) until freedom from pain is achieved (normally at 200mg 3-4 times daily). In the majority of patients a dosage of 200mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, dosage of 1600mg carbamazepine 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:

Dosage in Trigeminal neuralgia

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Carbamazepine 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 daily dose of 1600mg given in divided doses is reached. The usual daily dosage range is 400 – 600mg, 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.

Method of administration

Carbamazepine is given orally in tablet form, usually in two or three divided doses. It may be taken during, after or between meals with a little liquid e.g. a glass of water.

4.3 Contraindications

Hypersensitivity to carbamazepine, or structurally related drugs, eg tricyclic anti-depressants or to any of the excipients listed in section 6.1.

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).

Carbamazepine use is not recommended in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5).

4.4 Special warnings and precautions for use

Warnings

Agranulocytosis and aplastic anaemia have been associated with carbamazepine; however, due to the very low incidence of these conditions, meaningful risk estimate for carbamazepine 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 person per million per year for aplastic anaemia.

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

Patients and their relatives should be made aware of early toxic signs and symptoms indicative of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult their 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). However, treatment with carbamazepine should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Carbamazepine 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 carbamazepine 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 with 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 carbamazepine. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. 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, carbamazepine 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).

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first months of treatment.

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

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

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

HLA-B* 1502 allele – in Han Chinese, Thai and other Asian populations

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as 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 the general population to 26% among subjects of 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 and usually disappear after a few days or weeks either during the course of the treatment or following a decrease in the dose. However, worsening of the rash or accompanying symptoms, and severe skin reactions are indications for the immediate withdrawal of carbamazepine. Patients should be kept under close surveillance since it may be difficult to differentiate the early signs of a more serious skin reaction from mild transient ones. Patients with serious dermatological reactions (such as SJS, TEN, also known as Lyell’s syndrome) may require hospitalisation, as these conditions may be life-threatening and may be fatal.

The risk of less severe adverse cutaneous reactions such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption) is not predicted by the HLA-B*1502 allele.

Hypersensitivity

Carbamazepine 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). If the signs and symptoms of hypersensitivity reactions occur, carbamazepine should be immediately withdrawn.

25-30 % of patients who exhibit hypersensitivity reactions to carbamazepine, may also experience them with oxcarbazepine.

In addition, cross-hypersensitivity may occur between carbamazepine and phenytoin.

Carbamazepine may exacerbate seizures in patients with mixed seizures, which include absences, either typical or atypical, and therefore should be used with caution in these conditions. Carbamazepine should be discontinued in cases where seizures are exacerbated.

Seizure frequency may be increased during the switchover from oral formulations to suppositories.

Dose reduction and withdrawal effects

Abrupt withdrawal of carbamazepine may precipitate seizures therefore carbamazepine withdrawal should be gradual. If treatment with carbamazepine 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.

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

Endocrinological effects

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

Patients taking carbamazepine and requiring hormonal contraception should receive a preparation containing not less than 50 μg oestrogen or the 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 section 4.5).

Precautions

Carbamazepine 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 carbamazepine.

In patients with severe cardiovascular diseases, or with hepatic or renal disorders and in elderly patients, the initial dosage should be small and the increments titrated against the patient’s condition. 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 hyponatremia 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

Carbamazepine 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 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 carbamazepine 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 carbamazepine 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).

Female patients of childbearing potential should be warned that the concurrent use of carbamazepine with hormonal contraceptives may render this type of contraceptive ineffective (see sections 4.5 and 4.6). Alternative non-hormonal forms of contraception are recommended when using carbamazepine.

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. Adverse reactions could be induced if inhibitors of CYP 3A4 were co-administered, resulting in increased carbamazepine plasma concentrations. In contrast, co-administration of CYP 3A4 inducers may lead to a decrease in the serum carbamazepine level and therapeutic effect, by increasing the rate of carbamazepine metabolism.

Furthermore, the rate of carbamazepine metabolism may be reduced by the discontinuation of a CYP3A4 inducer, leading to an increase in the plasma carbamazepine 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.

The formation of the 10, 11-transdiol derivative from carbamazepine 10, 11-epoxide is catalysed by human microsomal epoxide hydrolase. In a manner similar to that described above, increased plasma concentrations of carbamazepine-10, 11-epoxide may be the result of co-administration of human microsomal epoxide hydralase inhibitors.

Interactions resulting in a contraindication

Carbamazepine is structurally related to tricyclic antidepressants. Therefore, carbamazepine should not be administered with, or within a minimum of two weeks of cessation of monoamine oxidase inhibitors (MAOI) therapy or longer if the clinical situation permits (see contraindications).

The effect of carbamazepine on the 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 therefore need 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 and acenocoumarol).

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

Antiemetics: aprepitant

Antiepileptics: clobazam, clonazepam, ethosuximide, lamotrigine, 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.

Agents that may decrease the plasma levels of carbamazepine:

The dose of carbamazepine 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).

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

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

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

Agents that may raise carbamazepine plasma levels

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

Combinations that require specific consideration:

Increased carbamazepine-induced toxicity has been reported upon the concomitant use of carbamazepine and levetiracetam.

Co-administration with isoniazid may lead to increased isoniazid induced hepatotoxicity.

Co-administration with some diuretics (hydrochlorothiazide or furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonise the effects of non-depolarising muscle relaxants such as pancuronium: the dosage may need to be raised and the patient monitored closely for an unexpectedly rapid recovery from neuromuscular blockade.

The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Co-administration with major tranquilisers (eg haloperidol, thioridazine) or metoclopramide may also cause an increase in neurological side effects.

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, of 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:

The offspring of mothers with untreated epilepsy are known to be more prone to developmental disorders such as malformations. Developmental disorders and malformations, including spina bifida and also congenital anomalies e.g. craniofacial defects such as clept lip/palate, cardiovascular malformations, hypospadias and anomalies involving various body systems, have also been reported in association with maternal carbamazepine use. Patients should therefore 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).

Taking these data into consideration:

– Pregnant women with epilepsy should be treated with special care.

– If women receiving carbamazepine become pregnant or plan to become pregnant, or if the problem of initiating treatment with carbamazepine 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 childbearing potential carbamazepine 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.

Monitoring and prevention

Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency during pregnancy, which may contribute to the increased incidence of birth defects in the offspring of treated epileptic mothers. Folic acid supplementation is therefore recommended before and during pregnancy.

In the neonate

It is recommended that vitamin K₁ be given to the mother during the last few weeks of pregnancy, in order to avoid bleeding disorders in the offspring. Vitamin K₁ should also be given to the neonate.

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

Women of child-bearing potential and contraceptive measures

Due to enzyme induction, carbamazepine may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of child bearing potential should be advised to use alternative contraceptive methods while on treatment with carbamazepine.

Breast-feeding:

Carbamazepine passes into breast milk (about 25-60% of the plasma concentration). Thus, the benefits of breast-feeding should be weighed against the risks to the infant. Infants of breast-feeding mothers should be monitored for possible adverse reactions (e.g. allergic skin reactions, excessive somnolence). 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.

Fertility:

Reports of impaired male fertility and/or abnormal spermatogenesis are very rare.

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 reported with carbamazepine, especially in the early stages 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 safety profile

Provided a gradually increasing dosage scheme is followed, carbamazepine is generally well tolerated but side effects may occur particularly at the start of the treatment or if the initial dose 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 disappear spontaneously after a few days or following a temporary reduction in dosage. 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).

* In some Asian countries also reported as rare. See also section 4.4.

**Additional adverse drug reactions from spontaneous reports (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with carbamazepine via spontaneous case reports and literature cases. Because these reactions are reported voluntary from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ class in MedRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

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.

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, agitation, somnolence, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.

Respiratory system: respiratory depression and pulmonary oedema.

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

Gastrointestinal system: delayed gastric emptying, reduced bowel motility, vomiting.

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 caused by carbamazepine’s ADH-like effect.

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

Treatment:

There is no specific antidote.

The patients’ clinical condition should initially guide the management: admission to hospital, confirmation of carbamazepine poisoning and assessment of the size of the overdose by measurement of the plasma level of the drug.

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 the signs and symptoms of overdose may occur on the second or third day due to delayed absorption.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent; Dibenzazepine derivative.

Carbamazepine is an anti-epileptic agent used to control generalised tonic-clonic (grand mal) and partial (simple and complex) seizures with or without secondary generalisation, including combinations of these types of seizures. Its mode of action in epilepsy is not fully understood but some of its actions resemble those of phenytoin.

Mechanism of action

The mechanism of carbamazepine action has only been partially solved. Its main mechanism of action may involve the inhibition of repetitive firing of sodium-dependent action potentials via use- and voltage-dependent blockage of sodium channels in depolarised neurons. In addition, carbamazepine also stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharge and reduces synaptic propagation of electrical impulses.

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 slowly, but almost completely absorbed from the gastro-intestinal tract. Following single oral doses of carbamazepine tablets, mean peak plasma concentrations of the unmetabolised substance are found within 12 hours. The mean peak concentration of unmetabolised carbamazepine in the plasma after a single oral dose of 400mg carbamazepine (tablets) is approximately 4.5 μg/ml. The rate and extent of absorption is not significantly influenced by the ingestion of food.

Within about 1-2 weeks, steady state plasma concentrations of carbamazepine are attained, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, pre-treatment status, dose and duration of treatment.

The bioavailability in different preparations of carbamazepine may vary; the bioavailability of carbamazepine in various oral formulations has been shown to lie between 85-100%. To avoid reduced effect or the risk of breakthrough seizures or excessive side effects, the formulation should not be altered.

Distribution

Carbamazepine is widely distributed throughout the body and approximately 70-80% of carbamazepine is bound to plasma proteins. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in plasma (20-30%). In addition, carbamazepine crosses the placental barrier. In breast milk, concentrations of carbamazepine equivalent to 25-60% of the corresponding plasma levels were found.

The apparent volume of distribution, assuming complete absorption of carbamazepine, ranges from 0.8 to 1.9 L/kg.

Biotransformation

Carbamazepine is extensively metabolised in the liver and one of its primary metabolites, carbamazepine-10, 11-epoxide has been reported to have about one-third of the anti-epileptic activity of carbamazepine.

Cytochrome P450 3A4 is the major isoform responsible for the formation of carbamazepine-10, 11-epoxide. The further metabolism of carbamazepine-10, 11-epoxide by human microsomal epoxide hydrolase results in the formation of the 10, 11-transdiol derivative. A minor metabolite related to this pathway is 9-hydroxy-methyl-10-carbomoyl acridan. After a single dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway.

The biotransformation of carbamazepine also leads to various monohydroxylated compounds as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Elimination

Following a single oral dose of carbamazepine, the elimination half-life of unmetabolised carbamazepine averages approximately 36 hours. In comparison, it averages only 16-24 hours after repeated administration, due to the auto-induction of the hepatic mono-oxygenase system, although this is dependent on the duration of the medication. Moreover, the metabolism of carbamazepine is readily induced by drugs, such as phenytoin and phenobarbitone, which induce hepatic microsomal enzymes. In patients receiving concomitant treatment with enzyme-inducing drugs, half-lives of 9-10 hours have been found.

Following single oral doses of the pharmacologically active metabolite carbamazepine 10, 11-epoxide, the elimination half-life is approximately 6 hours.

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

Characteristics in patients

There is considerable interindividual variance in the steady state plasma concentration of carbamazepine (or its ‘therapeutic range’). A range between 4-12 μg/ml, corresponding to 17-50 μmol/L, has been reported for the majority of patients. The concentration of the pharmacologically active metabolite, carbamazepine 10, 11-epoxide, is approximately 30% of carbamazepine levels.

Children may require higher doses of carbamazepine (inmg/kg) than adults to maintain therapeutic concentrations, owing to enhanced carbamazepine elimination. When compared with young adults, there is no indication of altered carbamazepine pharmacokinetics in elderly patients.

Data on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function are not available.

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

In animals studies in mice, rats and rabbits oral administration of carbamazepine during organogenesis led to increased embryo-foetal mortality and foetal growth retardation at daily doses which were associated with maternal toxicity (above 200mg/kg/day). Carbamazepine was teratogenic in a number of studies, particularly in mice, however showed no or only minor teratogenic potential at doses relevant to humans. In a reproduction study in rats, nursing offspring demonstrated a reduced weight gain at a maternal dosage level of 192mg/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 tablet contains:

Cellulose, microcrystalline, Starch, pregelatinised, Silica, colloidal anhydrous, Talc, Magnesium stearate, Sodium starch glycollate (Type A).

Red Oxide of Iron and Titanium Dioxide.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in a dry place below 25°C

6.5 Nature and contents of container

PVdC coated PVC/aluminium foil blister packs in packs of 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Carbamazepine Tablets USP 400mg Taj Pharma

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

1. 1. • Keep this leaflet. You may need to read it again.
      • If you have any further questions, ask your doctor or pharmacist.
      • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
      • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. 1. 1. What Carbamazepine is and what it is used for
      2. What you need to know before you take Carbamazepine
      3. How to take Carbamazepine
      4. Possible side effects
      5. How to store Carbamazepine
      6. Contents of the pack and other information
      1. What Carbamazepine is and what it is used for

Carbamazepine contains carbamazepine, which belongs to a group of medicines called Anti-epileptics.

Carbamazepine can be used to treat the following different conditions:

1. 1. • Some forms of epilepsy.
      • Pain in the face caused by trigeminal neuralgia (nerve pain).
      • To help control serious mood disorders when some other medicines don’t work.

If you are not sure why you are taking this medicine, ask your doctor.

1. 1. 1. What you need to know before you take Carbamazepine

A small number of people being treated with anti-epileptics such as carbamazepine have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your doctor.

Serious skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with the use of carbamazepine, appearing initially as reddish target-like spots or circular patches often with central blisters on the trunk.

Frequently, the rash can involve ulcers of the mouth, throat, nose, genitals and conjunctivitis (red and swollen eyes). These potentially life-threatening skin rashes are often preceded by influenza-like symptoms fever, headache, body ache (flu-like symptoms). The rash may progress to widespread blistering or peeling of the skin. The highest risk for occurrence of serious skin reactions is within the first months of treatment.

If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of carbamazepine, you must not be re-started on carbamazepine at any time.

These serious skin reactions can be more common in people from some Asian countries. The risk of these reactions in patients of Han Chinese or Thai origin may be predicted by testing a blood sample of these patients. Your doctor should be able to advise if a blood test is necessary before taking carbamazepine.

If you develop a rash or these skin symptoms, stop taking carbamazepine and contact your doctor immediately.

Do not take Carbamazepine:

1. 1. • If you are allergic to carbamazepine or any of the ingredients of this medicine (see section 6).
      • Signs of a hypersensitivity reaction include swelling of the face or mouth (angioedema), breathing problems, runny nose, skin rash, blistering or peeling
        • If you are allergic to similar drugs such as oxcarbazepine or phenytoin or a tricyclic antidepressant (e.g. amitriptyline)
        • If you have a heart condition or had a problem with your bone marrow
        • If you or a member of your family has the rare blood pigment disorder called porphyria
        • If you are already taking medicine to treat a mental illness called a monoamine oxidase inhibitor (MAOI), such as phenelzine (or have taken an MAOI in the last two weeks).

Warnings and precautions

Talk to your doctor or pharmacist before taking Carbamazepine:

1. 1. • If you have heart disease
      • If you have a history of liver or kidney disease
      • If you have kidney problems associated with low sodium blood level or if you have kidney problems and you are taking certain medicines that lower sodium blood levels (diuretics such as hydrochlorothiazide or furosemide)
      • If you have glaucoma (increased pressure in the eye)
      • If you have a difficulty to retain your urine
      • If you have suffered from a mental illness in the past
      • If you are elderly
      • If you suffer from the sort of epilepsy where you get mixed seizures, which include absences
      • If you have blood disorders (including those caused by other drugs) or if you have ever suffered a reaction to any other medicine, which has affected your blood, for example a low white blood cell count (leucopenia)
      • If you have had interrupted courses of treatment with carbamazepine.

Your doctor may want to have regular blood and liver tests and in some cases, urine tests, before you start taking Carbamazepine and from time to time during your treatment. This is quite usual and nothing to worry about.

Children and adolescents

Do not give this medicine to children less than 5 years old.

Other medicines and Carbamazepine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines:

1. 1. • Other antiepileptics e.g. lamotrigine, phenytoin, fosphenytoin, primidone, sodium valproate,
      • Phenobarbitone, ethosuximide, oxcarbazepine, tiagabine, topiramate, vigabatrin, levetiracetam,
      • Progabide
      • Anticoagulants to thin the blood e.g. warfarin, acenocoumarol
      • Cimetidine or omeprazole, to treat heartburn or stomach ulcers
      • Medicine to treat mental illness e.g. lithium, haloperidol, thioridazine, olanzapine, risperidone, clozapine, quetiapine
      • Paliperidone or aripiprazole, to treat schizophrenia
      • Sedatives e.g. clobazam, clonazepam, alprazolam, valnoctamide
      • Antidepressants e.g. imipramine, fluoxetine, amitriptyline, clomipramine, nortriptyline, mianserin, sertraline, paroxteine, fluvoxamine, citalopram, trazodone
      • The herbal remedy St John’s wort (Hypericum perforatum) should not be taken while taking Carbamazepine. Consult your doctor before stopping the St John’s wort preparation.
      • Metoclopramide or aprepitant, often used to treat sickness
      • Antibiotics e.g. doxycycline, isoniazid, erythromycin, clarithromycin, ciprofloxacin
      • Isoniazid, rifampicin (used to treat tuberculosis)
      • Antifungals e.g. itraconazole, fluconazole, ketoconazole, voriconazole, albendazole
      • Corticosteroids e.g. prednisolone, dexamethasone
      • Cyclosporine, tacrolimus or sirolimus, immunosuppressants
      • Painkillers containing paracetamol, dextropropoxyphene, methadone, tramadol, buprenorphine
      • Medicine to treat heart conditions e.g. felodipine, isradipine, digoxin, verapamil, diltiazem
      • Diuretics (‘water’ tablets) e.g. furosemide, hydrochlorothiazide
      • Acetazolamide, to treat glaucoma
      • Muscle relaxants, often used during operations e.g. pancuronium
      • isotretinoin, used to treat acne
      • Theophylline and aminophylline, for asthma
      • Diazole and gestrinone (used in the treatment of endometriosis)
      • Hormonal contraceptives e.g. pills, patches, injections or implants; as the effectiveness of these may be reduced and there will be a risk of getting pregnant. Your doctor can advise you about an alternative form of contraception.
      • Hormone Replacement Therapy (HRT) e.g. tibolone
      • Tadalafil, used to treat impotence
      • Drugs to treat cancer e.g. imatinib, lapatinib, toremifene, cisplatin, doxorubicin, temsirolimus, cyclophosphamide
      • Mefloquine, used to treat malaria
      • Drugs to treat HIV known as protease inhibitors (e.g. indinavir, ritonavir, saquinavir)
      • Levothyroxine to treat hypothyroidism
      • The anti-smoking aid, bupropion
      • Antihistamines to treat allergies and hayfever, such as loratadine
      • Medicine or supplements containing Vitamin B (nicotinamide).

Carbamazepine with drink and alcohol

Do not drink alcohol while taking Carbamazepine as this may increase the chance of side effects. The risk

of side effects may also be increased if you eat grapefruit or drink grapefruit juice.

Pregnancy and breast-feeding

If you are planning to become pregnant, talk to your doctor first. If you do get pregnant while taking

Carbamazepine you must tell the doctor straightaway. With all anti-epileptic treatment, there is a risk of harm to the unborn baby, but it is important that your epilepsy remains well controlled. If you are pregnant and need to take an anticonvulsant, you are likely to be taking only one anticonvulsant. Your doctor will monitor you and your unborn child closely. It is important that you fully understand the risks and benefits, to both you and your baby, of taking Carbamazepine tablets.

Carbamazepine can pass into breast milk. Talk to your doctor before you decide to breast-feed. If you do breast feed and you take Carbamazepine, tell your doctor straight away if your child becomes very drowsy or suffers from skin reactions or yellow skin and eyes, dark urine or pale stools.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this any medicine.

Driving and operating machines

Carbamazepine tablets can make you feel dizzy or drowsy especially at the start of treatment or when the dose is changed. If you are affected in this way, or if your eyesight is affected or you have a lack of muscular coordination, you should not drive or operate machinery.

1. 1. 1. How to take Carbamazepine

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Your doctor is likely to start treatment with a low dose and slowly increase it to suit your own needs.

Ask your doctor or pharmacist if you are unsure about the correct dose but the recommended doses are as follows:

EPILEPSY

Adults: The recommended starting dose is 100 mg to 200 mg of Carbamazepine once or twice daily. Your doctor will slowly increase this dose to control your fits until the best response is obtained, often 800 to 1200 mg daily in divided doses, although higher doses may be necessary.

Use in children and adolescents: Carbamazepine tablets should not be given to children under 5 years old.

The recommended daily dose for children between 5 and 10 years old is 400 mg to 600 mg of

Carbamazepine, divided up throughout the day. Children over 10 years old may be given a total daily dose of between 600 mg and 1000 mg of Carbamazepine, divided up throughout the day.

Your doctor will use another antiepileptic medicine e.g. phenytoin, if Carbamazepine is withdrawn suddenly.

TRIGEMINAL NEURALGIA

The starting dose is 200 to 400 mg daily (100 mg twice daily in elderly patients). Your doctor may increase the dose until you are free from pain. In the majority of patients a dosage of 200 mg three or four times a day is enough to treat the pain. In some cases, a dose of up to 1600 mg Carbamazepine daily may be needed. Once the pain goes away (remission), the doctor will slowly reduce your dose of Carbamazepine. The maximum recommended dose is 1200 mg a day. If possible the doctor may gradually stop your treatment until another attack occurs.

TREATMENT OF MOOD SWINGS

The starting dose is 400 mg of Carbamazepine daily, divided up throughout the day. This dose may be increased slowly until your symptoms are controlled or until the maximum daily dose of 1600 mg of

Carbamazepine is reached. The usual daily dose range is 400 – 600 mg in divided doses.

Elderly

Elderly patients may be more sensitive to the effects of Carbamazepine so the doctor may prescribe smaller doses than those stated above.

Cardiac, hepatic or renal impairment

Patients who suffer from heart, liver or kidney problems may also be prescribed lower doses of Carbamazepine.

Method of administration

Swallow the tablet whole, with a glass of water. Do not chew, crush or suck the tablet

Take during, after or between meals.

If you take more Carbamazepine than you should

If you take more Carbamazepine than you should, contact your doctor or local hospital emergency department immediately. Take the container and any remaining tablets with you.

If you experience difficulty in breathing, a fast and irregular heartbeat, loss of consciousness, fainting, shakiness, sickness and/or vomiting, your dose may be too high. Stop taking your medicine and inform your doctor without delay.

If you forget to take a dose

If you forget to take a dose take it as soon as you remember unless it is nearly time for your next dose.

Do not take double dose to make up for a forgotten dose.

If you stop taking Carbamazepine suddenly

If you stop taking Carbamazepine suddenly you may suffer unpleasant side effects. Always ask your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

1. 1. 1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects are more common at the start of treatment, but usually disappear after a few days or when the dose is adjusted to be right for you.

Tell your doctor or go to your nearest hospital emergency department immediately if you suffer from the following serious side effects:

Very common: may affect more than 1 in 10 people

1. 1. • A low white cell count (leucopenia) causing more infections than usual.

Uncommon: may affect up to 1 in 100 people

1. 1. • Severe peeling of the skin which can affect a large area of your body

Rare: may affect up to 1 in 1,000 people

1. 1. • have difficulty breathing, experience chest pain, wheezing and coughing, a rash, itching, facial swelling or feel faint, all symptoms of a severe allergic reaction
      • Fever, skin rash, joint pain, and abnormalities in blood and liver function tests (these may be the signs of a multi-organ sensitivity disorder)
      • suffer from pain in your joints and muscles, have a rash across the bridge of your nose and cheeks, and have problems breathing (symptoms of the rare reaction, systemic lupus erythematosus)
      • Experiences yellowing of your skin or the whites of your eyes, which may in some cases indicate inflammation of the liver.

Very rare: may affect up to 1 in 10,000 people

1. 1. • notice any unusual signs of mental illness or confusion
      • Potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported (see section 2). Symptoms include worsening of a skin rash, blistering of the lips, eyes or mouth or a severe skin reaction accompanied by fever. These reactions may be more frequent in those of Chinese and Thai origin.
      • suffer from a sore throat, high temperature or both
      • A sudden increase in body temperature, extremely high blood pressure and severe convulsions (neuroleptic malignant syndrome)
      • have severe or persistent pain in the stomach region that spreads to the lower back, often with nausea and vomiting (pancreatitis)
      • meningitis (signs and symptoms include fever, feeling sick, being sick, headache, stiff neck, extreme sensitivity to sunlight, twitching of muscles, abnormal blood test results)
      • feel feverish or notice unexplained bruising or bleeding of your skin which could show you have anaemia (a change in your blood)
      • Heart and circulatory problems including a blood clot (thrombosis), which can cause tenderness, swelling, pain chest, shortness of breath; heart failure (symptoms include shortness of breath, swelling of feet or legs due to fluid build-up, getting tired easily after light physical activity)
      • Blood changes including:
      • decreases in white blood cells (agranulocytosis) causing more infections than usual with symptoms like fever, severe chills, sore throat or mouth ulcers
      • conditions in which red blood cells, white blood cells and platelets are all reduced innumber
      • Liver failure (symptoms include yellowing of your skin or the white of your eyes, dark urine, light coloured bowel motions, nausea, vomiting, and feeling generally unwell)
      • Severe allergic reactions (signs include wheezing, coughing, difficulty in breathing, feeling faint, rash, itching, swelling of the face, lips, mouth, tongue or throat).

Not known: frequency cannot be estimated from the available data

1. 1. • Severe skin reactions, accompanied by feeling unwell, fever and changes in blood results.

Other side effects that can occur:

Very common (may affect more than 1 in 10 people):

1. 1. • Feeling dizzy, tired or drowsy
      • Difficulty controlling movements and feeling unsteady
      • Feeling or being sick
      • Skin reactions, including hives (urticaria) which may be severe
      • Changes in liver enzyme levels (usually without any symptoms).

Common (may affect up to 1 in 10 people):

1. 1. • swollen ankles or lower legs, fluid retention weight gain
      • low sodium levels in the blood causing headache, confusion, being sick, lethargy, muscular
      • twitching, convulsions
      • double vision, eyesight changes e.g. blurred vision
      • dry mouth
      • headache
      • changes in the blood including an increased tendency to bruise or bleed
      • eosinophilia (increase in some white blood cells)
      • Increase in alkaline phosphatase (an enzyme found in body tissues such as liver and bone).

Uncommon (may affect up to 1 in 100 people):

1. 1. • abnormal movements or uncontrollable muscle spasms involving the arms, legs, eye, head, neck and other parts of the body
      • shaking (tremor)
      • diarrhoea or constipation
      • Increased levels of certain enzymes in the body (seen in a blood test).

Rare (may affect up to 1 in 1000 people):

1. 1. • Folic acid deficiency
      • Increased levels of white blood cells in the body (seen in a blood test), fever
      • Disease of the lymph glands.
      • Hallucinations (seeing or hearing things that are not there)
      • Depression or mood changes
      • Feeling restless, aggressive or agitated
      • Feeling confused
      • Numbness or tingling in the hands or feet, weakness of the arms or legs
      • Muscle weakness, loss of muscle control, speech problems, uncontrolled movements of the face and tongue
      • Loss of appetite
      • Raised or low blood pressure
      • Changes in heart rhythm
      • Stomach pain
      • Itching (pruritus).

Very rare (may affect up to 1 in 10,000 people):

1. 1. • Porphyria (a disorder of blood pigment)
      • Swelling of the breasts, leaking of milk from the breasts, which may occur in both males and females
      • Softening of the bones, osteoporosis
      • Abnormal results from thyroid tests
      • Raised fat levels in the blood
      • Changes in taste or hearing, ringing in the ears
      • ‘Sticky’ eyes (conjunctivitis), cataracts, raised pressure in the eyes
      • A racing or slowed heartbeat, feeling faint, collapse
      • Prominent superficial veins
      • Difficulty breathing, pneumonia, inflammation of the lungs, fever
      • Sore mouth or tongue, swollen tongue
      • Changes in skin pigmentation
      • Purple or red-brown spots visible through the skin (purpura)
      • Skin sensitive to light, acne, excessive sweating, hair loss or growth on the body or face
      • Joint pain, muscle pain or cramp
      • Kidney problems, difficulty passing urine or passing more urine than usual, blood or protein in the urine
      • Sexual difficulties including reduced male fertility, loss of sexual desire or drive, inability to get or maintain an erection
      • A decreased quantity of immunoglobulins in the blood (hypogammaglobulinaemia) which leads to a lowered immunity and an increase in the number of infections.

Not known (frequency cannot be estimated from the available data):

1. 1. • There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the bone) and fractures. Check with your doctor or pharmacist if you are on long-term antiepileptic medication, have a history of osteoporosis, or take steroids.
      • Abdominal pain and fever (signs of inflammation of the colon)
      • Reactivation of herpes virus infection
      • Complete loss of nails
      • Memory loss.

Reporting of side effects

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any side effect not listed in this leaflet.

1. 1. 1. How to store Carbamazepine

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the foil, carton or bottle after ‘EXP’.

The expiry date refers to the last day of that month.

Store your medicine in a dry place below 25°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

1. 1. 1. Contents of the pack and other information

What Carbamazepine contains

There are three strengths of your medicine available. Each tablet contains either 100 mg, 200 mg or 400 mg of the active substance carbamazepine.

The other ingredients are cellulose, microcrystalline; starch, pregelatinised; silica, colloidal anhydrous; talc; magnesium stearate and sodium starch glycollate (Type A).

What Carbamazepine looks like and contents of the pack

Carbamazepine is available in plastic bottles or foil blisters in packs of 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500 tablets.

Not all pack sizes may be marketed.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com