Carbamazepine Extended-Release Tablets USP 100mg Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT

Carbamazepine Extended-Release Tablets USP 100mg Taj Pharma
Carbamazepine Extended-Release Tablets USP 200mg Taj Pharma
Carbamazepine Extended-Release Tablets USP 300mg Taj Pharma
Carbamazepine Extended-Release Tablets USP 400mg Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Carbamazepine Extended-Release Tablets USP 100mg Taj Pharma
Each film-coated Extended-Release tablet contains:
Carbamazepine USP 100mg
Excipients: Q.S.

b) Carbamazepine Extended-Release Tablets USP 200mg Taj Pharma
Each film-coated Extended-Release tablet contains:
Carbamazepine USP 200mg
Excipients: Q.S.

c) Carbamazepine Extended-Release Tablets USP 300mg Taj Pharma
Each film-coated Extended-Release tablet contains:
Carbamazepine USP 300mg
Excipients: Q.S.

d) Carbamazepine Extended-Release Tablets USP 400mg Taj Pharma
Each film-coated Extended-Release tablet contains:
Carbamazepine USP 400mg
Excipients: Q.S.

For the full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Film-coated Extended-Release Tablets.

  1. CLINICAL PARTICULARS
    • Therapeutic indications
  • Epilepsy
  • generalised tonic-clonic
  • partial seizures
  • For the paroxysmal pain of trigeminal neuralgia.
  • For the prophylaxis of manic or hypomanic phases of manic-depressive psychosis in patients unresponsive or with contraindications to lithium therapy.

Posology and method of administration

Posology

Doses should be based on seizure control and the development of clinical intolerance. Plasma levels are indicative whether a patient is within or outside the therapeutic range in order to explain a lack of seizure control or development of intolerance. This may be particularly useful, if combination therapy is used. Therapeutic plasma levels of Carbamazepine Taj Pharma are typically between 4 – 12 µg/l corresponding to a dosage of 200 – 400mg per day.

A maximum daily dose of 1600 – 2000 mg may be required in adults.

When patients are transferred from an immediate-release Carbamazepine Taj Pharma product, the same total daily dose will generally be suitable. In a few patients, it may be necessary to increase the total daily dose, particularly when it is used with other antiepileptics.

In patients with severe cardio-vascular disease, liver disease or renal damage and in older people a reduced dose may be sufficient.

Furthermore the dose required by some patients may differ substantially from the recommendation for initial and maintenance dose below, due to increased metabolism caused by auto-induction of hepatic enzymes or drug interactions during combination therapy.

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 Taj Pharma-associated Stevens-Johnson syndrome (SJS) (see information on genetic testings and cutaneous reactions in section 4.4).

Dosage recommendations:

Epilepsy:

Treatment is started with a low dose set individually according to the type and severity of symptoms. The dose is then slowly increased to the optimal maintenance dose to suit the patient.

It is recommended that a Carbamazepine Taj Pharma monotherapy treatment is used whenever possible. When treatment is changed from another drug to Carbamazepine Taj Pharma the dose of the other antiepileptic drug should be reduced slowly.

If a change of therapy to a different antiepileptic drug is required, the change may not be done in one sudden step, but must be done gradually in small increments.

Carbamazepine Taj Pharma therapy is discontinued by slow dose reduction.

Initial dose Maintenance dose
Adults 100 – 200mg once or twice daily 400 – 600mg morning and night
Children 5-10 years* 400mg at night (or 100mg morning and night) 100 – 200mg morning and 200 – 400mg at night
Children 10-15 years 200mg at night (or 100mg morning and night) 100 – 400mg morning and 400mg – 600mg at night

 

Carbamazepine Taj Pharma tablets can be broken in half to treat children/adults with divided doses where necessary.

* Carbamazepine Taj Pharma tablets are not generally suitable for children under the age of 5 years. A conventional tablet or syrup presentation of Carbamazepine Taj Pharma may be given.

Antiepileptic therapy is a long-term treatment.

In general, a dose reduction or withdrawal of antiepileptic medication may be considered, when patients are seizure-free for at least two or three years. Instead of age dependant dose adjustment, children may outgrow the dose per kg body weight.

Prevention of paroxysmal pain of trigeminal neuralgia:

The recommended initial daily dose is 100 – 400 mg/day Carbamazepine Taj Pharma. The lower initial dose may be sufficient for older or sensitive patients. The dose is increased until the patient is free of pain, generally with a dose of 600 – 800 mg/day taken in 1 – 2 doses with a maximum dose of 1600 mg. The dose may be gradually reduced if the patient is pain-free thereafter, and may possibly be stopped after a few weeks of treatment, if there is no recurrence of pain.

Prophylaxis of manic-depressive psychosis

An initial dose of 100 – 400 mg daily in divided doses, increased gradually until symptoms are controlled, or a maximum of 800 mg, in exceptional cases maximum 1600 mg, in divided doses is reached. The recommended maintenance dose is 400 – 600 mg daily, given in divided doses.

Prophylaxis of manic-depressive psychosis is a long-term treatment.

In order to prevent a drug interaction, it is necessary to keep the plasma level of Carbamazepine Taj Pharma below 8 µg/ml and lithium at a low therapeutic dosage (0.3 – 0.8 mval/L), if in exceptional cases Carbamazepine Taj Pharma is used in combination with lithium for the prophylaxis of manic depressive psychosis, which cannot be controlled with lithium treatment alone. Neuroleptic treatment must not be done concurrently and must have been discontinued at least 8 weeks beforehand.

The impairment of the ability to react quickly appears in particular with combination therapy with lithium (see section 4.7).

Method of administration

The tablet can be divided into equal halves and the daily dose is normally taken in two divided doses, during or after a meal with a drink of water. The tablets should be swallowed whole and not chewed or crushed.

Patients who have difficulties in swallowing, may take the tablets in water following their disintegration into their granules. The characteristics of the tablets are maintained for a short period of time after their suspension. Therefore the suspension should be taken immediately.

  • Contraindications

Carbamazepine Taj Pharma may not be taken with:

  • known bone marrow depression.
  • atrio ventricular conduction abnormalities.
  • hypersensitivity to the active substance or structurally related drugs (for example tricyclic antidepressants) or to any of the excipients listed in section 6.1.
  • history of hepatic porphyrias (g.acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
  • concomitant treatment with monoamine oxidase inhibitors (MAOIs) (see section 4.5)
  • concomitant treatment with voriconazole (see section 4.5).
  • herbal preparations containing St. John’s wort (Hypericum perforatum) (see section 4.5).
    • Special warnings and precautions for use

Suicidal ideation and behaviour

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 antiepileptic 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 Taj Pharma. 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 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 Taj Pharma. 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 the severe cutaneous reactions known as Stevens-Johnson syndrome (SJS) when treated with Carbamazepine Taj Pharma. The prevalence of HLA-B*1502 carrier is about 10% of Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with Carbamazepine Taj Pharma (see section 4.2). If these individuals test positive, Carbamazepine Taj Pharma 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 rarely occur.

There are some data that suggest an increased risk of serious Carbamazepine Taj Pharma-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 Taj Pharma induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalised 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 Taj Pharma induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% 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 Taj Pharma treatment.

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

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 weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, carbamazapine 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 carbamazapine, carbamazapine must not be re-started in this patient at any time.

Limitation of genetic screening

Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with Carbamazepine Taj Pharma will not develop SJS/TEN and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with Carbamazepine Taj Pharma will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from these severe cutaneous adverse reactions such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

Other dermatological reactions

Mild skin reactions e.g. isolated macular or macropapular exanthemata, can also occur and are mostly transient and not hazardous, and 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 to 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-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from Carbamazepine Taj Pharma and may predict the risk of these reactions from Carbamazepine Taj Pharma, such as anticonvulsant hypersensitivity syndrome or non- serious rash (maculopapular eruption). However, the HLA-B*1502 allele has not been found to predict the risk of these aforementioned skin reactions.

Carbamazepine Taj Pharma may only be used after careful risk/benefit evaluation and with special care during the following conditions:

  • haematological disturbances
  • disturbed sodium metabolism
  • severe cardiac, liver and kidney dysfunction
  • pregnancy and lactation
  • myotonic dystrophy, as cardiac conduction abnormalities are likely in these patients

Haematological events

The occurrence of agranulocytosis and aplastic anaemia has been associated with Carbamazepine Taj Pharma; however, due to the very low frequency it is difficult to estimate the risk. In the untreated population, the probability of occurrence is 4.7 cases/million/year for agranulocytosis and 2 cases/million/year for aplastic anaemia.

Blood counts, platelet count and serum biochemistry including iron and electrolytes should be checked before commencing treatment with Carbamazepine Taj Pharma. Blood counts should be performed on a monthly basis for the first five months. Thereafter 2-4 times a year.

Clinical monitoring is of primary importance during the entire treatment period. Carbamazepine Taj Pharma must be discontinued, if severe leucopenia or thrombocytopenia appear.

A temporary or lasting lowering of the number of leukocytes or thrombocytes is often seen during Carbamazepine Taj Pharma treatment, but is usually transient and does not indicate the onset of agranulocytosis or aplastic anaemia. However, Carbamazepine Taj Pharma must be discontinued if severe leucopenia (mainly neutropenia) or thrombocytopenia accompanied by clinical manifestations e.g. fever or sore throat or significant depression of the bone marrow appear.

If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage, nausea, yellowing of the skin, and liver enlargement appears, the patient should be advised to consult his physician immediately.

In patients with severe cardio-vascular disease, liver disease or renal damage and in older people a special observation is necessary. Doses should be adapted to each case.

Seizures

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

As with other antiepileptic drugs some patients may experience an increase in seizure frequency or the onset of new types of seizures. These phenomena may also be the consequence of an overdosage, a decrease in plasma concentrations of concomitant antiepileptic treatment, or a paradoxical effect.

Hepatic function

Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in older patients. Patients must be instructed to contact the doctor immediately should symptoms of hepatitis occur such as fatigue, loss of appetite, nausea, yellowing of the skin or enlarged liver. Treatment with Carbamazepine Taj Pharma should be suspended, if signs and symptoms of liver dysfunction develop.

Renal function

Baseline and periodic complete urinalysis and BUN determinations are recommended.

Hypersensitivity reactions

Carbamazepine Taj Pharma 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, which can affect the skin, liver (including intrahepatic bile ducts), haematopoietic organs and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8).

The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome, including maculopapular rash.

Patients who have exhibited hypersensitivity reactions to Carbamazepine Taj Pharma should be informed that approximately 25-30% of the patients experience hypersensitivity reactions to oxcarbazepine. Cross-hypersensitivity can occur between Carbamazepine Taj Pharma and phenytoin.

Treatment should be discontinued immediately, if severe hypersensitivity reactions occur.

Hyponatraemia

Hyponatraemia can occur when taking Carbamazepine Taj Pharma. In patients with pre-existing kidney disorders associated with low serum sodium concentrations, or in patients who are being concomitantly treated with medicines that lower serum sodium concentration e.g. diuretics, the serum sodium concentration should be determined before treatment. The serum sodium concentration should be monitored after two weeks and then monthly for three months or according to the clinical necessity. Older patients are particularly susceptible to these risk factors and if hyponatraemia is diagnosed, water restriction is an important countermeasure.

Hypothyroidism

Carbamazepine Taj Pharma can reduce serum thyroid hormone concentrations through enzyme induction, requiring an increased dose of hormone replacement therapy (HRT) in patients with hypothyroidism. Monitoring the thyroid function is recommended in order to adjust the HRT dose.

Due to the possibility of photosensitivity, patients should avoid excessive exposure to sunlight during Carbamazepine Taj Pharma therapy.

Monitoring plasma levels

Although correlations between dosage and plasma levels of Carbamazepine Taj Pharma and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations: dramatic increase in seizure frequency; during pregnancy; when treating children or adolescents; in suspected absorption disorders; for verification of compliance; in suspected toxicity where more than one drug is being used (see section 4.5).

Dose reduction and withdrawal

Abrupt withdrawal of Carbamazepine Taj Pharma may precipitate seizures. Patients should be gradually weaned off Carbamazepine Taj Pharma over a period of a few months. If treatment with Carbamazepine Taj Pharma has to be withdrawn abruptly, the switch to another antiepileptic drug should if necessary be effected under the cover of a suitable drug e.g. i.v. or rectal benzodiazepines, or i.v. phenytoin.

Endocrinological effects

Breakthrough bleeding has been reported in women taking Carbamazepine Taj Pharma while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Carbamazepine Taj Pharma and women of childbearing potential should be advised to consider using alternative forms of birth control while taking Carbamazepine Taj Pharma (see section 4.6).

Precautions:

Patients with glaucoma and urinary retention should be informed about possible hazards associated with Carbamazepine Taj Pharma’s mild anticholinergic activity. The intra-ocular pressure and kidney function of these patients should be checked regularly.

High doses of Carbamazepine Taj Pharma could result in activation of latent psychosis and possibly agitation or confusion in older patients.

Alcohol ingestion is not recommended, Carbamazepine Taj Pharma may increase its effects.

  • Interaction with other medicinal products and other forms of interaction

Cytochrome P450 inducers and inhibitors

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalysing formulation of the active metabolite Carbamazepine Taj Pharma-10,11-epoxide. Co-administration of inhibitors of CYP3A4 may result in increased Carbamazepine Taj Pharma plasma concentrations, which could induce adverse reactions. Co-administration of CYP3A4 inducers might increase the rate of Carbamazepine Taj Pharma metabolism, thus leading to a potential decrease in Carbamazepine Taj Pharma serum level and potential decrease in the therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of Carbamazepine Taj Pharma, leading to an increase in Carbamazepine Taj Pharma plasma levels.

Carbamazepine Taj Pharma is a strong inducer of CYP3A4 and other phase I and II enzyme systems in the liver. Concomitant use of Carbamazepine Taj Pharma may increase the metabolism and thus decrease the plasma concentrations of several drugs that are eliminated by metabolism.

It should be noted especially that rifampicin is known to also be a very strong inducer of CYP 450 and reduces Carbamazepine Taj Pharma levels.

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

Monoamine oxidase inhibitors

Because it is structurally related to tricyclic antidepressants, it is not recommended to give Carbamazepine Taj Pharma in combination with monoamine oxidase inhibitors (MAOIs). MAOIs should be discontinued at least 2 weeks before Carbamazepine Taj Pharma therapy is started if the clinical situation permits (see section 4.3).

Drugs that may decrease Carbamazepine Taj Pharma plasma levels

The plasma level of Carbamazepine Taj Pharma may be decreased by other enzyme inducers such as:

Antiepileptics: phenobarbital, phenytoin, primidone, felbamate (~25%), methosuximide, oxcarbazepine, fosphenytoin, progabide, valpromide, valproic acid, phensuximide, and clonazepam

Antimalarials: mefloquine

Bronchodilatators or anti-asthma drugs: theophylline, aminophylline

Antituberculosis: rifampicin,

Antineoplastics: cisplatin or doxorubicin

Cardiovascular drugs: digoxin

Dermatological drugs: isotretinoin

Due to potential interactions during combination therapy of epilepsy, plasma levels should be regularly monitored, and dosage adjusted accordingly as required. Blood assays of their respective plasma levels may vary from one patient to another, and moreover are usually bi-directional.

Serum levels of Carbamazepine Taj Pharma can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes, which may persist for at least 2 weeks after cessation of treatment with St. John’s wort. For patients taking St. John’s wort, serum levels of Carbamazepine Taj Pharma should be monitored and St. John’s wort stopped. Carbamazepine Taj Pharma levels may increase on stopping St. John’s wort. The dose of Carbamazepine Taj Pharma may need adjusting.

Drugs that increase the active metabolite Carbamazepine Taj Pharma-10,11-epoxide plasma levels

The plasma level of the active Carbamazepine Taj Pharma-10,11-epoxide metabolite may be increased by quetiapine, progabide, loxapine, valnoctamide, valpromide, valproic acid, felbamate (~50%), primidone, clonazepam and digoxin.

Drugs that may increase Carbamazepine Taj Pharma plasma levels

Raised plasma levels of Carbamazepine Taj Pharma may lead to the symptoms listed under section 4.8 e.g. dizziness, tiredness, unsteady gait, double vision. The Carbamazepine Taj Pharma plasma level should be checked and the dosage reduced, if necessary, when used concomitantly with:

Analgesic, anti-inflammatory drugs: dextropropoxyphene, propoxyphene, ibuprofen

Androgens: danazol

Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin

Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine

Antiepileptics: felbamate, lamotrigine, phenobarbital, primidone, stiripentol, vigabatrin

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

Antihistamines: loratadine, terfenadine

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

Muscle relaxants: oxybutynin, dantrolene

Neuroleptics: loxapine, olanzapine, quetiapine

Platelet aggregation inhibitors: ticlopidine

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

Effect of Carbamazepine Taj Pharma on plasma levels of other drugs taken concomitantly

Carbamazepine Taj Pharma may decrease, diminish or even abolish the activity of certain drugs. Concurrent use of Carbamazepine Taj Pharma with the following drug substances may require dose adjustment to ensure the required clinical response, especially when starting or discontinuing Carbamazepine Taj Pharma –

Analgesics, anti-inflammatory agents: fentanyl, methadone, buprenorphine, paracetamol (long term administration of Carbamazepine Taj Pharma and paracetamol may be associated with hepatotoxicity), phenazone, tramadol

Antibiotics: doxycycline, rifabutin

Anticoagulants: oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol and acenocoumarol)

Antidepressants: bupropion, citalopram, mianserin, sertraline, nefazodone, trazodone

Tricyclic antidepressants: imipramine, amitriptyline, nortriptyline, clomipramine

Antiemetics: aprepitant

Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, zonisamide.

Antifungals: caspofungin, itraconazole, voriconazole. Alternative anitconvulsants may be recommended in patients treated with itraconazole or voriconazole

Anihelmintics: albendrazole, praziquantel

Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus

Antipsychotics: clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, aripiprazole, paliperidone, ziprasidone

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

Anxiolytics: alprazolam, midazolam, clobazam

Bronchodilatators or antiasthmatic drugs: theophylline

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

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

Corticosteroids: prednisolone, dexamethasone

Drugs used in erectile dysfunction: tadalafil

Immunosuppressants: ciclosporin, everolimus, tacrolimus, sirolimus

Thyroid agents: levothyroxine

Other drug interactions: quinidine, hydroquinidine, methylphenidate, propranolol, flunarizine, products containing oestrogens or progesterones (gestrinone, tibolone, toremifene)

Hormonal contraceptives

For products containing oestrogens and/or progestogens, including oral contraceptives and hormone replacement therapy (see section 4.4), reliable alternative contraceptive methods should be used. In patients taking the pill breakthrough bleeding or spotting may appear suddenly due to a decreased activity of the contraceptive. As a result, Carbamazepine Taj Pharma may cause a failure of the therapeutic effect of drugs containing oestrogens and/or progesterone containing drugs.

Carbamazepine Taj Pharma may lower the plasma level of bupropion and may increase the level of its metabolite hydroxybupropion.

Other drug combinations to be taken into consideration

Concurrent use of Carbamazepine Taj Pharma and other psychotropic drugs, e.g. neuroleptics, antidepressants, sedatives, hypnotics, analgesics, sedative antihistaminics, may increase the occurrence of neurological side effects.

There is an indication of a higher risk of developing Stevens-Johnson syndrome with concomitant use of neuroleptics.

Co-administration of Carbamazepine Taj Pharma and paracetamol may reduce the bioavailability of paracetamol (acetaminophen) and long term co-administration may be associated with hepatotoxicity.

The concomitant use of Carbamazepine Taj Pharma and lithium or metoclopramide on the one hand and neuroleptics (haloperidol, thioridazine) on the other can favour the occurrence of neurological undesirable effects. In patients treated with neuroleptics, it must be noted that Carbamazepine Taj Pharma reduces the plasma levels of these medicinal products and can therefore cause worsening of the disease profile. Dosage adjustment of the neuroleptic may be necessary.

Risk of neurotoxic effects may be increased with concomitant use of Carbamazepine Taj Pharma (ataxia) and lithium (cerebellar syndrome), despite the lithium plasma concentrations being in the normal range (see section 4.2). The following additional neurotoxic symptoms can be noted: unsteady gait, horizontal nystagmus, increased involuntary muscle reflexes, muscle twitching. These neurological effects are reversible after stopping the lithium.

The hepatic toxicity of isoniazid may be increased by Carbamazepine Taj Pharma.

The combination of Carbamazepine Taj Pharma with hypokalaemic diuretics (loop and thiazide diuretics) e.g. hydrochlorothiazide and furosemide, may cause hyponatraemia (see section 4.4).

Concomitant administration of Carbamazepine Taj Pharma and antiarrhythmics, cyclic antidepressants or erythromycin, increases the risk of cardiac conduction abnormalities.

The activity of muscle relaxants like pancuronium may be reduced by Carbamazepine Taj Pharma. A rapid recovery from neuromuscular blockade is therefore possible. Patients must be supervised accordingly and the dosage of the relaxant increased, if necessary.

Carbamazepine Taj Pharma plasma levels must be checked during concurrent treatment with isotretinoin (acne treatment), as it has been reported to unpredictably alter the bioavailability of Carbamazepine Taj Pharma and its active metabolite.

Carbamazepine Taj Pharma appears to increase the elimination of thyroid hormones and thus increase the hormone requirement of hypothyroid patients. A thyroid test should therefore be performed at the start and discontinuation of Carbamazepine Taj Pharma therapy in patients receiving thyroid hormone substitution. Dosage adjustment of thyroid hormone may be required.

A toxic serotonin-syndrome may be produced, if Carbamazepine Taj Pharma is taken together with drugs, which inhibit serotonin re-uptake (e.g. fluoxetine).

The severe haematological side effects of clozapine may be increased if used in combination with Carbamazepine Taj Pharma.

Concomitant use of Carbamazepine Taj Pharma and levetiracetam has been reported to increase Carbamazepine Taj Pharma-induced toxicity.

An increase in hypersensitivity (e.g. rash, hypereosinophilia) may occur when procarbazine is taken concurrently.

Carbamazepine Taj Pharma, like other psychoactive drugs, may reduce alcohol tolerance. Therefore patients should abstain from alcohol during treatment.

Interference with serological examinations

Due to its interference with HPLC analysis, Carbamazepine Taj Pharma can lead to false positives for perphenazine concentrations. Carbamazepine Taj Pharma and its 10,11-epoxide metabolite can lead to false positive concentrations of tricyclic antidepressants in fluorescence polarised immunoassay method.

  • Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and antiepileptic drugs in general:

It has been shown that in the offspring of epileptic women, the prevalence of malformations is two to three times greater than the rate of about 3% found in the general population. In the treated population an increase in malformed children has been noted with polytherapy, however the extent to which the treatment and/or the illness are respectively responsible has not been elucidated as yet.

The most frequently encountered malformations are labial fusion defects and cardiovascular malformations.

Risk linked to Carbamazepine Taj Pharma:

Animal experiments have provided evidence of a teratogenic effect.

In humans, the number of women treated with Carbamazepine Taj Pharma in the first term trimester of pregnancy in the various prospective studies is still too limited for a firm conclusion to be drawn about whether this risk of malformation is real. However, some studies suggest that Carbamazepine Taj Pharma may cause an increase in neural tube closure anomalies, e.g. spina bifida, myelomeningocele (the risk reaches 1% which is 10-fold higher than the normal rate), malformations for which an antenatal diagnostic is possible and other congenital abnormalities e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems.

Taking these data into consideration:

Carbamazepine Taj Pharma may be used during pregnancy only after careful risk/benefit evaluation. Women of childbearing age should be advised of the necessity to plan and ensure supervision of pregnancy.

If a woman is pregnant or plans to become pregnant, the necessity of treatment should be reconsidered. In epilepsy, if possible, Carbamazepine Taj Pharma should be prescribed as a monotherapy, and minimum effective doses should be given, based on clinical response only. Monitoring of plasma concentrations of unbound Carbamazepine Taj Pharma may be useful (see section 4.2).

In women of childbearing age Carbamazepine Taj Pharma 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.

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

Monitoring and prevention:

The prevention of neural tube anomalies by folic acid in pregnant women treated with Carbamazepine Taj Pharma is not fully demonstrated at present. However, taking into account that folic acid deficiency due to the enzyme induction caused by Carbamazepine Taj Pharma may be a contributory factor for foetal abnormality, it may therefore be beneficial to take folic acid before (2 months) and during pregnancy.

Patients should be informed of the increased risk of malformations and access to prenatal screening be made available. A specific antenatal diagnosis can be proposed even for women with a supplementary treatment of folic acid.

In the new-born child:

Enzymatic inducers have provoked:

Uncommon: bleeding disorders occurring in the first 24 hours of the life of a treated mother’s child. Prevention by oral vitamin K1 to the mother, in the month prior to the birth, and an adapted dose to the new-born child at the moment of birth, seem appropriate.

Rarely: problems with the phosphocalcic metabolism and bone mineralisation.

A few cases of convulsions and/or respiratory depression in newborn babies have been reported, as well as some cases of vomiting, diarrhoea and/or reduced nutritional intake have been observed in connection with administration of antiepileptics. These could be signs of withdrawal syndrome in newborn babies.

Breast-feeding

Carbamazepine Taj Pharma and its main metabolite, Carbamazepine Taj Pharma-epoxide, are both present in breast milk in concentrations of about 25 – 60 % of the total plasma concentration. Due to the possible onset of non-dose-dependent adverse effects in the neonate, breast-feeding is not recommended during treatment for safety reasons. Breast-feeding should be stopped if signs of sedation become apparent.

There are some reports of cholestatic hepatitis in newborn babies who were exposed to Carbamazepine Taj Pharma antenatally or during breast-feeding. As a result, breast-fed children whose mothers are being treated with Carbamazepine Taj Pharma should be carefully monitored for undesirable hepatobiliary effects.

Fertility

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

Women of child bearing age and contraception

Due to the adverse interactions of Carbamazepine Taj Pharma with oestrogen and/or progesterone containing drugs, an alternative method of contraception should be used (see section 4.5).

  • Effects on ability to drive and use machines

Carbamazapine has major influence on the ability to drive and use machines. It affects patients’ reactions, causing dizziness, drowsiness, fatigue, ataxia, double vision, blurred vision, especially in the early stages of treatment. This may be further influenced by higher dose levels or the use of Carbamazepine Taj Pharma in combination with other centrally acting drugs or in conjunction with alcohol consumption. Patients should be warned of the possible hazards when driving or operating machinery.

  • Undesirable effects

The following undesirable effects appear dependent on the dose in particular at the start of therapy, too high initial dose or in older patients. These symptoms may abate spontaneously within a few days or if the dose is transiently reduced:

dizziness, headache, ataxia, drowsiness, fatigue, diplopia, nausea, vomiting and 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 fractional doses.

Side effects listed according to organ system with the frequency estimate 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) and not known (cannot be estimated from the available data):

Infections and infestations

Not known: Reactivation of an infection with human herpes virus 6

Blood and lymphatic system disorders

Very common: Leucopenia

Common: eosinophilia, thrombocytopenia

Rare: Lymphadenopathy, leucocytosis

Very rare: Agranulocytosis, aplastic anaemia, pure red cell aplasia, anaemia, megaloblastic anaemia, reticulocytosis, haemolytic anaemia, enlarged spleen, pancytopenia

Not known: Bone marrow depression

According to literature sources the most frequent disorder is benign leucopenia, 10% of the cases being of a transient nature, 2% persistent.

Immune system disorders

Uncommon: Delayed multi-organ hypersensitivity disorder with fever, skin rashes, vasculitis, swollen lymph nodes, pseudolymphoma, painful joints (arthralgia), leucopenia, eosinophilia, hypogammaglobulinaemia, enlargement of liver and spleen or altered liver function tests and vanishing bile duct syndrome occurring in various combinations. Other organs such as lung, kidney, pancreas, colon and cardiac muscle may also be affected

Very rare: Generalised acute allergic reactions, anaphylactic reactions, angioedema, hypogammaglobulinaemia

Not known: Drug rash with eosinophilia and systemic symptoms (DRESS)

Endocrine disorders

Common: Weight gain, hyponatraemia

Metabolism and nutrition disorders

Common: Fluid retention

Rare: Folic acid deficiency, reduced appetite

Psychiatric disorders

Uncommon: Confusion and agitation in older patients, depressive disorders, aggressive behaviour, thinking difficulties, hallucinations (visual or auditory), activation of latent psychosis

Rare: Restlessness, mania

Very rare: Phobias

Nervous system disorders

Very common: Dizziness, somnolence, sedation, ataxia (atactic and cerebral disturbances)

Common: Headache

Uncommon: Lack of drive, involuntary movements like asterixis, tremor, dystonia or tics or nystagmus.

Rare: Dyskinetic disorders like orofacial dyskinesia, choreoathetosis, eye movement disturbances, speech disorders, paraesthesia, neuropathy peripheral, polyneuropathy, peripheral neuropathy, paresis

Very rare: Taste disturbances, neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia

Not known: Memory impairment

Eye disorders

Common: Accommodation disorders, diplopia

Rare: Lenticular opacities

Very rare: Conjunctivitis, retinotoxicity, cataracts

Ear and labyrinth disorders

Uncommon: Tinnitus

Very rare: Change in pitch perception, hypoacusis and hyperacusis

Cardiac disorders

Uncommon: Conduction disorders, AV-block, in isolated cases with syncope, bradycardia, cardiac arrhythmias, aggravation of coronary artery disease, congestive heart failure

Vascular disorders

Uncommon: Vasculitis

Rare: Hypertension, hypotension

Very rare: Thrombophlebitis, thrombo-embolism, circulatory collapse

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary hypersensitivity reactions with fever, dyspnoea, pneumonitis or pneumonia (alveolitis), lung fibrosis

Gastrointestinal disorders

Very common: Nausea, vomiting

Common: Loss of appetite, dry mouth

Uncommon: Diarrhoea, constipation

Rare: Abdominal pain

Very rare: Stomatitis, gingivitis, glossitis, pancreatitis

Not known: Colitis

Hepatobiliary disorders

Rare: Jaundice, hepatitis (cholestatic, hepatocellular, granulomatous, mixed type), vanishing bile duct syndrome, liver failure

Skin and subcutaneous tissue disorders

Very common: Allergic skin reactions with or without fever like urticaria (which may be severe)

Uncommon: Pruritus, exfoliative dermatitis, erythroderma, alopecia, hyperhidrosis

Rare: Systemic lupus erythematosus

Very rare: Severe cutaneous adverse reactions (SCARS): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see section 4.4), alterations in skin pigmentation, acne, hirsutism, photosensitivity, erythema exudativum, multiforme and nodosum, purpura, acute generalised exanthematous pustulosis (AGEP)

Not known: Lichenoid keratosis, onychomadesis

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 Taj Pharma 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).

Musculoskeletal and connective tissue disorders

Rare: Muscle weakness

Very rare: Arthralgia, muscle pain, muscle spasms, bone metabolism disorder

Not known: Fracture

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

Carbamazepine Taj Pharma may increase the metabolism of 25-OH-Cholecalciferol leading to a decreased calcium level, which rarely causes osteomalacia, arthralgia, myalgia and muscle cramps.

Renal and urinary disorders

Uncommon: Renal impairment such as proteinuria, haematuria, oliguria, elevated BUN/azotaemia

Rare: Other micturition disorders like dysuria, pollakiuria, urinary frequency and urinary retention

Very rare: Renal failure, interstitial nephritis

Reproductive system and breast disorders

Rare: Gynaecomastia, galactorrhoea

Very rare: Sexual dysfunction like impotence, decreased libido and impaired male fertility and/or abnormal spermatogenesis (reduces sperm count and/or motility)

Congenital, familial and genetic disorders

Very rare: Porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda)

General disorders and administration site conditions

Very common: Fatigue

Common: Oedema

Investigations

Very common: Elevated gamma-GT (due to hepatic enzyme induction), usually not clinically relevant

Common: Elevated alkaline phosphatase in the blood, reduced plasma osmolality due to an antidiuretic hormone (ADH)–like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion, neurological abnormalities

Uncommon: Increased transaminases

Very rare: Elevated levels of cholesterol, including HDL cholesterol, and triglycerides, increased intraocular pressure, abnormal thyroid function tests: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased, increase in serum cortisol

Carbamazepine Taj Pharma may lower the plasma levels of folic acid and vitamin B12, and may increase the plasma level of homocysteine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

  • Overdose

Carbamazepine Taj Pharma overdose has been reported only with very high doses (4 – 20 g). Plasma levels were always above 20 µg/ml. A plasma level of 38 µg/ml was not lethal for the patient. Lethal cases of Carbamazepine Taj Pharma overdose have been reported in literature.

Symptoms

The presenting signs and symptoms of overdosage involve the central nervous, cardiovascular, gastrointestinal, musculoskeletal, renal or respiratory systems.

Central nervous system: CNS depression, disorientation, somnolence, agitation, hallucination, coma, stupor, vertigo, restlessness, confusion, blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, opisthotonus, involuntary movements, tremor, flushing, seizures, EEG dysrhythmia, hypothermia, mydriasis.

Respiratory system: Respiratory depression, pulmonary oedema, cyanosis, respiratory arrest.

Cardiovascular system: Tachycardia, changes in blood pressure (hypotension and at times hypertension), cardiac arrhythmias, AV block, cardiac arrest, flushing, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.

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

Musculoskeletal system: Rhabdomyolysis

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

Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatinine phosphokinase, leucocytosis, leucopenia, neutropenia, glycosuria, acetonuria.

Management of symptoms

There is no specific antidote for Carbamazepine Taj Pharma overdose.

Management of symptoms due to overdosage will vary according to the patient’s condition. This includes admission to hospital. Measurement of the plasma levels to confirm Carbamazepine Taj Pharma poisoning and to ascertain the size of the overdose. Evacuation of the stomach, gastric lavage, and administration of activated charcoal or laxative. Delayed evacuation of the stomach may lead to 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, if required.

Special recommendations:

Hypotension: administer dopamine or dobutamine i.v.

Disturbances of cardiac rhythm: to be managed on an individual basis.

Convulsions: administer a benzodiazepine (e.g. diazepam) or another anticonvulsant, e.g. phenobarbitone (with caution because of increased respiratory depression) or paraldehyde.

Hyponatraemia (water intoxication): fluid restriction and slow careful NaCl 0.9 % infusion i.v.

These measures may be useful in preventing brain damage.

Charcoal haemoperfusion has been recommended. Haemodialysis is an effective option in the treatment of Carbamazepine Taj Pharma overdose. Forced diuresis, and peritoneal dialysis have been reported not to be effective.

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

  1. PHARMACOLOGICAL PROPERTIES
    • Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptic

Mechanism of action

It is thought to block cyclic-AMP mediated calcium influx associated with transmitter release, and it is known to be an adenosine receptor antagonist: either of these actions might account for its antiepileptic action. Work in animals has shown that it has inhibitory effects on hippocampal discharges and it also inhibits the reticulo-thalamic and thalamocortical projections which are involved in tonic-clonic seizures.

Antiepileptics have membrane-stabilising properties which have been found useful in the relief of neurogenic pain especially where there is a lancinating element, as in trigeminal neuralgia.

  • Pharmacokinetic properties

Absorption

Carbamazepine Taj Pharma is almost completely absorbed but the rate of absorption is slow and may vary between patients.

Peak plasma concentrations of the unchanged active substance are attained within 24 hours. The bioavailability of Carbamazepine Taj Pharma has been shown to lie between 85 – 100 % and is unaffected by food.

Evaluation of literature allows the conclusion concerning therapeutic and toxic plasma levels that seizures are controlled at plasma levels between 4 and 12 µg/ml, levels above 20 µg/ml resulted in a deterioration of symptoms. Control of pain of trigeminal neuralgia was effective at plasma levels between 5 and 18 µg/ml. Side effects start appearing at plasma levels above 8–9 µg/ml.

Distribution

Carbamazepine Taj Pharma is 70 – 80 % bound to plasma. The proportion of unbound Carbamazepine Taj Pharma is constant at a concentration of up to 50 μg/ml. The pharmacologically active metabolite Carbamazepine Taj Pharma-10,11-epoxide is bound to plasma protein at 48-53% (about 0.74 L/kg).

The concentration of Carbamazepine Taj Pharma in the cerebrospinal fluid is 33% of the current plasma concentration. The concentration of unchanged substance in the saliva represents the unbound portion in plasma, i.e. 20 – 30 % of total plasma concentration. In breast milk the concentration is 25 – 60% of total plasma concentration. Carbamazepine Taj Pharma crosses the placental barrier. Apparent volume of distribution: 0.8 – 1.9 L/kg.

Biotransformation

Carbamazepine Taj Pharma is extensively metabolised in the liver, mainly by oxidative pathways of which only the metabolite Carbamazepine Taj Pharma-epoxide is pharmacologically active. This may constitute up to 30 % of the circulating active material originality as Carbamazepine Taj Pharma. The inactive 10,11-diol represents the final stage of Carbamazepine Taj Pharma biotransformation. In children, the relatively high rate of metabolism of the drug may require higher dose (in mg/kg b.w.) of Carbamazepine Taj Pharma to maintain therapeutic concentrations.

Elimination

Only about 1 % of the administered dose is excreted in the urine in the unchanged form. A greater part is excreted in the urine almost entirely in the form of its metabolites; some is excreted in faeces.

Plasma clearance in healthy subjects is about 19.8 ± 2.7 ml/h/kg, in patients under monotherapy about 54.6 ± 6.7 ml/h/kg, in patients under combination therapy about 113.3 ± 33.4 ml/h/kg.

The elimination half-life of unchanged drug in the plasma averages approximately 36 hours following a single dose, whereas after repeated administration, it averages only 16 – 24 hours, depending on the duration of the medication. In patients receiving co-medication with other enzyme-inducing drugs such as phenytoin, phenobarbitone, half-life values averaging 9-10 hours have been observed.

Special population

Carbamazepine Taj Pharma should be used with caution in patients with renal impairment.

In advanced hepatic disease, Carbamazepine Taj Pharma metabolism may be impaired.

The pharmacokinetics of Carbamazepine Taj Pharma are unaltered in older people but its metabolism may be affected by hepatic dysfunction. The formulation of Carbamazepine Taj Pharma produces a substantial reduction in intra-dose fluctuations in Carbamazepine Taj Pharma concentrations and tolerability and seizure control in patients with epilepsy may be improved. The  formulation should be considered in patients receiving high doses who suffer intermittent adverse effects such as diplopia, nausea, dizziness and tiredness and may offer the opportunity to reduce the dosage regimen.

  • Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of Carbamazepine Taj Pharma in humans.

Carcinogenicity

In rats treated with Carbamazepine Taj Pharma for 2 years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence that this observation is of importance for the therapeutic use of Carbamazepine Taj Pharma in humans.

Reproductive toxicity

In animal studies in mice, rats and rabbits oral administration of Carbamazepine Taj Pharma during organogenesis led to an increased embryo-foetal mortality and foetal growth retardation at daily doses which were associated with maternal toxicity (above 200mg/400mg/kg/day). Carbamazepine Taj Pharma 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 reproductive study in rats, nursing offspring exhibited reduced weight gain at a maternal dosage level of 192 mg/kg/day.

  1. PHARMACEUTICAL PARTICULARS

List of excipients

Ammonio methacrylate copolymer (type B) (contains: sorbic acid and sodium hydroxide), Methacrylic acid – ethyl acrylate copolymer (1:1) (contains: sodium laurilsulfate and polysorbate 80), Triacetin, Talc, Cellulose, microcrystalline, Crospovidone, Silica, colloidal anhydrous, Magnesium stearate

Incompatibilities

Not applicable

Shelf life

3 years

Special precautions for storage

No special precautions for storage

Nature and contents of container

Each film coated Extended-Release tablets contain Carbamzepine 100mg, 200mg, 300mg and 400mg
Child-proof containers:

PVC/PVDC/Al blisters.

Pack sizes: Blisters: 7, 14, 28, 30, 50, 90, 100 and 500mg modified-release tablets.

Not all pack sizes may be marketed.

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 Extended-Release Tablets USP 100mg
Taj Pharma

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

Carbamazepine Taj Pharma

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

  • Keep this leaflet. You may need to read it
  • If you have any further questions, ask your doctor or
  • 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
  • If you get any side effects, talk to your doctor of pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

WHAT IS IN THIS LEAFLET

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

1.  WHAT CARBAMAZEPINE IS AND WHAT IT IS USED FOR

Carbamazepine Taj Pharma is specially formulated to release the active ingredient gradually.

Carbamazepine Taj Pharma, the active ingredient, can affect the body in several different ways. It is an anticonvulsant medicine (prevents fits), it can also modify some types of pain and can control mood disorders.

Carbamazepine Taj Pharma is used

  • To treat some forms of epilepsy
  • To treat a painful condition of the face called trigeminal neuralgia
  • To help control serious mood disorders when some other medicines don’t

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE CARBAMAZEPINE

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

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 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.

If you develop a rash or these skin symptoms, stop taking Carbamazepine Taj Pharma, and contact your doctor immediately and tell them that you are taking this medicine.

Do not take Carbamazepine Taj Pharma

  • if you are allergic to carbamazepine or similar medicines such as
  • oxcarbazepine, or to any of a related group of medicines known as tricyclic antidepressants (such as amitriptyline or imipramine). If you are allergic to carbamazepine there is a one in four (25%) chance that you could also have an allergic reaction to oxcarbazepine,
  • if you are allergic to any of the other ingredients of Carbamazepine Taj Pharma (listed in section 6),
  • if you have any heart problems,
  • if you have ever had problems with your bone marrow,
  • if you have or ever had blood disorders such as acute intermittent porphyria, variegate porphyria or porphyria cutanea tarda,
  • if you have taken medicines called monoamine oxidase inhibitors (MAOIs), used to treat depression, within the last 14 days,
  • if you are taking voriconazole for a fungal infection,
  • if you are taking anything containing St. John’s

Warnings and precautions

Talk to your doctor or pharmacist before taking Carbamazepine Taj Pharma

  • if you have liver or kidney disease
  • if you suffer from glaucoma (increased pressure in the eye). It is important to visit your optician regularly while taking Carbamazepine Taj Pharma
  • if you suffer from the sort of epilepsy where you get mixed seizures which include absences (clouding of consciousness)
  • if you are elderly
  • if you are allergic to an epilepsy medicine called phenytoin
  • if you have a condition called hypothyroidism and are taking hormone replacement therapy (HRT)
  • if you suffer from urinary retention, an inability to urinate

Avoid strong sunlight or excessive lengths of time in strong sunlight as this may trigger skin reactions.

You may be required to regularly provide blood and/or urine samples before and during treatment to check the levels of carbamazepine in your blood and to identify any problems before they become serious.

Other medicines and Carbamazepine Taj Pharma

Because of the way that Carbamazepine Taj Pharma works, it can affect, and be affected by lots of other things that you might be eating or medicines you are taking.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including herbal medicines. This is especially important for the following:

  • Hormone contraceptives, g. pills, patches, injections or implants. Carbamazepine Taj Pharma affects the way the contraceptive works in your body, and you may get breakthrough bleeding or spotting. It may also make the contraceptive not work and there will be a risk of getting pregnant. Your doctor will be able to advise you about this, and you should use other contraceptives.
  • Hormone Replacement Therapy (HRT) such as tibolone. Carbamazepine Taj Pharma can make HRT less
  • Any medicines for depression or anxiety such as alprazolam, amitriptyline, citalopram, clobazam, clomipramine, desipamine, fluoxetine, fluvoxamine, imipramine, mianserin, midazolam, nefazodone, nortriptyline, paroxetine, sertraline, trazodone or
  • Corticosteroids (‘steroids’) such as dexamethasone or prednisolone. You might be taking these for inflammatory conditions such as asthma, inflammatory bowel disease, muscle and joint

Anticoagulants to stop your blood clotting such as acenocoumarol, dicoumarol, phenprocoumon, ticlopidine or warfarin.

  • Antibiotics to treat infections including skin infections and TB such as ciprofloxacin, clarithromycin, doxycycline, erythromycin, isoniazid, josamycin, rifampicin, rifabutin or troleandomycin.
  • Antifungals to treat fungal infections such as caspofungin, fluconazole, itraconazole, ketoconazole or
  • Painkillers containing paracetamol, dextropropoxyphene, fentanyl, ibuprofen, phenazone, propoxyphene, tramadol, methadone or
  • Other medicines to treat epilepsy such as clobazam, clonazepam, felbamate, flunarizine, fosphenytoin, lamotrigine, levetiracetam, methosuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin, primidone, progabide, stiripentol, tiagabine, topiramate, valproic acid, valpromide, vigabatrin or
  • Medicines for high blood pressure or heart problems such as atorvastatin, cerivastatin, digoxin, diltiazem, felodipine, hydroquinidine, isradipine, ivradipine, propranolol, quinidine, simvastatin or verapamil.
  • Antihistamines (medicines to treat allergy such as hayfever, itch, etc) such as loratadine or terfenadine.
  • Diuretics (water tablets) such as hydrochlorothiazide or
  • Cimetidine or omeprazole (medicines to treat gastric ulcers).
  • Isotretinoin (a medicine for the treatment of acne).
  • Metoclopramide (an anti-sickness medication).
  • Lithium (a medicine for bipolar disorder).
  • Medicines for sickness or nausea (antiemetics) such as aprepitant.
  • Acetazolamide (a medicine to treat glaucoma – increased pressure in the eye).
  • Danazol or gestrinone (treatments for endometriosis).
  • Theophylline or aminophylline (used in the treatment of asthma).
  • Medicines that reduce the activity of the body’s natural defences (immunosuppressant) such as ciclosporin (used after transplant operations, but also sometimes in the treatment of arthritis or psoriasis), everolimus, sirolimus or
  • Medicines to treat schizophrenia such as aripiprazole, bromperidol, clozapine, haloperidol, loxapine, olanzapine, paliperidone, quetiapine, risperidone or
  • Cancer medicines such as cisplatin cyclophosphamide, doxorubicin, imatinib, lapatinib, procarbazine, temsirolimus or
  • The antimalarial medicine,
  • Medicines to treat HIV such as indinavir, ritonavir or
  • Levothyroxine (used to treat hypothyroidism).
  • Muscle relaxant medicines such as pancuronium, dantrolene or
  • Bupropion (used to help stop smoking).
  • Methylphenidate (used to treat attention-deficit, hyperactivity disorder (ADHD).
  • Medicines or supplements containing Vitamin B (nicotinamide).
  • Medicines to treat parasitic worm infections such as albendrazole or
  • Tadalafil – a medicine used for men with erection

If you are taking medicines for depression, tell your doctor or hospital staff that you are taking carbamazepine if you need to have a blood test to monitor the levels of medicine in your blood.

Carbamazepine Taj Pharma with food, drink and alcohol

Do not take your tablets with grapefruit or grapefruit juice as this may increase the likelihood of side effects from Carbamazepine Taj Pharma.

Drinking alcohol may affect you more than usual. You should not drink alcohol during treatment.

Pregnancy, breast-feeding and fertility

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 medicine.

Pregnancy

Carbamazepine Taj Pharma affects the way hormonal contraceptives work and there is a risk of getting pregnant. You should use other contraceptives. You must discuss your epilepsy treatment with your doctor well before you become pregnant. If you do get pregnant while taking Carbamazepine Taj Pharma do not stop taking this medicine and tell the doctor straightaway. It is important that your epilepsy remains well controlled, but, as with other antiepilepsy treatments, there is a risk of harm to the baby. You should be able to have an antenatal scan to check for any problems. Make sure you are very clear about the risks and the benefits of taking Carbamazepine Taj Pharma.

Breast-feeding

Mothers taking Carbamazepine Taj Pharma can breast-feed their babies, but you must tell the doctor as soon as possible if you think that the baby is suffering side effects such as excessive sleepiness or skin reactions because you are taking Carbamazepine Taj Pharma.

Fertility

Taking this medicine may affect male fertility. If you have any questions talk to your doctor.

Driving and using machines

Carbamazepine Taj Pharma may 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 (blurred or double vision), you should not drive or operate machinery.

3. 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 will usually start Carbamazepine Taj Pharma at a fairly low dose which can then be increased to suit you individually. The dose needed varies between patients. You may be told to take a dose two or three times a day.

To treat epilepsy the recommended doses are:

Adults:

The recommended starting dose is 100-400 mg a day in one or two doses. The dose may then be increased to 800-1,200 mg a day, in two doses, although higher doses may be necessary. If you are elderly you might require a lower dose.

Use in children and adolescents:

Aged 5-10 years: The recommended starting dose is 200 mg at night (or 100 mg morning and night). The dose may then be increased to 300-600 mg a day in two doses.

Aged 10-15 years: The recommended starting dose is 200 mg at night (or 100 mg morning and night). The dose may then be increased to 500-1,000 mg a day in two doses.

Carbamazepine Taj Pharma is not recommended for children under 5.

To treat trigeminal neuralgia the recommended starting dose is 100-400 mg a day. The dose may be increased to: 600-800 mg a day in two doses, with a maximum dose of 1600 mg.

To treat mood swings the recommended starting dose is 100-400 mg a day. The dose may be increased to: 400- 600 mg a day in two doses with a maximum dose of 800 mg.

Method of administration

For oral use.

You can take Carbamazepine Taj Pharma during, after or between meals. Swallow the tablets whole with a drink. Do not chew them. If you have difficulty swallowing the tablets you can add them to a glass of water where the tablets will break apart. If you do this you must drink all of the mixture as soon as the tablets have broken apart.

The tablet can be divided into equal doses.

If you take more Carbamazepine Taj Pharma than you should
If you take too many Carbamazepine Taj Pharma immediately tell your doctor or your nearest hospital casualty department. Take the medicine pack with you so that people can see what you have taken. You may feel sick, be sick, constipated, you may be unable to urinate, hallucinate, be confused, have blurred vision, slurred speech, uncontrollable eye movements, dilated pupils, uncontrollable movements such as muscle spasms, loss of coordination, shallow, difficulty or stopping breathing, respiratory, changes to your heartbeat or a heart attack.

If you forget to take Carbamazepine Taj Pharma

Take it as soon as you remember unless it is almost time for your next dose. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Carbamazepine Taj Pharma

Do not stop taking your tablets suddenly. Speak to your doctor first. If your dose needs to be reduced, this will be done slowly.

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

4. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious

Stop taking Carbamazepine Taj Pharma and tell your doctor straight away if you notice:

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

  • an increase in the number of infections you get which may cause fever, severe chills, sore throat, or mouth ulcers (this may indicate you have a low number of white blood cells in your body)

Uncommon (may affect up to 1 in 100 people)

  • difficulty breathing, especially with exercise. You may have a dry, hacking cough or wheezing with rapid or irregular heartbeats, swelling to ankles, feet or lower legs, loss of appetite, dizziness, tiredness or confusion (this may indicate your heart isn’t working properly)
  • fever, skin rash, swollen glands, joint pain, and abnormalities in blood and liver function tests (these may be the signs of a multi-organ sensitivity disorder)
  • difficulty thinking, seeing or hearing things that aren’t there (hallucinations), increased agitation or false-beliefs (delusions)

Rare (may affect up to 1 in 1,000 people)

  • tingling, pins and needles sensation, numbness, burning or sharp stabbing pain in your hands and feet, feel physically weak or uncoordinated ( this may indicate you have inflammation in or damaged some of the nerves in the body)
  • yellowing of your skin or whites of the eyes, dark urine, pale stools, tiredness, fever, nausea, weakness, drowsiness and abdominal pain, with test results showing abnormal liver function (these may indicate you have problems with your liver or a blockage in the bile duct)
  • pain in your joints and muscles, a rash across the bridge of the nose and cheeks and problems with breathing (these may be the signs of a rare reaction known as systemic lupus erythematosus)
  • inability to completely empty your bladder. You may have a poor urinary stream with an interrupted flow, be straining to urinate with a delay in trying to urinate and urinating (these signs indicate you may have a condition called urinary retention)

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

  • tiredness, shortness of breath, cold hands or feet or pale skin, difficulty in healing after a cut or unexplained bruising or bleeding (this may indicate you have a low number of red blood cells or platelets in your body)
  • wheezing and coughing, difficulty in breathing, feeling faint, rash, itching or swelling in the face, lips, tongue or throat (these may be the signs of a severe allergic reaction)
  • severe abdominal pain, red urine, severe constipation or hallucinations (these are signs that you have a condition called porphyria). Your skin may also become fragile and blister when exposed to light
  • shortness of breath, difficulty swallowing or difficulty walking. You may shake or have uncontrollable movements (this may indicate you have a condition called neuroleptic malignant syndrome)
  • sensitivity to light, stiff neck, body aches, sore throat, severe headache, flu-like symptoms (these may indicate you have a type of meningitis that can’t be passed on to others)
  • circulatory problems such as cold hands and feet, prominent veins in the neck, rapid shallow breathing or weak, irregular heart beat

Serious skin reactions such as rash, red skin, blistering and bleeding of the lips, eyes or mouth, or skin peeling accompanied by fever have been reported (these may indicate Stevens-Johnson syndrome ortoxic epidermal necrolysis – see section 2). These reactions may be more frequent in patients of Chinese or Thai origin

  • severe pain in the area near the stomach that spreads to the back (this may indicate you have problems with your pancreas)
  • producing little or no urine, pain or difficulty when passing urine, cloudy or dark urine, blood in the urine or lower back pain (these may indicate serious problems with your kidneys)
  • increase in eye pressure (this is known as glaucoma)
  • lung or breathing problems with fever, coughing which may produce phlegm or blood, or chills

Not known (cannot be estimated from the available data)

  • infection caused by humanherpesvirus 6

Other side effects include:

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

  • Dizziness, tiredness or drowsiness
  • feeling unsteady or finding it difficult to control movements
  • feeling or being sick
  • changes in liver enzyme levels (usually without any symptoms)
  • skin reactions, with or without fever, for example a red itchy rash (known as hives) which may be severe

Common (may affect up to 1 in 10 people)

  • fluid retention and swelling
  • weight increase
  • low sodium or other salts (electrolytes) in the blood that might result in confusion or behavioural changes.
  • headache
  • double or blurred vision, problems with your eye
  • dry mouth, loss of appetite

Uncommon (may affect up to 1 in 100 people)

  • fever, skin rash, swollen glands, joint pain, and abnormalities in blood and liver function tests (these may be the signs of a multi-organ sensitivity disorder)
  • confusion, agitation (these may occur especially in the elderly)
  • feeling sad or low (also known as depression)
  • aggression
  • abnormal involuntary movements including tremor, spasms, or tics
  • lack of drive or motivation
  • abnormal eye movements
  • ringing in the ear (also known as tinnitus)
  • irregular or slow heartbeat, you may faint
  • chest pain, a thumping sensation in your chest together with breathlessness
  • diarrhoea, constipation
  • itchy skin, scaly or flaky skin, areas of redness which may be sore and tender due to inflammation of blood vessels
  • hair loss
  • excessive sweating
  • increase in urea or nitrogen containing compounds in the blood

Rare (may affect up to 1 in 1,000 people)

  • lumps on the neck or armpit (may be signs of a disease of the lymph glands)
  • sore mouth or dark skin (may be signs of a lack of folic acid in the body)
  • restlessness
  • over-excitable moods with uninhibited behaviour
  • involuntary movements of the face (such as a grimace) or twisting or writhing movements of the body
  • speech problems muscle weakness causing loss of movement
  • swelling of the breasts and discharge of milk which may occur in both males and females
  • cloudy vision
  • high blood pressure (which may make you feel dizzy, with flushed face, headache, fatigue and nervousness)
  • low blood pressure (the signs of which are feeling faint, light headed, dizzy, confused, having blurred vision)
  • stomach pain
  • increased or decreased desire to pass urine

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

  • Unable to eat a large meal or feeling full without eating, discomfort, fullness or pain in the upper left side of the stomach. You may also be tired, have weight loss or bleed easily. These are signs you may have an enlarged spleen
  • persistent fear of (and desire to avoid) a particular object or situation (phobias)
  • abnormal thyroid function tests
  • osteomalacia (which may be noticed as pain on walking and bowing of the long bones in the legs)
  • brittle bones (known as osteoporosis)
  • increased blood fat levels, increased blood cortisol or prolactin levels in the blood
  • taste disturbances
  • itchy, watery, sore eyes with crusty eyelids (known as conjunctivitis)
  • hearing disorders such as pitch changes in sound, loss of hearing or increased sensitivity to sound
  • swelling or redness along a vein which is painful or tender to touch or skin discoloration and prominent superficial veins (may be signs of circulatory problems such as a blood clot)
  • inflammation or swelling of the stomach, mouth (gums) or tongue
  • increased sensitivity of the skin to sunlight
  • changes in skin colour
  • acne
  • increased hair growth on the body and face
  • purple or brown spots on the skin
  • pain in the joints or muscles
  • sexual difficulties which may include reduced male fertility such as abnormal sperm
  • loss of libido or impotence

Not known (cannot be estimated from the available data)

  • problems with your memory
  • diarrhoea which may contain mucus or blood. You may have stomach pain or a fever
  • single small skin lesion
  • shedding of finger and toe nails
  • broken bones

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.

Reporting of side effects

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

5. 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 carton after EXP. The expiry date refers to the last day of that month.

This medicine has no special storage requirements.

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.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Carbamazepine Taj Pharma contains

Each film coated Extended-Release Tablets contains Carbamazepine Taj Pharma 100mg, 200mg, 300mg, 400mg

The other ingredients are ammonio methacrylate copolymer type B (contains sorbic acid and sodium hydroxide), methacrylic acid-ethyl acrylate copolymer (contains sodium laurilsulfate and polysorbate), triacetin, talc, microcrystalline cellulose, crospovidone, colloidal anhydrous silica and magnesium stearate.

What Carbamazepine Taj Pharma looks like and contents of the pack

PVC/PVDC/Al blisters.

Pack sizes: Blisters: 7, 14, 28, 30, 50, 90, 100 and 500mg modified-release tablets.

Not all pack sizes may be marketed.

  1. 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