SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Carbamazepine Taro 100 mg/5 ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of the oral suspension contains 100 mg Carbamazepine.

Excipients with known effect:

Sorbitol and sunset yellow (E110)

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Oral suspension

An orange to pale orange suspension.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Carbamazepine Taro 100 mg/5 ml Oral Suspension is indicated for:

Epilepsy (generalised tonic-clonic and partial seizures). Carbamazepine Taro 100 mg/5 ml Oral Suspension is indicated for use in newly diagnosed patients with epilepsy and those patients whose epilepsy is not adequately controlled on their current therapy.

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

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 in genetic testing’s and cutaneous reactions in section 4.4)

Posology

Carbamazepine Taro 100 mg/5 ml Oral Suspension should be given orally.

It is advised that the dosage is increased gradually and should be adjusted to suit the needs of the individual patient.

Since a given dose of Carbamazepine Taro 100 mg/5 ml Oral Suspension will produce higher peak levels than the same dose of carbamazepine in tablet form, it is advisable to start with low doses of the liquid and to increase them slowly so as to avoid adverse effects on the central nervous system such as dizziness and lethargy.

When switching a patient from tablets to liquid the same overall dose may be used but smaller, more frequent doses.

Epilepsy (generalised tonic-clonic and partial seizure)

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

Adults

Carbamazepine Taro 100 mg/5 ml oral suspension should be taken in a number of divided doses.

An initial dose of 100-200 mg once or twice daily is recommended. The dose should be gradually increased until the optimum response is obtained, often 8001200 mg daily. In some cases, doses of 1600-2000 mg daily may be necessary. The dose should be adjusted to suit the needs of the individual patient. It may be useful to monitor the plasma concentration of carbamazepine to establish the optimum dose.

Elderly

Same as adults, but it is recommended that the initial dose be small. Carbamazepine should be used with caution in elderly patients due to potential drug interactions.

Paediatric population

The dose should be gradually increased until the optimum response is obtained.

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

The dose should be adjusted to suit the needs of the individual patient. It may be useful to monitor the plasma concentration of carbamazepine to establish the optimum dose.

Trigeminal neuralgia

The individual dosage requirements can vary considerably. It is recommended that the initial dose be small but in some patients, a high dose early in treatment may be required.

Slowly raise the initial dosage of 200 - 400 mg daily (100 mg twice daily in elderly patients) until freedom from pain is achieved (normally at 200 mg 3 - 4 time daily). In the majority of patients a dosage of 200 mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, doses of 1600 mg daily may be needed. However, once the pain is in remission, the dosage should be gradually reduced to the lowest possible maintenance level.

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

An initial dose of 100 - 200 mg daily, in divided doses, increasing gradually until symptoms are controlled or a total of 1600 mg in divided doses is reached.

The usual maintenance dose is 400-600 mg daily, given in divided doses.

Method of Administration

Carbamazepine Taro 100 mg/5 ml oral suspension is given orally, either before, during or between meals. Shake well before use.

4.3 Contraindications

The use of carbamazepine is contraindicated in patients:

* with hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* with known sensitivity to structurally related drugs-(e.g. tricyclic antidepressants)

* receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs).

4.4 Special warnings and precautions for use Warnings

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for carbamazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of carbamazepine.

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, 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.

Cutaneous reactions

Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Steven-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.

The is growing evidence of the role of different HLA alleles in predisposing patients to immune-medicated 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. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with Carbamazepine (see section 4.2). If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B* 1502 have a low risk of SJS, although the reactions may still very rarely occur.

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

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

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

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

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of 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.

Agranulocytosis and aplastic anaemia have been associated with carbamazepine; however, due to the very low incidence of these conditions, meaningful risk estimates for carbamazepine is difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.

Blood counts, platelet counts and serum biochemistry including electrolytes and indices of hepatic function should be checked before commencing treatment with carbamazepine. Blood counts should also be performed before and periodically during treatment. Clinical monitoring is of primary importance during the entire treatment period.

Patients and their relatives should be informed on how to recognise early toxic signs and symptoms indicative of a potential haematological problem, or of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appears, the patient should be advised to consult his physician immediately.

Treatment should be discontinued if the patient develops leucopenia accompanied by clinical manifestations e.g. fever or sore throat or significant depression of the bone marrow.

If treatment with carbamazepine has to be withdrawn, alternative anti-epileptic drugs should be prescribed.

Hepatic impairment

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.

Treatment with carbamazepine 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 Taro 100 mg/5 ml Oral Suspension suspended pending the outcome of the evaluation.

Mild skin reactions e.g. isolated mascular or maculopapular exanthemata, 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, the patient should be kept under close surveillance and a worsening of rash or accompanying of symptoms are an indication for the immediate withdrawal of carbamazepine.

Reports of severe dermatologic reactions including Lyell's syndrome (toxic epidermal necrolysis) and Stevens-Johnson syndrome necessitate immediate withdrawal.

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

Abrupt withdrawal of carbamazepine may precipitate seizures.

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

Cross-hypersensitivity can occur between carbamazepine and oxcarbazepine (Trileptal) in approximately 25 - 30% of patients.

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

Isolated reports of impaired male fertility and/or abnormal spermatogenesis are on file. A causal relationship has not been established.

Use with Oestrogen and/or progestogen preparations: Due to hepatic enzyme induction, carbamazepine may cause failure of the therapeutic effect of oestrogen and/or progestogen containing products. This may result in failure of contraception, recurrence of symptoms or breakthrough bleeding or spotting.

Patients taking carbamazepine and requiring oral contraception should receive a preparation containing not less than 50 pg oestrogen or use of some alternative non-hormonal method of contraception should be considered.

Although correlation between dosages and plasma levels and clinical efficacy or tolerability are rather tenuous. Monitoring of plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see 4.5 Interaction with other Medicaments and other forms of Interaction).

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

Carbamazepine should be used after a critical risk benefit appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs or interrupted course of therapy with carbamazepine. Baseline and periodic complete urinalysis and BUN determinations are recommended.

Patients with glaucoma should be informed about possible hazards associated with carbamazepine’s mild anticholinergic activity.

High doses of carbamazepine could result in activation of latent psychosis and possibly agitation or confusion in elderly patients.

Patients should avoid excessive exposure to sunlight during carbamazepine therapy due to possible photosensitivity.

This product contains the colouring sunset yellow FCF (E110). It may cause allergic reactions.

This product contains Sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This product contains potassium sorbate (E202). Each 5 ml of suspension contains less than 1 mmol (39 mg) of potassium, i.e. essentially “potassium free”.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

Since reduced plasma levels might result in therapeutic failure and 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.

Agents that may raise carbamazepine plasma levels:

Some drugs have been shown to increase carbamazepine serum levels. These include: isoniazid, calcium antagonists (verapamil, diltiazem), dextropropoxyphene, viloxazine, selective serotonin re-uptake inhibitors (e.g. fluoxetine, fluvoxamine), cimetidine, acetazolamide, danazol, possibly desipramine and nicotinamide (only in adults and at high doses), nefazodone, macrolide antibiotics (e.g. erythromycin, clarithromycin), azole antifungals (e.g itraconazole, fluconazole, ketoconazole, voriconazole), terfenadine, loratadine, protease inhibitors for HIV treatments (e.g. ritonavir). Since raised carbamazepine levels may produce signs of overdosage (eg dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma levels monitored.

Concomitant administration of grapefruit or grapefruit juice may increase carbamazepine serum concentrations.

Agents that may decrease carbamazepine plasma levels:

Plasma levels of carbamazepine may be reduced by phenobarbitone, phenytoin, primidone, theophylline, rifampicin, cisplatin or doxorubicin. Although the data are partly contradictory, possibly clonazepam, or valproic acid, oxcarbazepine. Mefloquine may antagonise the anti-epileptic effect of carbamazepine.

Valproic acid, valpromide and primidone have been reported to increase the degree of conversion of carbamazepine to the active metabolite carbamazepine-10, 11-epoxide.

Isotretinoin has been reported to alter unpredictably the bioavailability and/or clearance of carbamazepine and carbamazepine-10, 11-epoxide; carbamazepine plasma concentrations should be monitored.

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

Felbamat has been reported to lower the plasma concentration of carbamazepine and to enhance the plasma level of the active metabolite carbamazepine 10, 11-epoxide.

Effects of carbamazepine on plasma levels of concomitant agents:

Induction of hepatic enzymes in response to carbamazepine may increase the metabolism and reduce the effectiveness of other drugs that are metabolised in the liver. These include: levothyroxine, clobazam, clonazepam, ethosuximide, primidone, valproic acid, alprazolam, corticosteroids, cyclosporin, digoxin, doxycycline, dihydropyridine calcium-channel blockers (e.g. felodipine, nifedipine, nilvadipine), protease-inhibitors (e.g. indinavir, saquinavir, ritonavir,) haloperidol, imipramine, methadone, tramadol, hormonal contraceptive agents, (alternate contraceptive methods should be considered see section 4.4) gestrinone, tibolone, toremifene, theophylline, warfarin, lamotrigine, tiagabine, topiramate, tricyclic antidepressants: clozapine, oxcarbazepine, olanzapine, itraconazole, voriconazole, risperidone, nefazodone and felbamat.

The concurrent administration of carbamazepine has been reported to both raise and lower phenytoin levels and in rare instances mephenytoin plasma levels have been reported to increase.

Carbamazepine may reduce the effect of anticoagulant drugs.

Combinations to be taken into consideration:

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

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

Neurotoxic reactions have occurred when carbamazepine has been used together with lithium in spite of lithium plasma concentrations being within the therapeutic range.

Combined use of carbamazepine with metoclopramide or major tranquilliser e.g. haloperidol and thioridazine may result in an increase in neurological side-effects.

Because carbamazepine is structurally related to tricyclic anti-depressants, the use of carbamazepine suspension is not recommended in combination with monoamine oxidase inhibitors (MAOIs). Before administering carbamazepine suspension, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Use of carbamazepine with some diuretics such as frusemide, may lead to symptomatic hyponatraemia.

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

Carbamazepine, like any other psychoactive drug, may reduce the patient’s tolerance to alcohol. It is therefore advised that patients refrain from alcohol during treatment. Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications, such as phenobarbitone.

Literature research provides an indication of a higher risk of developing a Steven-Johnson’s Syndrome when carbamazepine is administered together with neuroleptics.

4.6 Fertility, pregnancy and lactation

Please refer to section 5.3 (Preclinical safety data) for detailed reproductive toxicity information.

In women of childbearing age, carbamazepine should be administered as monotherapy whenever possible 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 drug as monotherapy.

If pregnancy occurs in a woman receiving carbamazepine or if the use of carbamazepine is considered necessary during pregnancy, the need to control seizures in the mother should be carefully weighed against the possible risk to the foetus. This is particularly important during the first three months of pregnancy. Minimum effective doses should be given and monitoring of plasma levels is recommended.

In no case should treatment be stopped without the advice of a physician, because epileptic seizures may harm the unborn child.

Cases of developmental disorders and malformations, including spina bifida, other congenital anomalies e.g. craniofacial defects, cardiovascular malformations and anomalies involving various body systems, have been reported in association with carbamazepine. However, offspring of mothers with untreated epilepsy are known to be prone to an increased incidence of development disorders and conclusive evidence that carbamazepine given alone increases the risk further is not available. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

Anti-epileptic drugs may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy.

Bleeding disorders in the newborn caused by anti-epileptic agents have been reported. As a precaution, Vitamin K₁ should be administered as a preventive measure in the last weeks of pregnancy and to the newborn.

Breast-feeding

Carbamazepine and its main metabolite, carbamazepine epoxide, are both present in breast milk in concentrations of about 25-60% of the total plasma concentration. Breast feeding is not contraindicated, because the amount of drug ingested by the breast-fed infant is too small (maximum 10%) to cause adverse pharmacological effects. However, as with all drugs, the benefits of breastfeeding should be weighed against the remote possibility of an adverse effect occurring in the infant.

Mothers taking carbamazepine may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).

4.7 Effects on ability to drive and use machines

The patients reactions may be impaired, especially in the early stages of treatment. Patients should be warned of the possible hazards when driving or operating machinery.

4.8 Undesirable effects

Side effects may occur at the start of treatment or if the initial dose is too high. These effects are generally transient and include dizziness, fatigue, drowsiness, unsteadiness, nausea and vomiting. The most severe side effects have been observed in the haemopoietic system, the skin and the cardiovascular system.

The development of CNS undesirable effects in patients receiving maintenance treatment may be a manifestation of relative overdose 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.

Literature research indicates that carbamazepine may lead to neuromalignant syndrome, especially in conjunction with neuroleptics. Also, that carbamazepine may lower the plasma levels of folic acid and vitamin B12, and may increase the plasma level of homocysteine. It is possible that carbamazepine may lead to exacerbation of multiple sclerosis.

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).

Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

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.

Frequencies in this table are defined using the following convention: very common (>1/10) common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Central nervous system:

Neurological:

Very Common: dizziness, ataxia, drowsiness, fatigue.

Common: headache, diplopia, accommodation disorders (blurred vision).

Uncommon', abnormal involuntary movements (tremor, asterixis, dystonia, tics), nystagmus.

Rare: choreoathetotic disorders, orofacial dyskinesia, oculomotor disturbances, speech disorders (eg dysarthria or slurred speech), peripheral neuritis, paraesthesiae, muscle weakness, and paretic symptoms). Cases of neuroleptic malignant syndrome have been reported. The causative role of carbamazepine in inducing or contributing to the development of a neuromalignant syndrome especially in conjunction with neuroleptics is unclear.

Psychiatric:

Rare: hallucinations (visual or acoustic), depression, loss of appetite, restlessness, aggressive behaviour, agitation, confusion.

Very rare: activation of psychosis.

Skin and appendages:

Very Common: allergic skin reactions, urticaria, which may be severe. Uncommon: exfoliative dermatitis and erythroderma.

Rare: systemic lupus erythematosus-like syndrome, pruritus.

Very Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, sweating, hair loss, hirsutism.

Blood:

Very common: leucopenia.

Common: eosinophilia, thrombocytopenia.

Rare: leucocytosis, lymphadenopathy, folic acid deficiency.

Very rare: agranulocytosis, aplastic anaemia, pure red cell aplasia, megaloblastic anaemia, acute intermittent porphyria, reticulocytosis, and possibly haemolytic anaemia.

Liver:

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

Common: elevated alkaline phosphatase.

Uncommon: elevated transaminases.

Rare: jaundice, hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type.

Very rare: granulomatous hepatitis, hepatic failure.

Gastro-intestinal tract:

Very common: nausea, vomiting.

Common: dryness of the mouth, with suppositories occasional rectal irritation may occur.

Uncommon: diarrhoea or constipation.

Rare: abdominal pain.

Very rare: colitis, glossitis, stomatitis, pancreatitis.

Hypersensitivity reactions:

Rare: a delayed multi-organ hypersensitivity disorder (of serum sickness type) with fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (eg lungs, kidneys, pancreas, myocardium, colon).

Very rare: aseptic meningitis, with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioedema. Treatment must be discontinued immediately if such hypersensitivity reactions occur.

Cardiovascular system:

Rare: disturbances of cardiac conduction.

Very rare: bradycardia, arrhythmias, AV-block with syncope, collapse, congestive heart failure, hypertension or hypotension, aggravation of coronary artery disease, thrombophlebitis, thrombo-embolism.

Endocrine system and metabolism:

Common: Hyponatraemia, fluid retention, oedema, weight gain, and reduced plasma osmolarity due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion, neurological abnormalities.

Very rare:

-    increase in prolactin with or without clinical symptoms such as gynaecomastia or galactorrhoea. Impaired male fertility and/or abnormal spermatogenesis.

-    abnormal thyroid function tests: decreased L-thyroxine (FT₄, T₄, T₃) and increased TSH, usually without clinical manifestations.

-    disturbances of bone metabolism (decrease in plasma calcium and 25-OH-cholecalciferol), leading to osteomalacia.

-    elevated levels of cholesterol, including HDL cholesterol, and trigylcerides.

Urogenital system:

Very rare: interstitial nephritis and renal failure. Renal dysfunction including albuminuria, haematuria, oliguria and elevated BUN/azotaemia, urinary frequency, urinary retention, sexual disturbances/impotence.

Sense organs:

Very rare: taste disturbances; lens opacities, conjunctivitis, tinnitus, hyperacusis, hypoacusis, changes in pitch perception.

Musculoskeletal system:

Very rare: arthralgia, muscle pain or cramp.

Respiratory tract:

Very rare: pulmonary hypersensitivity characterised by fever, dyspnoea, pneumonitis or pneumonia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs and symptoms

There is no specific antidote for carbamazepine overdose. The presenting signs and symptoms of overdosage involve the central nervous, cardiovascular or respiratory systems.

Central nervous system: CNS depression, disorientation, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia.

Respiratory system: Respiratory depression, pulmonary oedema. Cardiovascular system: Tachycardia, changes in blood pressure (hypotension and at times hypertension), cardiac arrhythmias, conduction disturbance with widening of QRS complex; syncope.

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

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

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

Treatment

Management of symptoms due to overdosage will vary according to the patient’s condition. This includes possible admission to hospital. Measurement of the plasma levels to confirm carbamazepine poisoning and to ascertain the size of the overdose. Evacuation of the stomach, gastric lavage, and administration of activated charcoal. 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 iv. 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 iv. These measures may be useful in preventing brain damage.

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

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

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptic, ATC code: N03A FO1

Carbamazepine is a dibenzazepine derivative with anti-epileptic, neurotropic and psychotropic properties.

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 anti-epileptic action. Work in animals have shown that is 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

5.2    Pharmacokinetic properties Absorption

Carbamazepine 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 has been shown to lie between 85-100% and is unaffected by food. Carbamazepine is 70 - 80% bound to plasma.

Distribution

The concentration of unchanged substance in the CSF and 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 crosses the placental barrier. Apparent volume of distribution: 0.8-1.5 L/kg.

Metabolism

Carbamazepine is extensively metabolised in the liver, mainly by oxidative pathways. The only pharmacologically active metabolite is carbamazepine epoxide. This may constitute up to 30% of the circulating active material as carbamazepine. The inactive 10,11-diol represents the final stage of carbamazepine biotransformation.

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.

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.

Patients with renal impairment

Carbamazepine should be used with caution in patients with renal impairment. Patients with hepatic impairment

In advanced hepatic disease, carbamazepine metabolism may be impaired. Additional data of clinical significance

The pharmacokinetics of carbamazepine are unaltered in the elderly but its metabolism may be affected by hepatic dysfunction. In children, the relatively high rate of metabolism of the drug may require a higher dose (in mg/Kg b.w.) of carbamazepine to maintain therapeutic concentrations.

5.3 Preclinical safety data

In vitro and in vivo mutagenicity tests with carbamazepine did not give an indication of a mutagenic potential. A carcinogenicity study over two years in rats indicated an increased incidence of hepatomas in rats. However, there is no evidence that this observation is of importance for the therapeutic use of carbamazepine in humans.

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

6.    PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sucralose Poloxamer 188,

Xanthan gum,

Potassium sorbate,

Propylene glycol,

Citric acid monohydrate,

Sunset yellow (E110),

Sorbitol,

Flavour Orange natural and artificial Purified water.

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life 2 years.

6.4    Special precautions for storage

Do not store above 25°C.

Keep the container tightly closed.

6.5    Nature and content of container

Amber PET/Glass bottles using a polypropylene child resistant plastic cap. Pack size: 300ml & 500 ml.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Taro Pharmaceuticals (UK) Limited,

4100 Park Approach

Thorpe Park

Leeds

LS15 8GB

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 15842/0032

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/03/2008

10    DATE OF REVISION OF THE TEXT

03/07/2015