Tegretol retard

Overdose

Signs and symptoms

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

Respiratory system: Respiratory depression, pulmonary oedema.

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

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

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

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

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

Treatment

There is no specific antidote.

Management should initially be guided by the patient's clinical condition; admission to hospital. Measurement of the plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose.

Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse during recovery from intoxication. Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.

Special recommendations:

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

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

Shelf life

24 months

Incompatibilities

None known

List of excipients

Each 200mg and 400mg tablet contains colloidal silicon dioxide, ethylcellulose aqueous dispersion (30%), microcrystalline cellulose, ethyl acrylate/methyl methacrylate copolymer, magnesium stearate, croscarmellose sodium type A, talc, hydroxypropylmethylcellulose, glyceryl polyoxyethylene glycol stearate, red iron oxide (E.172), yellow iron oxide (E.172) and titanium dioxide (E.171).

Pharmaceutical form

Prolonged Release Tablet.

The 200mg tablets are beige-orange, oval, slightly biconvex, coated tablets with a score on each side. One side bears the imprint “H/C”, the other “C/G”.

The 400mg tablets are brownish-orange, oval, slightly biconvex coated tablets with a score on each side. One side bears the imprint “ENE/ENE”, the other “C/G”.

Undesirable effects

Summary of the safety profile

Particularly at the start of treatment with Tegretol, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions.

The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and divide the daily dosage into smaller (i.e. 3-4) fractional doses.

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

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

Blood and lymphatic system disorders

Very common:

leucopenia.

Common:

thrombocytopenia, eosinophilia.

Rare:

leucocytosis, lymphadenopathy.

Very rare:

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

Not known:

bone marrow depression.

Immune system disorders

Rare:

a delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon).

Very rare:

anaphylactic reaction, oedema angioedema, hypogammaglobulinaemia.

Not known**:

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Infections and infestations

Not known**:

reactivation of Human herpesvirus 6 infection.

Endocrine disorders

Common:

Oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.

Very rare:

galactorrhoea, gynaecomastia,

Metabolism and nutrition disorders

Rare:

folate deficiency, decreased appetite.

Very rare:

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

Psychiatric disorders

Rare:

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

Very rare:

activation of psychosis.

Nervous system disorders

Very common:

ataxia, dizziness, somnolence.

Common:

diplopia, headache.

Uncommon:

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

Rare:

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

Very rare:

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

Not known**:

sedation, memory impairment

Eye disorders

Common:

accommodation disorders (e.g. blurred vision)

Very rare:

lenticular opacities, conjunctivitis.

Ear and labyrinth disorders

Very rare:

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

Cardiac disorders

Rare:

cardiac conduction disorders.

Very rare:

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

Vascular disorders

Rare:

hypertension or hypotension.

Very Rare:

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

Respiratory, thoracic and mediastinal disorders

Very rare:

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

Gastro-intestinal disorders

Very common:

vomiting, nausea.

Common:

dry mouth, with suppositories rectal irritation may occur.

Uncommon:

diarrhoea, constipation.

Rare:

abdominal pain.

Very rare:

Pancreatitis, glossitis, stomatitis,.

Not known**:

colitis.

Hepatobiliary disorders

Rare:

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

Very rare:

hepatic failure, granulomatous liver disease.

Skin and subcutaneous tissue disorders:

Very common:

urticaria, which may be severe dermatitus allergic,

Uncommon:

dermatitis exfoliative.

Rare:

systemic lupus erythematosus, pruritus.

Very rare:

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

Not known**:

Acute Generalized Exanthematous Pustulosis (AGEP)**, lichenoid keratosis, onychomadesis.

Musculoskeletal, connective tissue and bone disorders

Rare:

muscular weakness.

Very rare:

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

Not known**:

fracture.

Renal and urinary disorders

Very rare:

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

Reproductive System

Very rare:

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

General disorders and administration site conditions

Very common:

fatigue.

Investigations

Very common:

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

Common:

blood alkaline phosphatase increased.

Uncommon:

transaminases increased.

Very rare:

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

Not known**:

bone density decreased.

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

The following adverse drug reactions have been derived from post-marketing experience with Tegretol via spontaneous case reports and literature cases.4 for further information).

Reporting of suspected adverse reactions

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

Tegretol Retard price

We have no data on the cost of the drug.
However, we will provide data for each active ingredient

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, local tolerance, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of carbamazepine in humans.

Carcinogenicity

In rats treated with carbamazepine for two years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence to date that these observations are of any relevance to the therapeutic use of carbamazepine in humans.

Reproductive toxicity

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

Fertility

In chronic toxicity studies dose related testicular atrophy and aspermatogenesis occurred in rats receiving carbamazepine. The safety margin for this effect is not known.

Therapeutic indications

Epilepsy - generalised tonic-clonic and partial seizures. Tegretol Prolonged Release is indicated in newly diagnosed patients with epilepsy and in those patients who are uncontrolled or unable to tolerate their current anti-convulsant 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 psychoses in patients unresponsive to lithium therapy.

Pharmacodynamic properties

Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent; (ATC Code: N03 AF01). Dibenzazepine derivative.

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.

The mechanism of action of carbamazepine, the active substance of Tegretol, has only been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarised neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.

Pharmacokinetic properties

Absorption

Carbamazepine is almost completely absorbed but the rate of absorption from the tablets is slow and may vary amongst the various formulations and between patients. Peak concentrations of active substance in the plasma are attained within 24 hours of administration of single dose of Tegretol Prolonged Release tablets.

The prolonged release formulation shows about 15% lower bioavailability than standard preparations due mainly to the considerable reduction in peak plasma levels occasioned by prolonged release of the same dosage of carbamazepine. Plasma concentrations show less fluctuation but auto-induction of carbamazepine occurs as with standard carbamazepine preparations.

The bioavailability of Tegretol in various oral formulations has been shown to lie between 85-100%.

Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tegretol.

Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pre-treatment status, dosage, and duration of treatment.

Different preparations of carbamazepine may vary in bioavailability; to avoid reduced effect or risk of breakthrough seizures or excessive side effects, it may be prudent to avoid changing the formulation.

Distribution

Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.

Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

Biotransformation

Carbamazepine is metabolised in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-transdiol derivative and its glucuronide as the main metabolites.

Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of carbamazepine 10, 11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. 9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway.

Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Elimination

The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other enzyme-inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9-10 hours have been found.

The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

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

Characteristics in patients

The steady-state plasma concentrations of carbamazepine considered as “therapeutic range” vary considerably inter-individually; for the majority of patients a range between 4-12µg/ml corresponding to 17-50µmol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults to maintain therapeutic concentrations.

There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.

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

Date of revision of the text

04 January 2018

Name of the medicinal product

Tegretol® Prolonged Release 200mg and 400mg Tablets

Marketing authorisation holder

Novartis Pharmaceuticals UK Limited

Trading as Geigy Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Nature and contents of container

Tegretol Prolonged Release Tablets 200mg and 400mg come in PVC/PE/PVdC blister packs of 56 tablets.

Marketing authorisation number(s)

Tegretol Prolonged Release 200mg Tablets:

PL 00101/0457

Tegretol Prolonged Release 400mg Tablets:

PL 00101/0458

Qualitative and quantitative composition

The active ingredient is 5H-dibenzo[b,f]azepine-5-carboxamide.

Each coated tablet contains 200mg or 400mg carbamazepine Ph.Eur.

Special warnings and precautions for use

Warnings

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

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

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

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. However, treatment with Tegretol should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Tegretol should also be discontinued if any evidence of significant bone marrow depression appears.

Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.

Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.

Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Tegretol suspended pending the outcome of the evaluation.

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

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

Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome) and Stevens Johnson syndrome (SJS) have been reported very rarely with Tegretol. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tegretol. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell's syndrome/TEN) appear, Tegretol should be withdrawn at once and alternative therapy should be considered.

Cutaneous reactions

Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.

There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.

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

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine. 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 in people of European descent and the Japanese.

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

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.

There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.

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

Other dermatologic reactions

Mild skin reactions e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).

Hypersensitivity

Tegretol may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations.

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be withdrawn immediately.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

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

An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.

Dose reduction and withdrawal effects

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

Endocrinological effects

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

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

Monitoring of plasma levels

Although correlations between dosages and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

Epilepsy:

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

Adults: It is advised that with all formulations of Tegretol, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.

Elderly: Due to the potential for drug interactions, the dosage of Tegretol should be selected with caution in elderly patients.

Children and adolescents: It is advised that with all formulations of Tegretol, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.

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

Age

up to 5 years:

5-10 years:

10-15 years:

>15 years of age:

Tegretol Prolonged Release Tablets are not recommended

400-600mg daily

600-1000mg

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

Maximum recommended dose

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

6-15 years of age: 1000mg/day

>15 years of age: 1200mg/day.

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

When Tegretol is added to existing antiepileptic therapy, this should be done gradually while maintaining or, if necessary, adapting the dosage of the other antiepileptic(s) (see 4.5 Interaction with other Medicaments and other forms of Interaction).

Trigeminal neuralgia:

Slowly raise the initial dosage of 200-400mg daily until freedom from pain is achieved (normally at 200mg 3-4 times daily). In the majority of patients a dosage of 200mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, doses of 1600mg Tegretol daily may be needed. However, once the pain is in remission, the dosage should be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.

Elderly:

Dosage in Trigeminal neuralgia

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

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

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

Initial starting dose of 400mg daily, in divided doses, increasing gradually until symptoms are controlled or a total of 1600mg given in divided doses is reached. The usual dosage range is 400-600mg daily, given in divided doses.

Special populations

Renal impairment / Hepatic impairment

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

Special precautions for disposal and other handling

None

Date of first authorisation/renewal of the authorisation

4 July 1997 / 5 December 2008