1. Name Of The Medicinal Product
Tegretol® 125mg Suppositories
Tegretol® 250mg Suppositories
2. Qualitative And Quantitative Composition
The active ingredient is 5H-dibenzo[b,f]azepine-5-carboxamide (carbamazepine).
Each suppository contains 125 mg or 250 mg carbamazepine Ph.Eur.
3. Pharmaceutical Form
White to practically white, torpedo-shaped suppositories.
4. Clinical Particulars
4.1 Therapeutic Indications
Epilepsy - generalised tonic-clonic and partial seizures.
Note: Tegretol is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences.
No clinical data are available on the use of Tegretol Suppositories in indications other than epilepsy.
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 section 4.4).
Epilepsy:
Adults, Elderly and Children: 125 mg and 250 mg suppositories are available for short-term use as replacement therapy (maximum period recommended: 7 days) in patients for whom oral treatment is temporarily not possible, for example in post-operative or unconscious subjects.
When switching from oral formulations to suppositories the dosage should be increased by approximately 25% (the 125 and 250mg suppositories correspond to 100 and 200mg tablets respectively). The final dose adjustment should always depend on the clinical response in the individual patient (plasma level monitoring is recommended). Tegretol Suppositories have been shown to provide plasma levels which are well within the therapeutic range (see Pharmacokinetics).
Where Suppositories are used the maximum daily dose is limited to 1000mg (250mg qid at 6 hour intervals, see Pharmacokinetics).
Due to the potential for drug interactions, the dosage of Tegretol should be selected with caution in elderly patients.
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).
Route of administration: Rectal.
4.3 Contraindications
Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.
Patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
The use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5 Interaction with other medicinal products and other forms of interaction).
4.4 Special Warnings And Precautions For Use
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 (see Section 4.8 Undesirable Effects). However, treatment with Tegretol should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Tegretol should also be discontinued if any evidence of significant bone marrow depression appears.
Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.
Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.
Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Tegretol suspended pending the outcome of the evaluation.
Suicidal ideation and behaviour have been reported in patients treated with 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. 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.
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. 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.
It is not definitely known whether all individuals of south east-Asian ancestry are at risk due to lack of data.
The allele HLA-B*1502 has been shown not to be associated to SJS in the Caucasian population.
Mild skin reactions e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).
Tegretol may trigger hypersensitivity reactions, including multi-organ hypersensitivity reactions, 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 Undesirable Effects).
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be withdrawn immediately.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).
Cross-hypersensitivity can occur between carbamazepine and 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.
Abrupt withdrawal of Tegretol may precipitate seizures:
If treatment with Tegretol 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.).
Tegretol and oestrogen and/or progestogen preparations
Due to hepatic enzyme induction, Tegretol 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 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.
Although correlations between dosages and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see 4.5 Interaction with other Medicaments and other forms of Interaction).
Precautions
Tegretol should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.
Baseline and periodic complete urinalysis and BUN determinations are recommended.
Tegretol has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be warned and advised regarding possible hazards.
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of inhibitors of CYP 3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration of CYP 3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and therapeutic effect.
Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by induction of their metabolism.
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.
Agents that may raise carbamazepine plasma levels:
Isoniazid, verapamil, diltiazem, ritonavir, dextropropoxyphene, fluoxetine, fluvoxamine, paroxetine, possibly cimetidine, omeprazole, acetazolamide, danazol, nicotinamide (in adults, only in high dosage), trazodone, vigabatrin, macrolide antibiotics (e.g. erythromycin, clarithromycin), azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole), loratadine, olanzapine, grapefruit juice, protease inhibitors for HIV treatment (e.g. ritonavir).
Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored.
Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels:
Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
Agents that may decrease carbamazepine plasma levels:
Phenobarbitone, phenytoin and fosphenytoin, primidone or theophylline, aminophylline, rifampicin, cisplatin or doxorubicin and, although the data are partly contradictory, possibly also clonazepam or oxcarbazepine. Mefloquine may antagonise the antiepileptic effect of Tegretol. The dose of Tegretol may consequently have to be adjusted.
Isotretinoin has been reported to alter 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).
Effect of Tegretol on plasma levels of concomitant agents:
Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirement: levothyroxine, clobazam, clonazepam, ethosuximide, primidone, valproic acid, alprazolam, corticosteroids, (e.g. prednisolone, dexamethasone); ciclosporin, digoxin, doxycycline; dihydropyridine derivatives, e.g. felodipine and isradipine; indinavir, saquinavir, ritonavir, haloperidol, imipramine, buprenorphine, methadone, paracetamol, tramadol, products containing oestrogens and/or progestogens (alternative contraceptive methods should be considered) see Section 4.4 “Special Warnings and Precautions for Use”, gestrinone, tibolone, toremifene, theophylline, oral anticoagulants (warfarin and acenocoumarol), lamotrigine, tiagabine, topiramate, bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine), clozapine, oxcarbazapine, olanzapine, quetiapine, itraconazole, imatinib and risperidone.
Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine, and there have been rare reports of an increase in plasma mephenytoin.
Combinations that require specific consideration:
Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Combined use of carbamazepine with metoclopramide or major tranquillisers, e.g. haloperidol, thioridazine, may also result in an increase in neurological side-effects.
Because it (carbamazepine) is structurally related to tricyclic anti-depressants, the use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs); before administering Tegretol, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (e.g. pancuronium). Their dosage should be raised and patients monitored closely for a more rapid recovery from neuromuscular blockade than expected.
Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.
4.6 Pregnancy And Lactation
Pregnancy
In animals (mice, rats and rabbits) oral administration of carbamazepine during organogenesis led to increased embryo mortality at a daily doses which caused maternal toxicity (above 200mg/kg b.w. daily i.e. 20 times the usual human dosage). In the rat there was also some evidence of abortion at 300mg/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 b.w. daily orally) caused defects (mainly dilatation of cerebral ventricles in 4.7% of exposed foetuses as compared with 1.3% in controls).
Pregnant women with epilepsy should be treated with special care.
In women of childbearing age Tegretol should, wherever possible, be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy.
If women receiving Tegretol become pregnant or plan to become pregnant, or if the problem of initiating treatment with Tegretol arises during pregnancy, the drug's potential benefits must be carefully weighed against its possible hazards, particularly in the first three months of pregnancy. Minimum effective doses should be given and monitoring of plasma levels is recommended.
During pregnancy, an effective antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.
Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental disorders, including malformations. The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk has been reported, although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. However, there are reports on developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with Tegretol. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy.
In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1, be given to the mother during the last weeks of pregnancy as well as to the neonate.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Tegretol use. These reactions may represent a neonatal withdrawal syndrome.
Use during lactation:
Carbamazepine passes into the breast milk (about 25-60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Tegretol may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).
Fertility:
There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.
4.7 Effects On Ability To Drive And Use Machines
The patient's ability to react may be impaired by dizziness and drowsiness caused by Tegretol, especially at the start of treatment or in connection with dose adjustments; patients should therefore exercise due caution when driving a vehicle or operating machinery.
4.8 Undesirable Effects
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.
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (> 1/10) common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
Blood and lymphatic system disorders
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Very common:
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Leucopenia
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Common
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Thrombocytopenia, eosinophilia.
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Rare
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Leucocytosis, lymphadenopathy, folic acid deficiency.
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Very rare
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Agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda, reticulocytosis, and possibly haemolytic anaemia.
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Immune system disorders
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Rare:
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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).
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Very rare:
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Aseptic meningitis, with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic oedema.
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Endocrine disorders
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Common:
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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.
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Very rare:
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Blood prolactin increased with or without clinical symptoms such as galactorrhoea, gynaecomastia, abnormal thyroid function tests; decreased l-thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol), leading to osteomalacia /osteoporosis, increased blood cholesterol, including HDL cholesterol and triglycerides.
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Psychiatric disorders
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Rare:
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Hallucinations (visual or auditory), depression, anorexia, restlessness, aggression, agitation, confusional state.
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Very rare:
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Activation of psychosis.
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Nervous system disorders
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Very common:
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Dizziness, ataxia, drowsiness, fatigue.
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Common:
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Headache, diplopia, accommodation disorders (e.g. blurred vision).
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Uncommon:
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Abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus.
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Rare:
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Orofacial dyskinesia, eye movement disturbances, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, muscle weakness, and paresis
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Very rare:
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Taste disturbances, neuroleptic malignant syndrome
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Eye disorders
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Very rare:
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lenticular opacities, conjunctivitis, intraocular pressure increased
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Ear and labyrinth disorders
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Very rare:
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hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.
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Cardiac disorders
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Rare:
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Cardiac conduction disorders, hypertension or hypotension.
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Very rare:
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Bradycardia, arrhythmia, atrioventricular block with syncope, circulatory collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thrombo-embolism (e.g. pulmonary embolism).
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Respiratory, thoracic and mediastinal disorders
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Very rare:
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Pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia.
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Gastro-intestinal disorders
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Very common:
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Nausea, vomiting.
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Common:
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Dry mouth, with suppositories rectal irritation may occur.
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Uncommon:
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Diarrhoea, constipation.
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Rare:
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Abdominal pain
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Very rare:
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Glossitis, stomatitis, pancreatitis.
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Hepatobiliary disorders
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Very common:
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Increased-gamma-GT (due to hepatic enzyme induction), usually not clinically relevant.
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Common:
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Increased blood alkaline phosphatase.
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Uncommon:
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Increased transaminases.
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Rare:
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Hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice.
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Very rare:
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Granulomatous hepatitis. Hepatic failure.
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Skin and subcutaneous tissue disorders:
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Very common:
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Dermatitis allergic, urticaria, which may be severe.
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Uncommon:
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Exfoliative dermatitis and erythroderma.
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Rare:
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Systemic lupus erythematosus, pruritus.
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Very rare:
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Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss, hirsutism.
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Musculoskeletal, connective tissue and bone disorders
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Very rare:
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Arthralgia, muscle pain, muscle spasms.
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Renal and urinary disorders
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Very rare:
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Interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/ azotaemia), urinary frequency, urinary retention, sexual disturbances/impotence.
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Reproductive System
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Very rare:
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Spermatogenesis abnormal (with decreased sperm count and/or motility).
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Investigations
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Very rare:
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Hypogammaglobulinaemia
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* In some Asian countries also reported as rare. See also section 4.4 Special warnings and precautions for use.
4.9 Overdose
Signs and symptoms
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, 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.
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:
Hypotension: Administer dopamine or dobutamine i.v.
Disturbances of cardiac rhythm: To be handled on an individual basis.
Convulsions: Administer a benzodiazepine (e.g. diazepam) or another antiepileptic, e.g. phenobarbitone (with caution because of increased respiratory depression) or paraldehyde.
Hyponatraemia (water intoxication): Fluid restriction and slow and careful NaCl 0.9% infusion i.v. These measures may be useful in preventing brain damage.
Charcoal haemoperfusion has been recommended. Forced diuresis, haemodialysis, and peritoneal dialysis have been reported to be not effective.
Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent; (ATC Code: N03 AF01). Dibenzazepine derivative.
As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.
The mechanism of action of carbamazepine, the active substance of Tegretol, has only been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of 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.
5.2 Pharmacokinetic Properties
Absorption
As measured by AUC calculations the total bioavailability of carbamazepine from Tegretol suppositories is approximately 25% less than from oral formulations. For doses up to 300mg approximately 75% of the total amount absorbed reaches the general circulation within 6 hours of application. For these reasons the maximum recommended daily dose is limited to 250mg qid (1000mg per day), the equivalent to 800mg per day orally. Clinical trials have shown that when Tegretol suppositories are substituted for oral dosage forms plasma levels within the range 5-8µg/ml (19-34µmol/l) are reached. It should be possible, therefore, to maintain therapeutically effective plasma levels in most patients.
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 abo
