Tegretol

/ Novartis

The tablets and the oral suspension (to be shaken before use) may be taken during, after, or between meals. Tablets should be taken with a little liquid. The CR tablets (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a little liquid. The oral suspension (one measure = 5 mL = 100 mg; half a measure = 2.5 mL = 50 mg) is particularly suitable for patients who have difficulty in swallowing tablets or need initial careful adjustment of the dosage. As a result of slow, controlled release of the active substance from the CR tablets, these are designed to be taken in a twice-daily dosage regimen. Since a given dose of Tegretol oral suspension will produce higher peak levels than the same dose in tablet form, it is advisable to start with low doses and increase them slowly so as to avoid adverse reactions. Switching patients from Tegretol tablets to oral suspension: this should be done by giving the same number of mg per day in smaller, more frequent doses (e.g. oral suspension three times a day (t.i.d.) instead of tablets twice a day (b.i.d)). Switching patients from conventional tablets to CR tablets: clinical experience shows that in some patients the dosage in the form of CR tablets may need to be increased. Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tegretol should be selected with caution in elderly patients.
Epilepsy: When possible, Tegretol should be prescribed as monotherapy. Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained. Determination of plasma levels may help in establishing the optimum dosage. 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).
Adults Oral forms: Initially, 100 to 200 mg once or twice daily; the dosage should be slowly raised until – generally at 400 mg 2 to 3 times daily – an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be appropriate.
Children Oral forms: For children aged 4 years or less, a starting dose of 20 to 60 mg/day, increasing by 20 to 60 mg every second day, is recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increasing at weekly intervals by 100 mg. Maintenance dosage: 10 to 20 mg/kg body weight daily in divided doses, e.g.
Up to 1 year of age 100 to 200 mg daily (= 5 to 10mL = 1-2 measures of oral suspension)
1 to 5 years of age 200 to 400 mg daily (= 10 to 20 mL = 2× 1-2 measures of oral suspension)
6 to 10 years of age 400 to 600 mg daily (= 20 to 30 mL = 2-3× 2 measures of oral suspension)
11 to 15 years of age 600 to 1000 mg daily (= 30 to 50 mL = 3× 2-3 measures of oral suspension (plus an extra measure of 5 mL in case of administration of 1000 mg).
Renal impairment / Hepatic impairment: No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
Acute mania and maintenance treatment of bipolar affective disorders: Dosage range: about 400 to 1600 mg daily, the usual dosage being 400 to 600 mg daily given in 2 to 3 divided doses. In acute mania, the dosage should be increased rather quickly, whereas small dosage increments are recommended for maintenance therapy of bipolar disorders in order to ensure optimal tolerability.
Trigeminal neuralgia: The initial dosage of 200 to 400 mg should be slowly raised daily until freedom from pain is achieved (normally at 200 mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. In elderly patients, an initial dose of 100 mg twice daily is recommended.
Diabetes insipidus centralis: Average dosage for adults: 200 mg 2 to 3 times daily. In children the dosage should be reduced proportionally to the child’s age and body weight.
Maximum recommended dose:
Up to 6 years of age: 35 mg/kg/day
6-15 years of age: 1000 mg/day
>15 years of age: 1200 mg/day.

Epilepsy, trigeminal neuralgia, diabetes insipidous, mania, prophylaxis of manic-depression.

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation. Patients with atrioventricular block. Patients with a history of bone-marrow depression. Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). The use of Tegretol is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs).

Tegretol should be given only under medical supervision. 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.
Haematological effects: 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. Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tegretol. However, in the majority of cases these effects prove transient and are unlikely to signal the onset of either aplastic anaemia or agranulocytosis. Nonetheless, complete pretreatment blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained at baseline, and periodically thereafter. 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. Tegretol should be discontinued if any evidence of significant bone-marrow depression appears. Patients should be made aware of early toxic signs and symptoms 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.
Serious dermatologic reactions: Serious dermatologic 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.
For full details see prescribing information.

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), and allergic skin reactions. The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor plasma levels.
For full details see prescribing information.

The use of Tegretol is contraindicated 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.
Since raised plasma carbamazepine levels may result in adverse reactions, the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances: dextropropoxyphene, ibuprofen, danazol, macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacine), possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine, stiripentol, vigabatrin, azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole), Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole. loratadine, terfenadine, olanzapine, isoniazid, protease inhibitors for HIV treatment (e.g. ritonavir), acetazolamide, diltiazem, verapamil, possibly cimetidine, omeprazole, oxybutynin, dantrolene, ticlopidine, grapefruit juice, nicotinamide (only in high dosage).
Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions, the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances: Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
The dose of Tegretol may have to be adjusted when used concomitantly with the substances: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam, cisplatin or doxorubicin, rifampicin, theophylline, aminophylline, mefloquine may antagonise the anticonvulsant effect of carbamazepine. isotretinoin, herbal preparations containing St John’s wort (Hypericum perforatum).
For full details see prescribing information.

Pregnancy: Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations.Although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking, 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 the use of Tegretol. Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth was 3.0% (95% CI 2.1 to 4.2%) among mothers exposed to carbamazepine monotherapy in the first trimester and 1.1% (95% CI 0.35 to 2.5%) among pregnant women not taking any antiepileptic drug (relative risk 2.7, 95% CI 1.1 to 7.0). Taking these data into consideration:
– Pregnant women with epilepsy should be treated with special care.
– If women receiving 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 3 months of pregnancy.
– 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.
– Minimum effective doses should be given and monitoring of plasma levels is recommended.
– Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
– During pregnancy, an effective antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.
Monitoring and prevention: Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency. 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 the neonate: 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 anticonvulsant 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.
Lactation: Carbamazepine passes into the breast milk (about 25 to 60% of 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).
For full details see prescribing information.

Signs and symptoms: The presenting signs and symptoms of overdose usually involve the central nervous, cardiovascular, and respiratory systems.
Central nervous system: CNS depression; disorientation, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: Respiratory depression, pulmonary oedema.
Cardiovascular system: Tachycardia, hypotension, at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.
Gastrointestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.
Renal function:  Retention of urine, oliguria or anuria; fluid retention, water intoxication due to an ADH-like effect of carbamazepine.
Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.
Management: 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 hemoperfusion 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.

Storage: Tablets: store below 25°C and protect from moisture. CR tablets: store below 25°C and protect from moisture. Syrup: store below 30°C and protect from light. After first opening of the bottle, store below 25°C and use within 3 months.