Epitol 100 mg, 200 mg, 200 mg CR and 400 mg CR Tablets

COMPOSITION

  • Each Epitol 100 mg chewable tablet contains: 100 mg carbamazepine.
  • Each Epitol 200 mg tablet contains: 200 mg carbamazepine.
  • Each Epitol 200 mg CR tablet contains: 200 mg carbamazepine (controlled-release).
  • Each Epitol 400 mg CR tablet contains: 400 mg carbamazepine (controlled-release).

INDICATIONS

  • Epitol is indicated in epilepsy, complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization, generalized tonic clonic seizures, and mixed form of seizures.
  • Epitol is usually not effective in absence (petit mal) and myoclonic seizures.
  • Epitol is suitable for both monotherapy and combination therapy.
  • Epitol is indicated in acute mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.
  • Epitol is indicated in idiopathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis (either typical or atypical).
  • Epitol is indicated in painful diabetic neuropathy, alcohol withdrawal syndrome, idiopathic glossopharyngeal neuralgia and diabetes insipidus centralis.

SIDE EFFECTS

The most frequently observed adverse reactions, particularly during the initial phases of therapy are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

Loss of appetite, dryness of the mouth, visual and gastrointestinal disturbances and rashes may occur but these side effects usually disappear within 7-14 days or following a temporary reduction in the dosage.

At a concentration of 8.5 to 10 mcg/ml CNS side effects are frequently reported.

Leucopenia, agranulocytosis, thrombocytopenia, aplastic anemia and jaundice have rarely been reported.

DOSAGE AND ADMINISTRATION

Epitol tablets and chewable tablets may be taken during, after or between meals. The chewable tablets are particularly suitable for patients who have difficulty in swallowing tablets or need careful adjustment of the dosage.

Epilepsy: Epitol treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained. When Epitol is added to existing anti-epileptic therapy, this should be done gradually while maintaining, or adapting, the dosage of the other anti-epileptic(s).

Adults: Initially 100-200 mg once or twice daily. Slowly raise the dosage of Epitol until generally 400 mg 2-3 times daily or until an optimum response is obtained. In some patients, 1600 mg or even 2000 mg daily may be appropriate.

Children: Children over 4 years of age will start with 100 mg/day of Epitol, increasing at weekly intervals by 100 mg.
Maintenance dosage: 10-20 mg/kg body weight daily, i.e.

  • 4-5 years of age: 200-400 mg daily
  • 6-10 years of age: 400-600 mg daily
  • 11-15 years of age: 600-1000 mg daily

Dosage should be given in intervals of 6-8 hours to minimize fluctuations in plasma concentration.

Trigeminal neuralgia: Slowly raise the initial dosage of 200-400 mg daily of Epitol until freedom from pain is achieved (normally at 200 mg 3-4 times daily). Then gradually reduce the dosage of ńĆarbapex to the lowest possible maintenance level. In elderly patients, an initial dose of 100 mg daily is recommended.

Painful diabetic neuropathy: Average dosage: 200 mg 2-4 times daily.

Acute mania and maintenance treatment of bipolar disorders: Dosage range: about 400-1600 mg daily of Epitol, the usual dosage being 400-600 mg daily given in 2-3 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 provide optimal tolerability.

WARNINGS AND PRECAUTIONS

Anti-epileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Carbamazepine should be given only under medical supervision taking these medical considerations into account:

Blood counting and liver function test should be performed before starting the treatment and monthly thereafter. If there is a decrease in leucocytes and/or platelet count or if severe deterioration in liver function test occurred, carbamazepine should be discontinued.

If signs and symptoms suggestive of severe skin reactions appear, carbamazepine should be withdrawn at once.

Carbamazepine has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be closely observed during therapy.

Abrupt withdrawal of carbamazepine may precipitate seizures.

Pregnancy and lactation

Carbamazepine should not be taken in pregnancy unless the benefits clearly outweigh the risks. In women of childbearing age, carbamazepine should be prescribed as monotherapy (whenever possible). Carbamazepine has been reported to aggravate folic acid deficiency.

During lactation, concentration of carbamazepine in milk is approximately 60% of the maternal plasma concentration. Because of the potential of serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

DRUG INTERACTIONS

  • 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.
  • Co-administration of inhibitors of CYP 3A4 may result in increased plasma concentrations which could induce adverse reactions.
  • Carbamazepine may render oral contraceptives less effective, so women are advised to use alternative method of contraception.

CONTRAINDICATIONS

  • Known hypersensitivity to carbamazepine or structurally related drug (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 acute intermittent porphyria.
  • Because it is structurally related to tricyclic antidepressants, the use of carbamazepine is not recommended in combination with monoamine oxidase inhibitors (MAOIs); before administering carbamazepine, MAOIS should be discontinued for a minimum of 2 weeks or longer if the clinical situation permits.

PHARMACOLOGICAL ACTION

Carbamazepine is absorbed almost completely but relatively slowly form the tablets. With the chewable tablets, mean peak plasma concentrations are attained within 2 hours and with respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms.

After a single oral dose of 400 mg carbamazepine tablets, the mean peak concentration of unchanged carbamazepine in the plasma is approximately 4.5 mcg/ml. When CR tablets are administered singly and repeatedly, they yield about 25% lower peak concentrations of active substance in plasma than the conventional tablets; the peaks are attained within 24 hours.

The CR tablets provide statistically significant decrease in Cmin at steady state and its bioavailability is about 15% lower than that of other oral dosage forms.

Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form. Steady state plasma concentrations of carbamazepine are attained within about 1-2 weeks. Peak
concentrations in plasma are 2 to 6 hours following oral ingestion and therapeutic concentrations are in the range of 3-6 mcg/ml. Half life in plasma is 21 to 53 hours and is reduced to 8-27 hours in children.

Carbamazepine enters the cerebrospinal fluid, crosses the placenta and is secreted in milk. In blood, it is taken up by red blood cells. Carbamazepine and its epoxide metabolite binds to plasma protein at the extent of 70 to 80% and about 50% respectively. Less than 1% of a dose is excreted unchanged in the urine, and about 25% is excreted in the urine as 10,11- dihydroxymetabolite.

Mechanism of action

Carbamazepine stabilizes 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 depolarized neurons may be its main mechanism of action. Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the
anti-epileptic effects, the depressant effect on dopamine and noradrenalin turnover could be responsible for the antimanic properties of carbamazepine.

Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principle metabolite of carbamazepine (carbamazepine-10, 11-epoxide) has anticonvulsant activity as demonstrated in several vivo animal models of seizures.

Referance Code: N03AF01