Section 3.4.2

Carbamazepine

General Description

Carbamazepine (Tegretol) is an iminostilbene drug, structurally similar to imipramine and approved in the United States for the treatment of temporal lobe epilepsy and trigeminal neuralgia. A large body of literature data supports the use of carbamazepine for the treatment of acute mania and for the prophylactic treatment of bipolar disorder.

Indications for Medication

For manic episodes, carbamazepine may be as effective as lithium. Current clinical and research studies suggest that carbamazepine may be more effective in the treatment of rapid-cyclic bipolar disorder patients or patients with dysphoric manic episodes.

For manic episodes, carbamazepine may be used alone or it may be combined with antipsychotic drug treatment. Co-administration of carbamazepine with a neuroleptic may increase the risk of carbamazepine-induced CNS adverse effects such as drowsiness, dizziness and ataxia.

For manic episodes, carbamazepine may be added to lithium. If this combination proves effective, lithium should be gradually withdrawn to see if the patient could be treated successful with carbamazepine alone. When using carbamazepine with lithium, any antipsychotics, sedatives or anticholinergic drugs should be used at the lowest dose level (or withdrawn) to reduce the risk of carbamazepine-induced CNS adverse effects.

For bipolar disorder, carbamazepine may be used alone or in combination with lithium. Carbamazepine is effective in prophylaxis as it reduces the frequency of both manic and depressive episodes in 50-70% of patients.

For bipolar disorder, carbamazepine can be used with valproate preparations. If carbamazepine and valproic acid are used in combination, the dosage of carbamazepine may need to be decreased because valproic acid displaces the binding of the carbamazepine, resulting in a higher blood level.

For schizophrenia and schizoaffective disorder, carbamazepine may also be an effective adjunctive treatment. Additional literature reports also document efficacy in schizophrenia and schizoaffective disorder patients with outbursts of impulsive, aggressive behavior.

For depressive disorders, carbamazepine is an effective treatment in some patients. Approximately 25-35% of depressed patients respond to carbamazepine treatment. Carbamazepine may be an alternative treatment in depressed patients who have not responded to the more traditional antidepressants.

For impulsive-control disorders, carbamazepine has been reported to be effective in controlling impulsive, aggressive behavior in non-psychotic patients. Carbamazepine should be used after clinical trials with other medications such as lithium, propranolol (Inderal), and antipsychotics.

Clinical Guidelines

The patient's medical history should include information about preexisting hematological, hepatic and cardiac diseases, because all three can be relative contraindications to carbamazepine treatment.

Laboratory examination should include a complete blood count with platelet count, liver function tests, serum electrolytes and an electrocardiogram in patients over the age of 40 or in patients with pre-existing cardiac disease.

The usual starting dose of carbamazepine is 200mg given orally two times a day. The dosage should be raised gradually (even in inpatient settings) at a rate of not more than 200mg a day until a dosage of 600-1000mg a day is reached. Gradual titration will decrease minor adverse effects such as nausea, vomiting, drowsiness and dizziness.

The therapeutic range for psychiatric indications for carbamazepine is higher than the therapeutic range for treatment of epilepsy. Efficacy for psychiatric symptoms occurs with blood levels of 8-12mcg pr ml. The dosage required to achieve these blood levels usually ranges from 400-1600mg a day in divided doses with a mean dose around 1000mg a day.

Carbamazepine should be taken with meals and stored in a cool, dry place. Carbamazepine stored in the bathroom medicine cabinet may lose up to one third of its activity.

Adverse Effects

The most serious potential adverse effects of carbamazepine are agranulocytosis and aplastic anemia. These blood dyscrasias occur in approximately 1 in 20,000 patients treated with carbamazepine. Complete laboratory blood tests should be performed every two weeks during the first two months of treatment and quarterly after that initial two month trial.

Patients should inform the physician immediately if fever, sore throat, infections, mouth ulcers, easy bruising, pallor, weakness, petechiae, or bleeding develop. Any of these symptoms should dictate a laboratory testing and a possible referral to a hematologist.

Carbamazepine should be discontinued if laboratory values are lower than any of the following: total white blood cell count 3000mm3, neutrophils 1500mm3, erythrocytes 4.0 x 106 per mm3, reticulocyte count 0.3 percent, serum iron level 150mg per ml.

Carbamazepine may cause both hypersensitivity hepatitis associated with increases in liver enzymes and a cholestasis associated with elevated bilirubin and alkaline phosphatase. Hepatitis will reoccur if the drug is reintroduced and can be fatal.

Carbamazepine can cause a severe form of erythema multiforme, called the Stevens-Johnson syndrome. This dermatologic condition requires discontinuation of the drug. Other less serious dermatologic effects include urticarial and pruritic and erythematous rashes.

Carbamazepine may cause a number of gastrointestinal adverse effects. These effects include nausea, vomiting, gastric distress, constipation, diarrhea and anorexia.

Carbamazepine may cause adverse central nervous system effects. Acute confusion can occur with carbamazepine alone; but it more frequently occurs when the drug is combined with lithium or an antipsychotic. The CNS symptoms may include drowsiness, ataxia, hyperreflexia, clonus and tremor.

Carbamazepine may cause thyroid effects, including a decrease in triodothyronine (T3), thyroxine (T4), and the free T4 index. The development of hypothyroidism is rare. Patients who are taking carbamazepine and lithium are at greater risk for the development of hypothyroidism.

Although the data is somewhat preliminary, carbamazepine may increase the risk of a number of serious birth defects. The use of carbamazepine in pregnancy, therefore, should be avoided. Carbamazepine is secreted in breast milk. Women taking carbamazepine should not breast feed their babies.

In general, the adverse effects from carbamazepine are dose related. The highest risk of adverse effects occurs with plasma concentrations above 9mcg per ml. Blood levels may therefore assist in the assessment of the risk of adverse effects.

Drug-Drug Interactions

Carbamazepine interacts with many medications. These interactions may increase or decrease the blood level of carbamazepine; and they may increase or decrease the blood level of the other medications.

Carbamazepine may also induce its own metabolism during the initial several weeks of treatment at a given dose, and it therefore may require further dosing adjustments on this basis.

The following drugs increase carbamazepine levels (and efficacy): danazol, diltiazem, erythromycin, influenza vaccine, isoniazid, verapamil, cimetidine, nicotinamide, propoxyphene, valproic acid and fluoxetine.

The following drugs decrease carbamazepine levels (and efficacy): phenobarbital, phenytoin, primidone and theophylline.

Carbamazepine may increase the levels and effectiveness of the following drugs: clomipramine, desmethylclomipramine and phenytoin.

Carbamazepine may decrease the levels and effectiveness of the following drugs: clonazepam, cyclosporine, dexamethasone, dicumarol, doxycycline, ethosuximide, haloperidol, pregnancy tests, theophylline, valproic acid, warfarin and tricyclic antidepressants.

Co-administration of carbamazepine with lithium, antipsychotic, or calcium channel blockers (like verapamil, nifedipine and diltiazem) can precipitate carbamazepine-induced CNS adverse effects. Co-administration of carbamazepine with clozapine may induce agranulocytosis.

Carbamazepine should not be coadministered with monamine oxidase inhibitors. The MAOIs should be discontinued for a two week washout period before starting any carbamazepine treatment.

Carbamazepine may cause breakthrough bleeding in women receiving concomitant oral contraceptives. The reliability of oral contraceptives may be adversely affected.

The consent form for this medication is "Mood Stabilizer (Anti-convulsant)."