Carbamazepine agranulocytosis with

Carbamazepine and possibly the antidepressant mirtazapine should not be coadministered with clozapine because these drugs may further increase the risk of agranulocytosis. In addition, the antidepressant bupropion should not be coprescribed with clozapine because it may increase clozapine s seizure risk. 

Care should be taken when prescribing other medications with clozapine. The mood stabilizer carbamazepine (Tegretol) and perhaps the antidepressant mirtazap-ine (Remeron) should not be taken with clozapine because they might further increase the risk of agranulocytosis. Likewise, the antidepressant bupropion (Wellbutrin, Zyban) should not be taken with clozapine because it may add to the seizure risk. 

Aplastic anemia and agranulocytosis have been reported in association with carbamazepine therapy. The risk of developing these reactions is 5 to 8 times greater than in the general population. Consider discontinuation of the drug if any evidence of significant bone marrow depression develops. 

Clozapine is contraindicated in patients who have myeloprohf-erative disorders or who are immunocompromised as a result of diseases such as active tuberculosis or human immunodeficiency virus infection because of their increased risk for agranulocytosis. Concomitant administration of medications that are associated with bone marrow suppression, such as carbamazepine, is also contraindicated. 

Because of the potential for hematological and hepatic toxicity, carbamazepine should not be administered to patients with liver disease or thrombocytopenia or to those at risk for agranulocytosis. For this reason, carbamazepine is strictly contraindicated in patients receiving clozapine. Because of reports of teratogenicity, including increased risks of spina bifida (Rosa 1991), microcephaly (Bertol-lini et al. 1987), and craniofacial defects (Jones et al. 1989), carbamazepine is relatively contraindicated in pregnant women. Pretreatment evaluation should include a complete blood count and determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 

The anticonvulsant therapeutic range for plasma concentrations of carbamazepine is 4 to 12 pg/mL. Hematological assessment in patients on carbamazepine therapy is appropriate because aplastic anemia and agranulocytosis have been reported in association with its use. 

Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic anemia and agranulocytosis. Most of these have been in elderly patients with trigeminal neuralgia, and most have occurred within the first 4 months of treatment. The mild and persistent leukopenia seen in some patients is not necessarily an indication to stop treatment but requires careful monitoring. The most common idiosyncratic reaction is an erythematous skin rash other responses such as hepatic dysfunction are unusual. 

Carbamazepine has a moderate anticholinergic action that may cause symptoms of dry mouth and constipation. CNS effects include somnolence, ataxia, diplopia, loss of accommodation, dizziness, and headache, which are most prominent with overdosage. Erythroderma, photosensitivity, and skin rashes may also be seen, and, rarely, Stevens-Johnson syndrome or systemic lupus-like syndrome also occur. The drug also has other serious adverse effects, such as suppression of ventricular automaticity, and, rarely, blood dyscrasias (e.g.. agranulocytosis, leukopenia, thrombocytopenia, and aplastic anemia). Due to hepatic metabolism, hepatocellular and cholestatic jaundice may also be seen. 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

Carbamazepine is metabolized in the liver to carbamtizepine-10, 11-epoxide, an active metabolite that partly contributes to both its anticonvulsant action and neurotoxicity. In contrast to phenytoin. there is u linear increa.se in serum concentration with dosage. Mild neurotoxic effects are common (nau.sea. dizziness, drowsiness, blurred vision and ataxia] and often detemiine the limit of dosage. Agranulocytosis is a rarer idiosyncratic reaction to carbamazepine. 

---