Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.13 Carbamazepine and Oxcarbazepine

Dermatologic Effects.  About 10 to 15 percent of those treated with carbamazepine develop a benign maculopapular rash within the first 3 weeks of treatment. Stopping the medica- tion usually leads to resolution of the rash. Some patients may experience life-threatening dermatologic syndromes, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The possible emer- gence of these serious dermatologic problems causes most clini- cians to discontinue carbamazepine use in people who develop any type of rash. The risk of drug rash is about equal between valproic acid and carbamazepine in the first 2 months of use but is subsequently much higher for carbamazepine. If carbamaze- pine seems to be the only effective drug for a person who has a benign rash with carbamazepine treatment, a retrial of the drug can be undertaken. Many patients can be rechallenged without reemergence of the rash. Pretreatment with prednisone (Deltas- one; 40 mg a day) may suppress the rash, although other symp- toms of an allergic reaction (e.g., fever and pneumonitis) may develop even with steroid pretreatment. Renal Effects.  Carbamazepine is occasionally used to treat diabetes insipidus not associated with lithium use. This activity results from direct or indirect effects at the vasopressin receptor. It may also lead to the development of hyponatremia and water intoxication in some patients, particularly elderly persons, or when used in high doses. Other Adverse Effects.  Carbamazepine decreases cardiac conduction (although less than the tricyclic drugs do) and can thus exacerbate preexisting cardiac disease. Carbamazepine should be used with caution in persons with glaucoma, prostatic hypertrophy, diabetes, or a history of alcohol abuse. Carbam- azepine occasionally activates vasopressin receptor function, which results in a condition resembling the syndrome of secre- tion of inappropriate antidiuretic hormone, characterized by hyponatremia and, rarely, water intoxication. This is the oppo- site of the renal effects of lithium (i.e., nephrogenic diabetes insipidus). Augmentation of lithium with carbamazepine does not reverse the lithium effect, however. Emergence of confusion, severe weakness, or headache in a person taking carbamazepine should prompt measurement of serum electrolytes. Carbamazepine use rarely elicits an immune hypersensitiv- ity response consisting of fever, rash, eosinophilia, and possibly fatal myocarditis. Cleft palate, fingernail hypoplasia, microcephaly, and spina bifida in infants may be associated with the maternal use of carbamazepine during pregnancy. Pregnant women should not use carbamazepine unless absolutely necessary. All women with childbearing potential should take 1 to 4 mg of folic acid daily even if they are not trying to conceive. Carbamazepine is secreted in breast milk. Drug Interactions Carbamazepine decreases serum concentrations of numerous drugs as a result of prominent induction of hepatic CYP3A4 (Table 29.13-2). Monitoring for a decrease in clinical effects is frequently indicated. Carbamazepine can decrease the blood concentrations of oral contraceptives, resulting in break- through bleeding and uncertain prophylaxis against pregnancy.

Table 29.13-2 Carbamazepine: Drug Interactions

Effect of Carbamazepine on Plasma Concentrations of Concomitant Agents Carbamazepine may decrease drug plasma concentration of: Acetaminophen Alprazolam Amitriptyline Bupropion Clomipramine Clonazepam Clozapine

Agents that May Affect Carbamazepine Plasma Concentrations Agents that may increase carbamazepine plasma concentration:

Allopurinol Cimetidine Clarithromycin Danazol Diltiazem Erythromycin Fluoxetine Fluvoxamine Gemfibrozil Itraconazole Ketoconazole Isoniazid a

Cyclosporine Desipramine Dicumarol Doxepin

Doxycycline Ethosuximide Felbamate Fentanyl Fluphenazine Haloperidol Hormonal contraceptives

Itraconazole Lamotrigine Loratadine Macrolides Nefazodone

Nicotinamide Propoxyphene Terfenadine Troleandomycin

Imipramine Lamotrigine Methadone Methsuximide Methylprednisolone

Valproate a Verapamil Viloxazine Drugs that may decrease carbamazepine plasma

Nimodipino Pancuronium Phensuximide Phenytoin Primidone Theophylline Valproate Warfarin

concentrations Carbamazepine

(autoinduction)

Cisplatin Doxorubicin HCl Felbamate Phenobarbital

Carbamazepine may increase drug plasma concentrations of Clomipramine

Phenytoin Primidone Rifampin b Theophylline Valproate

Phenytoin Primidone

a Increased concentrations of the active 10,11-epoxide. b Decreased concentrations of carbamazepine and increased concentrations of the 10,11-epoxide. (Table by Carlos A. Zarate, Jr., M.D., and Mauricio Tohen, M.D.)

Carbamazepine should not be administered with monoamine oxidase inhibitors (MAOIs), which should be discontinued at least 2 weeks before initiating treatment with carbamaze- pine. Grapefruit juice inhibits the hepatic metabolism of car- bamazepine. When carbamazepine and valproate are used in combination, the dosage of carbamazepine should be decreased because valproate displaces carbamazepine bind- ing on proteins, and the dosage of valproate may need to be increased.