Drug-Drug Interaction

CARBAMAZEPINE/CLOZAPINE

MECHANISM OF ACTION
Carbamazepine may induce the metabolism of clozapine. Both carbamazepine and clozapine have been reported to induce agranulocytosis, although the exact mechanism is unknown.(1,2)

DISCUSSION
The manufacturer of clozapine states that clozapine should not be used concurrently with agents known to cause agranulocytosis because of the possibility of synergistic effects on the risk and/or severity of bone marrow suppression.(1)

CLINICAL EFFECTS
Concomitant administration may result in decreased clozapine levels and possibly decreased effectiveness of clozapine. Additionally, the risk of agranulocytosis may be increased during concomitant administration.

SEVERITY LEVEL
2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

PATIENT MANAGEMENT
Concurrent therapy with clozapine and carbamazepine should be approached with caution.(1) If concurrent therapy is warranted, clozapine levels should be monitored during the initiation and withdrawal of carbamazepine. Clozapine dosage adjustments may be necessary.

PREDISPOSING FACTORS
None determined.

REFERENCES

1. Clozaril (clozapine tablets) US prescribing information. Novartis .Clozaril (clozapine tablets) US prescribing information. Novartis Pharmaceuticals Corporation January 14, 2010.
2. Gerson SL, Lieberman JA, Friedenberg WR, Lee D, Marx JJ Jr, Meltzer H. .Gerson SL, Lieberman JA, Friedenberg WR, Lee D, Marx JJ Jr, Meltzer H. Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet 1991 Jul 27;338(8761):262-3.
3. Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after .Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet 1988 Dec 24-31;2(8626-8627):1500.
4. Raitasuo V, Lehtovaara R, Huttunen MO. Carbamazepine and plasma levels of .Raitasuo V, Lehtovaara R, Huttunen MO. Carbamazepine and plasma levels of clozapine. Am J Psychiatry 1993 Jan;150(1):169.
5. Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine .Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine to oxcarbazepine on the plasma levels of neuroleptics. A case report. Psychopharmacology (Berl) 1994 Sep;116(1):115-6.
6. Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition .Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994 Aug; 16(4):368-74.