Important note: Information in this article was accurate in 2004. The state of the art may have changed since the publication date.
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Food and Drug Administration - May 21, 2004
Richard Klein, Kimberly Struble
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir.
It is likely that CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered.
The following label changes include modifications to the CLINICAL PHARMACOLOGY section:
Metabolism
In vitro studies in human liver microsomes show that trazodone is metabolized to an active metabolite, m-chlorophenylpiperazine (mCPP) by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may beinvolved in metabolism of trazodone have not been well characterized.
Elimination
In some patients DESYREL may accumulate in the plasma.
Drug-Drug Interactions
See also PRECAUTIONS: Drug Interactions. In vitro drug metabolism studies reveal that trazodone is a substrate of the cytochrome P450 3A4(CYP3A4) enzyme and trazodone metabolism can be inhibited by the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The C(max) of trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered.
Additionally, the Drug Interactions sub-section within the PRECAUTIONS section has been updated with the following information:
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the C(max), AUC, and elimination half-life, and decreased clearance of trazodone after administration of ritonavir twice daily for 2 days. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered.
It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole or nefazodone may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered.
You can access the entire Dear Healthcare Provider Letter at http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_DHCP.pdf
The complete product label is available at http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_PI.pdf
Richard Klein, Office of Special Health Issues - Food and Drug Administration
Kimberly Struble, Division of Antiviral Drug Products - Food and Drug Administration
040521
FD040503
SOURCE: Food and Drug Administration (FDA).
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