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FDA and Bristol-Myers Squibb recently notified healthcare professionals of revisions to the CLINICAL PHARMACOLOGY and PRECAUTIONS sections of the product labeling for DESYREL (trazodone hydrochloride) Tablets, indicated for the treatment of depression.
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 be
involved 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 Cmax 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 Cmax, 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
The complete product label is available at
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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