Sunovion Pharmaceuticals Inc. has recently become aware of the article “Juice interactions: What patients need to know” by Maria G. Tanzi in the March 2013 Pharmacy Today OTC Supplement. The article has a few inaccuracies regarding our product Latuda (lurasidone).
Lurasidone is metabolized mainly via cytochrome P450 (CYP)3A4 and is contraindicated with strong CYP3A4 inhibitors and inducers. Sunovion has conducted drug interaction studies with ketoconazole (strong CYP3A4 inhibitor), diltiazem (moderate CYP3A4 inhibitor), and rifampin (strong CYP3A4 inducer) detailed in the full prescribing information (PI; sections 7.1 and 12.3). However, studies with grapefruit have not been conducted. Furthermore, even though there may be a possible drug interaction with lurasidone and grapefruit because lurasidone is mainly metabolized via CYP3A4, the listed dose-related adverse events—torsades de pointes, orthostatic hypotension, and syncope—are unlikely to occur, and these were not dose-related adverse events reported in the clinical development program.
Tanzi stated that the information was obtained from an article published in CMAJ. The authors of the CMAJ article wrote that they used information from the Canadian product monographs of recently approved drugs to predict the risk of adverse events caused by enhanced systemic drug concentration resulting from impaired drug metabolism. They predicted a “very high” interaction risk for lurasidone administered with grapefruit juice and predicted dose-related adverse events of torsades de pointes, orthostatic hypotension, and syncope. The predicted dose-related adverse events are in no way supported by the information in the Canadian product monograph or U.S. PI for lurasidone. The clinical data described in these documents are clear that there was no evidence of any dose–response relationship for the effect of lurasidone on QT interval or the incidence of orthostatic hypotension or syncope.
The incidence of orthostatic hypotension and syncope events from the short-term, placebo-controlled studies in patients taking Latuda and placebo, respectively, was 0.3% (5/1,508) and 0.1% (1/708) for orthostatic hypotension and 0.1% (2/1,508) and 0% (0/708) for syncope. In short-term clinical trials, orthostatic hypotension occurred with a frequency of 0.2%, 0%, 1.0%, and 0.8% with Latuda 40 mg, 80 mg, 120 mg, and 160 mg, respectively, compared with 0.1% with placebo (PI section 5.8). Torsades de pointes was not reported in the clinical development program, and the Latuda PI does not contain a “Warning and Precaution” for QTc prolongation. The clinical development program also included a dedicated QTc study with a supratherapeutic dose of lurasidone of 600 mg which had negligible effect on QTc interval. In addition, in the short-term, placebo-controlled studies, no postbaseline QT prolongations exceeding 500 msec were reported in patients treated with Latuda (PI section 12.2).