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FDA is requiring a new warning be added to the prescribing information for saquinavir (Invirase) detailing the drug's potential to prolong both QT and PR intervals on an electrocardiogram, and thus potentially cause the dangerous abnormal heart rhythms called torsades de pointes and complete heart block.
FDA is requiring a new warning be added to the prescribing information for saquinavir (Invirase) detailing the drug's potential to prolong both QT and PR intervals on an electrocardiogram, and thus potentially cause the dangerous abnormal heart rhythms called torsades de pointes (TDP) and complete heart block. This action comes after FDA finished its review of pertinent clinical study data it began earlier in 2010.
Saquinavir is a human immunodeficiency virus (HIV)-1 protease inhibitor indicated for the treatment of HIV-1 infection in combination with ritonavir (Norvir) and other antiretroviral agents. It was initially approved by FDA as a capsule in 1995 and as a tablet in 2004.
As part of their review, officials at FDA reviewed the findings of a clinical study that evaluated the effect of saquinavir/ritonavir on the electrical activity of the heart. Fifty-nine healthy adults were randomly assigned to receive either saquinavir/ritonavir at a therapeutic dose of 1,000 mg/100 mg twice daily or at a supratherapeutic dose of 1,500 mg/100 mg twice daily, moxifloxacin 400 mg once daily as an active control, or placebo as part of a crossover study design. Electrocardiograms were taken on day 3. The researchers found the maximum mean time-matched differences in QT interval from placebo after baseline correction were 18.9 and 30.2 msec for the approved and supratherapeutic doses of saquinavir/ritonavir, respectively.
The maximum mean PR interval changes relative to the pre-dose baseline value were 25 msec and 34 msec in the 2 ritonavir-boosted saquinavir treatment groups. As a result, PR interval prolongation of >200 msec was observed in 40% and 47% of subjects receiving the approved and supratherapeutic doses of saquinavir/ritonavir.
According to the Agency's safety announcement, both TDP and complete heart block have been reported in patients taking saquinavir along with ritonavir.
The Agency is now suggesting caution in using saquinavir in patients at particular risk for abnormal heart rhythms, including those with preexisting heart disease or rhythm or heart rate problems. Furthermore, they are recommending an electrocardiogram be performed in patients prior to drug initiation and that prescribers consider ongoing monitoring for abnormal heart rhythms.
FDA. FDA Drug Safety Communication: Invirase (saquinavir) labels now contain updated risk information on abnormal heart rhythms [10-21-2010]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm230096.htm. Accessed December 9, 2010.
Invirase [package insert]. San Fransico, CA: Genentech, Inc.; 2010.