October 21, 2010
The U.S. Food and Drug Administration is notifying the public that new risk information has been added to the label of the antiviral drug Invirase (saquinavir), describing a potential change in the electrical activity of the heart when Invirase is used with another antiviral medication, Norvir (ritonavir). Changes in the electrical activity of the heart may lead to abnormal heart rhythms.
In February 2010, FDA announced it was reviewing clinical trial data about a potentially serious effect on the heart from the use of Invirase in combination with Norvir.
This new risk information has been added to the Warnings and Precautions, Contraindications, and Clinical Pharmacology sections of the Invirase label. In addition, the FDA will require that a Medication Guide be given to patients when picking up a prescription for Invirase. The Medication Guide will include information on the risk of abnormal heart rhythms.
The medications Invirase and Norvir are given together to treat HIV infection. Norvir must be given at a low dose with Invirase in order to increase the level of Invirase in the body. This is a process known as 'boosting' and it lowers the daily number of Invirase capsules or tablets that a patient needs to take. Patients with HIV infection take several antiviral medications together to block replication of the virus in the body and help them live longer.
The potential changes to the electrical activity of the heart associated with Invirase/Norvir, known as prolonged QT or PR intervals, can be seen on an electrocardiogram (EKG). This new information was derived from a clinical study designed to study a drug's impact on the electrical activity of the heart. A prolonged QT interval can lead to a serious abnormal rhythm called torsades de pointes, which can be fatal. Torsades de pointes has been reported in patients taking Invirase with Norvir. A prolonged PR interval can lead to a serious abnormal rhythm called complete heart block. Complete heart block has been reported in patients taking Invirase with Norvir.
Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. [See Data Summary.]
The FDA has evaluated data from a clinical study assessing the effects of Invirase/Norvir on the QT interval. The study-specific corrected QTc interval (QTcS) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 59 healthy adults, with electrocardiogram (EKG) measurements on Day 3. The maximum mean time-matched (95% upper confidence bound) differences in QTcS interval from placebo after baseline-correction were 18.9 (22.0) and 30.2 (33.4) msec for the approved dose of 1000/100 mg twice daily and a supratherapeutic dose of 1500/100 mg twice daily of Invirase/Norvir, respectively. There is a delayed effect between QTc interval change and drug concentrations, with the maximum placebo-adjusted baseline-corrected QTcS observed at about 12-20 hours post-dose. Although based on multiple cross-study comparisons, the Day 3 mean Cmax of Invirase/Norvir 1000/100 mg twice daily in this healthy volunteer study was estimated to be about 3-fold higher than the mean steady state Cmax observed with Invirase/Norvir 1000/100 mg twice daily in HIV-1 infected patients.
In the same study, PR interval prolongation of >200 msec was also observed in 40% and 47% of subjects receiving Invirase/Norvir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3. Three subjects (3%) in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of >200 msec. The maximum mean PR interval changes relative to the pre-dose baseline value were 25 msec and 34 msec in the two ritonavir-boosted INVIRASE treatment groups, 1000/100 mg twice daily and 1500/100 mg twice daily, respectively.
In summary, the data show that Invirase/Norvir may affect the electrical activity of the heart through prolongation of the PR or QT intervals which may result in abnormal heart rhythms. Due to this risk, the Warnings and Precautions, Contraindications, and Clinical Pharmacology sections of the Invirase label have been updated. Healthcare professionals should read the new changes to the Invirase label carefully if they are considering or currently prescribing Invirase to their patients. An EKG should be performed prior to initiation of treatment. Healthcare professionals should also consider whether ongoing EKG monitoring is appropriate for their patients and when it should be done.