Saquinavir prolongation of QT interval: Rocheissue Dear Doctor letter
On 5 July 2010 Roche issued the following letter to health care providers. These results followed an FDA mandated phase 4 in HIV-negative volunteers.
Association of saquinavir (Invirase) with arrhythmogenic risk due to prolongation of the QT and PR intervals
Dear Healthcare Professional
Roche, in coordination with the European Medicines Agency, would like to notify you of the risk of QT prolongation associated with saquinavir (Invirase), and the subsequent important safety-related addition to the Summary of Product Characteristics (SmPC) for Invirase.
Healthcare professionals should note that:
- Saquinavir is contraindicated in patients with congenital or acquired QT prolongation or other predisposing conditions for cardiac arrhythmias, including concurrent therapy with other drugs that prolong the QT and/or PR interval.
- The combination of saquinavir with drugs known to increase the plasma level of saquinavir is not recommended and should be avoided when alternative treatment options are available.
- Saquinavir should be discontinued in case of arrhythmias, QT or PR prolongation.
- The recommended dose of saquinavir should not be exceeded since the magnitude of QT and PR prolongation may increase with increased plasma levels of saquinavir.
- Baseline and follow-up electrocardiogram recording should be considered (e.g. in patients taking concomitant medication known to increase the plasma level of saquinavir).
- Patients should be warned of the arrhythmogenic risk and told to report any signs of cardiac arrhythmias (e.g. chest palpitations, syncope, presyncope) to their physician.
For detailed information on the administration and use of saquinavir, please refer to the Summary of Product Characteristics.
Further information on the safety concern
Saquinavir is indicated for the treatment of HIV-1 infected adult patients. Saquinavir should only be given in combination with ritonavir and other antiretroviral medicinal products.
The effects of therapeutic (1000/100 mg twice daily) and supra-therapeutic (1500/100 mg twice daily) doses of saquinavir/ritonavir on the QT interval were evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg) study in healthy male and female volunteers:
In the therapeutic and the supra-therapeutic arm 11% and 18% of subjects, respectively, had a QTcS* between 450 and 480 msec. In the moxifloxacin active control group, none of the subjects had a QTcS over 450 msec. No study subjects experienced QT prolongation > 500 msec or torsade de pointes in the study.
PR interval prolongation of > 200 msec was observed in 40% and 47% of subjects receiving saquinavir/ritonavir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, and in 3% and 5% of subjects in the moxifloxacin active control group and the placebo arm, respectively.
Events of syncope/presyncope occurred at a higher than expected rate and were seen more frequently under treatment with saquinavir/ritonavir.
The Patient Information Leaflet will be revised in accordance with the updated Summary of Product Characteristics.