Saquinavir: update on potential risk of arrhythmia

Saquinavir at a reduced dose for the first week of treatment

From:
Medicines and Healthcare products Regulatory Agency
Published
11 December 2014
Therapeutic area:
Infectious disease

Article date: December 2010

Saquinavir (Invirase) is a protease inhibitor indicated in combination with ritonavir and other antiretroviral drugs for treatment of HIV infection. The standard dose of saquinavir/ritonavir in adults and adolescents older than 16 years is 1000 mg/100 mg twice daily.

Previous advice for saquinavir

In August 2010, we reported that the product information for saquinavir had recently been updated to reflect the results of a QT study[footnote 1] in healthy volunteers. This study found that saquinavir had dose-dependent effects on the QT and PR interval that were greater than those seen with moxifloxacin, the active control drug.

As a result, saquinavir is contraindicated in patients at high risk of arrhythmia, and in patients using other medicines that may cause QT or PR prolongation, such as the other protease inhibitors atazanavir and lopinavir, and methadone. Baseline and follow-up electrocardiogram recording in patients taking concomitant drugs known to increase the plasma levels of saquinavir is also recommended (eg, potent inhibitors of the cytochrome p450 3A4 enzyme such as the protease inhibitor nelfinavir, the antifungal itraconazole, and proton pump inhibitors such as omeprazole).

More recently, the potential clinical effect of these findings on the safe and effective use of saquinavir has been reviewed within Europe. Despite the potentially proarrhythmic effects observed in the QT study, no signal of clinical events has been detected from post-licensing safety monitoring since saquinavir was authorised in 1996. However, an absence of case reports is not sufficient to exclude a risk in saquinavir-treated patients.

Treatment-naïve patients

Patients considered to be at the highest risk of QT and PR prolongation with saquinavir are those not previously exposed to any antiretroviral drugs (ie, treatment-naïve patients), with the greatest risk being in the first week of treatment.

On the basis of pharmacokinetic modelling, the European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended that, as an additional precautionary measure, half the standard dose of saquinavir should be used for the first week of therapy: ie, 500 mg saquinavir plus 100 mg ritonavir, twice daily. Pharmacokinetic modelling has shown that this lower dose will minimise QT prolongation during the period when patients are most at risk, while maintaining sufficient antiretroviral activity. The potential risk of arrhythmia in treatment-naïve patients receiving the reduced initial dose will be further investigated in a new study.

The benefits of saquinavir in the authorised indication continue to outweigh the risks.

Advice for healthcare professionals:

  • cautions and monitoring

    • do not use saquinavir 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
    • if possible, avoid use of saquinavir with drugs known to increase the plasma level of saquinavir. If no alternative treatment options are available, see below
    • in all patients starting saquinavir, electrocardiography should be done before initiating treatment, and after approximately 3–4 days of therapy
    • do not use saquinavir in patients with a QT interval of >450 milliseconds
    • discontinue saquinavir if patients develop: QT prolongation of >480 milliseconds or >20 milliseconds from pretreatment measurement; PR prolongation; or arrhythmias
    • warn patients of the arrhythmogenic risk with saquinavir and the need to report any signs of cardiac arrhythmias to their physician (eg, chest palpitations, syncope, presyncope)

  • dose recommendations

    • in antiretroviral-treatment-naïve patients, use a reduced dose of saquinavir (ie, 500 mg plus 100 mg ritonavir, twice daily) for the first week of therapy
    • do not exceed the recommended dose of saquinavir because the magnitude of QT and PR prolongation is likely to increase with raised plasma levels of saquinavir

Further information

European Medicines Agency press release

Drug Safety Update, August 2010

Letter for healthcare professionals sent in July 2010

Article citation: Drug Safety Update Dec 2010 vol 4 issue 5: A1.

  1. Anson BD, et al. Lancet 2005; 365: 682–86. ↩

Updates to this page

Published 11 December 2014
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