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The 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 in combination with 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. The FDA is also requiring a medication guide for patients using Invirase that will describe the potential risk of abnormal heart rhythms.
The medications Invirase and Norvir are given together to treat HIV infection. Norvir is given at a low dose with Invirase to increase the level of Invirase in the body. This process, known as ‘boosting,’ lowers the daily number of Invirase capsules or tablets that a patient needs to take.
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 with underlying heart conditions or those who have existing heart rate or rhythm problems are at particular risk. [See Data Summary, below].
Additional Information for Patients
- Do not stop taking Invirase/Norvir without talking to your healthcare professional.
- Review your cardiovascular medical history and current medications with your healthcare professional. Discuss any concerns about Invirase/Norvir with your healthcare professional.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Invirase and other medicines may affect each other, causing unwanted side effects.
- Seek immediate care if you experience an abnormal heart rate or rhythm or other symptoms including dizziness, lightheadedness, fainting or heart palpitations.
- Report any side effects you experience to the FDA MedWatch program.
Additional Information for HCPs
- Read the new changes in the Invirase label carefully if you are considering or currently prescribing this medication to your patients. Note that Invirase is contraindicated in certain patients.
- An electrocardiogram (EKG) should be performed prior to initiation of treatment. In addition, consider whether ongoing EKG monitoring is appropriate for your patient and when it should be done. Patients with a QT interval > 450 msec should not receive ritonavir-boosted Invirase. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy. Patients with a QT interval > 480 msec or with prolongation over pre-treatment by > 20 msec should discontinue Invirase/Norvir. A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of EKG assessment to confirm EKG findings.
- Advise patients to contact a healthcare professional immediately if they experience symptoms of an abnormal heart rate or rhythm while taking Invirase/Norvir.
- Report adverse events involving Invirase/Norvir to the FDA MedWatch program.
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.
The revised Invirase label can be viewed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020628s033,021785s010lbl.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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U.S. Food & Drug Administration (FDA) · 10903 New Hampshire Ave · Silver Spring, MD 20993 · 800-439-1420
| Date: | Fri, 22 Oct 2010 18:05:19 -0500 |
| From: | "U.S. Food & Drug Administration (FDA)" <fda@xxxxxxxxxxxxxxxxxxxxxxx> |
| To: | Preview <fda@xxxxxxxxxxxxxxxxxxxxxxx> |
| Subject: | HIV/AIDS Update - Invirase (saquinavir) labels updated with important risk information about abnormal heart rhythms |
| Content-Type: | text/plain; charset=us-ascii |
You are receiving this message as a subscriber to the FDA HIV/AIDS electronic list serve. The purpose of the list serve is to relay important information about HIV/AIDS-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
*Please do not reply to this message.*
The 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 in combination with 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 [ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm201221.htm ].
This new risk information has been added to the "Warnings and Precautions", "Contraindications, "and" Clinical Pharmacology" sections of the Invirase label. The FDA is also requiring a medication guide for patients using Invirase that will describe the potential risk of abnormal heart rhythms.
The medications Invirase and Norvir are given together to treat HIV infection. Norvir is given at a low dose with Invirase to increase the level of Invirase in the body. This process, known as 'boosting,' lowers the daily number of Invirase capsules or tablets that a patient needs to take.
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 with underlying heart conditions or those who have existing heart rate or rhythm problems are at particular risk. [See Data Summary, below [ http://www.fda.gov/drugs/DrugSafety/ucm230096.htm#summary ]].
*Additional Information for Patients*
* Do not stop taking Invirase/Norvir without talking to your healthcare professional.
* Review your cardiovascular medical history and current medications with your healthcare professional. Discuss any concerns about Invirase/Norvir with your healthcare professional.
* Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Invirase and other medicines may affect each other, causing unwanted side effects.
* Seek immediate care if you experience an abnormal heart rate or rhythm or other symptoms including dizziness, lightheadedness, fainting or heart palpitations.
* Report any side effects you experience to the FDA MedWatch program [ https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm ].
*Additional Information for HCPs*
* Read the new changes in the Invirase label carefully if you are considering or currently prescribing this medication to your patients. Note that Invirase is contraindicated in certain patients.
* An electrocardiogram (EKG) should be performed prior to initiation of treatment. In addition, consider whether ongoing EKG monitoring is appropriate for your patient and when it should be done. Patients with a QT interval > 450 msec should not receive ritonavir-boosted Invirase. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy. Patients with a QT interval > 480 msec or with prolongation over pre-treatment by > 20 msec
should discontinue Invirase/Norvir. A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of EKG assessment to confirm EKG findings.
* Advise patients to contact a healthcare professional immediately if they experience symptoms of an abnormal heart rate or rhythm while taking Invirase/Norvir.
* Report adverse events involving Invirase/Norvir to the FDA MedWatch program [ https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm ].
*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.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Manage your FDA Subscriptions:
- Update your preferences or unsubscribe
- Questions about this service? support@xxxxxxxxxxxxxxx
- Other inquiries? webmail@xxxxxxxxxx
U.S. Food & Drug Administration (FDA) · 10903 New Hampshire Ave · Silver Spring, MD 20993 · 800-439-1420
