FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury
Facts about statins and protease inhibitors
- Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”).
- HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV.
- HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.
- A side effect of taking HIV protease inhibitors is increased cholesterol and triglyceride (fat) levels. Therefore, some patients taking HIV protease inhibitors may need to take cholesterol-lowering medicines such as statins.
The U.S. Food and Drug Administration (FDA) is issuing updated recommendations concerning drug-drug interactions between drugs for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. The labels for both the HIV protease inhibitors and the affected statins have been updated to contain consistent information about the drug-drug interactions. These labels also have been updated to include dosing recommendations for those statins that may safely be co-administered with HIV or HCV protease inhibitors (see Statin Dose Limitations below).
Healthcare professionals should refer to the current drug labels for protease inhibitors and statins for the latest recommendations on prescribing these drugs.
Patients should contact their healthcare professional if they have any questions or concerns about taking protease inhibitors and statins.
- Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) protease inhibitors can interact with cholesterol-lowering statins to increase the risk of muscle injury.
- Patients should inform their healthcare professional about all medicines that they are taking or plan to take prior to starting an HIV or HCV protease inhibitor or statin.
- HIV and HCV protease inhibitors should never be taken (are contraindicated) with lovastatin (Mevacor) and simvastatin (Zocor) (see Statin Dose Limitations below).
- Patients should contact their healthcare professional if they have any questions or concerns about HIV or HCV protease inhibitors or statins.
- Patients should report side effects from the use of HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.
- Co-administration of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors with certain statins can increase the risk of myopathy/rhabdomyolysis.
- Healthcare professionals should follow the recommendations in the drug labels when prescribing HIV or HCV protease inhibitors with statins (also see Statin Dose Limitations below).
- Healthcare professionals should report adverse events involving HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.
The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed. Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin.
Lovastatin and simvastatin
Lovastatin and simvastatin are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Therefore, strong CYP3A4 inhibitors are predicted to significantly increase lovastatin and simvastatin exposures. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold, and the drug interaction appears to result in rhabdomyolysis.1 Itraconazole increases simvastatin exposure up to 13-fold. Hence, other CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors, and the hepatitis C virus (HCV) protease inhibitors boceprevir and telaprevir, are also expected to significantly increase lovastatin and simvastatin exposures. Therefore, concomitant administration of lovastatin and simvastatin with HIV protease inhibitors or HCV protease inhibitors (boceprevir and telaprevir) is contraindicated.
The HIV protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure up to 3-fold. For these combinations, the dose of rosuvastatin should be limited to 10 mg.
Statin Dose Limitations
Table Press Source
- Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995;333:664-5.
Source : FDA
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FDA Drug Safety Communication: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and patients that drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can potentially reduce the effectiveness of these medicines when they are used together.
Patients should not stop taking any of their medicines without talking to their healthcare professional. Patients should contact their healthcare professional if they have any questions or concerns.
Healthcare professionals who have started patients infected with both chronic HCV and HIV on Victrelis and antiretroviral therapy containing a ritonavir-boosted protease inhibitor should closely monitor patients for HCV treatment response and for potential HCV and HIV virologic rebound.
A drug interaction study showed that taking boceprevir (Victrelis) with ritonavir (Norvir) in combination with atazanavir (Reyataz) or darunavir (Prezista), or with Kaletra (lopinavir/ritonavir) reduced the blood levels of the HIV medicines and boceprevir in the body (see Data Summary below). FDA will be updating the Victrelis drug label to include information about these drug interactions.
Merck and Company has issued a Dear Healthcare Professional letter (PDF - 67KB) with information about this drug interaction study.
Additional Information for Patients
- Drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and ritonavir used in combination with other human immunodeficiency virus (HIV) protease inhibitors can potentially reduce the effectiveness of these medicines when they are used together.
- Patients should not stop taking any of their medicines without talking to their healthcare professional.
- Patients should contact their healthcare professional if they have any questions or concerns about Victrelis or HIV protease inhibitors.
- Patients should report side effects from the use of Victrelis or HIV protease inhibitors to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.
Additional Information for Healthcare Professionals
- Drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and ritonavir-boosted atazanavir, lopinavir, and darunavir can potentially reduce the effectiveness of these medicines when co-administered.
- Healthcare professionals who have initiated Victrelis in combination with peginterferon alfa and ribavirin in HIV-HCV co-infected patients on fully suppressive antiretroviral therapy containing a ritonavir-boosted protease inhibitor should discuss these findings with those patients, and closely monitor those patients for HCV treatment response and for potential HCV and HIV virologic rebound.
- Victrelis (boceprevir) and Incivek (telaprevir) were approved in May, 2011, each in combination with peginterferon alfa and ribavirin for treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. Neither NS3/4A protease inhibitor is approved for treatment of patients co-infected with HIV. Drug interaction data with telaprevir and ritonavir-boosted HIV protease inhibitors can be found in the Incivek drug label (PDF - 314KB). Information about clinical trials in HIV-HCV co-infected patients can be found at ClinicalTrials.gov.
- Healthcare professionals should report adverse events involving Victrelis or HIV protease inhibitors to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.
A pharmacokinetic study evaluated drug interactions between boceprevir (Victrelis) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors in healthy volunteers (n=39). In the study, concomitant administration of Victrelis (boceprevir) with ritonavir (Norvir) in combination with atazanavir (Reyataz), darunavir (Prezista), or with lopinavir/ritonavir (Kaletra) resulted in reduced exposures of the HIV medicines and boceprevir. Victrelis reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir, and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in area under the curve (AUC) and peak concentration (Cmax) of atazanavir, lopinavir, and darunavir. Co-administration of ritonavir-boosted atazanavir with Victrelis did not alter the exposure (AUC) of boceprevir, but co-administration of Victrelis with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the AUC of boceprevir by 45 and 32 percent, respectively.
.Facts about Victrelis (boceprevir) and HIV protease inhibitors
- Victrelis is a hepatitis C virus (HCV) protease inhibitor used with the medicines peginterferon alfa and ribavirin to treat chronic (long-lasting) hepatitis C infection in adults who have not been treated before or who have failed previous treatment.
- HIV protease inhibitors are a class of anti-viral drugs used to treat HIV infection.
- Ritonavir is an HIV protease inhibitor used to “boost” other HIV protease inhibitors, increasing their levels in the blood and making them more effective.
Source : FDA (Feb 2012)
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FDA Drug Safety Communication: Safety Review update of Abacavir and possible increased risk of heart attack
The U.S. Food and Drug Administration (FDA) is updating the public about its ongoing safety review of abacavir and a possible increased risk of heart attack. Abacavir is an antiviral medication used in combination with other antiretroviral drugs for the treatment of HIV-1 infection. Available medications that contain abacavir include Ziagen, Trizivir, and Epzicom.There has been conflicting information on the potential increased risk of heart attack with abacavir treatment. An increased risk of heart attack (myocardial infarction or MI) has been seen in several observational studies and one randomized controlled trial (RCT) with abacavir. However, an increased risk of heart attack has not been seen in other RCTs and the safety database maintained by the drug manufacturer.
FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated abacavir. This meta-analysis did not show an increased risk of MI associated with the use of abacavir. Healthcare professionals should continue to prescribe abacavir according to the professional label. Patients should not stop taking their abacavir without first talking to their healthcare professional.
FDA will continue to communicate any new safety information to the public as it becomes available.
Additional Information for Patients
Do not stop taking abacavir without talking to your healthcare professional.
- Discuss any questions or concerns about abacavir with your healthcare professional.
any side effects you experience to the FDA MedWatch program using the
information in the “Contact Us” box at the bottom of the page.
- Continue to prescribe abacavir according to the professional label.
- Be aware there are conflicting data on whether abacavir treatment increases the risk of MI. However, the FDA’s recent meta-analysis of 26 RCTs found no statistically significant difference in MI events between patients who received abacavir and those who did not.
adverse events involving abacavir to the FDA MedWatch program, using
the information in the “Contact Us” box at the bottom of the page.
FDA’s primary objective was to explore the association of abacavir with MI. A literature search was conducted among four databases (International Pharmaceutical Abstracts [IPA], Intelos, Embase and Scopus) for all clinical trials that included a randomized abacavir treatment arm. The FDA manually reviewed the results of the search to identify RCTs that met the following criteria: conducted in adults, sample size greater than 50 subjects, trial status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel-Haenszel method, with risk difference, odds ratio (OR), and a 95% confidence interval (CI), was used for the primary analysis based on trial-level summaries; the unit of analysis was the subject, and the stratification factor was the trial. For trials with more than two arms, abacavir versus non-abacavir arms were compared.
Data from 26 RCTs conducted from 1996 to 2010 (16 trials from the drug manufacturer database, 5 from the AIDS Clinical Trials Group (ACTG), and 5 from academic centers were included in the meta-analysis conducted by FDA. The MI outcomes were reported for 9868 subjects randomized to receive either an antiretroviral regimen that included abacavir or a non-abacavir containing comparison drug regimen. A total of 46 MI events were reported, including 24 MI events from 5028 subjects randomized to an abacavir-containing regimen and 22 MI events from 4840 subjects randomized to a non-abacavir regimen. No statistically significant association between MI and the abacavir-containing regimen was detected (Mantel-Haenszel OR 1.02, 95% CI 0.56 – 1.84). For a review of this meta-analysis, see http://www.retroconference.org/2011/Abstracts/42436.htm1
- No Association of Myocardial Infarction with ABC Use: An FDA Meta-analysis2 3
- Information on Abacavir (marketed as Ziagen) and Abacavir-containing Medications4
Source : FDA (03/03/2011)
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New Label Changes for Commonly Prescribed HIV Drug Invirase
Drug associated with a life-threatening heart abnormality when used with another antiviral medicine
The U.S. Food and Drug Administration today announced that new safety information has been added to the label for the HIV antiviral drug Invirase (saquinavir), describing potentially life-threatening side effects on the heart when used with Norvir (ritonavir), another HIV antiviral medication.
In February 2010, the agency warned patients and health care professionals that when used together, the two drugs could cause prolongation of the QT and PR intervals--indicators of heart rhythm activity seen on an electrocardiogram.
Prolongation of the QT interval may lead to a condition known as torsades de pointes, an abnormal heart rhythm. With torsades de pointes, patients may experience lightheadedness, fainting or abnormal heart beats. In some cases, torsades de pointes may progress to a life-threatening irregular heart beat known as ventricular fibrillation.
Prolongation of the PR interval may also lead to an abnormal heart rhythm known as heart block. With heart block, patients may experience lightheadedness, fainting or abnormal heartbeats.
The FDA is also requiring a medication guide for patients using Invirase that will describe these potential risks. Patients at greater risk of developing one of the serious heart events described above include those with underlying heart conditions or those that have existing heart rate or rhythm problems.
“These heart conditions could potentially be life-threatening and we want to assure that health care providers and patients are adequately informed of the risks,” said Edward Cox, M.D., M.P.H, director, Office of Antimicrobial Products in FDA's Center for Drug Evaluation and Research. “Patients should talk to their doctor if they have any concerns about their treatment. Certain drugs may interact with Invirase and increase the risk of developing these side effects, so patients should be sure to tell their doctor about other medicines they may be taking, including non-prescription medicines, vitamins, and herbal supplements.”
Patients and health care professionals should report any side effects from the use of Invirase to the FDA’s MedWatch program.
Invirase is an antiretroviral medication first approved in 1995, and used in combination with Norvir and other antiretroviral medicines to treat HIV in adults. Invirase does not cure HIV infection, may not prevent development of HIV-related illnesses and may not prevent the spread of HIV to other people.
Invirase is marketed by San Francisco-based Genentech, a subsidiary of the Roche Group. Norvir is marketed by Abbott Laboratories based in Abbott Park, Ill.
For more information:
FDA: Drug Safety Communication: Invirase labels now contain updated risk information on abnormal heart rhythms
HHS: AIDS News and Resources
Ongoing Safety Review of Invirase and Possible Association with Abnormal Heart Rhythms
The U.S. Food and Drug Administration (FDA) is reviewing data about a potentially serious effect on the heart from the use of Invirase (saquinavir) in combination with Norvir (ritonavir).
While FDA's review is ongoing,, the preliminary data suggests that the two drugs may prolong the QT or PR interval which may lead to torsade de pointes or heart block.
Invirase and Norvir are antiviral medications given together to treat HIV infection. Norvir is 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."
The study data were submitted by Roche, the manufacturer of Invirase, based on FDA's request that all manufacturers of protease inhibitors, including Invirase, conduct a thorough QT study to evaluate the effect these drugs have on the QT and PR intervals.
The preliminary data show that when Invirase boosted with Norvir (1000mg/100mg) was given to healthy patients, ages 18 to 55 years, there was a dose-dependent prolongation of the QT and PR intervals.
The magnitude of the effect and clinical implications of QT and PR interval prolongation are still being reviewed by FDA. However, these finding suggests that some patients using Invirase boosted with Norvir may be at an increased risk for developing abnormal heart rhythms.
In particular, this risk may be increased in patients using other medications known to cause QT interval prolongation such as Class IA and Class III antiarrhythmic drugs or in patients with a history of QT interval prolongation.
FDA recommends that healthcare professionals:
- Not use Invirase in patients with a history of QT interval prolongation, preexisting conduction system disease, ischemic heart disease, cardiomyopathy, or underlying structural heart disease.
- Not use Invirase in patients who are currently using Class IA (such as quinidine) or Class III (such as amiodarone) antiarrhythmic drugs or other drugs that may prolong the QT or PR interval.
- Report any adverse events associated with the use of Invirase to FDA's MedWatch program.
Videx and Videx EC (Didanosine)antiretroviral medication used to treat HIV infection - adverse event in the liver, non-cirrhotic portal hypertension - 42 reported cases, 4 deaths
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals about a rare, but serious adverse event in the liver, non-cirrhotic portal hypertension, associated with the use of didanosine, marketed as Videx and Videx EC, a delayed-release version of Videx.
Didanosine is an antiretroviral medication used to treat HIV infection.
Non-cirrhotic portal hypertension is rare in the United States and occurs when blood flow in the portal vein slows down. This slowed blood flow can lead to the development of esophageal varices. The increased pressure can cause the varices to break open resulting in serious bleeding and, in some cases, death.
FDA became aware of 42 cases of non-cirrhotic portal hypertension through the adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the Warnings and Precautions section of the prescribing information.
Other liver adverse events such as lactic acidosis, hepatomegaly with steatosis, and liver failure have been reported with the use of didanosine alone and in combination with other antiviral drugs and are already included in the prescribing information.
Of the 42 post-marketing cases of non-cirrhotic portal hypertension in patients using didanosine:
- Twenty-six were males, 14 were females, and in two no gender was specified.
- The ages ranged from 10 years to 66 years.
- Duration of didanosine treatment ranged from months to years before development of non-cirrhotic portal hypertension.
- Definitive cases of non-cirrhotic portal hypertension were confirmed by biopsy and had no alternative etiology for the diagnosis.
- Banding/ligation of esophageal varices in 8 patients.
- Transjugular intrahepatic portosystemic shunt (TIPSS) procedure in three patients.
- Liver transplantation in 3 patients.
- Hemorrhage from esophageal varices in two patients.
- Progressive liver failure in one patient.
- A combination of multi-organ failure, cerebral hemorrhage, sepsis, and lactic acidosis in one patient.
LINK TO ARTICLE/PODCAST