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FDA and GlaxoSmithKline Warn Fosamprenavir (Lexiva) May Be Linked to Increased Risk of Blood Lipid Elevation and Heart Attacks

SUMMARY: On December 3, the U.S. Food and Drug Administration (FDA) and manufacturer GlaxoSmithKline (GSK) issued a "Dear Healthcare Provider" letter alerting clinicians about a potential association between use of the protease inhibitor fosamprenavir (Lexiva) and dyslipidemia (abnormal blood fat levels) and myocardial infarction (heart attack). The warning is based on data from a French study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2009) this past February, showing that fosamprenavir increased the risk of myocardial infarction by 52%. GSK has modified the "Warnings and Precautions" section of the fosamprenavir prescribing information, and recommends that triglyceride and cholesterol testing should be performed prior to starting fosamprenavir and at periodic intervals during therapy.

Below is an edited excerpt from the recent letter.

Full fosamprenavir prescribing information, including complete safety information, is available at www.lexiva.com/index.html.

Dear Healthcare Professional:

Lexiva (fosamprenavir calcium) Tablets and Oral Suspension: Myocardial Infarction and Dyslipidemia GlaxoSmithKline would like to inform you of data presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) relating to a potential association between Lexiva Tablets and Oral Suspension and myocardial infarction in HIV infected adults.

Action Being Taken by GSK

GSK has added myocardial infarction and hypercholesterolemia to the Adverse Reactions section of the Lexiva Tablets and Oral Suspension prescribing information (Section 6.2 Postmarketing Experience). Elevations in triglyceride levels are already described in the Adverse Reactions section of the Lexiva Tablets and Oral Suspension prescribing information (Section 5.8 Warnings and Precautions, Section 6.1 Clinical Trials).

GSK has modified the existing Warnings and Precautions statement (Section 5.8 Lipid Elevations) in the prescribing information for Lexiva Tablets and Oral Suspension to highlight that increases in cholesterol have occurred with treatment. This statement highlights the importance of lipids management by including a recommendation that triglyceride and cholesterol testing should be performed prior to initiating therapy with Lexiva Tablets and Oral Suspension and at periodic intervals during therapy. GSK is in communication with FDA and this issue will be closely monitored.

Key Messages

A case-control study nested in the French Hospital Database on HIV [FHDH ANRS CO4] has reported an association between exposure to fosamprenavir/amprenavir and an increased risk of myocardial infarction (Odds Ratio (OR): 1.52 per additional year of exposure; 95% CI, 1.19-1.95). [Lang S, Mary-Krause M, Cotte L et al. CROI 2009, Abstract #43LB
Myocardial infarction has already been identified as a signal for the protease inhibitor (PI) class in general; the reported association is plausible and may be related to the propensity for this drug class to raise blood lipids [The D:A:D Study Group 2007].
Prescribers are reminded that HIV infection itself has been associated with lipid disorders and ischemic heart disease.
Triglyceride and cholesterol levels should be checked prior to initiating therapy with Lexiva Tablets and Oral Suspension and at periodic intervals during therapy. Appropriate clinical management of lipid disorders should be initiated as required.
Other modifiable risk factors for cardiovascular disease (such as hypertension, diabetes, and smoking) should also be monitored in HIV-infected subjects and managed as clinically appropriate.

Labeling Recommendations

Details of the new labeling for Lexiva Tablets and Oral Suspension are described under "Action Being Taken by GSK." Please read the enclosed Prescribing Information for the full text describing these labeling changes. Available at http://www.lexiva.com/index.html.

Action Required by Healthcare Professionals

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients. Clinical examination should include evaluation for physical signs of fat redistribution.
Triglyceride and cholesterol levels should be checked prior to initiating therapy with Lexiva Tablets and Oral Suspension and at periodic intervals during therapy. Appropriate clinical management of lipid disorders should be initiated as required.

Other modifiable risk factors for cardiovascular disease (such as hypertension, diabetes and smoking) should be monitored in HIV-infected subjects and managed as clinically appropriate.

Supporting Information

At an international HIV conference (CROI, February 2009), data from a case-control study nested within the French Hospital Database on HIV were reported [Abstract #43LB].

The objective of the study, requested by the European Medicines Evaluation Agency (EMEA), was to analyze the effect of exposure to specific nucleoside reverse transcriptase inhibitors (NRTIs) and PIs on the risk of myocardial infarction. Several conditional logistic regression models were used to assess the association of (i) cumulative exposure to specific NRTIs, (ii) recent (current or within 6 months) and past exposure (>6 months ago) to specific NRTIs, and (iii) cumulative exposure to specific PIs on the risk of myocardial infarction. The study reported an association between an increased risk of myocardial infarction and cumulative exposure to fosamprenavir/amprenavir (OR 1.52 per additional year of exposure; 95% CI, 1.19-1.95).

Myocardial infarction has already been identified as a signal for the PI class in the ongoing observational Data Collection on Adverse Events of Anti-HIV Drugs (DAD) cohort. Specific analysis of ART [antiretroviral therapy] drug classes showed the relative risk of myocardial infarction to be higher with PI therapy (16% increase per year) compared with other ART classes. The signal is plausible and may be partly explained by the propensity of the PI class to raise blood lipids.

Suppression of viral replication in HIV disease with antiretroviral therapy is of the utmost importance. Patients should NOT discontinue treatment on their own. All treatment decisions should be explored in consultation with healthcare professionals.
Physicians should continue to monitor a patient's cardiovascular risk as part of regular reviews and seek to adjust modifiable risk factors. The profile of each antiretroviral agent is different and treatment decisions should always be personalized for an individual patient with careful consideration of the overall absolute risks and the benefits of effective long-term treatment.

Indication, Important Safety Information, and Full Prescribing Information for Lexiva Tablets and Oral Suspension are available at http://www.lexiva.com/index.html.


Call for Reporting

GlaxoSmithKline reminds healthcare professionals to continue to report adverse reactions to FDA MedWatch at 1-800-FDA-1088 or www.fda.gov/medwatch in accordance with the national spontaneous reporting system rules.

GlaxoSmithKline encourages healthcare professionals to continue to report suspected adverse reactions, pregnancy, overdose and unexpected benefits of Lexiva Tablets and Oral Suspension to GSK at 1-888-825-5249.

12/08/09

Source
Food and Drug Administration. GlaxoSmithKline and FDA Inform Healthcare Professionals of New Warnings for Lexiva (fosamprenavir calcium). FDA Alert. December 3, 2009.



 




 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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