FDA Issues Safety Review of Ziagen and Videx; GlaxoSmithKline Responds

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FDA Issues Safety Review of Ziagen and Videx; GlaxoSmithKline Responds

The FDA has issued an Early Communication about recent findings of The Data Collection on Adverse Events of Anti-HIV Drugs Study (D:A:D Study). Data analyses from this study indicate a higher risk of heart attack in patients infected with HIV-1 who were taking Ziagen (abacavir) or Videx (didanosine) as part of their drug therapy. GlaxoSmithKline has posted a statement responding to the FDA ‘s safety review.

Posted below is the FDA’s Early Communication, followed by the GSK statement:

Early Communication about an Ongoing Safety
Review of Ziagen (Abacavir) and Videx (Didanosine)

This information reflects FDA's current analysis of available data concerning these drugs. Posting this information does not mean that FDA has concluded a causal relationship exists between the drug products and the emerging safety issue. Nor does it mean that FDA is advising healthcare professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion as to whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available.

FDA has been made aware of recent findings from analyses of data collected from "The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study". The D:A:D Study is a large observational study of 33,347 HIV-1 infected patients living in North America, Europe and Australia. Patients in this study are being followed to evaluate the short- and long-term adverse effects of treatment with anti-HIV drugs.

Analyses of data collected through February 1, 2007 examined the risk of myocardial infarction (heart attack) in patients taking selected HIV drugs from the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (Retrovir), stavudine (Zerit), abacavir (Ziagen), didanosine (Videx), and lamivudine Epivir). The analyses, specifically, describe the relative risk of heart attack among cumulative use, recent use (currently using or use within the past 6 months), and past use (last use greater than 6 months ago) of these drugs.

These analyses showed that recent use of abacavir or didanosine was associated with an increased risk of heart attack. Patients taking either of these drugs had a greater chance of developing a heart attack than patients taking other medications. The risk did not appear to increase over time, but remained stable and appeared to be reversible after abacavir or didanosine were stopped.

In late 2007, GlaxoSmithKline (GSK), the manufacturer of abacavir, received the preliminary findings from the D:A:D Study analyses and conducted a search of their own clinical study databases. The results of the GSK analysis are inconclusive, but did not show an increased risk.

Bristol Myers Squibb (BMS), the manufacturer of didanosine, conducted an analysis of their clinical databases, and similarly, found no increased risk for heart attack with didanosine use. The results of the BMS analysis are also inconclusive.

Key findings from the D:A:D Study are as follows:

• The excess risk of heart attack in patients taking at least some NRTIs appears to be greater in patients with other risk factors for heart disease. Risk factors include a history of heart disease, high cholesterol, high blood pressure, diabetes, smoking, and age.

• Certain analyses found the risk of heart attack increased by 49% in patients taking didanosine and increased by 90% in patients taking abacavir.

• The increased risk for heart attack remained stable over the course of treatment and the effect was not seen 6 months after stopping the drugs.

FDA currently believes analyses conducted with D:A:D Study data are incomplete; no analyses were conducted evaluating the risk of heart attack when patients take tenofovir or emtricitabine, two other drugs in the class of NRTIs. However, FDA continues to evaluate the overall risks and benefits of abacavir and didanosine.

This evaluation may result in the need to revise labeling for the products. Until this evaluation is complete, healthcare providers should evaluate the potential risks and benefits of each HIV-1 antiretroviral drug their patients are taking, including abacavir and didanosine.

This early communication is in keeping with FDA's commitment to inform the public about ongoing safety reviews of drugs. FDA will work with the manufacturers of abacavir and didanosine to fully evaluate the risks and benefits associated with the use of these products as part of an HIV treatment regimen. As soon as this process is complete, FDA will communicate the conclusions and recommendations to the public.

The FDA urges healthcare professionals to promptly report serious and unexpected adverse reactions associated with abacavir to the FDA MedWatch reporting program, as described below.

• online at www.fda.gov/medwatch/report.htm

• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787

• faxing the form to 1-800-FDA-0178

• by phone at 1-800-332-1088

Consumer Information Sheet for Ziagen

3/28/08

Source
US Food and Drug Administration

Community Statement: GSK Statement in Response to DAD Data on Abacavir

Dear Community Member:

GlaxoSmithKline [NYSE:GSK] has been notified by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) group that new data from an observational database suggests a possible association between anti-retroviral therapy (ART) regimens that contain abacavir and an increased risk of heart attack. Conversely, analyses of GlaxoSmithKline data show no increased risk of heart attack associated with abacavir.

Accumulated data was sufficient for the D:A:D to analyze five commonly used nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, didanosine, stavudine, lamivudine and abacavir. The D:A:D findings of increased risk of heart attack with abacavir are unexpected, as there appears to be no biological reason in the way abacavir works that would explain these findings. In fact, abacavir has often been chosen due to its favorable lipid and glucose profile.

However, GlaxoSmithKline takes this information seriously, and continues to work with the D:A:D group to ensure that physicians, patients and appropriate regulatory agencies understand this information in order to make the most appropriate treatment decisions for their patients.

In an announcement today, the FDA stated that they currently believe the analyses conducted with the D:A:D Study data are incomplete. The FDA is considering, but has not reached a conclusion as to whether this information warrants any regulatory action. The FDA intends to update their communications when additional information or analyses become available.

D:A:D Database Findings

The D:A:D data indicate that patients who have received abacavir in the most recent 6 months appear to have an increased relative risk for myocardial infarction of 1.9. Overall this is an uncommon event: 6.1 events/1000 patient years among patients who had taken abacavir in the last 6 months versus 2.6 events/1000 patient years for those who had not (a difference of 3.5 events per 1000 patient years). By comparison to this doubling of relative risk, smoking can increase a person’s risk of heart attack by two or three times, while high cholesterol can increase the risk of heart attack up to six times. As the D:A:D position paper states, for patients who smoke: ”…stopping smoking would do more to reduce the risk of having a heart attack and other serious diseases more than by stopping abacavir:”

GlaxoSmithKline has analyzed the company’s internal databases, which include information from external post marketing surveillance reports and data from 54 clinical trials with more than 14,000 patients, over 9,600 of whom were on abacavir. The analyses of GlaxoSmithKline data show no increased risk of heart attack associated with abacavir. In addition, GlaxoSmithKline is not aware of any confirmed increased risk of heart attack with abacavir in the published literature.

The D:A:D presented its data in a poster session at the Conference on Retroviruses and Opportunistic Infections (CROI), on February 4, 2008, in Boston, MA. The D:A:D position statement and other information is available at http://www.cphiv.dk/

Implications for Managing HIV

The analysis of the D:A:D database is complex, and the D:A:D group has stated that potential confounding factors cannot be entirely excluded, though the analysis has sought to adjust for a number of variables. The D:A:D group has stated that these results are therefore not sufficient to prove what causes the increased risk.

In a pooled analysis of 54 clinical trials no excess risk of myocardial infarction was observed with abacavir use. No biological mechanism linking abacavir treatment with myocardial infarction has so far been identified. GlaxoSmithKline believes that in totality, the data on the association of myocardial infarction with abacavir treatment are inconclusive at this time.

HIV is a serious, life-threatening disease, and a number of factors go into choosing the right therapy. Therefore, GlaxoSmithKline believes that:

Patients should NOT discontinue treatment on their own.

Although the D:A:D study data suggest a relative risk increase in heart attack risk for patients who are starting or continuing abacavir, that risk remains low in absolute terms, and therefore abacavir remains an important treatment option for those patients.

The total patient profile including comorbidities, concomitant medications, previous retroviral experience, as well as the underlying risk of coronary heart disease should be considered when prescribing HIV antiretroviral therapy, including abacavir. Action should be taken to minimize modifiable cardiovascular risk factors in all patients (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) in line with current guidelines.

About HAART Therapy

Highly Active Anti-Retroviral Therapy (HAART) has revolutionized HIV treatment and dramatically extended the lifespan of HIV patients. The NRTI class, including abacavir, remains a cornerstone of HIV therapy; approximately 25% of HIV patients on HAART take abacavir as a proven medicine effective in treating HIV. For patients who have failed previous therapy, abacavir may be an essential part of treatment.

As with all medicines, physicians and patients must weigh the risks of the disease against the risks and benefits of the medicines available to treat it. Certain risks may be able to be managed as part of standard HIV patient care.

About Glaxo SmithKline

GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

3/28/08

Source
S Marc Meachem, Product Communications, GlaxoSmithKline. Community Statement: GSK Statement in Response to DAD Data on Abacavir. March 27, 2008.