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Viracept Warning-Dear Dr Letter
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September 10, 2007
VIRACEPT (nelfinavir mesylate) 250 mg, 625 mg tablets, and Powder for Oral Suspension
IMPORTANT INFORMATION FOR PRESCRIBERS
Dear Healthcare Professional:
The purpose of this letter is to inform you of the presence of ethyl methanesulfonate (EMS), a processrelated impurity in Viracept (nelfinavir mesylate) and to provide guidance on the use of Viracept in pregnant
women and pediatric patients.
In June 2007, excess levels of EMS were detected in Roche Ltd- manufactured active pharmaceutical ingredient of Viracept; subsequently Roche recalled Viracept from all their European Union (EU) markets. EMS is a process-related impurity formed during manufacture of Viracept. EMS is a potential human
carcinogen (Class 2B). Data from animal studies indicate EMS is teratogenic, mutagenic and carcinogenic; however, no data from humans exists.
In response to the Roche EU recall, the Food and Drug Administration (FDA) asked Pfizer to implement a new specification to limit the presence of EMS in Pfizer- manufactured Viracept products marketed in the United States. Pfizer commenced testing all active ingredients and found levels of EMS substantially lower than those associated with the Roche EU recall. Testing continues. Pfizer and FDA have agreed on interim and long term specifications of EMS in Viracept at levels substantially lower than those that prompted the Roche EU recall. Only product meeting the interim specifications will be released for patient use in the US.
Pfizer is taking this step to balance the need to maintain the availability of Viracept as a therapeutic alternative for patients and prevent unexpected interruption of HIV-1 antiretroviral treatment with the need to minimize patient exposure to a potential carcinogen.
The agreed interim specification limits the theoretical lifetime increased cancer risk in adults to less than 17 cases per 100,000 exposed. The long term specification for levels of EMS limits the theoretical lifetime increased cancer risk in adults to less than 1 case per 100,000 exposed. Current estimates of the background incidence of cancer in the HIV population are about 20-30 cases per 1000 patient-years.
MANAGEMENT OF PEDIATRIC PATIENTS
While no data on the impact of high EMS levels in humans exist, toxicology experts generally agree that the lifetime risk associated with exposure to a carcinogen is about 3-fold greater among pediatric patients between 2 and 16 years of age and even higher among pediatric patients younger than 2 years of age; this potentially greater risk was used to determine acceptable levels of EMS in formulations used in the pediatric population. For pediatric patients who are stable on Viracept-containing regimens, the FDA and Pfizer agree that the benefit-risk ratio remains favorable and those patients may continue to receive Viracept. Pediatric patients who need to begin HIV treatment should not start regimens containing Viracept until further notice.
We encourage you to refer to specific recommendations for the use of antiretroviral agents in pediatric HIV-1 infected patients from the United States Department of Health and Human Services (DHHS) guidelines.[1]
MANAGEMENT OF PREGNANT WOMEN
We currently do not have information on the ability of EMS to cross the placenta nor enter breast milk. In the Antiretroviral Pregnancy Registry involving over 6000 HIV infected pregnant women, no significant difference in the prevalence of birth defects between women who used Viracept and those who used other antiretroviral therapy was observed. Nonetheless, FDA is recommending that pregnant women limit their exposure to EMS during pregnancy. Pregnant women who need to begin antiretroviral therapy should not be offered regimens containing Viracept until further notice. As a precautionary measure, pregnant women currently receiving Viracept should be switched to an alternative antiretroviral therapy while Pfizer and FDA work to implement the long term EMS specification for Viracept. We encourage you to refer to specific recommendations for the use of antiretroviral agents in pregnant HIV-1 infected patients from the United States Department of Health and Human Services (DHHS) guidelines[2], in determining an alternative treatment option.
Maintaining the health of the mother and preventing transmission of HIV to the fetus are of paramount importance. For pregnant women with no alternative treatment options, FDA and Pfizer agree that the risk-benefit ratio remains favorable for the continued use of Viracept.
ALL OTHER PATIENTS
There is no change in the recommended use of Viracept for all other patients. Please see enclosed full prescribing information. In considering the best treatment for patients, please be aware that many HIV antiretroviral medications are carcinogenic in animal studies. In addition, some HIV antiretroviral
medications are mutagenic or are teratogenic. Despite these findings, available information shows the benefits of HIV-1 antiretroviral treatment outweigh the risks of using these products or completely stopping HIV treatment. Please see individual product labeling for additional information. Pfizer and FDA continue to work together to define a long-term, globally harmonized plan, which appropriately limits EMS levels within Viracept while still ensuring an uninterrupted supply of the medication to patients.
Sincerely,
Michael Berelowitz MB ChB, FACP, FCP(SA)
Senior Vice President
Global Medical
Head Worldwide Development, New York
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