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Pfizer Inc
235 East 42nd Street
New York, NY 10017-5755
VIRACEPT® (nelfinavir mesylate) 250 mg, 625 mg tablets, and Powder for Oral Suspension IMPORTANT INFORMATION FOR PRESCRIBERS
The purpose of this letter is to inform you of the presence of ethyl methanesulfonate (EMS), a process-related impurity in Viracept (nelfinavir mesylate) and to provide guidance on the use of Viracept in pregnantwomen and pediatric patients.
In June 2007, excess levels of EMS were detected in Roche Ltd- manufactured active pharmaceuticalingredient 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 anew specification to limit the presence of EMS in Pfizer- manufactured Viracept products marketed in theUnited States. Pfizer commenced testing all active ingredients and found levels of EMS substantially lowerthan those associated with the Roche EU recall. Testing continues. Pfizer and FDA have agreed on interimand long term specifications of EMS in Viracept at levels substantially lower than those that prompted theRoche 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 therapeuticalternative 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 lifetimeincreased 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 themedication to patients.
Michael Berelowitz MB ChB, FACP, FCP(SA) Senior Vice PresidentGlobal MedicalHead Worldwide Development, New York Safety Information
VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
Nelfinavir is principally metabolized by the liver; it can be used in patients with mild hepatic impairmentwithout any dose adjustment. VIRACEPT should not be use in patients with either moderate or severehepatic impairment.
Exercise caution when administering VIRACEPT with drugs that induce CYP3A, and with potentially toxicdrugs that are metabolized by CYP3A, including those that prolong the QT interval.
VRU00027 2007 Pfizer Inc. All rights reserved. Printed in USA/September 2007 TOTAL RECOVERED FIBER
Safety Information cont’d.
In clinical studies (n>5000), the most common adverse event, diarrhea, was moderate to severe in 14% to 20% of patients. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRACEPT. Redistribution/accumulation of body fat has been reported in patients receiving antiretroviral therapy. A causal relationship has not been established, and long-term consequences are not known at this time. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported with protease inhibitors. There are no adequate and well-controlled studies in pregnant women taking VIRACEPT. VIRACEPT should be used in pregnancy only if clearly needed. VIRACEPT use is contraindicated with amiodarone, quinidine, triazolam, midazolam, ergot derivatives, and pimozide. VIRACEPT should not be coadministered with St. John's wort, simvastatin, lovastatin, rifampin, and omeprazole. Rifabutin dose should be reduced by 50%. PDE5 inhibitors should be prescribed with caution. Increased bleeding in patients with hemophilia type A or B has been reported with protease inhibitors. . Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. October 26, 2006; 1-126. Available at http://www.aidsinfo.nih.gov 2. Public Health Service Taskforce: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. October 12, 2006; 1-65. Available at http://www.aidsinfo.nih.gov. VRU00027 2007 Pfizer Inc. All rights reserved. Printed in USA/September 2007 L RECOVERED FIBER

Source: http://enewsletter.csmc.edu/Pulse/2007/October-12/Documents/VIRACEPT_HCPLetter_9_10_07-54868.pdf