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Viracept warning from Pfizer-Dear Dr Letter
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VIRACEPT (nelfinavir mesylate) 250 mg, 625 mg tablets, and Powder for Oral Suspension
IMPORTANT INFORMATION FOR PRESCRIBERS
September 10, 2007
Dear Healthcare Professional:
The purpose of this letter is to inform you of the presence of ethyl methane sulfonate (EMS), a process-related substance in Viracept (nelfinavir mesylate) and to provide guidance on the use of Viracept in pregnant women.
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 markets. EMS is a process-related substance formed during manufacture of nelfinavir mesylate. 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 recall, the US Food and Drug Administration asked Pfizer to implement a new specification to limit the presence of EMS in Pfizer- manufactured Viracept products marketed in the US. Pfizer commenced testing all product and agreed with FDA on interim and long term acceptable levels of EMS in Viracept at levels substantially less than those that prompted the Roche recall. Only product meeting the agreed specifications will be released for patient use. Pfizer is taking this step to balance the need to maintain the availability of nelfinavir mesylate 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.
While no data on the impact of high EMS levels in humans exist, 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. 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.
MANAGEMENT OF PREGNANT WOMEN
An important consideration includes management of pregnant women. EMS is a known teratogen and a potent mutagen in animals; however, we currently do not have information on the ability of EMS to cross the placenta or enter breast milk. In a pregnancy registry involving over 6000 HIV infected pregnant women, no significant difference in the incidence 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. Accordingly, it is recommended that pregnant women 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 in pregnant HIV-1 infected patients from the United States Department of Health and Human Services (DHHS) guidelines[1], in determining an alternative treatment option.
Viracept remains available for patients; however, we believe this information is important for prescribers so they can consider this information, and other relevant information, in deciding whether to prescribe, or continue to prescribe, nelfinavir mesylate for their patients. 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 mutagens 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, MD
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 impairment without any dose adjustment. VIRACEPT should not be use in patients with either moderate or severe hepatic impairment.
Exercise caution when administering VIRACEPT with drugs that induce CYP3A, and with potentially toxic drugs that are metabolized by CYP3A, including those that prolong the QT interval.
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
[1] 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.
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