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Home > Topics > Emerging Issues > NLF Contamination
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Special Considerations regarding Detection of Contaminants in Antiretrovirals and Use of Nelfinavir for Pregnant Women and Children in Resource-Poor Countries

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Nelfinavir Impurity Alert Summary

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Nelfinavir (Viracept) manufactured in Europe--by Roche Laboratories--was recalled from the market in July 2007 because of high levels of ethyl methanesulfonate (EMS), a byproduct of manufacturing. EMS is teratogenic, mutagenic, and carcinogenic in animals. In humans, there is no evidence of birth defects or malignancy caused by EMS.

Nelfinavir manufactured in the United States-- by Pfizer--has lower levels of EMS. However, the U.S. Food and Drug Administration (FDA) and Pfizer issued a "Dear Healthcare Professional" letter advising of the potential toxicity of EMS in nelfinavir, and specified maximum EMS limits. ( 2 ) The U.S. Department of Health and Human Services (DHHS), as well as the FDA and Pfizer, have made recommendations for the use of nelfinavir. ( 3 ) These include the following:

transparent gif bullet The individual patient should be considered when weighing the potential risks and benefits of using nelfinavir.
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transparent gif bullet Nelfinavir should not be given to pregnant women or to women who anticipate pregnancy, if other treatment options are available. Pregnant women who are taking nelfinavir should change to another antiretroviral (ARV) agent.
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transparent gif bullet Nelfinavir should not be initiated for pediatric patients.
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transparent gif bullet For nonpregnant adults and in children who currently are taking nelfinavir as part of an effective ARV regimen, nelfinavir may either be continued or changed.
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transparent gif bullet Nelfinavir may be used if no alternative ARVs are available; in this situation, the anticipated benefits of taking the drug likely outweigh risks.
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Commentary regarding Detection of Contaminants in Antiretrovirals and Use of Nelfinavir for Pregnant Women and Children in Resource-Poor Countries

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In June 2007, Roche recalled nelfinavir, a protease inhibitor and second-line drug for antiretroviral therapy (ART), following reports from several patients that their tablets had a "peculiar odor." Investigations at the manufacturing plant in Switzerland revealed that the odor was a result of contamination by EMS, a "byproduct of manufacture" usually present in extremely low amounts of < 3 parts per million ( 1 ). Roche's investigations found varying levels of EMS contamination in different batches of the drug, some of which were as high as 2,300 parts per million, exceeding the limits set by regulatory agencies. The contaminated drug had been distributed to Botswana, Burkina Faso, Cameroon, Egypt, France, Germany, Iran, Italy, Kenya, Mali, Mexico, Mozambique, Nigeria, Portugal, South Africa, Spain, Taiwan, Uganda, Ukraine, and the United Kingdom. Nelfinavir distributed in Canada, Japan, and the United States is manufactured by Pfizer, and investigations found no level of EMS above that previously approved by the FDA.

In June, the World Health Organization (WHO) recommended that existing stocks of nelfinavir manufactured in Europe should be quarantined and that all remaining nelfinavir formulations returned to Roche. Roche, Pfizer, the FDA, and European regulatory agencies all published recommendations regarding the use of nelfinavir for adults, and warned against its use for young children and pregnant women, populations that might be at increased risk of toxicity even with lower levels of contamination.( 2 3 4 5 ) The FDA, the DHHS Perinatal Panel, European Medicines Agency (EMEA), and the WHO currently recommend that children beginning ART should not start new regimens containing nelfinavir. Those already taking the drug can continue to do so, though the WHO recommends substitution of alternative agents. Pregnant women should not start taking nelfinavir and those already taking nelfinavir should switch to a different drug.( 2 3 4 5 )

Roche reportedly has reduced EMS to acceptable levels, and the EMEA recently has recommended resumption of nelfinavir manufacture in Europe; however, it is likely to be some time before nelfinavir is available again throughout the world. Unfortunately, recommended nelfinavir substitutes for pregnant women and children that are widely available in developed countries may not be available in resource-poor areas. Some estimates state that as many as 22,000 patients in resource-poor countries are currently receiving treatment with nelfinavir.( 6 )

Many questions arise from this series of events, and 4 months after the recall was announced, few answers are evident. First, it remains unclear how to manage patients who currently are taking nelfinavir, particularly in resource-poor settings where delays or interruptions in treatment and inadequate treatment for HIV-infected children are associated with an unacceptably high mortality rate. Uncertainties regarding the levels and potential effects of the EMS in nelfinavir, coupled with lack of data in humans on teratogenicity, genotoxicity, and carcinogenicity, prevent clinicians from making well-informed decisions about the use of nelfinavir. However, the benefits of combination ART in controlling the progression of HIV and the high degree of efficacy of combination therapy in preventing mother-to-child HIV transmission are clear. In resource-poor countries, unless suitable alternatives are available, continuing nelfinavir treatment for patients who are responding positively to therapy would seem to offer the greatest benefit and the lowest risk.

Of course, troubling questions remain about the safety of the nelfinavir manufacturing process and the lack of data on drug toxicity in susceptible populations. Little is actually known about the short- and long-term toxicity of EMS, especially in pregnant women and fetuses, about placental passage of nelfinavir and secretion in breast milk, and about precisely what impact contamination by EMS might have on populations of patients with increased sensitivity to toxicity.

No information has been published on the quality control measures that Roche used to monitor levels of EMS produced during the manufacture of nelfinavir, and there have been no explanations of why the toxicity was not discovered until patients receiving the drug noticed a "peculiar odor." One would want to believe that a compound known to be associated with teratogenicity, genotoxicity, and carcinogenicity, and known to be integral to the manufacturing process, would have undergone regular intensive monitoring.( 6 ) The fact that this contamination occurred in a drug manufactured by a large and reputable pharmaceutical company with a long history of drug development and quality control also raises questions regarding safety measures adopted by makers of generic drugs that produce many of the antiretrovirals available in developing countries.

Finally, there are a number of issues regarding drug safety and distribution. How will clinics in resource-poor countries be notified about recalled or unsafe drugs? If drugs are returned to the manufacturer, who is responsible for subsequent replacement of the drug? What alternative drugs will be available? Who is responsible for providing substitute ARVs so as not to interrupt antiretroviral treatment? If, as the manufacturer suggests, it may take months to replace existing stocks of nelfinavir, how long will it take in resource-poor countries? These questions currently have no clear answers. Let us hope that the problems specific to the nelfinavir contamination and the broader concerns highlighted by this issue result in improved safety and availability of ARVs for all.

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References

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  1. Lewcock A. Contamination Leads to EU-Wide Viracept Recall . In-PharmaTechnologist.com. June 7, 2007.
  2. U.S. Food and Drug Administration. Questions and Answers Regarding Health Concerns and Potential Shortage of Nelfinavir (Marketed as Viracept) . September 10, 2007.
  3. U.S. Department of Health and Human Services. DHHS Panel on Antiretroviral Therapy Guidelines for Adults and Adolescents--Notice on Nelfinavir FDA-Pfizer Letter . September 13, 2007.
  4. European Medicines Agency. Questions and Answers on the Follow-Up to the Viracept Recall . London; June 21, 2007.
  5. World Health Organization WHO Statement on Roche's Viracept Recall . June 14, 2007.
  6. Collins S. Treatment Alert. Update on Nelfinavir Recall: Plan for Safety Registries . HIV Treatment Bulletin. August/September 2007.
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