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Nelfinavir (Viracept)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of nelfinavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for nelfinavir treatment
Special Issues - Safety
References
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Drug Labeling (Package Insert)
Nelfinavir (Viracept)
Class

Protease inhibitor

Background
U.S. Manufacturer

Pfizer

Approval

Nelfinavir received approval from the U.S. Food and Drug Administration (FDA) in 1997 for the treatment of adults and children with HIV infection. Initial approval was based on studies showing increases in CD4 T-lymphocyte counts and reductions in HIV viral load in individuals receiving nelfinavir either alone or in combination with 1 or 2 nucleoside analogues. These changes were superior to those seen with nucleoside analogues alone.

Formulation and Dosing

Nelfinavir is available in tablets for adult and pediatric dosing. The oral powder formulation is no longer available. For adults or children who are unable to swallow pills, the tablets may be crushed or dissolved in water.

Dosing of Nelfinavir
Adult1,250 mg BID
750 mg TID
Pediatric*Age <2 yearsNot FDA approved; serum drug levels variable
Age 2-13 years45-55 mg/kg BID or 25-35 mg/kg TID
AdolescentAdult dose

Key to abbreviations: BID, twice daily; TID, 3 times daily.

*In pediatric patients, nelfinavir exposure is highly variable.

Nelfinavir must be taken with a meal.
No dose adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Combinations

Regimens consisting of 2 nucleoside analogues and nelfinavir have been found to provide potent suppression of viral load in previously untreated individuals. Regimens containing nelfinavir have also been studied in treatment-experienced individuals (see "Use in Inital vs Subsequent Therapy").

Nelfinavir is an inhibitor of cytochrome P450 3A (CYP3A). Coadministration with nelfinavir may therefore cause clinically significant alterations in serum levels of several drugs, including other protease inhibitors, certain benzodiazepines, oral contraceptives, and ergot derivatives. Because nelfinavir is also metabolized in part by CYP3A, drugs that affect this enzyme system, such as ketoconazole, rifampin, and rifabutin, may affect nelfinavir levels. Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.

Use in Initial vs Subsequent Therapy

Treatment guidelines of the U.S. Department of Health and Human Services state that nelfinavir is "not recommended" for initial treatment of HIV infection in adults and adolescents, because it is less effective than other agents.

Failure of a regimen containing nelfinavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed, but there is evidence that changing to a regimen containing ritonavir + another protease inhibitor (eg, saquinavir) may achieve long-term suppression of viral load following failure of an initial nelfinavir-containing regimen.(1)

Nelfinavir has been studied as a component of subsequent therapies. In patients with nucleoside analogue experience, combinations containing nelfinavir + efavirenz were effective at suppressing viral load.(2) Nelfinavir combined with saquinavir and nucleoside analogues has been studied in patients without prior protease inhibitor use and compares favorably with regimens containing one protease inhibitor.(3) In patients with virologic relapse on indinavir-containing regimens, regimens containing nelfinavir + efavirenz + abacavir + adefovir were effective in the short term, especially if the viral load was <15,000 copies/mL at the time of switching.(4)

Factors Affecting Adherence

The most common symptomatic side effect of nelfinavir is diarrhea, which usually can be controlled with nonprescription antidiarrheals or antimotility agents. As with other protease inhibitors, nelfinavir may cause dyslipidemia and abnormalities of body fat distribution.

It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with a protease inhibitor is initiated.

Nelfinavir has been studied in patients taking the drug during pregnancy; it is classified as an FDA Pregnancy Category B drug. However, the FDA recommends that it not be used for the treatment of pregnant women (see "Special Issues" below).

Resistance

Resistance to nelfinavir is associated with the selection of 1 or more of several resistance mutations.

Implications of nelfinavir resistance for treatment with other antiretrovirals

Resistance mutations selected by nelfinavir may or may not confer or contribute to resistance against other protease inhibitors. The commonly selected D30N mutation does not appear to be associated with resistance to other drugs, while the L90M mutation, which is less commonly selected by nelfinavir, confers or contributes to resistance to all other protease inhibitors.

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing nelfinavir.

Implications of resistance to other antiretrovirals for nelfinavir treatment

The likelihood of sustained response to nelfinavir is diminished in the setting of resistance to other protease inhibitors.

Genotypic or phenotypic resistance testing may be useful in predicting the likelihood of response to nelfinavir following failure of regimens containing other protease inhibitors.

Special Issues - Safety

In 2007, nelfinavir manufactured in Europe was recalled from the market because of high levels of ethyl methane mesylate (EMS). Nelfinavir manufactured in United States was found to have lower levels of EMS than the European product. However, the FDA recommended that pregnant women not be treated with nelfinavir and that pediatric patients not be initiated on nelfinavir. By early 2008, nelfinavir manufactured both in Europe and in the United States was determined to meet safety standards, and the FDA and European Medicines Agency had lifted its warnings about safety. 5

References
1.   Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K. Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-8.
2.   Albrecht MA, Bosch RJ, Hammer SM, Liou SH, Kessler H, Para MF, Eron J, Valdez H, Dehlinger M, Katzenstein DA; AIDS Clinical Trials Group 364 Study Team. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med. 2001;345(6):398-407.
3.   Moyle G, Pozniak A, Opravil M, Clumeck N, DelFraissy JF, Johnson M, Pelgrom J, Reynes J, Vittecoq D, DeLora P, Salgo M, Duff F. The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe. J Acquir Immune Defic Syndr 2000;23:128-37.
4.   Hammer SM, Bassett R, Squires KE, Fischl MA, Demeter LM, Currier JS, Mellors JW, Morse GD, Eron JJ, Santana JL, DeGruttola V; ACTG 372B/D Study Team. A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV-1-infected persons with virological failure receiving indinavir. Antivir Ther. 2003 Dec;8(6):507-18.
5.  Pfizer. Viracept (nelfinavir mesylate) 250 mg, 625 mg tablets, and Powder for Oral Suspension, Important Information for Prescribers (Dear Healthcare Professional Letter). May 6, 2008. Available online at http://aidsinfo.nih.gov/contentfiles/NFV_prescribing_info.pdf