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Nelfinavir Nelfinavir 625 Viracept
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Brand Name: Viracept  Audio
Drug Class: Protease Inhibitors

Drug Description
Nelfinavir, a synthetic antiretroviral agent, is a nonpeptidic protease inhibitor (PI).[1]

HIV/AIDS-Related Uses
Nelfinavir mesylate was approved by the FDA on March 14, 1997, for use in combination with other antiretroviral agents for the treatment of HIV infection in adults and children 2 years of age or older.[2][3] It is also used in conjunction with other antiretroviral agents for postexposure prophylaxis in healthcare workers and other individuals exposed occupationally to blood, tissues, or other body fluids associated with a risk for transmission of HIV.[4]

In June 2007, high levels of ethyl methanesulfonate (EMS), a chemical used during the making of nelfinavir, were detected in European-made nelfinavir by the European manufacturer Roche Ltd. The U.S. manufacturer Pfizer released a statement in September 2007 to inform doctors that some amounts of EMS have been detected in nelfinavir manufactured in the United States. EMS may cause cancer in humans; in animals, EMS has caused birth defects and cancer.[5]

European-made nelfinavir was recalled in June 2007 by the European Union because of high levels of EMS.

As of March 31, 2008, Pfizer and FDA agreed on a final limit for EMS and nelfinavir is now safe for all patient populations, including pregnant females and pediatric patients.[6]

Dosing Information

Mode of Delivery
Oral.[7]

Dosage Form
Film-coated tablets containing nelfinavir 250 mg or 625 mg.[8]

Oral powder containing nelfinavir free base 50 mg per 1 g powder.[9]

The recommended dose of nelfinavir is 1,250 mg (five 250-mg tablets or two 625-mg tablets) twice daily or 750 mg (three 250-mg tablets) three times daily.[10]

The recommended dose of nelfinavir for children age 2 years and older is 45 to 55 mg/kg per dose twice daily, or 25 to 35 mg/kg per dose three times daily.[11]

Storage
Store nelfinavir mesylate tablets and powder between 15 C and 30 C (59 F and 86 F) in the original tightly closed container.[12]

Oral powder may be mixed with a small amount of water, milk, formula, soy products, or other dietary supplements. Mixed powder may be stored in the refrigerator for up to 6 hours.[13]

Pharmacology
Nelfinavir is a selective, competitive, reversible inhibitor of HIV protease, an enzyme that plays an essential role in HIV replication. Nelfinavir is pharmacologically related to other HIV PIs but is structurally different from these and other antiretroviral drugs that are currently available. Nelfinavir's structure inhibits the function of HIV protease, interfering with the formation of essential viral proteins. The drug is active in both acutely and chronically infected cells; chronically infected cells are not affected by nucleoside reverse transcriptase inhibitors (NRTIs). Although nelfinavir does not affect early stages of the HIV replication cycle, it does interfere with the production of infectious HIV, limiting further spread of the virus.[14]

Nelfinavir is active against HIV-1 and -2. Unlike nucleoside analogue antiretroviral agents, nelfinavir's antiviral activity does not require intracellular conversion to an active metabolite. PIs, including nelfinavir, act at a different stage of HIV replication than do NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). In vitro studies indicate that the antiretroviral effects of HIV PIs and some NRTIs or NNRTIs may be synergistic.[15]

Nelfinavir is well absorbed following oral administration, with peak plasma concentrations attained within 2 to 4 hours when 500 to 800 mg doses are administered with food. Distribution of nelfinavir into human tissues has not been fully characterized; however, following oral administration in animals, the volume of nelfinavir distribution suggests extensive tissue distribution. Results from a study of HIV infected adults receiving nelfinavir showed no detectable concentrations of the drug in cerebrospinal fluid in samples taken from 0.5 to 10 hours after administration.[16]

Highly variable drug exposure remains a significant problem with the use of nelfinavir in pediatric patients. Unpredictable drug exposure may be exacerbated in pediatric patients because of increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing.[17]

Nelfinavir is in FDA Pregnancy Category B. It is not known whether nelfinavir crosses the human placenta. There are no adequate and well-controlled studies to date using nelfinavir in pregnant women. Nelfinavir should be used during pregnancy only when clearly needed. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents, including nelfinavir. Physicians may register patients either online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether nelfinavir is distributed into human milk; however, it is distributed into milk in rats. Breastfeeding is not recommended for HIV infected mothers because of the potential for HIV transmission to the breastfed infant.[18]

Nelfinavir is more than 98% bound to plasma proteins.[19] Because nelfinavir is metabolized to many oxidative metabolites, principally by the liver, the manufacturer recommends caution when administering the drug to patients with hepatic impairment. Metabolism is mediated by several cytochrome (CYP) P450 isoenzymes, including CYP3A and CYP2C19. In patients older than 13 years, plasma elimination half-life is 3.5 to 5 hours; in children 2 to 13 years old, nelfinavir clearance is two to three times greater than in adults. Nelfinavir is excreted principally in the feces, both as unchanged drug and metabolites.[20]

Generally, multiple mutations are necessary for high level resistance to HIV PIs. Nelfinavir-resistant variants with more than one mutation have been isolated in vitro. In clinical trials, patients receiving nelfinavir had HIV variants with mutations at amino acid positions 30, 35, 36, 46, 71, 77, and 88. The principal initial amino acid change occurs at position 30 and appears necessary for nelfinavir resistance. In clinical studies, the overall incidence of the D30N mutation among patients receiving nelfinavir alone or in combination with NRTIs was 54.8%. The overall incidence for other mutations associated with primary resistance was 9.6% for the L90M substitution, whereas substitutions at 48, 82, or 84 were not observed.[21]

Clinical evidence suggests that some degree of cross resistance can occur among various HIV PIs; however, cross resistance between nelfinavir and other PIs has not been fully explored. Limited evidence suggests that mutations associated with decreased susceptibility to nelfinavir are different from those associated with decreased susceptibility to other PIs. Mutations associated with resistance to other PIs appear to confer high-level cross resistance to nelfinavir. Cross resistance between nelfinavir and NRTIs and NNRTIs is highly unlikely because these drugs target different enzymes.[22]

Adverse Events/Toxicity
Nelfinavir appears well tolerated; its principal adverse effects are mild to moderate diarrhea and nausea. Other reactions include flatulence and rash.[23]


Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy.[24]

Hyperlipidemia, increased bleeding in hemophilia patients, hyperglycemia, exacerbation of existing diabetes mellitus, and new onset diabetes mellitus have been reported in patients receiving PIs, including nelfinavir.[25]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine. During the initial phase of combination antiretroviral treatment, a patient whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), or tuberculosis, which may necessitate further evaluation and treatment.[26]

Drug And Food Interactions
Presence of food in the gastrointestinal tract substantially increases absorption of oral nelfinavir. Peak plasma concentration and area under the plasma concentration-time curve of nelfinavir are two- to threefold and three- to fivefold higher, respectively, when the drug is administered with a meal than when administered under fasting conditions.[27]

Metabolism of nelfinavir is mediated in part by the CYP450 enzymes CYP3A and CYP2C19. Drugs that induce these isoenzymes may reduce nelfinavir plasma concentration. Conversely, concomitant administration of nelfinavir with drugs that inhibit CYP3A may increase nelfinavir plasma concentrations. In addition, nelfinavir may alter the pharmacokinetics of other drugs that are metabolized by this enzyme system, creating the possibility of serious adverse effects. Dosage adjustments may be necessary in patients concurrently receiving nelfinavir and other drugs that are extensively metabolized by or that induce or inhibit the CYP3A isoenzyme.[28]

Concurrent use of nelfinavir with lovastatin or simvastatin is not recommended. Caution should be used when any HIV PIs, including nelfinavir, are used concurrently with other HMG-CoA reductase inhibitors that are metabolized by the CYP3A pathway (for example, atorvastatin or cerivastatin). The resulting increased concentration of statins may increase the risk of myopathy or rhabdomyolysis.[29]

Nelfinavir should not be coadministered with astemizole, cisapride, or terfenadine.[30]

Other drugs that should not be coadministered with nelfinavir include amiodarone, ergot derivatives, midazolam, quinidine, pimozide, rifampin, and triazolam. Nelfinavir may affect the hepatic metabolism of these drugs, creating the potential for serious or life-threatening effects.[31]

Concomitant use of products containing St. John's wort (Hypericum perforatum) with nelfinavir or other PIs is not recommended. St. John's wort is expected to substantially decrease plasma drug levels and may lead to loss of virologic response and possible resistance to nelfinavir or other PIs.

Caution should be used when prescribing sildenafil in patients receiving PIs, including nelfinavir. Coadministration of a PI with sildenafil is expected to substantially increase sildenafil concentrations and, possibly, sildenafil-associated adverse effects, including hypotension, visual changes, and priapism.[32]

Concomitant use of nelfinavir mesylate with certain other drugs may significantly increase or decrease plasma concentrations of nelfinavir or of the coadministered drug. Adjustment in dosage or regimen should be considered when nelfinavir is coadministered with any of the following drugs: delavirdine, indinavir, methadone, nevirapine, oral contraceptives containing ethinyl estradiol, rifabutin, ritonavir, or saquinavir.[33]

Other drugs that may have a significant interaction when coadministered with nelfinavir include azithromycin, carbamazepine, cyclosporine, didanosine, fluticasone propionate, phenobarbital, phenytoin, trazodone, sirolimus, and tacrolimus.[34]

Contraindications
Nelfinavir mesylate is contraindicated in patients with clinically significant hypersensitivity to the drug or any components in the formulation.[35]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Nelfinavir.

Chemistry

CAS Name
[3S-[2(2S*,3S*),3alpha,4abeta, 8abeta]]-N-(1,1-dimethylethyl)decahydro-2- [2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino]-4-(phenylthio)butyl]-3- isoquinoline carboxamide mono- methanesulfonate (salt)[36]

CAS Number
159989-65-8[37]

Molecular Formula
C32-H45-N3-O4-S.C-H4-O3-S[38]

Elemental Composition
C59.70%, H7.44%, N6.33%, O16.87%, S9.66%[39]

Molecular Weight
663.90 (Nelfinavir mesylate)[40]

Physical Description
White to off-white amorphous powder.[41]

Solubility
Slightly soluble in water at pH of 4.0 or less; freely soluble in methanol, ethanol, isopropanol, and propylene glycol.[42]

Other Names
NFV[43]

Further Reading
Viracept Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.

PMID/15880318 Bruno R, Sacchi P, Maiocchi L, Zocchetti C, Filice G. Hepatotoxicity and nelfinavir: a meta-analysis. Clin Gastroenterol Hepatol. 2005 May;3(5):482-8. Review.

PMID/16156881 Justesen US, Hansen IM, Andersen AB, Klitgaard NA, Black FT, Gerstoft J, Mathiesen LR, Pedersen C. The long-term pharmacokinetics and safety of adding low-dose ritonavir to a nelfinavir 1,2500 mg twice-daily regimen in HIV-infected patients. HIV Med. 2005 Sep;6(5):334-40.

PMID/16220085 King JR, Nachman S, Yogev R, Hodge J, Aldrovandi G, Hughes MD, Chen J, Wiznia A, Damle B, Acosta EP. Efficacy, Tolerability and Pharmacokinetics of Two Nelfinavir-Based Regimens in Human Immunodeficiency Virus-Infected Children and Adolescents: Pediatric AIDS Clinical Trials Group Protocol 403. Pediatr Infect Dis J. 2005 Oct:24(10):880-885.

PMID/16720565 Mira JA, Macías J, Girón-González JA, Merino D, González-Serrano M, Jiménez-Mejías ME, Caballero-Granado FJ, Torre-Cisneros J, Terrón A, Becker MI, Gómez-Mateos J, Arizcorreta-Yarza A, Pineda JA; Grupo Andaluz Para el Estudio de las Enfermedades Infecciosas (GAEI). Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother. 2006 Jul;58(1):140-6. Epub 2006 May 23.

PMID/18160009 Kakehasi FM, Tupinambás U, Cleto S, Aleixo A, Lin E, Melo VH, Aguiar RA, Pinto JA. Persistence of genotypic resistance to nelfinavir among women exposed to prophylactic antiretroviral therapy during pregnancy. AIDS Res Hum Retroviruses. 2007 Dec;23(12):1515-20.

PMID/16225378 Perry CM, Frampton JE, McCormack PL, Siddiqui MA, Cvetkovic RS. Nelfinavir: A Review of its Use in the Management of HIV Infection. Drugs. 2005;65(15):2209-44.

Manufacturer Information
Nelfinavir
  Pfizer Inc
  235 East 42nd Street
  New York,  NY  10017-5755
  (800) 438-1985
    

Viracept
  Pfizer Inc
  235 East 42nd Street
  New York,  NY  10017-5755
  (800) 438-1985
    

References
[1] AHFS Drug Information - 2007; p. 649
[2] FDA - Drugs Used in the Treatment of HIV Infection. Available at: http://www.fda.gov/oashi/aids/virals.html. Accessed 03/14/08.
[3] FDA - Drugs Used in the Treatment of Pediatric HIV Infection. Available at: http://www.fda.gov/oashi/aids/pedlbl.html. Accessed 03/14/08.
[4] AHFS Drug Information - 2007; p. 650
[5] FDA - Viracept (nelfinavir mesylate) 250 mg, 625 mg Tablets, Powder for Suspension: Important Information for Prescribers. [Dear Health Care Professional Letter]. New York: Pfizer; September 10, 2007 - Available at: http://www.fda.gov/medwatch/safety/2007/VIRACEPT_HCPLetter_9_10_07.pdf. Accessed 03/14/08.
[6] FDA - FDA - Viracept (nelfinavir mesylate) 250 mg, 625 mg Tablets, Powder for Suspension: Important Information for Prescribers. [Dear Health Care Professional Letter]. New York: Pfizer; May 6, 2008 - Available at: http://aidsinfo.nih.gov/contentfiles/NFV_prescribing_info.pdf. Accessed 05/09/08.
[7] AHFS Drug Information - 2007; p. 650
[8] FDA - Viracept Prescribing Information, 02/13/08, p. 28. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[9] FDA - Viracept Prescribing Information, 02/13/08, p. 29. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[10] FDA - Viracept Prescribing Information, 02/13/08, pp. 27-8. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[11] FDA - Viracept Prescribing Information, 02/13/08, pp. 27-8. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[12] FDA - Viracept Prescribing Information, 02/13/08, p. 29. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[13] FDA - Viracept Prescribing Information, 02/13/08, p. 28. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[14] AHFS Drug Information - 2007; pp. 655-6
[15] AHFS Drug Information - 2007; pp. 655-6
[16] AHFS Drug Information - 2007; p. 657
[17] FDA - Viracept Prescribing Information, 02/13/08, pp. 6, 23. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[18] FDA - Viracept Prescribing Information, 02/13/08, pp. 22-3. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[19] FDA - Viracept Prescribing Information, 02/13/08, p. 5. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[20] FDA - Viracept Prescribing Information, 02/13/08, pp. 5-6, 16. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[21] FDA - Viracept Prescribing Information, 02/13/08, p. 2. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[22] FDA - Viracept Prescribing Information, 02/13/08, p. 2. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[23] FDA - Viracept Prescribing Information, 02/13/08, pp. 24-5. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[24] FDA - Viracept Prescribing Information, 02/13/08, p. 17. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[25] FDA - Viracept Prescribing Information, 02/13/08, pp. 16-7. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[26] FDA - Viracept Prescribing Information, 02/13/08, p. 19 Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[27] FDA - Viracept Prescribing Information, 02/13/08, p. 4. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[28] FDA - Viracept Prescribing Information, 02/13/08, pp. 15-6. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[29] FDA - Viracept Prescribing Information, 02/13/08, p. 16. Available at: http://www.fda.gov/cder/foi/label/2008/02778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[30] AHFS Drug Information - 2007; pp. 653-4
[31] FDA - Viracept Prescribing Information, 02/13/08, p. 19. Available at: http://www.fda.gov/cder/foi/label/2008/02778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[32] FDA - Viracept Prescribing Information, 02/13/08, p. 16. Available at: http://www.fda.gov/cder/foi/label/2008/02778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[33] FDA - Viracept Prescribing Information, 02/13/08, pp. 7-8. Available at: http://www.fda.gov/cder/foi/label/2008/02778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[34] FDA - Viracept Prescribing Information, 02/13/08, pp. 20-3. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[35] FDA - Viracept Prescribing Information, 02/13/08, p. 15. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[36] FDA - Viracept Prescribing Information, 02/13/08, p. 1. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[37] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/14/08.
[38] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/14/08..
[39] Calculation. -
[40] FDA - Viracept Prescribing Information, 02/13/08, p. 1. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[41] FDA - Viracept Prescribing Information, 02/13/08, p. 1. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[42] FDA - Viracept Prescribing Information, 02/13/08, p. 1. Available at: http://www.fda.gov/cder/foi/label/2008/020778s029,020779s050,021503s011lbl.pdf. Accessed 03/14/08.
[43] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/14/08.
Updated March 14, 2008