Nelfinavir

Pronunciation

(nel FIN a veer)

U.S. Brand Names

Viracept®

Synonyms

NFV

Generic Available

Canadian Brand Names

Viracept®

Use

In combination with other antiretroviral therapy in the treatment of HIV infection

Pregnancy Risk Factor

Pregnancy Implications

The Perinatal HIV Guidelines Working Group recommends nelfinavir as the preferred PI in combination regimens during pregnancy, especially with HAART for perinatal prophylaxis. A dose of 1250 mg twice daily has been shown to provide adequate plasma levels; 750 mg 3 times/day produced low and variable levels. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to nelfinavir or any component of the formulation; concurrent therapy with amiodarone, ergot derivatives, midazolam, pimozide, quinidine, triazolam; additional medications which should not be coadministered (per manufacturer) include lovastatin and simvastatin

Warnings/Precautions

Nelfinavir is hepatically metabolized and has multiple drug interactions. A listing of medications that should not be used is available with each bottle and patients should be provided with this information. Use caution with hepatic impairment. Warn patients that redistribution of body fat can occur. New onset diabetes mellitus, exacerbation of diabetes, and hyperglycemia have been reported in HIV-infected patients receiving protease inhibitors. The oral powder contains phenylalanine; use caution in patients with phenylketonuria.

Adverse Reactions

>10%: Gastrointestinal: Diarrhea

2% to 10%:

Dermatologic: Rash

Gastrointestinal: Nausea, flatulence

Hematologic: Abnormal creatine kinase, hemoglobin, lymphocytes, neutrophils

Hepatic: Abnormal ALT, AST

<2% (Limited to important or life-threatening): Acute iritis, allergic reaction, amylase increased, anemia, anorexia, anxiety, arthralgia, back pain, body fat redistribution/accumulation, creatinine phosphokinase increased, dehydration, depression, diaphoresis, dizziness, dyspepsia, dyspnea, epigastric pain, fever, folliculitis, gamma glutamyl transpeptidase increased, gastrointestinal bleeding, headache, hepatitis, hyperkinesia, hyperglycemia, hyperlipemia, hyperuricemia, hypoglycemia, insomnia, kidney calculus, lactic dehydrogenase increased, leukopenia, maculopapular rash, myalgia, myasthenia, myopathy, pain, pancreatitis, paresthesia, pruritus, seizure, sexual dysfunction, sleep disorder, somnolence, suicidal ideation, thrombocytopenia, urticaria, vomiting, weakness

Postmarketing and/or case reports: Bilirubinemia; hypersensitivity reaction (bronchospasm, rash, edema); jaundice, metabolic acidosis, QTc prolongation, torsade de pointes

Overdosage/Toxicology

Limited data available; however, unabsorbed drug should be removed via gastric lavage and activated charcoal; significant symptoms beyond gastrointestinal disturbances are likely following acute overdose; hemodialysis will not be effective due to high protein binding of nelfinavir

Drug Interactions

Substrate of CYP2C8/9 (minor), 2C19 (major), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2B6 (weak), 2C8/9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (strong)

Amiodarone: Serum levels/toxicity may be increased by nelfinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Anticonvulsants: Phenobarbital, and carbamazepine may decrease serum levels and consequently effectiveness of nelfinavir. Nelfinavir may decrease plasma levels of phenytoin. Consider obtaining nelfinavir levels.

Azithromycin: Serum levels may be increased by azithromycin; monitor

Benzodiazepines: An increase in midazolam and triazolam serum levels may occur resulting in significant oversedation when administered with nelfinavir. Concurrent use is contraindicated. Use caution with other benzodiazepines.

Cisapride: Nelfinavir inhibits the metabolism of cisapride and should, not be administered concurrently due to risk of life-threatening cardiac arrhythmias.

CYP2C19 inducers: May decrease the levels/effects of nelfinavir. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of nelfinavir. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Nelfinavir may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Ergot alkaloids: Serum levels/toxicity may be increased by nelfinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

HMG-CoA reductase inhibitors: Nelfinavir may increase levels of HMG-CoA reductase inhibitors, increasing the risk of myopathy. Lovastatin and simvastatin should not be coadministered with nelfinavir (per manufacturer). Atorvastatin may be used with careful monitoring, in the lowest dose possible. Fluvastatin and pravastatin may have lowest risk.

Immunosuppressants: Nelfinavir may increase the serum levels of cyclosporine, sirolimus or tacrolimus.

Methadone: Serum levels of methadone are decreased by nelfinavir.

Non-nucleoside reverse transcriptase inhibitors: Nevirapine decreases serum levels of nelfinavir. When used with delavirdine, serum levels of nelfinavir are increased and levels of delavirdine are decreased. The safety of these combinations has not been established.

Oral contraceptives: Serum levels of the hormones in oral contraceptives may decrease significantly with administration of nelfinavir. Patients should use alternative methods of contraceptives during nelfinavir therapy. Ethinyl estradiol, norethindrone concentrations are decreased by nelfinavir.

Pimozide: Serum levels/toxicity may be increased by nelfinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Protease inhibitors: Serum levels of both nelfinavir and indinavir are increased with concurrent use; nelfinavir increases serum levels of saquinavir; ritonavir increase serum levels of nelfinavir. The safety of these combinations has not been established.

Quinidine: Serum levels/toxicity may be increased by nelfinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Rifabutin: A 200% increase in rifabutin plasma AUC has been observed when coadministered with nelfinavir (decrease rifabutin's dose by 50%).

Rifampin: Rifampin decreases nelfinavir's plasma AUC by ~82%; loss of virologic response and resistance may occur; the two drugs should not be administered together.

Sildenafil: Sildenafil serum concentration may be substantially increased (do not exceed single doses of 25 mg in 48 hours).

St John's wort ( Hypericum perforatum ): Appears to induce CYP3A enzymes and may lead to reduction in trough serum concentrations, which may lead to treatment failures. Alternatively, changes may involve P-glycoprotein. The two drugs should not be used together.

Tadalafil: Serum concentrations may be increased by nelfinavir. A maximum tadalafil dose of 10 mg in 72 hours is recommended with strong CYP3A4 inhibitors.

Vardenafil: Serum concentrations may be increased by nelfinavir. Specific dosage adjustment guidelines have not been established. Recommendations for other strong CYP3A4 inhibitors include vardenafil dose not to exceed 2.5 mg in 24 hours.

Ethanol/Nutrition/Herb Interactions

Food: Nelfinavir taken with food increases plasma concentration time curve (AUC) by two- to threefold. Do not administer with acidic food or juice (orange juice, apple juice, or applesauce) since the combination may have a bitter taste.

Herb/Nutraceutical: St John's wort may decrease nelfinavir serum concentrations; avoid concurrent use.

Stability

Store at room temperature. Oral powder (or dissolved tablets) diluted in nonacidic liquid is stable for 6 hours under refrigeration.

Mechanism of Action

Inhibits the HIV-1 protease; inhibition of the viral protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, noninfectious virus

Pharmacodynamics/Kinetics

Absorption: Food increases plasma concentration-time curve (AUC) by two- to threefold

Distribution: Vd: 2-7 L/kg

Protein binding: 98%

Metabolism: Hepatic via CYP2C19 and 3A4; major metabolite has activity comparable to parent drug

Half-life elimination: 3.5-5 hours

Time to peak, serum: 2-4 hours

Excretion: Feces (98% to 99%, 78% as metabolites, 22% as unchanged drug); urine (1% to 2%)

Dosage

Oral:

Children 2-13 years: 45-55 mg/kg twice daily or 25-35 mg/kg 3 times/day (maximum: 2500 mg/day); all doses should be taken with a meal. If tablets are unable to be taken, use oral powder in small amount of water, milk, formula, or dietary supplements; do not use acidic food/juice or store for >6 hours.

Adults: 750 mg 3 times/day with meals or 1250 mg twice daily with meals in combination with other antiretroviral therapies

Note: Dosage adjustments for nelfinavir when administered in combination with ritonavir: Nelfinavir 500-750 mg twice daily plus ritonavir 400 mg twice daily

Dosing adjustment in renal impairment: No adjustment needed

Dosing adjustment in hepatic impairment: Use caution

Administration

Mix powder or tablets in a small amount of water, milk, formula, soy milk, soy formula, or dietary supplement. Be sure entire contents is consumed to receive full dose. Do not use acidic food/juice to dilute due to bitter taste. One mixed, solution should be used immediately, but may be stored for up to 6 hours if refrigerated.

Monitoring Parameters

Liver function tests, viral load, CD4 count, triglycerides, cholesterol, blood glucose, CBC with differential

Dietary Considerations

Should be taken as scheduled with food. Oral powder contains phenylalanine 11.2 mg/g.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug is not a cure for HIV and has not been shown to reduce the risk of transmitting HIV to others. The long-term effects of use are not known. Take exactly as directed with food. Mix powder with nonacid, noncitric fluids, and do not store reconstituted powder mixture for longer than 6 hours. If unable to swallow tablets whole, the tablet may be dissolved in water or crushed in food. Mixed or dissolved tablets must be consumed within 6 hours. If you miss a dose, take as soon as possible and return to your regular schedule (never take a double dose). Frequent blood tests may be required with prolonged therapy. May cause nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report rash; respiratory difficulty; CNS changes (migraine, confusion, suicidal ideation); muscular or skeletal pain, weakness, or tremors; or other adverse reactions. Pregnancy/breast-feeding precautions: Use appropriate barrier contraceptive measures (as alternative to oral contraceptives) to reduce risk of transmitting infection and potential pregnancy. Do not breast-feed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Mouth ulcers.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness, anxiety, insomnia, difficulty concentrating, depression, and suicidal ideation

Mental Health: Effects on Psychiatric Treatment

May rarely cause leukopenia; use caution with clozapine and carbamazepine; concurrent use with midazolam and triazolam may produce oversedation; barbiturates and carbamazepine may decrease the effectiveness of nelfinavir. Concomitant use of nelfinavir and St John's wort is not recommended. Coadministration of protease inhibitors (nelfinavir) with St John's wort is expected to substantially decrease protease inhibitor serum concentrations leading to a loss of virologic response and possible resistance to nelfinavir or to the class of protease inhibitors.

Dosage Forms

Powder, oral: 50 mg/g (144 g) [contains phenylalanine 11.2 mg/g]

Tablet [film coated]: 250 mg, 625 mg

References

Deeks SG, Smith M, Holodniy M, et al, "HIV-1 Protease Inhibitors. A Review for Clinicians," JAMA , 1997, 277(2):145-53.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," March 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed April 7, 2004.

Havlir DV and Lange JM, "New Antiretrovirals and New Combinations," AIDS , 1998, 12(Suppl A):165-74.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction," Am J Health Syst Pharm , 1998, 55:2528-33.

Kakuda TN, Struble KA, and Piscitelli SC, "Protease Inhibitors for the Treatment of Human Immunodeficiency Virus Infection," Am J Health Syst Pharm , 1998, 55(3):233-54.

Kaufman MB and Simionatto C, "A Review of Protease Inhibitor-Induced Hyperglycemia," Pharmacotherapy , 1999, 19(1):114-7.

Kaul DR, Cinti SK, Carver PL, et al, "HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications," Pharmacotherapy , 1999, 19(3):281-98.

McDonald CK and Kuritzkes DR, "Human Immunodeficiency Virus Type 1 Protease Inhibitors," Arch Intern Med , 1997, 157(9):951-9.

Perry CM and Benfield P, "Nelfinavir," Drugs , 1997, 54(1):81-7.

"Public Health Service Task Force 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," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

Rana KZ and Dudley MN, "Human Immunodeficiency Virus Protease Inhibitors," Pharmacotherapy , 1999, 19(1):35-59.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," January 20, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed April 7, 2004.

International Brand Names

Filosfil® (AR); Nelfilea® (AR); Nelfinavir® (AR); Viracept® (AR, AT, AU, BE, BR, CA, CH, CL, CO, DE, DK, ES, FR, GB, HR, IE, IL, IT, NL, NO, NZ, PL, PT, RO, RU, SE, SI, TH, YU)

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