AHFS Class:

• HIV Protease Inhibitors 8:18.08.08

Generic Name(s):

• Nelfinavir Mesylate

Nelfinavir mesylate, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1

Treatment of HIV Infection

Nelfinavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age or older.1

Nelfinavir, a protease inhibitor (PI), was previously used as a component of a fully suppressive antiretroviral regimen; however, guidelines no longer recommend its use due to inferior virological efficacy and toxicities.200,201,202 Consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults

Nelfinavir has been evaluated for use in conjunction with nucleoside reverse transcriptase inhibitors (NRTIs) for initial antiretroviral therapy in antiretroviral-naïve adults in a phase 3, randomized, double-blind study (Study 511) that included 297 adults (median age 35 years; 89% male; 78% white) with HIV infection (mean baseline CD4⁺ count 288/mm³ and mean baseline plasma HIV-1 RNA levels 5.21 log₁₀ [160,394 copies/mL]).1,121 Patients were randomized to receive a 3-drug regimen of oral nelfinavir (500 or 750 mg 3 times daily), zidovudine (200 mg 3 times daily), and lamivudine (150 mg twice daily) or a 2-drug regimen of zidovudine and lamivudine.1,121 The primary outcome was antiretroviral activity, as assessed by plasma HIV-1 RNA levels and CD4⁺ count.121

At week 24, 67 or 50% of patients given nelfinavir 750 or 500 mg 3 times daily achieved an HIV-1 RNA level of <400 copies/mL; only 7% of patients given zidovudine/lamivudine alone achieved this outcome.121 An HIV-1 RNA level of <50 copies/mL was achieved in 55, 30, or 4% of patients given nelfinavir 750 mg, nelfinavir 500 mg, or zidovudine/lamivudine alone, respectively.121 At 48 weeks, 86% of patients given nelfinavir achieved an HIV-1 RNA level of <400 copies/mL.1 Mean change in CD4⁺ count for nelfinavir treated patients was +207.6 cells/mm³.1

Study 542 was a randomized, open-label trial comparing the efficacy of nelfinavir 1250 mg twice daily to nelfinavir 750 mg 3 times daily, both given in conjunction with stavudine (30-40 mg twice daily) and lamivudine (150 mg twice daily).1 Patients were a median 36 (range 18-83) years of age, 84% were male, and 91% were white.1 The mean baseline CD4⁺ count was 296 cells/mm³ and mean HIV-1 RNA level was 5 log₁₀ (100,706) copies/mL; all patients were naïve to treatment with PIs and had received <6 months of treatment with NRTIs.1 At 48 weeks, 323 patients given nelfinavir 1250 mg twice daily and 192 patients given a 3-times daily regimen of 750 mg were evaluable for efficacy.1 An HIV-1 RNA level of <400 copies/mL was seen in 61 or 58% of patients in the 2-times or 3-times daily nelfinavir regimen, respectively.1

Efficacy of a 3-drug regimen of nelfinavir (750 mg 3 times daily), zidovudine (300 mg twice daily), and lamivudine (150 mg twice daily) was compared to a 2-drug regimen (zidovudine/lamivudine plus placebo) in a placebo-controlled, randomized, double-blind study (AVANTI 3).1,500 A total of 105 antiretroviral-naïve adults (mean age of 35 years [range 22-59], 89% male; 88% white) were randomly assigned to treatment with either the 3-drug or 2-drug regimen.1,500 Baseline mean CD4⁺ count was 304 cells/mm³ and mean baseline plasma HIV-1 RNA levels was 4.8 log₁₀ (57,887) copies/mL.1 At 52 weeks, 54% of those receiving nelfinavir, zidovudine, and lamivudine had plasma HIV-1 RNA levels <50 copies/mL compared with only 13% of those receiving the two NRTIs alone.1

Antiretroviral-experienced Adults and Adolescents

Nelfinavir was evaluated for use in antiretroviral-experienced patients in a randomized, double-blind study (ACTG 364).1,501 The study enrolled 195 adult patients previously only treated with nucleoside analogues and with HIV-1 RNA levels ≥500 copies/mL.501 Patients received prolonged prior therapy with NRTIs and had completed 2 previous ACTG studies.1

Patients were randomly assigned to treatment with either nelfinavir (750 mg 3 times daily), efavirenz (600 mg daily), or nelfinavir plus efavirenz; all patients also received 2 nucleoside analogues (didanosine/stavudine, didanosine/lamivudine, or stavudine/lamivudine).1,501 The primary outcome was the proportion of patients with an HIV-1 RNA level of <500 copies/mL at 16 weeks, with a secondary outcome of HIV-1 RNA levels measured at 40 and 48 weeks.501 Enrolled patients were a median 41 (range 18-75) years of age , 88% male, and 74% white; mean baseline CD4⁺ counts were 389 cells/mm³ and mean plasma HIV-1 RNA levels were 3.9 log₁₀ (7,954) copies/mL.1 At 16 weeks, 64, 69, or 81% of patients in the nelfinavir, efavirenz, or nelfinavir/efavirenz groups achieved an HIV-1 RNA level of <500 copies/mL.501 At 48 weeks, 42, 62, or 72% of patients receiving nelfinavir, efavirenz, or nelfinavir/efavirenz, respectively, had plasma HIV-1 RNA levels <500 copies/mL.1 The 4-drug regimen that included both nelfinavir and efavirenz was more effective in suppressing viral load than either 3-drug regimen.501

Pediatric Patients

Safety and efficacy of nelfinavir in conjunction with zidovudine and didanosine were evaluated in a randomized, double-blind, placebo-controlled trial in 141 HIV-infected pediatric patients who received minimal prior antiretroviral therapy (Study 556).1 The mean age of the patients was 3.9 years (67% were 2-12 years of age, 33% were <2 years of age).1 The mean baseline HIV-1 plasma RNA level was 5 log₁₀copies/mL and the mean CD4⁺ count was 886 cells/mm³.1 In patients ≥2 years of age, 26% who received nelfinavir had plasma HIV-1 RNA levels <400 copies/mL at 48 weeks compared with 2% who received placebo.1 In children <2 years of age, only 1 of 27 patients in the placebo group and 2 of 20 patients in the nelfinavir group maintained an undetectable HIV RNA level at 48 weeks.1

PACTG 377 was a randomized, open-label study that enrolled 181 antiretroviral-experienced, PI-naïve patients between 4 months and 17 years of age (median 5.9 years of age).1,156 At baseline, the median HIV-1 RNA level was 4.4 log₁₀ copies/mL and the median CD4⁺ count was 690 cells/mm³.1 Patients were randomized to receive 1 of 3 nelfinavir-containing treatment regimens (nelfinavir plus stavudine/lamivudine, nelfinavir plus stavudine/nevirapine, or nelfinvair plus stavudine/lamivudine/nevirapine) or to stavudine/nevirapine/ritonavir.156 Nelfinavir was given 3 times a day.1 A fifth treatment arm (Substudy PACTG 725) included patients treated with stavudine/lamivudine with nelfinavir given twice daily.156 The primary outcome was HIV-1 RNA response.156

At 48 weeks, the proportions of patients with an HIV-1 RNA level of <400 copies/mL were 42, 30, 52, or 41% for nelfinavir/stavudine/lamivudine, nelfinavir/stavudine/nevirapine, nelfinavir/stavudine/lamivudine/nevirapine, or stavudine/nevirapine/ritonavir, respectively.1 No significant difference was seen between twice daily and 3-times daily nelfinavir.1

Some studies have shown poorer response rates in infants and children younger than 2 years of age† treated with nelfinavir compared to pediatric patients aged ≥2 years.1 PENTA-7 was a phase 1/2, open-label study evaluating efficacy of nelfinavir plus stavudine and didanosine in 20 HIV-infected infants <12 weeks of age†.1,502 At 48 weeks, 37 or 21% of 19 evaluable patients had an HIV-1 RNA level <400 or <50 copies/mL, respectively.502

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Nelfinavir, a PI, was previously a common component of a fully suppressive antiretroviral regimen.200 In the 2024 HHS adult and adolescent HIV treatment guideline, nelfinavir is no longer recommended for treatment of HIV infection due to inferior virological efficacy and toxicities.200

In the 2024 HHS pediatric HIV treatment guideline, nelfinavir is no longer recommended for use in the treatment of HIV infection due to inferior virological efficacy and toxicities.201

In the 2024 HHS perinatal HIV treatment guideline, nelfinavir is not recommended for use during pregnancy; if pregnancy occurs during nelfinavir therapy, nelfinavir should be discontinued and another recommended antiretroviral regimen should be initiated.202

General

Patient Monitoring

• Consider monitoring for hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus in patients receiving nelfinavir.1

Administration

Nelfinavir is administered orally 2 or 3 times daily.1

Nelfinavir should be taken with a meal; presence of food in the GI tract can increase bioavailability of the drug.1

Nelfinavir is commercially available as tablets (an oral powder for solution was discontinued).1

For patients unable to swallow tablets, the appropriate dose of tablets may be placed in a small amount of water and allowed to disperse.1 After the tablets dissolve, the cloudy liquid should be mixed well and immediately consumed.1 To ensure that the entire dose is consumed, the glass should be rinsed with water and the rinse swallowed.1

Nelfinavir tablets should not be mixed with acidic food or juice (e.g., apple juice, applesauce, orange juice) since the resulting mixture may have a bitter taste.1

If a dose of nelfinavir is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 If a dose is skipped, do not administer a double dose to make up for the missed dose.1

Store nelfinavir tablets at 15-30ºC in the original container.1

Dosage

Dosage of nelfinavir mesylate is expressed in terms of nelfinavir.1

Adults

Treatment of HIV Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, the recommended dosage of nelfinavir is 1.25 g (five 250-mg tablets or two 625-mg tablets) twice daily or 750 mg (three 250-mg tablets) three times daily.1

Pediatric Patients

Treatment of HIV Infection

Children 13 years of age or older may receive the usual adult dosage of nelfinavir.1 For the treatment of HIV-1 infection in children 2 to <13 years of age, the recommended dosage of nelfinavir (250-mg tablets) is 45-55 mg/kg twice daily or 25-35 mg/kg three times daily.1 The maximum recommended dosage is 1.25 g (five 250-mg tablets) twice daily or 750 mg (three 250-mg tablets) three times daily.1 Dosages exceeding the adult maximum dosage (2.5 g daily) have not been evaluated in children.1

See Full Prescribing Information for additional dosing guidelines for nelfinavir tablets based on age and body weight in pediatric patients.1

Pediatric HIV guidelines no longer recommend the use of nelfinavir in children or adolescents due to its variable pharmacokinetics and inferior efficacy.201

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary if nelfinavir is used in patients with mild hepatic impairment (Child-Pugh class A, score 5-6).1 The drug should not be used in patients with moderate or severe hepatic impairment (Child-Pugh class B or C, score ≥7).1

Renal Impairment

The manufacturer states that the safety and efficacy of nelfinavir have not been established in renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1 Clinical trials did not include a sufficient number of patients ≥65 years of age to determine whether there are differences in response compared to younger adults.1

Contraindications

• Concomitant use with drugs highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events (e.g., alfuzosin, amiodarone, cisapride, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, quinidine, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).1
• Concomitant use with drugs that are CYP3A inducers where significantly reduced nelfinavir plasma concentrations may be associated with a potential loss of virologic response, and possible development of resistance or cross-resistance to other antiretrovirals (e.g., rifampin, St. John's Wort [ Hypericum perforatum ]).1

Warnings/Precautions

Risk of Serious Adverse Reactions Due to Drug Interactions

Because nelfinavir is a CYP3A inhibitor, initiation in patients already receiving drugs metabolized by CYP3A, or the initiation of drugs metabolized by CYP3A in patients already receiving nelfinavir, may increase plasma concentrations of the drug metabolized by CYP3A.1 The initiation of drugs that inhibit or induce CYP3A may result in increased or decreased plasma concentrations of nelfinavir.1 These interactions may cause significant adverse reactions (potentially severe, life-threatening, or fatal) from increased exposure of the concomitant medication, adverse reactions from increased nelfinavir exposure, or a loss of virologic response to nelfinavir and development of resistance or cross-resistance.1

Nelfinavir should not be used concomitantly with certain drugs (e.g., alfuzosin, amiodarone, cisapride, ergot alkaloids, oral midazolam, pimozide, quinidine, sildenafil used for PAH, triazolam, lovastatin, simvastatin) because such use is likely to produce substantially increased plasma concentrations of these drugs and possibly precipitate serious arrhythmogenic, neurologic, or other toxicities.1 Nelfinavir also should not be used concomitantly with rifampin or St. John's wort ( Hypericum perforatum ), because these drugs can reduce plasma concentrations of nelfinavir, resulting in loss of therapeutic effect and possible development of resistance.1 Because there is a possibility of clinically important interactions when nelfinavir is used concomitantly with other drugs, patients should be instructed to inform their clinicians of their use of other drugs, including both prescription and nonprescription drugs, or dietary or herbal supplements such as St. John's wort.1 Consider the potential for drug interactions prior to, and throughout treatment with nelfinavir.1

Hepatic Impairment

Nelfinavir is metabolized in the liver.1 Plasma concentrations of nelfinavir are increased in patients with moderate hepatic impairment; the drug should not be used in patients with moderate or severe hepatic impairment (Child-Pugh class B or C, score 7 or greater).1

Diabetes Mellitus/Hyperglycemia

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus in HIV-infected individuals receiving an HIV protease inhibitor (PI; e.g., nelfinavir, ritonavir) has been reported during postmarketing surveillance.1 Diabetic ketoacidosis occurred in some patients.1 In most patients who discontinued HIV PI therapy, the hyperglycemic or diabetic episode resolved.1 A causal relationship between these episodes and HIV PI therapy has not been established.1

Hemophilia

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients with hemophilia A or hemophilia B receiving HIV PIs.1 Additional doses of factor VIII were necessary to control bleeding episodes in some patients.1 Protease inhibitor therapy was continued or reintroduced in more than half of reported cases.1 A causal relationship to HIV PIs has not been established.1

Fat Redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving HIV PIs, including nelfinavir.1 The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown.1 A causal relationship has not been established.1

Immune Reconstitution Syndrome

Patients receiving potent combination antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported in the setting of immune reconstitution; however, the time to onset is variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to nelfinavir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1

Hepatic adverse events, including hepatic enzyme elevations and hepatic failure, have been reported in pregnant patients exposed to nelfinavir.1 Based on the adverse event profile of nelfinavir, including hepatic adverse events, and literature reports of decreased drug exposure in the second and third trimesters, consider using alternative antiretroviral agents during pregnancy.1

Lactation

Limited data indicate that nelfinavir is present in breastmilk, and adverse effects from infant exposure to nelfinavir have been reported.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Females and Males of Reproductive Potential

The concomitant use of nelfinavir with estrogen-containing oral contraceptives may result in reduced efficacy of the contraceptive agent.1 Patients receiving nelfinavir and using oral contraceptives containing ethinyl estradiol or norethindrone should use additional or alternative contraceptives.1

Pediatric Use

Safety and efficacy of nelfinavir in pediatric patients younger than 2 years of age have not been established.1 The manufacturer states that while nelfinavir has been found to be safe at doses studied in pediatric patients younger than 2 years of age, a reliably effective dosage has not been established for this age group.1 In some studies, the response rate was lower in pediatric patients younger than 2 years of age than in those 2 years of age or older.1

Safety and efficacy of nelfinavir for treatment of HIV-1 infection in pediatric patients 2-13 years of age were evaluated in randomized, placebo-controlled trials in antiretroviral-naïve and antiretroviral-experienced pediatric patients.1 Safety and efficacy in adolescents 13 years of age and older is supported by controlled studies in adults.1

Use of nelfinavir in pediatric patients is associated with highly variable drug exposure.1 Unpredictable drug exposure may be exacerbated since pediatric patients clear nelfinavir more rapidly than adults.1 In addition, these patients may have difficulty with compliance and there may be inconsistent food intake with dosing.1

Geriatric Use

Clinical studies of nelfinavir to date have not included sufficient numbers of adults ≥65 years of age to determine whether geriatric patients respond differently to the drug than younger adults.1

Hepatic Impairment

Peak plasma concentrations and AUC of nelfinavir are not significantly affected in HIV-1 negative patients with mild hepatic impairment (Child-Pugh Class A) compared to normal hepatic function.1 In HIV-1 negative patients with moderate hepatic impairment (Child-Pugh Class B), peak plasma concentrations and AUC were increased by 22% and 62%, respectively, compared to normal hepatic function.1 Steady state pharmacokinetics of nelfinavir have not been evaluated in HIV-1 negative patients with severe hepatic impairment.1

The pharmacokinetics of nelfinavir have not been evaluated in HIV-1 infected patients with any degree of hepatic impairment.1

Nelfinavir should not be used in patients with moderate or severe hepatic impairment (Child-Pugh class B or C, score ≥7).1

Renal Impairment

The pharmacokinetics of nelfinavir have not been evaluated in patients with renal impairment.1

Common Adverse Effects

Adverse effects reported in at least 2% of adult and adolescent patients ≥13 years of age receiving nelfinavir include diarrhea, nausea, rash, and flatulence.1

The most commonly reported adverse effects in pediatric patients 2 to <13 years of age receiving nelfinavir include diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain.1

Metabolism of nelfinavir is mediated in part by the cytochrome P-450 isoenzymes CYP3A and CYP2C19 and the possibility exists that drugs that induce these isoenzymes may reduce nelfinavir plasma concentrations.1 Conversely, concomitant use of nelfinavir with drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations.1 In addition, nelfinavir is an inhibitor of CYP3A and the possibility exists that the drug may alter the pharmacokinetics of drugs metabolized by this isoenzyme.1 However, nelfinavir does not appear to have any appreciable inhibitory effect on CYP2D6, 2C9, 2C19, 2C8, 1A2, or 2E1 at clinically relevant concentrations1 The fact that dosage adjustments of nelfinavir and/or other drugs may be necessary in patients receiving concurrent therapy with drugs that are extensively metabolized by, or that induce or inhibit, CYP3A or CYP2C19 isoenzymes should be considered.1

Alfuzosin

Concomitant use of alfuzosin and nelfinavir may result in increased plasma concentrations of alfuzosin and potential for hypotension.1 Concomitant use of the drugs is contraindicated.1

Antifungal Agents

Concomitant use of ketoconazole (400 mg once daily for 7 days) and nelfinavir (500 mg 3 times daily for 5-6 days) resulted in a 35% increase in the AUC and a 25% increase in peak plasma concentrations of nelfinavir.1

Antimycobacterial Agents

Rifabutin

Concomitant use of nelfinavir and rifabutin affects the pharmacokinetics of both drugs.1 Concomitant use of rifabutin (300 mg daily for 8 days) and nelfinavir (750 mg 3 times daily for 7-8 days) resulted in a 207% increase in the AUC of rifabutin, a 146% increase in peak plasma concentrations of rifabutin, a 32% decrease in the AUC of nelfinavir, and a 24% decrease in peak plasma concentrations of nelfinavir.1 When a lower dosage of rifabutin (150 mg once daily for 7-8 days) was used concomitantly with the 3-times daily regimen of nelfinavir (750 mg 3 times daily for 7-8 days), the AUC of rifabutin was increased 83%, the peak plasma concentration of rifabutin was increased 19%, and the AUC and peak plasma concentration of nelfinavir were decreased 23 and 18%, respectively.1 When the lower dosage of rifabutin (150 mg once daily for 8 days) was administered with a twice-daily regimen of nelfinavir (1.25 g every 12 hours for 7-8 days), there were no effects on the AUC and plasma concentration of rifabutin.1

Because of the pharmacokinetic interaction between rifabutin and nelfinavir, the manufacturer of nelfinavir recommends that a reduced rifabutin dosage (50% of the usual dosage) be used when concomitant therapy with nelfinavir is necessary and states that the twice-daily nelfinavir regimen (1.25 g twice daily) is preferred in these patients.1

Rifampin

Concomitant use of rifampin and nelfinavir is contraindicated.1 Rifampin is a potent inducer of the CYP3A isoenzyme and can markedly reduce plasma concentrations of nelfinavir,1 this may lead to loss of antiretroviral effect and possible development of resistance to nelfinavir or other antiretroviral agents.1 Concomitant use of rifampin (600 mg daily for 7 days) and nelfinavir (750 mg 3 times daily for 5-6 days) resulted in an 83% decrease in the AUC of nelfinavir and a 76% decrease in peak plasma concentrations of nelfinavir.1

Antiretroviral Agents

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Results of in vitro studies indicate that the antiretroviral effects of nelfinavir and efavirenz or nevirapine are additive to synergistic against HIV-1.1

Efavirenz

Concomitant use of nelfinavir (750 mg every 8 hours) and efavirenz (600 mg daily) for 7 days increased the peak plasma concentration and AUC of nelfinavir by 21 and 20%, respectively, and decreased the peak plasma concentration and AUC of efavirenz by 12%.1

Nevirapine

In one study, concomitant use of nevirapine (200 mg once daily for 14 days, followed by 200 mg twice daily for 14 days) and nelfinavir (750 mg 3 times daily for 36 days) did not affect nelfinavir peak plasma concentrations or AUC, but resulted in a 32% decrease in trough plasma concentrations of the drug.1

Appropriate dosages for concomitant use of nelfinavir and nevirapine with respect to safety and efficacy have not been established.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies indicate that the antiretroviral effects of nelfinavir and some nucleoside reverse transcriptase inhibitors (NRTIs) are additive (e.g., didanosine) to synergistic (e.g., abacavir, emtricitabine, lamivudine, tenofovir, zidovudine) against HIV-1.1

Didanosine

Administration of didanosine (single 200-mg dose in the fasting state) 1 hour before nelfinavir (single 750-mg dose with food) did not affect the AUC or peak plasma concentration of nelfinavir.1

Because didanosine should be administered in the fasting state and nelfinavir should be administered with food to optimize GI absorption, concomitant nelfinavir and didanosine therapy should involve administering didanosine (without food) 1 hour before or 2 hours after nelfinavir (with food).1

Lamivudine

Concomitant use of lamivudine (single 150-mg dose) and nelfinavir (750 mg every 8 hours for 7-10 days) increased the AUC and peak plasma concentration of lamivudine by 10 and 31%, respectively.1

Zidovudine

Concomitant use of zidovudine (single 200-mg oral dose) and nelfinavir (750 mg 3 times daily for 7-10 days) resulted in a 35% decrease in the AUC of zidovudine and a 31% decrease in peak plasma concentrations of zidovudine.1

The AUC and peak plasma concentration of nelfinavir were unaffected in individuals who received nelfinavir (750 mg 3 times daily for 7-10 days) concomitantly with zidovudine (single 200-mg dose) and lamivudine (single 150-mg dose).1

HIV Protease Inhibitors (PIs)

Results of in vitro studies indicate that concomitant use of nelfinavir and lopinavir or ritonavir results in additive or antagonistic antiretroviral effects, and concomitant use with amprenavir (commercially available as fosamprenavir) or lopinavir results in synergistic antiretroviral effects.1

Ritonavir

Concomitant use of ritonavir and nelfinavir results in increased plasma concentrations of nelfinavir but does not appear to affect plasma concentrations of ritonavir.1 While administration of ritonavir (a single 500-mg dose) in individuals receiving nelfinavir (750 mg 3 times daily for 5 doses) did not affect the AUC or peak plasma concentration of ritonavir, administration of ritonavir (500 mg 2 times daily for 3 doses) and a single 750-mg dose of nelfinavir increased the AUC and peak plasma concentration of nelfinavir by 152 and 44%, respectively.1

The manufacturer of nelfinavir states that appropriate dosages of nelfinavir and ritonavir for concomitant therapy with respect to safety and efficacy have not been established.1

Bosentan

Concomitant use of bosentan and nelfinavir may increase plasma concentrations of bosentan.1

If bosentan and nelfinavir are used concomitantly, bosentan dosage should be initiated or adjusted to a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

Cardiovascular Agents

Cardiac Drugs and Hypotensive Agents

Concomitant use of nelfinavir and amiodarone or quinidine is contraindicated since nelfinavir is expected to produce substantially increased plasma concentrations of these cardiac drugs and increase the potential for serious adverse effects associated with the drugs.1

Antilipemic Agents

Concomitant use of certain hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) and PIs may increase plasma concentrations of the statin and increase the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.1

Atorvastatin

If atorvastatin and nelfinavir are used concomitantly, atorvastatin dosage should not exceed 40 mg daily; atorvastatin dosage should be titrated carefully and the lowest necessary dosage used.1

Concomitant use of atorvastatin (10 mg once daily for 28 days) and nelfinavir (1.25 g twice daily for 14 days) resulted in a 74 and 122% increase in the AUC and peak plasma concentration of atorvastatin, respectively.1

Lovastatin

Concomitant use of nelfinavir and lovastatin is contraindicated.1

Rosuvastatin

Concomitant use of rosuvastatin and nelfinavir may result in increased plasma concentrations of the statin.1

Simvastatin

Concomitant use of nelfinavir and simvastatin is contraindicated.1

Concomitant use of simvastatin (20 mg once daily for 28 days) and nelfinavir (1.25 g twice daily for 14 days) increased the AUC and peak plasma concentration of simvastatin by 505 and 517%, respectively.1

CNS Agents

Anticonvulsants

Concomitant use of phenytoin (300 mg once daily for 14 days) and nelfinavir (1.25 g twice daily for 7 days) decreased the AUC and plasma concentrations of phenytoin but did not affect the AUC or plasma concentrations of nelfinavir.1 Plasma/serum concentrations of phenytoin should be monitored in patients receiving phenytoin and nelfinavir; dosage adjustment of phenytoin may be required.1

Concomitant use of carbamazepine or phenobarbital with nelfinavir is expected to increase nelfinavir clearance and decrease plasma concentrations of the HIV PI.1

Opiate Agonists

Methadone

While concomitant use of methadone and nelfinavir does not appear to affect plasma concentrations of nelfinavir, administration of methadone (80 mg [range 59-101 mg] daily for at least 1 month) and nelfinavir (1.25 g twice daily for 8 days) decreased the AUC and peak plasma concentration of methadone (i.e., total plasma methadone concentration) by 47 and 46%, respectively.1

An increase in the maintenance dosage of methadone may be necessary.1

Sedatives and Hypnotics

Concomitant use of nelfinavir and oral midazolam or triazolam is contraindicated since nelfinavir is likely to interfere with the metabolism of these sedative hypnotics and increase the potential for extreme sedation.1

Colchicine

Concomitant use of nelfinavir and colchicine may result in increased plasma concentrations of colchicine.1 Because of the risk of colchicine toxicity, concomitant use with nelfinavir is not recommended in patients with renal or hepatic impairment.1

When colchicine is used for treatment of gout flares in patients receiving nelfinavir, the manufacturer of nelfinavir recommends that an initial colchicine dose of 0.6 mg be followed by 0.3 mg 1 hour later and that the dose be repeated no earlier than 3 days later.1

When colchicine is used for prophylaxis of gout flares in patients receiving nelfinavir, the manufacturer of nelfinavir recommends that the colchicine dosage be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving nelfinavir, the manufacturer of nelfinavir recommends that a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) be used.1

Corticosteroids

Concomitant use of fluticasone propionate with nelfinavir may result in increased concentrations of fluticasone.1 Caution is advised; alternatives to fluticasone therapy should be considered in patients receiving nelfinavir, especially when long-term use of the corticosteroid is anticipated.1

Ergot Alkaloids

Concomitant use of nelfinavir and ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine) is contraindicated since nelfinavir is expected to produce substantially increased plasma concentrations of these drugs and increase the potential for serious adverse effects associated with the drugs.1

Estrogens/Progestins

Concomitant use of nelfinavir (750 mg 3 times daily for 7 days) and ethinyl estradiol (35 mcg once daily for 15 days) decreased the peak plasma concentration and AUC of the estrogen by 28 and 47%, respectively.1 Concomitant use of nelfinavir (750 mg 3 times daily for 7 days) and norethindrone (0.4 mg once daily for 15 days) decreased the AUC of norethindrone by 18% but did not affect peak plasma concentrations.1

Patients receiving nelfinavir and using oral contraceptives containing ethinyl estradiol or norethindrone should use additional or alternative contraceptives.1

GI Agents

Proton-pump Inhibitors

Concomitant use of nelfinavir (1.25 g twice daily for 4 days) and omeprazole (40 mg once daily for 4 days given 30 minutes prior to nelfinavir dose) decreased the peak plasma concentration and AUC of nelfinavir by 37 and 36%, respectively.1

Concomitant use of a proton-pump inhibitor and nelfinavir may result in loss of virologic response and development of resistance.1

Immunosuppressive Agents

Concomitant use of nelfinavir and cyclosporine, sirolimus, or tacrolimus may result in increased plasma concentrations of the immunosuppressant and nelfinavir.1

Macrolides

Azithromycin

Concomitant use of azithromycin and nelfinavir may result in increased plasma concentrations and AUC of azithromycin but does not appear to result in clinically important changes in the plasma concentrations or AUC of nelfinavir.1 Administration of azithromycin (a single 1.2-g dose) in individuals receiving nelfinavir (750 mg 3 times daily for 11 days) increased the AUC and peak plasma concentration of azithromycin by 112 and 136%, respectively.1 In individuals who received azithromycin (a single 1.2-g dose) and nelfinavir (750 mg 3 times daily for 9 days), nelfinavir AUC and peak plasma concentration were decreased by 15 and 10%, respectively.1

Although dosage adjustments are not necessary when nelfinavir and azithromycin are used concomitantly, patients should be closely monitored for azithromycin adverse effects (e.g., hepatic enzyme abnormalities, hearing impairment).1

Phosphodiesterase Type 5 Inhibitors

Concomitant use of nelfinavir and phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) may result in substantially increased concentrations of the PDE5 inhibitor and increase the risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, priapism).1 Caution is advised and a reduction in dosage of the PDE5 inhibitor may be needed or, in some cases, concomitant use may be contraindicated.1 If used concomitantly, patients should be monitored closely for adverse effects.1

Sildenafil

If sildenafil (Revatio^®) is used for the treatment of pulmonary arterial hypertension (PAH), concomitant use of nelfinavir is contraindicated.1 A safe and effective dosage for concomitant use has not been established.1

If sildenafil is used for the treatment of erectile dysfunction, nelfinavir should be used concomitantly with caution and sildenafil dosage should not exceed 25 mg once every 48 hours.1

Tadalafil

If tadalafil is used for the treatment of PAH in patients receiving nelfinavir, tadalafil dosage should be initiated at or adjusted to 20 mg once daily; based on individual tolerability, tadalafil dosage can then be increased to 40 mg once daily.1

If tadalafil is used for the treatment of erectile dysfunction, nelfinavir should be used concomitantly with caution and tadalafil dosage should not exceed 10 mg once every 72 hours.1

Vardenafil

If vardenafil is used for the treatment of erectile dysfunction, nelfinavir should be used concomitantly with caution and vardenafil dosage should not exceed 2.5 mg once every 24 hours.1

Pimozide

Concomitant use of pimozide and nelfinavir is contraindicated since serious or life-threatening reactions (e.g., cardiac arrhythmias) may occur.1

Quetiapine

Concomitant use of nelfinavir with quetiapine may result in increased plasma concentrations of quetiapine.1 In patients already receiving quetiapine who are being initiated on nelfinavir, alternative antiretroviral therapy should be considered to avoid increased quetiapine exposure.1 If concomitant use cannot be avoided, a reduction in the quetiapine dose to 1/6th of the current dose and monitoring for adverse reactions due to quetiapine is recommended.1 Refer to the quetiapine prescribing information for further recommendations on monitoring for adverse reactions.1 In patients already receiving nelfinavir who are being initiated on quetiapine, refer to the prescribing information for quetiapine for further guidance on initial dosing and titration of quetiapine.1

Salmeterol

Concomitant use of salmeterol and nelfinavir is not recommended since concomitant use may result in increased salmeterol concentrations and increased risk of adverse events associated with the drug (e.g., QT prolongation, palpitations, sinus tachycardia).1

Trazodone

Concomitant use of trazodone with nelfinavir may result in increased plasma concentrations of trazodone.1 Caution is advised; a lower dosage of trazodone should be considered in patients receiving concomitant nelfinavir.1

Warfarin

Concomitant use of warfarin and nelfinavir may result in altered warfarin concentrations.1 The international normalized ratio (INR) should be monitored carefully if warfarin and nelfinavir are used concomitantly.1

Dietary and Herbal Supplements

St. John's Wort ( Hypericum perforatum )

Concomitant use of St. John's wort ( Hypericum perforatum ) and nelfinavir is contraindicated since such use is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance.1

Description

While the complete mechanism(s) of antiviral activity of nelfinavir has not been fully elucidated, nelfinavir appears to inhibit replication of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by interfering with HIV protease.1,2,3,4,7,92,120 The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor.1,2,3,4,92,120

Nelfinavir is a selective, competitive, reversible inhibitor of HIV protease.120 HIV protease, an aspartic endopeptidase that functions as a homodimer, plays an essential role in the HIV replication cycle and the formation of infectious virus.1,4,5,7 During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55 and p160) to form structural proteins of the virion core (i.e., p17, p24, p9, and p7) and essential viral enzymes (i.e., reverse transcriptase, integrase, and protease).1,4,5,7 By interfering with the formation of these essential proteins and enzymes, nelfinavir blocks maturation of the virus and causes the formation of nonfunctional, immature, noninfectious virions.1,4,5,7 Nelfinavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly.1,4,7,120

Unlike nucleoside reverse transcriptase inhibitors, the antiretroviral activity of nelfinavir does not depend on intracellular conversion to an active metabolite.1,4,7,8 Nelfinavir and other HIV protease inhibitors (e.g., atazanavir, amprenavir [commercially available as fosamprenavir], lopinavir, ritonavir) act at a different stage of the HIV replication cycle than other available antiretroviral agents, including nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors.1,4 Results of in vitro studies indicate that the antiretroviral effects of nelfinavir and nucleoside or nucleotide reverse transcriptase inhibitors may be additive (didanosine) or synergistic (abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine).1,4,120,125 In vitro studies also indicate that the antiretroviral effects of nelfinavir and nonnucleoside reverse transcriptase inhibitors (efavirenz, nevirapine) are synergistic against HIV-1.1 In vitro studies evaluating the antiretroviral effects of nelfinavir used with other HIV protease inhibitors (amprenavir, lopinavir, ritonavir) have resulted in variable results ranging from antagonism to synergism.1,120,125

A study in healthy individuals who received a single 750-mg dose of nelfinavir with food indicated that nelfinavir pharmacokinetics are similar following administration of 250-mg tablets or the oral powder (no longer commercially available in the US).1 Results of a multiple-dose study in HIV-infected individuals who received nelfinavir 1.25 g twice daily with food indicate that the commercially available 250-mg and 625-mg film-coated tablets are bioequivalent.1 Presence of food in the GI tract substantially increases the absorption of oral nelfinavir and decreases the pharmacokinetic variability of the drug relative to the fasting state.1 In a study in healthy individuals who received a single 1.25-g dose of nelfinavir as 250-mg tablets, peak plasma concentration and AUC were 2-5 times greater when the dose was administered with a meal (125-1000 kCal with 20-50% fat) rather than under fasting conditions.1 Preliminary data indicate that food has a similar effect when the drug is administered as 625-mg tablets.1

Following oral administration of a single 1.25-g dose of nelfinavir as two 625-mg tablets in fasting healthy individuals, the AUC of nelfinavir was 34% higher and peak plasma concentrations were 24% higher than values obtained when the dose was administered as five 250-mg tablets.1 When the same dose was given with food, AUC values were 24% higher with the 625-mg tablets but peak plasma concentrations were similar to values obtained with the 250-mg tablets.1 Following oral administration of multiple doses of nelfinavir 1.25 g twice daily with food, nelfinavir exposure (peak plasma concentration, AUC) at steady state in HIV-infected patients receiving two 625-mg tablets twice daily was similar to that in patients receiving five 250-mg tablets twice daily.1 Nelfinavir is more than 98% bound to plasma protein.1 The drug is distributed into human milk.1

The metabolic fate of nelfinavir has not been fully determined, but the drug is metabolized in the liver to many oxidative metabolites.1 In vitro studies indicate that metabolism of nelfinavir is mediated by several cytochrome P-450 isoenzymes, including CYP3A and CYP2C19.1 The plasma elimination half-life of nelfinavir is 3.5-5 hours.1 Nelfinavir is excreted principally in the feces, both as unchanged drug and metabolites.1 Following oral administration of a 750-mg dose of radiolabeled nelfinavir, 87% of the dose is recovered in feces (22% as unchanged drug) and 1-2% is recovered in urine (principally as unchanged drug).1 Pharmacokinetic studies have not revealed gender-related differences in the pharmacokinetics of nelfinavir; further study is needed to determine if there are race-related differences.1

Spectrum

Nelfinavir has a limited spectrum of antiviral activity.1,7,8 The drug is active in vitro against HIV-1 and HIV-2.1,7,8 The major metabolite of nelfinavir (M8) has in vitro antiviral activity similar to that of nelfinavir.1 The antiretroviral activity of nelfinavir has been evaluated in vitro in various cell culture systems, including lymphoblastoid and macrophage cell lines and peripheral blood mononuclear cells (PBMC), and generally has been assessed by measuring reverse transcriptase activity or inhibition of HIV p24 core antigen production.4,7,8

Depending on the cell culture system used, the EC₉₅ of nelfinavir (concentration of the drug required to inhibit 95% of detectable HIV replication) for HIV-1 has ranged from 7 to 196 nM.1

Resistance

Resistance to nelfinavir has been produced in vitro by serial passage of HIV-1 in the presence of increasing concentrations of the drug,1,7 and strains of HIV-1 with in vitro resistance to nelfinavir have emerged during therapy with the drug.1,9

Although the complete mechanism(s) of resistance or reduced susceptibility to nelfinavir has not been fully determined to date, mutation of HIV protease appears to be a principal mechanism of resistance.1,4,7,11 Nelfinavir-resistant variants containing more than one mutation that have been isolated in vitro include 30N/71V,80, 46I/84V, and 46I/84A.7 In patients receiving nelfinavir in clinical trials, HIV variants with mutations at HIV protease amino acid positions 30, 35, 36, 46, 71, 77, or 88 have been isolated,1 including D30N, M36I, M46I, A71T/V, and N88D/S.9 Molecular analysis of nelfinavir-resistant variants indicates the initial amino acid exchange principally occurs at position 30.1,9

In clinical studies, phenotypic and/or genotypic changes in HIV isolates were monitored for up to 82 weeks in patients receiving nelfinavir alone or in conjunction with nucleoside reverse transcriptase inhibitors.1,9,120 HIV variants with at least one mutation were isolated from more than 10% of evaluable isolates.1 In one subgroup of patients, 47% had phenotypic changes (i.e., 5-fold or greater decrease in susceptibility from baseline); clinical isolates with reduced susceptibility to nelfinavir contained D30N in association with one or more mutations in the HIV protease gene.1 The overall incidence of the D30N mutation in the viral protease of evaluable patients receiving nelfinavir alone or in conjunction with zidovudine and lamivudine or stavudine was 54.8%.1 The overall incidence of other mutations associated with primary resistance was 9.6% for the L90M substitution, whereas substitutions at 48, 82, or 84 were not observed.1

There is evidence from in vitro and in vivo studies that varying degree of cross-resistance can occur among the various HIV PIs.1,4,11,13,14 HIV-1 isolates containing the D30N mutation with high-level resistance to nelfinavir have been susceptible to amprenavir (commercially available as fosamprenavir), indinavir, lopinavir, and saquinavir in vitro.1 HIV-1 isolates containing the L90M mutation with moderate to high-level resistance to nelfinavir have had varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir in vitro.1 HIV-1 isolates with phenotypic and genotypic evidence of reduced susceptibility to amprenavir, indinavir, lopinavir, and/or saquinavir have demonstrated high-level cross-resistance to nelfinavir.1 Mutations associated with resistance to other HIV PIs appear to confer high-level resistance to nelfinavir.1

Based on results of in vitro studies, it has been suggested that mutations at certain sites (e.g., G48V, V82A/F/T, I84V, L90M) and/or certain patterns of multiple mutations are associated with cross-resistance among HIV PIs.1,4,10,16,17 However, limited evidence indicates that mutations associated with decreased susceptibility to nelfinavir (e.g., D30N) are different than those that have been associated with decreased susceptibility to other HIV PIs (i.e., indinavir, ritonavir, saquinavir).1,9

Advice to Patients

• Inform patients of the critical nature of adherence with HIV therapy and importance of remaining under the care of a clinician.1 Advise patients of the importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
• If a dose is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 If a dose is skipped, do not administer a double dose to make up for the missed dose.1
• Advise patients that redistribution/accumulation of body fat may occur, with unknown long-term health effects.1
• Inform patients that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur.1 Advise patients to inform their healthcare provider if an increase in thirst or urination develops while receiving nelfinavir.1
• If using oral contraceptives, advise patients to use an alternative or concomitant nonhormonal contraceptive measures.1
• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., PDE5 inhibitors) and OTC drugs and dietary or herbal products (e.g., St. John's Wort).1
• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform patients that an antiretroviral pregnancy registry is available that monitors fetal outcomes of infants exposed to nelfinavir.1 Providers can register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Aguoron Pharmaceuticals. Nelfinavir mesylate tablets and oral powder prescribing information. Research Triangle Park, NC; 2021 Mar.

2. Longer M, Shetty B, Zamansky I et al. Preformulation studies of a novel HIV protease inhibitor, AG1343. J Pharm Sci . 1995; 84:1090-3. [PubMed 8537887]

3. Kaldor SW, Kalish VJ, Davies JF et al. Viracept (nelfinavir mesylate, AG13430: a potent orally bioavailable inhibitor of HIV-1 protease. J Med Chem . 1997; 40:3979-85. [PubMed 9397180]

4. Moyle G, Gazzard B. Current knowledge and future prospects for the use of HIV protease inhibitors. Drugs . 1996; 51:701-12. [PubMed 8861542]

5. Vella S. Rationale and experience with reverse transcriptase inhibitors and protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 1):S58-61.

7. Patick AK, Mo H, Markowitz M et al. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob Agents Chemother . 1996; 40:292-7. [PubMed 8834868]

8. Shetty BV, Kosa MB, Khalil DA et al. Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother . 1996; 40:110-4. [PubMed 8787890]

9. Patick AK, Duran M, Cao Y et al. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob Agents Chemother . 1998; 42:2637-44. [PubMed 9756769]

10. Lech WJ, Wang G, Yang YL et al. In vivo sequence diversity of the protease of human immunodeficiency virus type 1: presence of protease inhibitor-resistant variants in untreated subjects. J Virol . 1996; 70:2038-43. [PubMed 8627733]

11. Ridky T, Leis J. Development of drug resistance to HIV-1 protease inhibitors. J Biol Chem . 1995; 270:29621-3. [PubMed 8530341]

13. Deeks SG, Smith M, Holodniy M et al. HIV-1 protease inhibitors: a review for clinicians. JAMA . 1997; 277:145-53. [PubMed 8990341]

14. Izzedine H, Diquet B, Launay-Vacher V et al. Pharmacokinetics of nelfinavir in an HIV patient with renal insufficiency. AIDS . 1999; 13:1989. [PubMed 10513666]

16. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis . 1995; 5:170-82.

17. Pollard RB. Use of proteinase inhibitors in clinical practice. Pharmacotherapy . 1994; 14:21-9S.

92. Gehlhaar DK, Verkhivker GM, Rejto PA et al. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem Biol . 1995; 2:317-24. [PubMed 9383433]

120. FDA summary basis of approval on nelfinavir. Rockville, MD; 1997.

121. Saag MS, Tebas P, Sension M et al. Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511). AIDS . 2001; 15:1971-8. [PubMed 11600825]

125. Patick AK, Boritzki TJ, Bloom LA. Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob Agents Chemother . 1997; 41:2159-64. [PubMed 9333041]

126. Aboulker JP, Babiker A, Chaix ML et al. Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. AIDS . 2004; 18:237-45. [PubMed 15075541]

127. Krogstad P, Wiznia A, Luzuriaga K et al. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis . 1999; 28:1109-18. [PubMed 10452644]

156. Wiznia A, Stanley K, Korgstad P et al. Combination nucleoside analog reverse trancriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial—PACTG 377. AIDS Res Hum Retroviruses . 2000; 16:1113-21. [PubMed 10954886]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (February 27, 2024). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov website. [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2024). Updates may be available at HIV.gov website. [Web]

500. Gartland M, AVANTI Study Group. AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naïve patients. Antivir Ther. 2001;6(2):127-134.

501. Albrecht M, Bosch R, Hammer S, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med. 2001;345(6):398-407.

502. Paediatric European Network for Treatment of AIDS (PENTA). Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. AIDS. 2004;18:237-245.