Nelfinavir Mesylate

Dosage Forms And Strengths

VIRACEPT 250 mg Tablet: Light-blue, capsule-shaped tablets with a clear film coating engraved with “VIRACEPT” on one side and “250 mg” on the other.

VIRACEPT 625 mg Tablet: White oval tablet with a clear film coating engraved with “V” on one side and “625” on the other.

VIRACEPT Oral Powder: Off-white powder containing 50 mg (as nelfinavir-free base) in each level scoopful (1 gram).

Storage And Handling

VIRACEPT (nelfinavir mesylate) 250 mg: Light-blue, capsule-shaped tablets with a clear film coating engraved with “VIRACEPT” on one side and “250 mg” on the other.

Bottles of 300 (250 mg) tablets – NDC 63010-010-30

VIRACEPT (nelfinavir mesylate) 625 mg: White oval tablet with a clear film coating engraved with “V” on one side and “625” on the other.

Bottles of 120 (625 mg) tablets – NDC 63010-027-70

VIRACEPT (nelfinavir mesylate) Oral Powder is available as a 50 mg/g off-white powder containing 50 mg (as nelfinavir free base) in each level scoopful (1 gram).

Multiple use bottles of 144 grams of powder with scoop …….NDC 63010-011-90

VIRACEPT tablets and oral powder should be stored at 15° to 30°C (59° to 86°F).

Keep container tightly closed. Dispense in original container.

Distributed by: ViiV Healthcare Company, Research Triangle Park, NC 27709. Revised: March 2015

Human experience of acute overdose with VIRACEPT is limited. There is no specific antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. Since nelfinavir is highly protein bound, dialysis is unlikely to significantly remove drug from blood.

Mechanism Of Action

Nelfinavir is an inhibitor of the HIV-1 protease [see Microbiology].

Pharmacodynamics

Effects on Electrocardiogram

The effect of Viracept at the recommended dose of 1250 mg twice daily on the QTcF interval administered with a low fat meal (20% fat) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled, crossover study in 66 healthy subjects. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baselinecorrection was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Viracept 3125 mg was administered following a 3-day administration of Viracept 1250 mg twice daily. The exposure at 3125 mg was 1.4-fold that at 1250 mg. The dose of 3125 mg in this study did not achieve the anticipated exposures in patients taking a high fat meal (50% fat) or with concomitant administration of drugs that could increase nelfinavir exposure [see Pharmacokinetics].

No subject in any group had an increase in QTcF of ≥ 60 milliseconds from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 milliseconds.

Pharmacokinetics

The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.

Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning and evening trough concentrations [Ctrough]) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 7.

Table 7: Summary of a Pharmacokinetic Study in HIV-positive Patients With Multiple Dosing of 1250 mg (Five 250 mg Tablets) BID for 28 Days and 750 mg (Three 250 mg Tablets) TID for 28 Days

The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.

In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax was comparable for both formulations. In HIV-1 infected subjects (N=21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (Cmax and AUC).

Table 8 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 x 625 mg tablets) to HIV-infected patients (N=21) for 14 days.

Table 8: Summary of the Steady State Pharmacokinetic Parameters (Mean ± SD) of Nelfinavir After Multiple Dose Administration of 1250 mg BID (2 x 625 mg Tablets) to HIV-infected Patients (N=21) for 14 Days.

In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of the 250 mg tablet and oral powder.

Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a single dose of 1250 mg of VIRACEPT 250 mg tablets (5 tablets) under fasted or fed conditions (three different meals). In a second study, healthy volunteers received single doses of 1250 mg VIRACEPT (5 x 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 9 and Table 10, respectively.

Table 9: Increase in AUC, Cmax and Tmax for Nelfinavir in Fed State Relative to Fasted State Following 1250 mg VIRACEPT (5 x 250 mg Tablets)

Table 10: Increase in Nelfinavir AUC, Cmax and Tmax in Fed Low Fat (20%) versus High Fat (50%) State Relative to Fasted State Following 1250 mg VIRACEPT (5 x 250 mg Tablets)

Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with VIRACEPT.

A food effect study has not been conducted with the 625 mg tablet. However, based on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg nelfinavir tablet appears comparable to that of the 250 mg tablets. VIRACEPT should be taken with a meal.

The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. Nelfinavir in serum is extensively protein-bound ( > 98%).

Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.

The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1-2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.

Specific Populations

The steady-state pharmacokinetics of nelfinavir (1250 mg BID for 2 weeks) was studied in HIV-seronegative subjects with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=6) hepatic impairment. When compared with subjects with normal hepatic function, the Cmax and AUC of nelfinavir were not significantly different in subjects with mild hepatic impairment but were increased by 22% and 62%, respectively, in subjects with moderate hepatic impairment. The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-seronegative subjects with severe hepatic impairment.

The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-positive patients with any degree of hepatic impairment.

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

No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.

The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving VIRACEPT three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 11.

Table 11: Summary of Steady-state AUC24 of Nelfinavir in Pediatric Studies

Pharmacokinetic data are also available for 86 patients (age 2 to 12 years) who received VIRACEPT 25-35 mg/kg TID in Study AG1343-556. The pharmacokinetic data from Study AG1343-556 were more variable than data from other studies conducted in the pediatric population; the 95% confidence interval for AUC24 was 9 to 121 mg·hr/L.

Overall, use of VIRACEPT in the pediatric population is associated with highly variable drug exposure. The high variability may be due to inconsistent food intake in pediatric patients [see DOSAGE AND ADMINISTRATION].

The pharmacokinetics of nelfinavir have not been studied in patients over 65 years of age.

Drug Interactions

CYP3A and CYP2C19 appear to be the predominant enzymes that metabolize nelfinavir in humans. The potential ability of nelfinavir to inhibit the major human cytochrome P450 enzymes (CYP3A, CYP2C19, CYP2D6, CYP2C9, CYP1A2 and CYP2E1) has been investigated in vitro. Only CYP3A was inhibited at concentrations in the therapeutic range. Specific drug interaction studies were performed with nelfinavir and a number of drugs. Table 12 summarizes the effects of nelfinavir on the geometric mean AUC, Cmax and Cmin of coadministered drugs. Table 13 shows the effects of coadministered drugs on the geometric mean AUC, Cmax and Cmin of nelfinavir.

Table 12: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIRACEPT

Table 13: Drug Interactions: Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of the Coadministered Drug

Microbiology

Nelfinavir is an inhibitor of the HIV-1 protease. Inhibition of the viral protease prevents cleavage of the gag and gag-pol polyprotein resulting in the production of immature, non-infectious virus.

The antiviral activity of nelfinavir has been demonstrated in both acute and/or chronic HIV infections in lymphoblastoid cell lines, peripheral blood lymphocytes, and monocytes/macrophages. Nelfinavir was found to be active against several laboratory strains and clinical isolates of HIV-1, and the HIV-2 strain ROD. The EC95 (95% effective concentration) of nelfinavir ranged from 7 to 196 nM. Drug combination studies with other HIV-1 protease inhibitors showed nelfinavir had antagonistic interactions with indinavir, additive interactions with ritonavir or saquinavir, and synergistic interactions with amprenavir and lopinavir. Minimal to no cellular cytotoxicity was observed with any of these protease inhibitors alone or in combination with nelfinavir. In combination with reverse transcriptase inhibitors, nelfinavir demonstrated additive (didanosine or stavudine) to synergistic (abacavir, delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, tenofovir, zalcitabine, or zidovudine) antiviral activity without enhanced cytotoxicity. Nelfinavir's anti-HIV activity was not antagonized by the anti-HCV drug ribavirin.

HIV-1 isolates with reduced susceptibility to nelfinavir have been selected in cell culture. HIV-1 isolates from selected patients treated with nelfinavir alone or in combination with reverse transcriptase inhibitors were monitored for phenotypic (n=19) and genotypic (n=195, 157 of which were evaluable) changes in clinical trials over a period of 2 to 82 weeks. One or more viral protease mutations at amino acid positions 30, 35, 36, 46, 71, 77, and 88 were detected in the HIV-1 of > 10% of patients with evaluable isolates. The overall incidence of the D30N substitution in the viral protease of evaluable isolates (n=157) from patients receiving nelfinavir monotherapy or nelfinavir in combination with zidovudine and lamivudine or stavudine was 54.8%. The overall incidence of other substitutions associated with primary protease inhibitor resistance was 9.6% for the L90M substitution, whereas substitutions at 48, 82, or 84 were not observed. Of the 19 clinical isolates for which both phenotypic and genotypic analyses were performed, 9 showed reduced susceptibility (5- to 93-fold) to nelfinavir in cell culture. All 9 isolates possessed one or more mutations in the viral protease gene. Amino acid position 30 appeared to be the most frequent mutation site.

Non-clinical Studies: Patient-derived recombinant HIV-1 isolates containing the D30N substitution (n=4) and demonstrating highlevel ( > 10-fold) nelfinavir-resistance remained susceptible ( < 2.5-fold resistance) to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Patient-derived recombinant HIV-1 isolates containing the L90M substitution (n=8) demonstrated moderate to high-level resistance to nelfinavir and had varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Most patient-derived recombinant isolates with phenotypic and genotypic evidence of reduced susceptibility ( > 2.5-fold) to amprenavir, indinavir, lopinavir, and/or saquinavir demonstrated high-level cross-resistance to nelfinavir. Amino acid substitutions associated with resistance to other protease inhibitors (e.g., G48V, V82A/F/T, I84V, L90M) appeared to confer high-level cross-resistance to nelfinavir. Following ritonavir therapy 6 of 7 clinical isolates with decreased ritonavir susceptibility (8- to 113-fold) compared to baseline also exhibited decreased susceptibility to nelfinavir (5- to 40-fold). Cross-resistance between nelfinavir and reverse transcriptase inhibitors is unlikely because different enzyme targets are involved. Clinical isolates (n=5) with decreased susceptibility to lamivudine, nevirapine, or zidovudine remain fully susceptible to nelfinavir.

Clinical Studies: There have been no controlled or comparative studies evaluating the virologic response to subsequent protease inhibitor-containing regimens in subjects who have demonstrated loss of virologic response to a nelfinavir-containing regimen. However, virologic response was evaluated in a single-arm prospective study of 26 subjects with extensive prior antiretroviral experience with reverse transcriptase inhibitors (mean 2.9) who had received nelfinavir for a mean duration of 59.7 weeks and were switched to a ritonavir (400 mg BID)/saquinavir hard-gel (400 mg BID)-containing regimen after a prolonged period of nelfinavir failure (median 48 weeks). Sequence analysis of HIV-1 isolates prior to switch demonstrated a D30N or an L90M substitution in 18 and 6 subjects, respectively. Subjects remained on therapy for a mean of 48 weeks (range 40 to 56 weeks) where 17 (65%) and 13 (50%) of the 26 subjects were treatment responders with HIV-1 RNA below the assay limit of detection ( < 500 HIV-1 RNA copies/mL, Chiron bDNA) at 24 and 48 weeks, respectively.

Clinical Studies

The efficacy of VIRACEPT is based on analyses of multiple clinical studies in HIV-1 infected antiretroviral treatment-naïve and experienced adult patients. In the adult clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA < 400 copies/mL (Studies 511 and 542), < 500 copies/mL (Study ACTG 364), or < 50 copies/mL (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the study's definition of virologic failure.

Studies In Antiretroviral Treatment Naïve Adult Patients

Study 511 is a double-blind, randomized, placebo-controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of VIRACEPT (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naïve HIV-1 infected patients. The median age was 35 years [range 21 to 63]; 89% were male and 78% were Caucasian. Mean baseline CD4 cell count was 288 cells/mm³ and mean baseline plasma HIV RNA was 5.21 log10 copies/mL (160,394 copies/mL). The proportion of patients with plasma HIV RNA < 400 copies/mL at Week 48 was 86%, as summarized in Figure 1. The mean change in CD4 cell count at Week 48 was 207.6 cells/mm³.

Figure 1: Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL

Study 542 is a, randomized, open-label trial comparing the HIV RNA suppression achieved by VIRACEPT 1250 mg BID versus VIRACEPT 750 mg TID in patients also receiving stavudine (d4T; 30-40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naïve to protease inhibitors. Mean baseline CD4 cell count was 296 cells/mm³ and mean baseline plasma HIV RNA was 5.0 log10 copies/mL (100,706 copies/mL).

Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm³ at 24 weeks and approximately 200 cells/mm³ at 48 weeks.

The percent of patients with HIV RNA < 400 copies/mL and the outcomes of patients through 48 weeks of treatment are summarized in Table 14.

Table 14: Outcomes of Randomized Treatment Through 48 Weeks

Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of VIRACEPT (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo in combination with ZDV and 3TC (n=52) administered to antiretroviral-naïve patients with HIV infection and a CD4 cell count between 150 and 500 cells/μL. Patients had a mean age of 35 (range 22-59), were 89% male, and 88% Caucasian. Mean baseline CD4 cell count was 304 cells/mm³ and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (57,887 copies/mL). The percent of patients with plasma HIV RNA < 50 copies/mL at 52 weeks was 54% for the (VIRACEPT + ZDV + 3TC)-treatment group and 13% for the (ZDV + 3TC)-treatment group.

Studies In Antiretroviral Treatment Experienced Adult Patients

Study ACTG 364 was a randomized, double-blind study that evaluated the combination of VIRACEPT 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs (either didanosine [ddI] + d4T, ddI + 3TC, or d4T + 3TC) in patients with prolonged prior nucleoside exposure who had completed 2 previous ACTG studies. Patients had a mean age of 41 years (range 18 to 75), were 88% male, and were 74% Caucasian. Mean baseline CD4 cell count was 389 cells/mm³ and mean baseline plasma HIV RNA was 3.9 log10 copies/Ml (7,954 copies/mL).

The percent of patients with plasma HIV RNA < 500 copies/mL at 48 weeks was 42%, 62%, and 72% for the VIRACEPT (n=66), EFV (n=65), and VIRACEPT + EFV (n=64) treatment groups, respectively.

Studies In Pediatric Patients

The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in pediatric patients 2 years of age up to 13 years were evaluated in 2 randomized studies.

Study 556 was a randomized, double-blind, placebo-controlled trial with VIRACEPT or placebo coadministered with ZDV and ddI in 141 HIV-positive children who had received minimal antiretroviral therapy. The mean age of the children was 3.9 years. Ninety four (67%) children were between 2-12 years, and 47 (33%) were < 2 years of age. The mean baseline HIV RNA value was 5.0 log for all patients and the mean CD4 cell count was 886 cells/mm³ for all patients. The efficacy of VIRACEPT measured by HIV RNA < 400 at 48 weeks in children ≥ 2 years of age was 26% compared to 2% of placebo patients (p=0.0008). In the children < 2 years of age, only 1 of 27 and 2 of 20 maintained an undetectable HIV RNA level at 48 weeks for placebo and VIRACEPT patients, respectively.

PACTG 377 was an open-label study that randomized 181 HIV treatment-experienced pediatric patients to receive: d4T+NVP+RTV, d4T+3TC+NFV, or d4T+3TC+NVP+NFV with NFV given on a TID schedule. The median age was 5.9 years and 46% were male. At baseline the median HIV RNA was 4.4 log and median CD4 cell count was 690 cells/mm³. Substudy PACTG 725 evaluated d4T+3TC+NFV with NFV given on a BID schedule. The proportion of patients with detectable viral load at baseline achieving HIV RNA < 400 copies/mL at 48 weeks was: 41% for d4T+NVP+RTV, 42% for d4T+3TC+NFV, 30% for d4T+NVP+NFV, and 52% for d4T+3TC+NVP+NFV. No significant clinical differences were identified between patients receiving VIRACEPT in BID or TID schedules.

VIRACEPT has been evaluated in 2 studies of young infants. The PENTA 7 study was an open-label study to evaluate the toxicity, tolerability, pharmacokinetics, and activity of NFV+d4T+ddI in 20 HIV-infected infants less than 12 weeks of age. PACTG 353 evaluated the pharmacokinetics and safety of VIRACEPT in infants born to HIV-infected women receiving NFV as part of combination therapy during pregnancy.

The following issues should be considered when initiating VIRACEPT in pediatric patients:

• In pediatric patients ≥ 2 years of age receiving VIRACEPT as part of triple combination antiretroviral therapy in randomized studies, the proportion of patients achieving a HIV RNA level < 400 copies/mL through 48 weeks ranged from 26% to 42%.
• Response rates in children < 2 years of age appeared to be poorer than those in patients ≥ 2 years of age in some studies.
• Highly variable drug exposure remains a significant problem in the use of VIRACEPT 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. Pharmacokinetic results from the pediatric studies are reported in Table 11 [see Pharmacokinetics].

The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in adolescent patients 13 years and older is supported by data from the adult clinical trials where some trials allowed enrolment of subjects 13 years and older. Thus, the data for adolescents and adults were analyzed collectively.

Your pharmacist can provide more information about nelfinavir.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience: Adults And Adolescents (13 Years and Older)

The safety of VIRACEPT was studied in over 5000 patients who received drug either alone or in combination with nucleoside analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity.

Drug-related clinical adverse experiences of moderate or severe intensity in ≥ 2% of patients treated with VIRACEPT coadministered with d4T and 3TC (Study 542) for up to 48 weeks, or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 4.

Table 4: Percentage of Patients with Treatment-Emergent* Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult and Adolescent Patients

Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase 2 and 3 clinical trials and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below.

Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS].

Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and vomiting.

Hemic/Lymphatic System: anemia, leukopenia, and thrombocytopenia.

Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT, SGPT, and gamma-glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver function tests abnormal.

Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy.

Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence, and suicide ideation.

Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.

Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria.

Special Senses: acute iritis and eye disorder.

Urogenital System: kidney calculus, sexual dysfunction, and urine abnormality.

The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 5. Marked laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient with a Grade 1 abnormality at baseline.

Table 5: Percentage of Patients by Treatment Group with Marked Laboratory Abnormalities* in > 2% of Patients

Clinical Trials Experience: Pediatrics (2 to Less than 13 Years of Age)

VIRACEPT has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during pediatric clinical trials was similar to that for adults.

The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported in 39% to 47% of pediatric patients receiving VIRACEPT in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VIRACEPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema).

Cardiovascular System: QTc prolongation, torsades de pointes.

Digestive System: jaundice.

Metabolic/Nutritional System: bilirubinemia, metabolic acidosis.

Read the entire FDA prescribing information for Viracept (Nelfinavir Mesylate)

Administration

Oral Administration

Administer orally 2 or 3 times daily with a meal.1

Tablets are film-coated to facilitate swallowing.1

For individuals unable to swallow tablets, place appropriate dose of 250-mg tablets in small amount of water and allow to disperse.1 After tablets dissolve, mix the cloudy liquid well and immediately consume.1 To ensure that entire dose is consumed, rinse glass with water and swallow the rinse.1

Dosage

Available as nelfinavir mesylate; dosage expressed as nelfinavir.1

Must be given in conjunction with other antiretrovirals.1

Pediatric Patients

Infants <2 years of age†: Reliably effective dosage not established;1 not recommended in this age group.201 (See Pediatric Use under Cautions.)

Children 2 to <13 years of age: 45–55 mg/kg twice daily or 25–35 mg/kg 3 times daily.1 (See Table 1.)

Children ≥13 years of age: 1.25 g (five 250-mg tablets or two 625-mg tablets) twice daily or 750 mg (three 250-mg tablets) 3 times daily.1

Adults

1.25 g (five 250-mg tablets or two 625-mg tablets) twice daily or 750 mg (three 250-mg tablets) 3 times daily.1

Prescribing Limits

Pediatric Patients

Children 2 to <13 years of age (tablets): Maximum 1.25 g (5 tablets) twice daily or 750 mg (3 tablets) 3 times daily.1 Dosages >2.5 g daily not studied in children.1

Special Populations

Hepatic Impairment

Dosage adjustment not needed in patients with mild hepatic impairment (Child-Pugh class A, score 5–6).1 Do not use in patients with moderate or severe hepatic impairment (Child-Pugh class B or C, score ≥7).1

Renal Impairment

Safety and efficacy not established;1 some experts state dosage adjustments not necessary.200

Contraindications

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, amiodarone, cisapride, ergot alkaloids, oral midazolam, pimozide, quinidine, sildenafil used for treatment of pulmonary arterial hypertension [PAH], triazolam).1 Concomitant use with drugs that may decrease nelfinavir concentrations (e.g., rifampin, St. John’s wort [Hypericum perforatum].1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Interactions

Concomitant use with certain drugs not recommended or requires particular caution.1 (See Specific Drugs under Interactions.)

Hyperglycemic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.1 82 130 131 132

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.1

Hemophilia A and B

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported with PIs; causal relationship not established.1 75 77 124

Caution in patients with a history of hemophilia type A or B.75 Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 137 138 139 140 141 142 143 144 Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.1

Immune Reconstitution Syndrome

During initial treatment, patients who respond 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) reported in the setting of immune reconstitution; time to onset is variable and can occur many months after initiation of antiretroviral therapy.1

HIV Resistance

Possibility of HIV resistance to nelfinavir and possible cross-resistance to other PIs.1 Effect of nelfinavir therapy on subsequent therapy with other PIs unclear.1

Ethyl Methane Sulfonate (EMS)

Nelfinavir preparations manufactured before 2008 may have contained low levels of ethyl methane sulfonate (EMS), an impurity produced by the manufacturing process.178 202 EMS has been teratogenic, mutagenic, and carcinogenic in animals; no human data exist and no increase in birth defects has been observed in the antiretroviral pregnancy registry.178 202 All nelfinavir preparations manufactured and released since March 31, 2008 meet EMS limits established by FDA for all patient populations, including children and pregnant women.202

Specific Populations

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state that nelfinavir not recommended for initial treatment regimens in antiretroviral-naive pregnant women.202 Clinical trial data in adults indicate lower rate of viral suppression with nelfinavir regimens compared with regimens containing the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) or efavirenz.202 If nelfinavir used for treatment of HIV-1 in pregnant women, experts recommend a dosage of 1.25 g twice daily.202

Pharmacokinetic data indicate plasma concentrations may be lower and more variable during late pregnancy.179 202 (See Special Populations under Pharmacokinetics.)

Available data suggest nelfinavir does not increase overall birth defect rate.202

Low concentrations distributed into human milk.168 202

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Safety and efficacy not established in infants and children <2 years of age.1 Some data collected in this age group, but reliably effective dosage not established.1 Some evidence that those <2 years of age have a lower response rate than older children.1

Consider that use of nelfinavir in children is associated with highly variable drug exposure.1 (See Pharmacokinetics.)

Use of nelfinavir in children 2–13 years of age supported by evidence from adequate and well-controlled studies in adults and pharmacokinetic and clinical studies supporting activity in pediatric patients.1 80 124 126 127 152 153 161 201 213 Diarrhea reported less frequently in children than in adults.80 124

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Do not use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥7).1

Safety and efficacy not established in patients with renal impairment;1 only limited pharmacokinetic information available.14 51 160

Common Adverse Effects

Diarrhea,1 nausea,1 flatulence,1 rash.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.