VIRACEPT

1 INDICATIONS AND USAGE VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. VIRACEPT is a protease inhibitor indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. ( 1 )

2 DOSAGE AND ADMINISTRATION • See full prescribing information for administration instructions ( 2 ) • Adults and adolescents 13 years and older (tablets): 1250 mg twice daily or 750 mg three times daily with a meal ( 2.1 ) • Children 2 to less than 13 years (oral powder or 250 mg tablets): 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily with a meal. Refer to Tables 1 and 2 of the full prescribing information for specific dosing guidelines based on age and body weight ( 2.2 ) 2.1 Adults and Adolescents (13 years and older) The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily. VIRACEPT should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in a small amount of water [see Dosage and Administration (2.3) ] . 2.2 Pediatric Patients (2 to less than 13 years) In children 2 years of age and older, the recommended oral dose of VIRACEPT Oral Powder or 250 mg tablets is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal . Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children. For children unable to swallow tablets, VIRACEPT 250 mg tablet(s) may be dissolved in a small amount of water or, VIRACEPT Oral Powder may be administered [see Dosage and Administration (2.3) ] . The healthcare provider should assess appropriate formulation and dosage for each patient. Tables 1 and 2 provide dosing guidelines for VIRACEPT tablets and powder based on age and body weight. Table 1: Dosing Table for Children 2 to less than 13 years of age (tablets) Body weight Twice daily (BID) 45 – 55 mg/kg ≥2 years Three times daily (TID) 25 – 35 mg/kg ≥2 years Number of tablets (250 mg) Number of tablets (250 mg) Kg 10 – 12 2 1 13 – 18 3 2 19 – 20 4 2 ≥21 4 – 5 For BID dosing, the maximum dose per day is 5 tablets BID 3 For TID dosing, the maximum dose per day is 3 tablets TID Table 2: Dosing Table for Children 2 to less than 13 years of age (powder) Body weight Twice daily (BID) 45 – 55 mg/kg Three times daily (TID) 25 – 35 mg/kg Kg Scoops of powder (50 mg/1 g) Teaspoons If a teaspoon is used to measure VIRACEPT oral powder, 1 level teaspoon contains 200 mg of VIRACEPT (4 level scoops equals 1 level teaspoon) of powder Scoops of powder (50 mg/1 g) Teaspoons of powder 9.0 to <10.5 10 21⁄2 6 11⁄2 10.5 to <12 11 23⁄4 7 13⁄4 12 to <14 13 31⁄4 8 2 14 to <16 15 33⁄4 9 21⁄4 16 to <18 Not recommended Use VIRACEPT 250 mg tablet Not recommended 10 21⁄2 18 to <23 Not recommended Not recommended 12 3 ≥23 Not recommended Not recommended 15 33⁄4 2.3 Method of Administration For Patients Unable to Swallow Viracept Tablets • Place VIRACEPT tablet(s) in small amount of water. • Once dissolved, mix the cloudy liquid well, and consume it immediately. • The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed. Viracept Oral Powder • Mix VIRACEPT Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements • Once mixed, the entire contents must be consumed in order to obtain the full dose. • If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours. • Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing VIRACEPT Oral Powder because the combination may result in a bitter taste. • VIRACEPT Oral Powder should not be reconstituted with water in its original container. 2.4 Hepatic Impairment VIRACEPT can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be used in patients with either moderate or severe hepatic impairment [see Warnings and Precautions (5.2) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] .

3 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). • Tablet: 250 mg, 625 mg nelfinavir free base ( 3 ) • Oral Powder: 50 mg/g nelfinavir free base ( 3 )

4 CONTRAINDICATIONS Coadministration of VIRACEPT is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of nelfinavir) are listed in Table 3 [also see Drug Interactions (7) , Table 6 ] . Table 3: Drugs That Are Contraindicated With VIRACEPT Drug Class Drugs Within Class That Are Contraindicated With VIRACEPT Clinical Comment Alpha 1-adrenoreceptor antagonist Alfuzosin Potentially increased alfuzosin concentrations can result in hypotension. Antiarrhythmics Amiodarone, quinidine Potential for serious and/or life-threatening cardiac arrhythmia. Antimycobacterial Agents Rifampin Plasma concentrations of nelfinavir can be reduced by concomitant use of rifampin. This may lead to loss of therapeutic effect and possible development of resistance to VIRACEPT or other coadministered antiretroviral agents. Antipsychotics Lurasidone Pimozide Potential for serious and/or life-threatening reactions. Potential for serious and/or life threatening reactions such as cardiac arrhythmias. Ergot Derivatives Dihydroergotamine, ergotamine, methylergonovine Potential for serious and/or life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI Motility Agent Cisapride Potential for serious and/or life threatening reactions such as cardiac arrhythmias. Herbal products St. John's wort ( Hypericum perforatum ) Plasma concentrations of nelfinavir can be reduced by concomitant use of the herbal preparation St. John's wort. This may lead to loss of therapeutic effect and possible development of resistance to VIRACEPT or other coadministered antiretroviral agents. HMG-CoA Reductase Inhibitors Lovastatin, Simvastatin Potential for serious reactions such as myopathy including rhabdomyolysis. PDE5 Inhibitors Sildenafil (Revatio ® ) [for treatment of pulmonary arterial hypertension] See Drug Interactions , Table 6 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction. A safe and effective dose has not been established when used with nelfinavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Sedative/Hypnotics Triazolam, oral midazolam Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. • Coadministration with drugs that are highly dependent on CYP3A for clearance and which elevated concentrations are associated with serious and/or life-threatening events ( 4 )

6 ADVERSE REACTIONS 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. • Most common adverse reactions (≥2%) of moderate or severe intensity in adults and adolescents (13 years and older) are diarrhea, nausea, rash, and flatulence ( 6.1 ) • Most common adverse reactions in pediatric patients (2 to less than 13 years) are diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 Includes those adverse events at least possibly, probably or definitely related to study drug or of unknown relationship and excludes concurrent HIV conditions Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult and Adolescent Patients Study 511 Study 542 24 weeks 48 weeks Adverse Events Placebo + ZDV/3TC (n=101) 500 mg TID VIRACEPT + ZDV/3TC (n=97) 750 mg TID VIRACEPT + ZDV/3TC (n=100) 1250 mg BID VIRACEPT + d4T/3TC (n=344) 750 mg TID VIRACEPT + d4T/3TC (n=210) Digestive System Diarrhea 3% 14% 20% 20% 15% Nausea 4% 3% 7% 3% 3% Flatulence 0 5% 2% 1% 1% Skin/Appendages Rash 1% 1% 3% 2% 1% 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 (5.7) ] . 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. Laboratory Abnormalities 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 Abn …

7 DRUG INTERACTIONS • Coadministration of VIRACEPT with other drugs ( CYP3A substrates) can alter the concentration of these other drugs , and other drugs (inhibitors and/or inducers of CYP3A or CYP2C19) may alter the concentrations of nelfinavir. The potential drug-drug concentrations must be considered prior to and during therapy ( 4 , 7 , 12.3 ) • VIRACEPT should be given with food one hour after or more than 2 hours before didanosine ( 7 ) 7.1 Potential for VIRACEPT to Affect Other Drugs Nelfinavir is an inhibitor of CYP3A. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) may result in increased plasma concentrations of such drugs that could increase or prolong both its therapeutic and adverse effects (see Tables 3 and 6 ). 7.2 Potential for Other Drugs to Affect VIRACEPT Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19, such as rifampin, may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations. 7.3 Established and Other Potentially Significant Drug Interactions Table 6 provides the effect on concentrations of VIRACEPT or concomitant drug as a result of coadministration with VIRACEPT. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) ( Tables 12 and 13 ) for magnitude of interaction] Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV Antiviral Agents: Reverse Transcriptase Inhibitors Delavirdine ↑ nelfinavir (C min ) ↓ delavirdine Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. Nevirapine ↓ nelfinavir (C min ) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). HIV Antiviral Agents: Protease Inhibitors Indinavir ↑ nelfinavir ↑ indinavir Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. Ritonavir ↑ nelfinavir ↔ ritonavir Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. Saquinavir ↑ nelfinavir ↑ saquinavir Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. ANTICOAGULANT Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. ANTICONVULSANTS Carbamazepine Phenobarbital Phenytoin ↓ nelfinavir ↓ phenytoin Concentrations of nelfinavir may be decreased. VIRACEPT may not be effect …

8 USE IN SPECIFIC POPULATIONS • Use during pregnancy if the potential benefit justifies the potential risk to the fetus ( 8.1 ) • Lactation: Patients infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VIRACEPT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Published reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients exposed to nelfinavir have been reported (see Clinical Considerations ). Due to VIRACEPT's overall adverse event profile, including hepatic adverse events, and literature reports of decreased exposures in second and third trimesters, consider alternative antiretroviral drugs during pregnancy. Available data from the APR suggests a statistically significant increase in overall risks of major birth defects with first trimester exposure with nelfinavir (3.9%) when compared with the background rate of 2.7% in one U.S. reference population (the Metropolitan Atlanta Congenital Defects Program [MACDP]), but the risk is similar to the background rate of 4.2% reported in another U.S. reference population (the Texas Birth Defects Registry [TBDR]). No pattern of defects was identified by the APR. The clinical relevance of this statistical finding is uncertain (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. In animal reproductive studies, no effects on embryo-fetal development were observed when nelfinavir was administered orally to pregnant rats and rabbits during organogenesis at systemic exposures similar to or less than human exposure (based on AUC) at the maximum recommended human dose (MRHD), respectively (see Data ) . Clinical Considerations Maternal Adverse Reactions There have been reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients receiving nelfinavir as part of combination treatment of HIV-1 infection. Consider alternative antiretroviral drugs during pregnancy. If VIRACEPT is used during pregnancy, clinical monitoring is recommended [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] . Data Human Data Based on prospective reports to the APR of over 1,200 live births following first trimester and over 2,700 live births following second and third trimester exposure to nelfinavir-containing regimens, there was an increase in overall rates of major birth defects (n=47) with nelfinavir when compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.9% (95% CI: 2.9% to 5.1%) with first trimester exposure to nelfinavir-containing regimens and 3.1% (95% CI: 2.5% to 3.9%) with the second/third trimester exposure to nelfinavir-containing regimens. The rate for nelfinavir-containing regimens is greater than the overall rates of defects in the MACDP (2.7%) but less than rates of defects in the TBDR (4.2%). Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes. The MACDP population is not disease specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. Animal Data Nelfinavir was administered orally to preg …

12.1 Mechanism of Action Nelfinavir is an inhibitor of the HIV-1 protease [see Microbiology (12.4) ] .

11 DESCRIPTION VIRACEPT ® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. VIRACEPT Tablets are available for oral administration as a light-blue, capsule-shaped tablet with a clear film coating in 250 mg strength (as nelfinavir-free base) and as a white oval tablet with a clear film coating in 625 mg strength (as nelfinavir-free base). Each tablet contains the following common inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide. VIRACEPT Oral Powder is available for oral administration in a 50 mg/g strength (as nelfinavir-free base) in bottles. The oral powder also contains the following inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The chemical name for nelfinavir mesylate is [3 S -[2(2 S* , 3 S* ), 3α,4aβ,8aβ]]- N -(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline carboxamide mono-methanesulfonate (salt) and the molecular weight is 663.90 (567.79 as the free base). Nelfinavir mesylate has the following structural formula: Nelfinavir mesylate is a white to off-white amorphous powder, slightly soluble in water at pH ≤4 and freely soluble in methanol, ethanol, 2-propanol and propylene glycol. Chemical Structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/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 .