Fosamprenavir

1 INDICATIONS AND USAGE Fosamprenavir calcium tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection. The following points should be considered when initiating therapy with fosamprenavir plus ritonavir in protease inhibitor-experienced patients: • The protease inhibitor-experienced patient trial was not large enough to reach a definitive conclusion that fosamprenavir plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2) ] . • Once-daily administration of fosamprenavir plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.2 , 2.3) , Clinical Studies (14.2 , 14.3) ]. • Dosing of fosamprenavir plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)] . Fosamprenavir calcium tablets are an HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 )

12.1 Mechanism of Action Fosamprenavir is an HIV-1 antiretroviral agent [see Microbiology (12.4) ] .

Mechanism of Action Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

2 DOSAGE AND ADMINISTRATION • Therapy-Naive Adults: Fosamprenavir 1,400 mg twice daily; fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. ( 2.2 ) • Protease Inhibitor-Experienced Adults: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. ( 2.2 ) • Pregnant Patients: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in women who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). ( 2.2 ) • Pediatric Patients (aged at least 4 weeks to 18 years): Dosage should be calculated based on body weight (kg) and should not exceed adult dose. ( 2.3 ) • Hepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. ( 2.4 ) Dosing Considerations • Fosamprenavir calcium tablets may be taken with or without food. ( 2.1 ) 2.1 General Dosing Information Fosamprenavir calcium tablets may be taken with or without food. Higher-than-approved dose combinations of fosamprenavir plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10) ] . When fosamprenavir is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir. 2.2 Adults Therapy-Naive Adults • Fosamprenavir 1,400 mg twice daily (without ritonavir). • Fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily. • Fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily. o Dosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3) ] . • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. o Dosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3) ] . Protease Inhibitor-Experienced Adults • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. o Dosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.3) ] . Data regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available. 2.3 Pediatric Patients (Aged at Least 4 Weeks to 18 Years) The recommended dosage of fosamprenavir in patients aged at least 4 weeks to 18 years should be calculated based on body weight (kg) and should not exceed the recommended adult dose (Table 1). Table 1. Twice-Daily Dosage Regimens by Weight for Protease Inhibitor-Naive Pediatric Patients (Aged 4 Weeks and Older) and for Protease Inhibitor-Experienced Pediatric Patients (Aged 6 Months and Older) Using Fosamprenavir Calcium Oral Suspension with Concurrent Ritonavir Weight Twice-Daily Dosage Regimen < 11 kg Fosamprenavir 45 mg/kg plus ritonavir 7 mg/kg When dosing with ritonavir, do not exceed the adult dose of fosamprenavir 700 mg/ritonavir 100 mg twice-daily dose. 11 kg - < 15 kg Fosamprenavir 30 mg/kg plus ritonavir 3 mg/kg 15 kg - < 20 kg Fosamprenavir 23 mg/kg plus ritonavir 3 mg/kg ≥ 20 kg Fosamprenavir 18 mg/kg plus ritonavir 3 mg/kg Alternatively, protease inhibitor-naive children aged 2 years and older can be administered fosamprenavir (without ritonavir) 30 mg p

6 ADVERSE REACTIONS • Severe or life-threatening skin reactions have been reported with the use of fosamprenavir [see Warnings and Precautions (5.2) ] . • The most common moderate to severe adverse reactions in clinical trials of fosamprenavir were diarrhea, rash, nausea, vomiting, and headache. • Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash. • In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. ( 6.1 ) • Vomiting and neutropenia were more frequent in pediatrics than in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adult Trials The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1– infected subjects to fosamprenavir calcium tablets, including 599 subjects exposed to fosamprenavir for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these subjects, 26% were female, 51% white, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir 1,400 mg twice daily; and 15% received fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir are shown in Tables 2 and 3. Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks. Table 2. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects Adverse Reaction APV30001 All subjects also received abacavir and lamivudine twice daily. APV30002 Fosamprenavir 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir 1,400 mg and Ritonavir 200 mg Once Daily (n = 322) Nelfinavir 1,250 mg Twice Daily (n = 327) Gastrointestinal Diarrhea 5% 18% 10% 18% Nausea 7% 4% 7% 5% Vomiting 2% 4% 6% 4% Abdominal pain 1% 0% 2% 2% Skin Rash 8% 2% 3% 2% General disorders Fatigue 2% 1% 4% 2% Nervous system Headache 2% 4% 3% 3% Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003) Adverse Reaction Fosamprenavir 700 mg and Ritonavir 100 mg Twice Daily All subjects also received 2 reverse transcriptase inhibitors. (n = 106) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily (n = 103) Gastrointestinal Diarrhea 13% 11% Nausea 3% 9% Vomiting 3% 5% Abdominal pain < 1% 2% Skin Rash 3% 0% Nervous system Headache 4% 2% Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with fosamprenavir in the pivotal efficacy trials. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had a median onset of 11 days after initiation of fosamprenavir and had a median duration of 13 days. Skin rash led to discontinuation of fosamprenavir in less than 1% of subjects. In some subjects with mild or moderate rash, dosing with fosamprenavir was often continued without interruption; if interrupted, reintroduction of fosamprenavir generally di

5 WARNINGS AND PRECAUTIONS • The concomitant use of fosamprenavir with ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.1 , 7.3 ) • Fosamprenavir should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. ( 5.2 ) • Fosamprenavir should be used with caution in patients with a known sulfonamide allergy. ( 5.3 ) • Use of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis B or C are at increased risk of transaminase elevations. ( 5.4 ) • Patients receiving fosamprenavir may develop new onset or exacerbations of diabetes mellitus, hyperglycemia ( 5.5 ), immune reconstitution syndrome ( 5.6 ), increase of body fat ( 5.7 ), and elevated triglyceride and cholesterol concentrations ( 5.8 ). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. • Acute hemolytic anemia has been reported with amprenavir. ( 5.9 ) • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. ( 5.10 ) • Nephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. ( 5.11 ) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of fosamprenavir/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir/ritonavir may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of fosamprenavir/ritonavir, respectively. These interactions may lead to: • clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • clinically significant adverse reactions from greater exposures of fosamprenavir/ritonavir. • loss of therapeutic effect of fosamprenavir/ritonavir and possible development of resistance. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during therapy with fosamprenavir/ritonavir; review concomitant medications during therapy with fosamprenavir/ritonavir; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) , Drug Interactions (7) ] . 5.2 Skin Reactions Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 subjects treated with fosamprenavir in clinical trials. Treatment with fosamprenavir should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6) ] . 5.3 Sulfa Allergy Fosamprenavir should be used with caution in patients with a known sulfonamide allergy. Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical trial of fosamprenavir used as the sole protease inhibitor, rash occurred in 2 of 10 subjects (20%) with a history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy. In 2 clinical trials of fosamprenavir plus low-dose ritonavir, rash occurred in 8 of 50 subjects (16%) with a history of sulfonamide allergy compared with 50 of 412 subjects (12%) with no history of sulfonamide allergy. 5.4 Hepatic Toxicity Use of fosamprenavir with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2) , Overdosage (10) ] . Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk

4 CONTRAINDICATIONS • Fosamprenavir calcium tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir. • Fosamprenavir calcium tablets are contraindicated when coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4 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 fosamprenavir and possible resistance) are listed below [see Drug Interactions (7), Clinical Pharmacology (12.3)]. The list of contraindicated drugs applies to the use of fosamprenavir with or without ritonavir, unless otherwise indicated. If fosamprenavir is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. • Fosamprenivir is contraindicated when coadministered with the following drugs: o Alpha 1-adrenoreceptor antagonist: Alfuzosin o Antiarrhythmics: Flecainide (with ritonavir ), propafenone (with ritonavir ) o Antimycobacterial: Rifampin o Antipsychotic: Lurasidone (with ritonavir ), pimozide o Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine o GI motility agent: Cisapride o Herbal product: St. John’s wort ( Hypericum perforatum ) o Lipid modifying agents: Lomitapide, lovastatin, simvastatin o Non-nucleoside reverse transcriptase inhibitor: Delavirdine o PDE5 inhibitor: Sildenafil (REVATIO ® ) (for treatment of pulmonary arterial hypertension) o Sedative/hypnotics: Midazolam, triazolam • Hypersensitivity to fosamprenavir or amprenavir (e.g., Stevens-Johnson syndrome). ( 4 ) • Drugs highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. ( 4 ) • Review ritonavir contraindications when used in combination. ( 4 )

10 OVERDOSAGE In a healthy volunteer repeat-dose pharmacokinetic trial evaluating high-dose combinations of fosamprenavir plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 2.5 x ULN) was observed with fosamprenavir 1,400 mg twice daily plus ritonavir 200 mg twice daily (4 of 25 subjects). Concurrent Grade 1/2 elevations in AST (greater than 1.25 x ULN) were noted in 3 of these 4 subjects. These transaminase elevations resolved following discontinuation of dosing. There is no known antidote for fosamprenavir. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis, although it is unlikely as amprenavir is highly protein bound. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.