Fosamprenavir Calcium

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 calcium tablets plus ritonavir in protease inhibitor-experienced patients: The protease inhibitor-experienced patient trial was not large enough to reach a definitive conclusion that fosamprenavir calcium tablets plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)] . Once-daily administration of fosamprenavir calcium tablets 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 calcium tablets plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)] . Fosamprenavir calcium tablets are HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)

2 DOSAGE AND ADMINISTRATION Therapy-Naive Adults: Fosamprenavir calcium tablets 1,400 mg twice daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) Protease Inhibitor-Experienced Adults: Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) Pregnant Patients: Fosamprenavir calcium tablets 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 calcium /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) Fosamprenavir Calcium Oral Suspension: Adults should take without food; pediatric patients should take with food. (2.1) 2.1 General Dosing Information Fosamprenavir calcium tablets may be taken with or without food. Adults should take fosamprenavir calcium oral suspension without food. Pediatric patients should take fosamprenavir calcium oral suspension with food [see Clinical Pharmacology (12.3)] . If emesis occurs within 30 minutes after dosing, re-dosing of fosamprenavir calcium oral suspension should occur. Higher-than-approved dose combinations of fosamprenavir calcium tablets plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)] . When fosamprenavir calcium tablets are used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir. 2.2 Adults Therapy-Naive Adults Fosamprenavir calcium tablets 1,400 mg twice daily (without ritonavir). Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily. Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)] . Dosing of fosamprenavir calcium tablets 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 calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 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 calcium /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 calcium tablets (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 calcium 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 …

5 WARNINGS AND PRECAUTIONS The concomitant use of fosamprenavir calcium 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 calcium should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) Fosamprenavir calcium 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 calcium 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 calcium/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir calcium/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 calcium/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 calcium/ritonavir. loss of therapeutic effect of fosamprenavir calcium/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 calcium/ritonavir; review concomitant medications during therapy with fosamprenavir calcium/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 calcium in clinical trials. Treatment with fosamprenavir calcium 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 calcium 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 calcium 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 calcium 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 calcium 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 o…

4 CONTRAINDICATIONS Fosamprenavir calcium is 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 is 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 calcium 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 calcium with or without ritonavir, unless otherwise indicated. If fosamprenavir calcium is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. Fosamprenavir calcium is contraindicated when coadministered with the following drugs: Alpha 1-adrenoreceptor antagonist: Alfuzosin Antiarrhythmics: Flecainide (with ritonavir ), propafenone (with ritonavir ) Antimycobacterial: Rifampin Antipsychotic: Lurasidone (with ritonavir ), pimozide Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agent: Cisapride Herbal product: St. John’s wort ( Hypericum perforatum ) Lipid modifying agents: Lomitapide, lovastatin, simvastatin Non-nucleoside reverse transcriptase inhibitor: Delavirdine PDE5 inhibitor: Sildenafil (Revatio) (for treatment of pulmonary arterial hypertension) Sedative/hypnotics: Midazolam, triazolam Hypersensitivity to fosamprenavir calcium 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)

7 DRUG INTERACTIONS Coadministration of fosamprenavir calcium with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3) Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3) Coadministration of fosamprenavir calcium or fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7) Coadministration of fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. (7) 7.1 Cytochrome P450 Inhibitors and Inducers Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4. Amprenavir is metabolized by CYP3A4. Coadministration of fosamprenavir calcium and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir calcium and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. The potential for drug interactions with fosamprenavir calcium changes when fosamprenavir calcium is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when fosamprenavir calcium is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir calcium plus ritonavir. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other enzymes, including glucuronosyl transferase. There are other agents that may result in serious and/or life-threatening drug interactions [see Contraindications (4)] . 7.2 Established and Other Potentially Significant Drug Interactions If fosamprenavir calcium is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions [see Contraindications (4), Clinical Pharmacology (12.3)] . Table 6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to fosamprenavir calcium with or without ritonavir, unless otherwise indicated. Table 6. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment HCV/HIV-Antiviral Agents HCV protease inhibitor: Boceprevir Fosamprenavir calcium: ↓ Amprenavir (predicted) ↔ or ↓ Boceprevir (predicted) Fosamprenavir calcium /ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of fosamprenavir calcium or fosamprenavir calcium/ ritonavir and boceprevir is not recommended. HCV protease inhibitor: Simeprevir Fosamprenavir calcium: ↔ Amprenavir (predicted) ↑ or ↓ Simeprevir (predicted) Fosamprenavir calcium /ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted) Coadministration of fosamprenavir calcium or fosamprenavir calcium/ritonavir and simeprevir is not recommended. HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) Fosamprenavir calcium: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) Fosamprenavir calcium /ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavircalcium 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of Fosamprenavircalcium /ritonavir and paritaprevir/ritonavir/omb…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir calcium during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Limited data are available for use of fosamprenavir calcium in pregnancy. fosamprenavir calcium 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir calcium/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data). There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data) . The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to 2 times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir. In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD. In the rat pre- and postnatal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately 2 times the exposure in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir (see Data). Clinical Considerations Virologic Monitoring During Pregnancy and the Postpartum Period: Based on limited data on the use of fosamprenavir calcium during pregnancy, no dosage adjustments are required for pregnant patients who are already on a stable twice-daily regimen of fosamprenavir calcium 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)] . In a clinical trial of 10 HIV-1–infected pregnant women treated with fosamprenavir calcium 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period. Therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Data, Dosage and Administration (2.2), Clinical Pharmacology (12.3)] . Pregnancy data with other dosage regimens of fosamprenavir calcium (with or without ritonavir) are not available. Data Human Data: fosamprenavir calcium 700 mg taken with ritonavir 100 mg twice daily in combination with a background regimen was evaluated in a clinical trial of 10 HIV-1–infected pregnant women during the second and third trimesters and postpartum. Subjects initiated fosamprenavir calcium /ritonavir during pregnancy at a median of 19 weeks’ gestation; 4 had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation. Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n = 6) or third trimeste…

6 ADVERSE REACTIONS Severe or life-threatening skin reactions have been reported with the use of fosamprenavir calcium [see Warnings and Precautions (5.2)]. The most common moderate to severe adverse reactions in clinical trials of fosamprenavir calcium were diarrhea, rash, nausea, vomiting, and headache. Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir calcium and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir calcium (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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 calcium 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 calcium 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir calcium 1,400 mg twice daily; and 15% received fosamprenavir calcium 700 mg twice daily plus ritonavir 100 mg twice daily. Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir calcium 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 a APV30002 a Fosamprenavir Calcium 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir Calcium 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% a All subjects also received abacavir and lamivudine twice daily. 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 Calcium 700 mg and Ritonavir 100 mg Twice Daily a (n = 106) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily a (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% a All subjects also received 2 reverse transcriptase inhibitors. Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with fosamprenavir calcium 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 calcium and had a median duration of 13 days. Skin rash led to discontinuation of fosamprenavir calcium in less than 1% of subjects. In some subjects with mild or moderate rash, d…