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 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 )

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 …

3 DOSAGE FORMS AND STRENGTHS Fosamprenavir Calcium Tablets, USP are available containing 700 mg of fosamprenavir as fosamprenavir calcium, USP. • The 700 mg tablets are pink, film-coated, modified capsule shaped, unscored tablets debossed with M on one side of the tablet and FT7 on the other side. • 700-mg tablets ( 3 )

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 )

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 5 x ULN) 6% 5% 8% 8% AST (> 5 x ULN) 6% 6% 6% 7% Serum lipase (> 2 x ULN) 8% 4% 6% 4% Triglycerides Fasting specimens. (> 750 mg/dL) 0% 1% 6% 2% Neutrophil count, absolute ( 750 mg/dL) 11% n = 100 for fosamprenavir plus ritonavir, n = 98 for lopinavir plus ritonavir. 6% Serum lipase (> 2 x ULN) 5% 12% ALT (> 5 x ULN) 4% 4% AST (> 5 x ULN) 4% 2% Glucose (> 251 mg/dL) 2% 2% Pediatric Trials Fosamprenavir with and without ritonavir was studied in 237 HIV-1– infected pediatric subjects aged at least 4 weeks to 18 years in 3 open-label trials; APV20002, APV20003, and APV29005 [see Clinical Studies (14.3) ] . Vomiting and neutropenia occurre …

7 DRUG INTERACTIONS • Coadministration of fosamprenavir 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 or fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. ( 7 ) • Coadministration of fosamprenavir 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 and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. The potential for drug interactions with fosamprenavir changes when fosamprenavir 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 is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir 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 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 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: ↓ Amprenavir (predicted) ↔ or ↓ Boceprevir (predicted) Fosamprenavir/ ritonavir: ↓ Amprenavir (predicted) ↓ Boceprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and boceprevir is not recommended. HCV protease inhibitor: Simeprevir Fosamprenavir: ↔ Amprenavir (predicted) ↑ or ↓ Simeprevir (predicted) Fosamprenavir/ ritonavir: ↔ Amprenavir (predicted) ↑ Simeprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and simeprevir is not recommended. HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) Fosamprenavir: ↑ Amprenavir (predicted) ↑ or ↔ Paritaprevir (predicted) Fosamprenavir/ ritonavir: ↑ or ↔ Amprenavir (predicted) ↑ Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/dasabuvir. Coadministration of fosamprenavir/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Delavirdine See Clinical Pharmacology (12.3) Tables 10 , 11 , 12 , or 13 for …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended due to 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 fosamprenavir 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 in pregnancy. Fosamprenavir 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/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 during pregnancy, no dosage adjustments are required for pregnant patients who are already on a stable twice-daily regimen of fosamprenavir 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 fosamprenvir 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 (with or without ritonavir) are not available. Data Human Data Fosamprenavir 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/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 t …

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.

11 DESCRIPTION Fosamprenavir calcium, USP is a prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium is (3 S )-tetrahydrofuran-3-yl (1 S ,2 R )-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3 S )(1 S ,2 R ) configuration. It has a molecular formula of C 25 H 34 CaN 3 O 9 PS and a molecular weight of 623.67. It has the following structural formula: Fosamprenavir calcium is a white to cream color powder with a solubility of approximately 0.31 mg per mL in water at 25°C. Fosamprenavir calcium tablets, USP are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir). Each 700-mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, silicified microcrystalline cellulose, titanium dioxide and triacetin. Meets USP Dissolution Test 2 Fosamprenavir Structural Formula

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Fosamprenavir Calcium Tablets, USP are available containing 700 mg of fosamprenavir as fosamprenavir calcium, USP. The 700 mg tablets are pink, film-coated, modified capsule shaped, unscored tablets debossed with M on one side of the tablet and FT7 on the other side. They are available as follows: NDC 0378-3520-91 bottles of 60 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Dispense in original container.