fosamprenavir 50 MG/ML Oral Suspension [Lexiva]

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)

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 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 Calcium 45 mg/kg plus ritonavir 7 mg/kg a 11 kg - < 15 kg Fosamprenavir Calcium 30 mg/kg plus ritonavir 3 mg/kg a 15 kg - < 20 kg Fosamprenavir Calcium 23 mg/kg plus ritonavir 3 mg/kg a ≥ 20 kg Fosamprenavir Calcium 18 mg/kg plus ritonavir 3 mg/kg a a When dosing with ritonavir, do not exceed the adult dose of fosamprenavir calcium 700 mg/ritonavir 100 mg twice-daily dose. Alternatively, protease inhibitor-naive children aged 2 years and older can be administered fosamprenavir calcium (without ritonavir) 30 mg per kg twice daily. Fosamprenavir calcium should only be administered to infants born at 38 weeks’ gestation or greater and who have attained a postnatal age of 28 days. For pediatric patients, pharmacokinetic and clinical data: do not support once-daily dosing of fosamprenavir calcium alone or in combination with ritonavir [see Clinical Studies (14.3)] . do not support administration of fosamprenavir calcium alone or in combination with ritonavir for protease inhibitor-experienced children younger than 6 months [see Clinical Pharmacology (12.3)] . do not support twice-daily dosing of fosamprenavir calcium without ritonavir in pediatric patients younger than 2 years [see Clinical Pharmacology (12.3)] . Other Dosing Considerations When administered without ritonavir, the adult regimen of fosamprenavir calcium tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg. When administered in combination with ritonavir, fosamprenavir calcium tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg. 2.4 Patients with Hepatic Impairment See Clinical Pharmacology (12.3) . Mild Hepatic Impairment (Child-Pugh Score Ranging from 5 to 6) Fosamprenavir calcium tablets should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). Moderate Hepatic Impairment (Child-Pugh Score Ranging from 7 to 9) Fosamprenavir calcium tablets should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). Severe Hepatic Impairment (Child-Pugh Score Ranging from 10 to 15) Fosamprenavir calcium tablets should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naive) or 300 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). There are no data to support dosing recommendations for pediatric patients with hepatic impairment.

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 or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with fosamprenavir calcium and patients should be monitored closely during treatment. 5.5 Diabetes/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including fosamprenavir calcium. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.7 Increase in Body Fat Increase of body fat has been observed in patients receiving protease inhibitors, including fosamprenavir calcium. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Lipid Elevations Treatment with fosamprenavir calcium plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol [see Adverse Reactions (6)] . Triglyceride and cholesterol testing should be performed prior to initiating therapy with fosamprenavir calcium and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate [see Drug Interactions (7)] . 5.9 Hemolytic Anemia Acute hemolytic anemia has been reported in a patient treated with amprenavir. 5.10 Patients with Hemophilia There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established. 5.11 Nephrolithiasis Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-1-infected patients receiving fosamprenavir calcium. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered. 5.12 Resistance/Cross-Resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with fosamprenavir calcium will have on the activity of subsequently administered protease inhibitors. Fosamprenavir calcium has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (14.2)] .

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 )

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.