AHFS Class:

• HIV Protease Inhibitors 8:18.08.08

Generic Name(s):

• Fosamprenavir Calcium

Fosamprenavir calcium, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1

Treatment of HIV Infection

Fosamprenavir is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection.1

Fosamprenavir, including ritonavir-boosted fosamprenavir, is not recommended as initial treatment of HIV due to the risk of treatment failure with unboosted regimens and less clinical data compared with other ritonavir-boosted regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults and Adolescents

Safety and efficacy of fosamprenavir in antiretroviral-naïve adults have been evaluated in 2 randomized, open-label studies (study APV30001 [NEAT] and study APV30002 [SOLO]).1,5,6

In the NEAT study, 249 treatment-naïve, HIV-infected adults (mean age, 37 years; median baseline plasma HIV-1 RNA level, 4.83 log₁₀ copies/mL; median baseline CD4⁺T-cell count, 212 cells/mm³) were randomized to receive a 3-drug regimen that included either fosamprenavir (1400 mg twice daily) or nelfinavir (1250 mg twice daily) in conjunction with abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).1,5 The primary outcome was the proportion of patients achieving an HIV-1 RNA level <400 copies/mL at 48 weeks.5 Additional outcomes included the proportion of patients with an HIV-1 RNA level <50 copies/mL and change from baseline in CD4⁺ T-cell count.5

At 48 weeks, 66 or 57% of those receiving the fosamprenavir regimen and 52 or 42% of those receiving the nelfinavir regimen had plasma HIV-1 RNA levels <400 or <50 copies/mL, respectively; the median increase in CD4⁺ T-cell count from baseline was 201 cells/mm³ in patients receiving the fosamprenavir regimen and 216 cells/mm³ in those receiving the nelfinavir regimen.1,5

In the SOLO study, 649 treatment-naïve, HIV-infected adults (mean age, 37 years; median baseline plasma HIV-1 RNA level, 4.8 log₁₀ copies/mL; median baseline CD4⁺ T-cell count, 170 cells/mm³) were randomized to receive a ritonavir-boosted regimen of fosamprenavir (1400 mg once daily with ritonavir 200 mg once daily), abacavir (300 mg twice daily), and lamivudine (150 mg twice daily) or a regimen of nelfinavir (1250 mg twice daily), abacavir (300 mg twice daily), and lamivudine (150 mg twice daily).1,6

The primary outcome was the proportion of patients achieving an HIV-1 RNA level <400 copies/mL at 48 weeks.6 Additional outcomes included the proportion of patients with an HIV-1 RNA level <50 copies/mL and change from baseline in CD4⁺ T-cell count.6

At 48 weeks, 69 or 58% of those receiving the ritonavir-boosted fosamprenavir regimen and 68 or 55% of those receiving the nelfinavir regimen had plasma HIV-1 RNA levels <400 or <50 copies/mL, respectively;1 the median increase in CD4⁺ T-cell count from baseline was 203 cells/mm³in patients receiving the ritonavir-boosted fosamprenavir regimen and 207 cells/mm³ in those receiving the nelfinavir regimen.1,6

A third study, the KLEAN trial, compared ritonavir-boosted fosamprenavir to ritonavir-boosted lopinavir in 878 treatment-naïve, HIV-1 infected adult patients.302 In this open-label, noninferiority trial, patients were randomized to treatment with either fosamprenavir/ritonavir 700/100 mg twice daily or lopinavir/ritonavir 400/100 mg twice daily.302 Patients also received abacavir/lamivudine 600/300 mg once daily.302 At 48 weeks, ritonavir-boosted fosamprenavir was found to be noninferior to ritonavir-boosted lopinavir, with 73 and 71% of patients in each group achieving the primary end point of HIV-1 RNA levels <400 copies/mL, respectively.302

Antiretroviral-experienced Adults and Adolescents

Fosamprenavir has been evaluated for use in HIV-infected adults who were treatment-experienced (previously received therapy with PIs).1 In a randomized, open-label, multicenter study (Study APV30003 [CONTEXT]), 315 adults with HIV infection (mean age, 42 years; median baseline plasma HIV-1 RNA level, 4.14 log₁₀copies/mL; median baseline CD4⁺ T-cell count, 263 cells/mm³) who had experienced virologic failure to 1 or 2 prior PI-containing regimens were randomized to receive a twice-daily regimen of ritonavir-boosted fosamprenavir (700 mg twice daily with ritonavir 100 mg twice daily), a once-daily ritonavir-boosted regimen of fosamprenavir (1400 mg once daily with ritonavir 200 mg once daily), or lopinavir/ritonavir (400 mg of lopinavir and 100 mg of ritonavir twice daily).1

At 48 weeks, 58 and 46% of those receiving twice-daily ritonavir-boosted fosamprenavir, 50 and 37% of those receiving once-daily ritonavir-boosted fosamprenavir, and 61 and 50% of those receiving lopinavir/ritonavir had plasma HIV-1 RNA levels <400 or <50 copies/mL, respectively.1 In addition, the median increase in CD4⁺T-cell count from baseline was 81 cells/mm³ in patients receiving fosamprenavir and ritonavir twice daily and 91 cells/mm³ in those receiving lopinavir/ritonavir.1

The manufacturer states that the study was not large enough to definitively conclude that a regimen that includes ritonavir-boosted fosamprenavir is clinically equivalent to a regimen that includes lopinavir/ritonavir.1

Pediatric Patients

Three clinical trials of fosamprenavir use in pediatric patients (aged 4 weeks to 18 years) have been conducted.1 In Study APV29005, a phase 2, open-label, noncomparative trial, children (2-18 years of age) received a twice-daily regimen of fosamprenavir (as oral suspension) with or without low-dose ritonavir in conjunction with a background regimen of 2 or 3 active NRTIs.1,300 Patients were enrolled into 1 of 4 cohorts, based on treatment experience and age, as follows: treatment-naïve aged 2 to <6 years; and treatment-experienced, aged 2 to <6 years, 6 to <12 years, or 12-18 years.300 Unboosted fosamprenavir was given to 20 PI-naïve patients aged 2 to <6 years; ritonavir-boosted fosamprenavir was given to PI-naïve (n=49) and PI-experienced patients (n=40) aged 2-18 years.300 Pharmacokinetics and adverse events were the primary study endpoints; antiviral response was a secondary outcome assessed.300

At 24 weeks, 65% of patients given unboosted fosamprenavir had plasma HIV-1 RNA levels <400 copies/mL with a median increase from baseline in CD4⁺ T-cell count of 350 cells/mm³.1 At 24 weeks, 71 or 55% of PI-naïve or PI-experienced patients who received ritonavir-boosted fosamprenavir had plasma HIV-1 RNA levels <400 copies/mL, respectively, with a median increase from baseline in CD4⁺ T-cell count of 184 cells/mm³ and 150 cells/mm³, respectively.1

In a second study (APV20002), a phase 2, open-label, noncomparative trial, 54 pediatric patients aged 4 weeks to <2 years (49 PI-naïve, 5 PI-experienced) received a twice-daily regimen of fosamprenavir (as oral suspension) with low-dose ritonavir ( ritonavir-boosted fosamprenavir) in conjunction with other antiretrovirals.1 Patients were enrolled into 1 of 2 cohorts: aged 4 weeks to <6 months or 6 months to <2 years.301 Pharmacokinetics and adverse events were the primary study endpoints; antiviral response was a secondary outcome assessed.301

At 24 weeks, 72% had plasma HIV-1 RNA levels <400 copies/mL and the median increase from baseline in CD4⁺ T-cell count was 400 cells/mm³ in those 4 weeks to <6 months of age and 278 cells/mm³ in those 6 months to 2 years of age.1 For both age cohorts, at 48 weeks, 65% of patients had HIV-1 RNA levels <400 copies/mL, and 61% achieved <50 copies/mL.301 Both age cohorts had increases in CD4⁺ T-cell counts, with a median change from baseline of +5% in both cohorts.301

In a third study (APV20003) in pediatric patients, a once-daily regimen of ritonavir-boosted fosamprenavir was evaluated.1 Pharmacokinetic data from this study do not support a once-daily dosing regimen in pediatric patients.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Fosamprenavir, a PI, was commonly used in combination with ritonavir, as part of a fully suppressive antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, fosamprenavir is not recommended as initial treatment of HIV due to the risk of treatment failure with unboosted regimens and less clinical data compared with other ritonavir-boosted regimens.200,201

In the 2023 HHS pediatric HIV treatment guideline, fosamprenavir is not recommended as initial treatment of HIV due to the risk of treatment failure with unboosted regimens and less clinical data compared with other ritonavir-boosted regimens.201

In the 2023 HHS perinatal HIV treatment guideline, fosamprenavir is not recommended for use during pregnancy; if pregnancy occurs, patients should be switched to a recommended regimen.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Fosamprenavir is used as an alternative regimen in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure † (PEP) in health-care personnel and other individuals only after expert consultation.199

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 These experts also state that fosamprenavir is one of several alternative agents that may be used for PEP regimens only after expert consultation.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

General

Pretreatment Screening

• Assess hepatic transaminases prior to initiation of fosamprenavir.1
• Assess cholesterol and triglycerides prior to initiation of fosamprenavir.1

Patient Monitoring

• Monitor hepatic transaminases closely during treatment with fosamprenavir.1
• Monitor cholesterol and triglycerides at periodic intervals during treatment with fosamprenavir.1
• Monitor viral load closely during treatment with fosamprenavir in pregnancy to ensure viral suppression is maintained.1

Dispensing and Administration Precautions

• Fosamprenavir is used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.1

Administration

Fosamprenavir calcium is administered orally as oral suspension or tablets.1

Oral Suspension

In pediatric patients, fosamprenavir calcium oral suspension should be administered with food.1 In adults, the oral suspension should be administered on an empty stomach since food decreases the rate and extent of absorption.1

Patients who vomit within 30 minutes of receiving a dose of fosamprenavir oral suspension should receive a repeat dose.1

The oral suspension should be stored at 5-30°C and should not be frozen.1 The taste of the suspension may be improved by refrigeration.1

The oral suspension should be shaken vigorously prior to each dose.1

Tablets

Fosamprenavir calcium tablets can be taken without regard to meals since pharmacokinetics are not affected.1

The tablets should be stored in a tightly closed container at 25°C, but may be exposed to 15-30°C.1

Dosage

Dosage of fosamprenavir calcium is expressed in terms of fosamprenavir.1

When fosamprenavir is used in combination with ritonavir, consult the full prescribing information for ritonavir.1

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naïve Adults

For initial treatment of HIV-1 infection in antiretroviral-naïve adults when a ritonavir-boosted regimen is used, the usual dosage is 1400 mg of fosamprenavir once daily (with ritonavir 100 mg or 200 mg once daily) or, alternatively, 700 mg of fosamprenavir twice daily (with ritonavir 100 mg twice daily).1 Higher dosages of fosamprenavir and/or ritonavir are not recommended and are associated with increased serum transaminase concentrations.1 Regimens containing 1400 mg of fosamprenavir once daily with ritonavir 100 mg once daily are supported by pharmacokinetic data.1 Regimens containing 700 mg of fosamprenavir twice daily with ritonavir 100 mg twice daily are supported by pharmacokinetic and safety data.1

If fosamprenavir is used without low-dose ritonavir in antiretroviral-naïve adults, the usual dosage is 1400 mg of fosamprenavir twice daily.1

Treatment of HIV Infection in Protease Inhibitor-experienced Adults

For treatment of HIV-1 infection in adults who previously received an HIV protease inhibitor (PI), a ritonavir-boosted regimen of 700 mg of fosamprenavir twice daily (with ritonavir 100 mg twice daily) is recommended.1 Higher dosages of fosamprenavir and/or ritonavir are not recommended and are associated with increased serum transaminase concentrations.1

Once-daily ritonavir-boosted fosamprenavir regimens are not recommended in PI-experienced adults.1

Treatment of HIV-1 Infection in Pregnant Adults

For treatment of HIV-1 infection in pregnant adults, a ritonavir-boosted regimen of 700 mg of fosamprenavir twice daily (with ritonavir 100 mg twice daily) is recommended.1 This dosing regimen should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir 700 mg and ritonavir 100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA <50 copies per mL).1 Because lower amprenavir concentrations have been observed during pregnancy, closely monitor viral load to ensure viral suppression is maintained.1

Information regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available.1

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of fosamprenavir is 1400 mg once daily with ritonavir 100 mg once daily.199 Alternatively, fosamprenavir 1400 mg twice daily can be used without ritonavir.199

The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Pediatric Dosage

Dosage of fosamprenavir in infants and children 4 weeks to 18 years of age is based on weight and should not exceed the recommended adult dosage.1 Only use fosamprenavir in infants born at 38 weeks' gestation or later who have attained a postnatal age of 28 days.1

A once-daily regimen of fosamprenavir (with or without low-dose ritonavir) is not recommended in any pediatric patient.1

Do not use fosamprenavir (with or without low-dose ritonavir) in PI-experienced pediatric patients younger than 6 months of age.1

Do not use a twice-daily regimen of fosamprenavir (without low-dose ritonavir) in PI-naïve or PI-experienced pediatric patients younger than 2 years of age.1

Treatment of HIV Infection in Protease Inhibitor-naïve Pediatric Patients

For treatment of HIV-1 infection in PI-naïve infants and children 4 weeks of age or older, a twice-daily regimen of fosamprenavir oral suspension can be given in conjunction with low-dose ritonavir ( ritonavir-boosted fosamprenavir).1 (See Table 1.)

Alternatively, PI-naïve pediatric patients ≥2 years of age can be administered fosamprenavir oral suspension (without ritonavir) in a dosage of 30 mg/kg twice daily.1

PI-naïve pediatric patients weighing ≥47 kg can receive fosamprenavir tablets in a dosage of 1400 mg twice daily (without ritonavir).1

PI-naïve pediatric patients weighing ≥39 kg can receive fosamprenavir tablets when used in combination with ritonavir.1

Treatment of HIV Infection in Protease Inhibitor-experienced Pediatric Patients

For treatment of HIV-1 infection in PI-experienced infants and children 6 months of age or older, a twice-daily regimen of fosamprenavir oral suspension can be given in conjunction with low-dose ritonavir ( ritonavir-boosted fosamprenavir).1 (See Table 2.)

Alternatively, PI-experienced pediatric patients weighing ≥47 kg can receive fosamprenavir tablets in a dosage of 1400 mg twice daily (without ritonavir).1

PI-experienced pediatric patients weighing ≥39 kg can receive fosamprenavir tablets when used in combination with ritonavir.1

Special Populations

Hepatic Impairment

Fosamprenavir (with or without low-dose ritonavir) should be used with caution in patients with hepatic impairment.1 Dosage reductions are necessary in adults with hepatic impairment.1 Data are not available to support dosage recommendations for pediatric patients with hepatic impairment.1

PI-naïve adults with mild hepatic impairment (Child-Pugh score 5-6) should receive fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 700 mg twice daily (without ritonavir).1 PI-experienced adults with mild hepatic impairment should receive fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily).1

PI-naïve adults with moderate hepatic impairment (Child-Pugh score 7-9) should receive fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 700 mg twice daily (without ritonavir).1 PI-experienced adults with moderate hepatic impairment should receive fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily).1

PI-naïve adults with severe hepatic impairment (Child-Pugh score 10-15) should receive fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 350 mg twice daily (without ritonavir).1 PI-experienced adults with severe hepatic impairment should receive fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily).1

Renal Impairment

The manufacturer makes no specific dosage recommendations in patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1 Dosage should be selected with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome) to fosamprenavir, amprenavir (active metabolite of fosamprenavir; no longer commercially available in the US), or any ingredient in the formulation.1
• Concomitant use with drugs highly dependent on cytochrome P-450 (CYP) isoenzyme 3A4 for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events.1 These drugs and other contraindicated drugs (which may lead to reduced efficacy of fosamprenavir and possible resistance) include: alfuzosin, cisapride, delavirdine, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), pimozide, sildenafil used for treatment of pulmonary arterial hypertension, lomitapide, lovastatin, simvastatin, midazolam, triazolam, rifampin, St. John's wort ( Hypericum perforatum ), flecainide (when used with fosamprenavir plus ritonavir), propafenone (when used with fosamprenavir plus ritonavir), and lurasidone (when used with fosamprenavir plus ritonavir).1 Unless otherwise noted, these contraindications apply to the use of fosamprenavir with or without ritonavir.1 When fosamprenavir is used in combination with ritonavir, consult the full prescribing information for ritonavir for additional considerations.1

Warnings/Precautions

Skin Reactions

Severe or life-threatening skin reactions have been reported in fosamprenavir-treated patients, including one case of Stevens-Johnson syndrome among 700 patients receiving the drug in clinical trials.1 Rash (usually maculopapular and of mild or moderate intensity, with or without pruritus) has been reported in about 19% of adults receiving fosamprenavir in clinical studies; manifestations had a median onset of 11 days after initiation of fosamprenavir and persisted for a median of 13 days.1

Some patients with mild or moderate rash have been able to continue fosamprenavir without interruption; reinitiation of fosamprenavir therapy following temporary interruption generally has not resulted in rash recurrence.1 Discontinue fosamprenavir if severe or life-threatening rash or moderate rash accompanied by systemic manifestations occurs.1

Sulfa Allergy

Fosamprenavir contains a sulfonamide moiety, which may cause allergic-type reactions (e.g., rash) in certain susceptible individuals.1 The potential for cross-sensitivity between drugs with sulfonamide moieties and fosamprenavir is unknown.1

Use fosamprenavir with caution in patients with known hypersensitivity to sulfonamide-containing drugs.1

Drug Interactions

Concomitant use of fosamprenavir (with or without low-dose ritonavir) with certain drugs is contraindicated or requires particular caution.1

When a ritonavir-boosted fosamprenavir regimen is used, consider the usual cautions, precautions, and contraindications associated with ritonavir.1

Initiation of ritonavir-boosted fosamprenavir in patients receiving cytochrome P-450 (CYP) isoenzyme 3A substrates or initiation of CYP3A substrates in patients already receiving ritonavir-boosted fosamprenavir may increase plasma concentrations of such substrate drugs.1 Initiation of CYP3A inhibitors or inducers may increase or decrease plasma concentrations of ritonavir-boosted fosamprenavir, respectively.1 Depending on the specific drug interaction, adverse effects related to increased exposures of the concomitant drug that could be serious, life-threatening, or fatal may occur or clinically important ritonavir-boosted fosamprenavir-associated adverse effects or loss of virologic effect of fosamprenavir and possible development of resistance could occur.1

Consider potential drug interactions prior to and during ritonavir-boosted fosamprenavir therapy.1 Review all drugs that the patient is receiving and monitor for adverse effects associated with other drugs used concomitantly with ritonavir-boosted fosamprenavir.1

Hepatic Toxicity

Elevations in serum AST and/or ALT concentrations (more than 5 times the upper limit of normal) have been reported in approximately 4-8% of adults receiving fosamprenavir in clinical studies.1

Perform appropriate liver function tests prior to initiating fosamprenavir, and closely monitor patients during treatment.1 Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection or marked elevations in transaminase concentrations prior to fosamprenavir therapy may be at increased risk for developing or worsening of transaminase elevations.1

Use of ritonavir-boosted fosamprenavir at higher than recommended dosages may result in serum transaminase elevations and should not be used.1

Diabetes and Hyperglycemia

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, and exacerbation of preexisting diabetes mellitus have been reported in patients receiving HIV protease inhibitors (PIs); diabetic ketoacidosis also has occurred in some cases.1 It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) for treatment of these events.1 Causal relationships between therapy with PIs and these events have not been established.1

Immune Reconstitution Syndrome

Patients receiving combination antiretroviral therapy, including ritonavir-boosted fosamprenavir, may experience immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex, M. tuberculosis , cytomegalovirus, Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have 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 antiretroviral therapy.1

Increase in Body Fat

Increase in body fat has been reported in patients receiving HIV PIs, including fosamprenavir.1 The mechanism and long-term consequences of these events are unknown; a causal relationship to fosamprenavir has not been established.1

Lipid Elevations

Increases in triglyceride and cholesterol concentrations have occurred in patients receiving ritonavir-boosted fosamprenavir.1 Perform triglyceride and cholesterol testing before initiating therapy with fosamprenavir and at periodic intervals during therapy; manage lipid disorders as clinically appropriate.1

Hemolytic Anemia

Acute hemolytic anemia has been reported in a patient who received amprenavir (no longer commercially available in the US).1

Hemophilia A and B

Spontaneous bleeding has been reported in patients with hemophilia A or B receiving HIV PIs.1 Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.1 Treatment with PIs was continued or restarted in many of the reported cases.1 A causal relationship between therapy with PIs and these episodes has not been established.1

Nephrolithiasis

Nephrolithiasis has been reported during postmarketing experience.1 If signs or symptoms of nephrolithiasis occur, consider temporarily interrupting or discontinuing fosamprenavir.1

Resistance and Cross-resistance

Possible amprenavir resistance may occur in patients treated with fosamprenavir.1 The possible effect of fosamprenavir therapy on subsequent therapy with other PIs is unknown.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1,202

In animal reproduction studies, no major adverse developmental outcomes were observed following oral administration of fosamprenavir.1 Systemic exposure to amprenavir (fosamprenavir's active metabolite) in rabbits or rats was less than or up to 2 times, respectively, the exposures in humans at the maximum recommended human dose (MRHD) with or without ritonavir.1 However, abortions were observed following oral administration of amprenavir in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD.1

In the pre- and postnatal development study in rats, toxicities to the offspring were observed at maternal systemic exposures 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 at the MRHD of fosamprenavir in combination with ritonavir.1

There are limited data on use of fosamprenavir in pregnancy.1 Data are insufficient to date to adequately assess the risk of birth defects and miscarriage in pregnant women receiving fosamprenavir.1 Based on prospective reports to the APR of 146 live births following exposures to fosamprenavir, 2 birth defects each were reported with first- and second/third- trimester exposures.1

The safety, efficacy, and pharmacokinetics of fosamprenavir 700 mg twice daily in combination with ritonavir 100 mg twice daily were studied in a clinical trial of HIV-1-infected pregnant women during the second and third trimesters and postpartum.1 The use of this regimen should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA <50 copies per mL).1 Total amprenavir exposures (AUC) were lower during pregnancy compared with the postpartum period; thus, closely monitor viral load to ensure viral suppression is maintained.1

Lactation

Amprenavir is distributed into milk in rats.1 It is not known whether amprenavir is distributed into human milk, affects human milk production, or affects the breast-fed infant.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Females and Males of Reproductive Potential

Fosamprenavir may reduce the efficacy of combined hormonal contraceptives.1 Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method during therapy with fosamprenavir.1

Pediatric Use

Three open-label studies have evaluated the safety, efficacy, and pharmacokinetics of fosamprenavir (with and without ritonavir) in PI-naïve and PI-experienced HIV-1-infected pediatric patients 4 weeks to <18 years of age and weighing ≥3 kg.1

Pharmacokinetics, safety, tolerability, and efficacy of fosamprenavir have not been established in pediatric patients younger than 4 weeks of age.1 Treatment with fosamprenavir is not recommended in PI-experienced pediatric patients younger than 6 months of age.1

Do not use once-daily regimens of fosamprenavir (with or without low-dose ritonavir) in pediatric patients.1 Do not use twice-daily regimens of fosamprenavir (without low-dose ritonavir) in pediatric patients <2 years of age.1

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether they respond differently from younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

The pharmacokinetics of fosamprenavir have not been studied in patients >65 years of age.1

Hepatic Impairment

Use fosamprenavir with caution in patients with hepatic impairment since amprenavir concentrations may be increased.1 Reduced dosage of fosamprenavir (with or without ritonavir) is recommended in adults with hepatic impairment (Child-Pugh score of 5 or greater); data are not available to make dosage recommendations for pediatric patients with hepatic impairment.1

Following administration of ritonavir-boosted fosamprenavir, the AUC of amprenavir is increased by approximately 22, 70, or 80% in those with mild, moderate, or severe hepatic impairment, respectively.1 Plasma protein binding is decreased in individuals with hepatic impairment.1

HIV-infected patients with chronic HBV or HCV coinfection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy may be at increased risk for developing or worsening of transaminase elevations.1

Renal Impairment

The pharmacokinetics of fosamprenavir have not been studied to date in adults with impaired renal function, but renal impairment is not expected to have a clinically important effect on the pharmacokinetics of the drug.1

Common Adverse Effects

The most common adverse effects (incidence ≥4%) in adults receiving fosamprenavir are diarrhea, nausea, vomiting, headache, and rash.1 Vomiting and neutropenia were reported more frequently in pediatric patients compared to adults.1

Because fosamprenavir is metabolized to amprenavir (the active metabolite) in vivo, interactions reported with amprenavir (no longer commercially available in the US) are expected to occur in patients receiving fosamprenavir.1 Results of studies using fosamprenavir may not be predictive of the magnitude of interaction with ritonavir-boosted fosamprenavir.1

If fosamprenavir is used in combination with ritonavir, also consider drug interactions reported with ritonavir; refer to the full prescribing for ritonavir for specific information.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Amprenavir, the active metabolite of fosamprenavir, inhibits and may also induce cytochrome P-450 (CYP) isoenzyme 3A4; there are potential pharmacokinetic interactions (altered metabolism of the other drug).1 Caution is advised if fosamprenavir is used concomitantly with substrates, inhibitors, or inducers of CYP3A4.1 Concomitant use with drugs with a narrow therapeutic index that are CYP3A4 substrates is not recommended.1

Amprenavir does not inhibit CYP isoenzymes 2D6, 1A2, 2C9, 2C19, or 2E1.1

Ritonavir is a potent CYP2D6 inhibitor; clinically important interactions with drugs metabolized by CYP2D6 are possible if coadministered with fosamprenavir plus ritonavir.1 Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6.1

Drugs Affecting or Affected by P-glycoprotein Transport

Amprenavir is a substrate of the P-glycoprotein (P-gp) transport system; in addition, the drug is an inducer of P-gp transport.1

Alfuzosin

Concomitant use of alfuzosin and fosamprenavir is contraindicated due to potential for increased alfuzosin concentrations that could result in hypotension.1

Antiarrhythmic Agents

Potential for a clinically significant pharmacokinetic interaction exists if ritonavir-boosted fosamprenavir is used concomitantly with flecainide or propafenone (increased plasma concentrations of the antiarrhythmic agent).1 Concomitant use of ritonavir-boosted fosamprenavir with flecainide or propafenone is contraindicated due to the potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)1

Potential for a clinically significant pharmacokinetic interaction also exists with amiodarone, disopyramide, systemic lidocaine, or quinidine (increased concentrations of the antiarrhythmic agent).1 Monitor plasma concentrations of the antiarrhythmic agent, if possible.1

Anticonvulsants

Carbamazepine, Phenobarbital, Phenytoin

Concomitant use of fosamprenavir (without low-dose ritonavir) and carbamazepine, phenobarbital, or phenytoin may decrease plasma amprenavir concentrations.1 Use these anticonvulsants with caution if used concomitantly with fosamprenavir; fosamprenavir may be less effective in patients taking these anticonvulsants.1

Concomitant use of ritonavir-boosted fosamprenavir and phenytoin may decrease plasma concentrations of phenytoin and increase amprenavir concentrations.1 Usual dosages of ritonavir-boosted fosamprenavir may be used in patients concurrently receiving phenytoin, but monitor phenytoin concentrations and increase phenytoin dosage as needed.1

Antifungal Agents

Itraconazole, Ketoconazole

Concomitant use of fosamprenavir and ketoconazole or itraconazole may result in increased concentrations of the antifungal agent.1 Increase monitoring for adverse effects.1

In patients receiving fosamprenavir (without low-dose ritonavir), a reduced antifungal dosage may be needed in those receiving ketoconazole or itraconazole dosages exceeding 400 mg daily.1 In those receiving ritonavir-boosted fosamprenavir, high dosages of ketoconazole or itraconazole (exceeding 200 mg daily) are not recommended.1

Antimycobacterial Agents

Rifabutin

Concomitant use of fosamprenavir with rifabutin results in increased rifabutin and rifabutin metabolite (25-O-desacetylrifabutin) concentrations.1

If fosamprenavir (without low-dose ritonavir) is used with rifabutin, reduce rifabutin dosage by at least 50% of the recommended dosage.1 If ritonavir-boosted fosamprenavir is used with rifabutin, reduce rifabutin dosage by at least 75% of the usual dosage of 300 mg daily (maximum dosage of 150 mg every other day or 3 times weekly).1 Also monitor for neutropenia by performing a complete blood count weekly and as clinically indicated.1

Rifampin

Concomitant use of fosamprenavir with rifampin results in decreased amprenavir concentrations.1 Concomitant use of fosamprenavir and rifampin is contraindicated since it may result in loss of virologic response and possible resistance to fosamprenavir or to other protease inhibitors (PIs).1

Antineoplastic Agents

Concomitant use of fosamprenavir (with or without ritonavir) with dasatinib, nilotinib, ibrutinib, vinblastine, or everolimus (all metabolized by CYP3A) may result in increased concentrations of the antineoplastic agent and potentially increase the risk of adverse events typically associated with them.1 If coadministration is necessary, consult the prescribing information for the antineoplastic drug.1

Antipsychotic Agents

Lurasidone

Concomitant use of fosamprenavir and lurasidone results in increased lurasidone concentrations.1

Concomitant use of ritonavir-boosted fosamprenavir and lurasidone is contraindicated due to potential for serious and/or life-threatening adverse reactions.1

If concomitant use of lurasidone and unboosted fosamprenavir is necessary, reduce lurasidone dosa consult the prescribing information for lurasidone for specific recommendations.1

Pimozide

Concomitant use of fosamprenavir and lurasidone results in increased pimozide concentrations.1

Concomitant use of fosamprenavir and pimozide is contraindicated due to potential for serious and/or life-threatening adverse reactions with pimozide (e.g., cardiac arrhythmias).1

Quetiapine

Concomitant use of fosamprenavir and quetiapine results in increased quetiapine concentrations.1

If fosamprenavir (with ritonavir) is initiated in a patient receiving a stable dosage of quetiapine, reduce dosage of quetiapine to one-sixth of the original dosage and monitor the patient for adverse reactions associated with the antipsychotic.1 If possible, consider alternative antiretroviral therapy to avoid increases in quetiapine exposures.1

If quetiapine is initiated in a patient already taking fosamprenavir (with ritonavir), refer to the quetiapine prescribing information for initial dosage and titration of quetiapine.1

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Pharmacokinetic interaction with maraviroc (increased plasma concentrations of maraviroc; decreased plasma concentrations of amprenavir).1

A maraviroc dosage of 150 mg twice daily should be used concomitantly with the usual dosage of ritonavir-boosted fosamprenavir.1 Do not use unboosted fosamprenavir concomitantly with maraviroc.1

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of fosamprenavir and dolutegravir decreases peak plasma concentrations of dolutegravir.1

If ritonavir-boosted fosamprenavir is used concurrently with dolutegravir, dolutegravir should be given in a dosage of 50 mg twice daily.1

In patients with documented or suspected INSTI resistance, use an alternative combination when possible.1

Raltegravir

Concomitant use of raltegravir and fosamprenavir (with or without low-dose ritonavir) results in decreased plasma concentrations of raltegravir and amprenavir.1

Appropriate dosages for concomitant use of raltegravir and fosamprenavir (with or without low-dose ritonavir) with respect to safety and efficacy not established.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Results of in vitro studies indicate that the antiretroviral effects of amprenavir (active metabolite of fosamprenavir) and NNRTIs (e.g., delavirdine, efavirenz, nevirapine) are not antagonistic against HIV-1.1

Delavirdine

Concomitant use of delavirdine and fosamprenavir (with or without low-dose ritonavir) results in increased plasma concentrations of amprenavir and decreased plasma concentrations of delavirdine.1

Concomitant use of fosamprenavir and delavirdine is contraindicated due to potential for loss of virologic response and possible resistance to delavirdine.1

Efavirenz

Concomitant use of efavirenz and fosamprenavir (with or without ritonavir) results in decreased amprenavir concentrations.1 Appropriate dosages for concomitant use of efavirenz and fosamprenavir with respect to safety and efficacy have not been established.1

When efavirenz is administered with fosamprenavir plus ritonavir once daily, an additional 100 mg/day (300 mg total) of ritonavir is recommended.1

When efavirenz is administered with fosamprenavir plus ritonavir twice daily, no change in ritonavir dosage is required.1

Nevirapine

Concomitant use of nevirapine and fosamprenavir (with or without ritonavir) results in decreased amprenavir concentrations and increased nevirapine concentrations.1

No dosage adjustment is required when nevirapine is administered with fosamprenavir plus ritonavir twice daily.1 Use of nevirapine with unboosted fosamprenavir is not recommended.1

Concomitant administration of nevirapine with a once-daily regimen of ritonavir-boosted fosamprenavir has not been studied.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies indicate that the antiretroviral effects of amprenavir (active metabolite of fosamprenavir) and NRTIs (abacavir, didanosine, lamivudine, tenofovir, zidovudine) are synergistic.1

Abacavir

Studies using amprenavir indicate that a pharmacokinetic interaction with abacavir is unlikely.1

Lamivudine

Pharmacokinetic interactions did not occur when a single 600-mg dose of amprenavir (active metabolite of fosamprenavir) was used concomitantly with a single 150-mg dose of lamivudine.1

Tenofovir

Concomitant use of tenofovir and ritonavir-boosted fosamprenavir did not alter the minimum plasma concentration of amprenavir.1

Zidovudine

Concomitant use of fosamprenavir (single 600-mg dose) and zidovudine (single 300-mg dose) increased zidovudine peak plasma concentrations and AUC by 40 and 31%, respectively.1 When amprenavir (single 600-mg dose) and zidovudine (single 300-mg dose) were used concomitantly, there was a 13% increase in the AUC of amprenavir, but no effect on amprenavir concentrations.1

HIV Protease Inhibitors (PIs)

Results of in vitro studies indicate that the antiretroviral effects of amprenavir (active metabolite of fosamprenavir) and PIs (atazanavir, lopinavir, nelfinavir, ritonavir, and saquinavir) are not antagonistic against HIV-1.1

Atazanavir

Concomitant use of atazanavir and ritonavir-boosted fosamprenavir may result in decreased plasma concentrations of atazanavir, with no change in plasma concentrations of amprenavir.1 Data are not available regarding concomitant use of fosamprenavir (without low-dose ritonavir) and atazanavir.1

Appropriate dosages for concomitant use of atazanavir and fosamprenavir (with or without low-dose ritonavir) with respect to safety and efficacy not established.1

Lopinavir

Concomitant use of fosamprenavir with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) results in decreased amprenavir and lopinavir concentrations.1 An increased incidence of adverse effects has been reported when the drugs were used concomitantly.1

Appropriate dosages for concomitant use with respect to safety and efficacy not established.1

Nelfinavir

Concomitant use of fosamprenavir (without low-dose ritonavir) and nelfinavir may result in increased plasma amprenavir concentrations; effect on nelfinavir concentrations is not well established.1 Concomitant use of ritonavir-boosted fosamprenavir and nelfinavir has not been evaluated to date.1

Appropriate dosages for concomitant use of fosamprenavir and nelfinavir with respect to safety and efficacy not established.1

Saquinavir

Studies using fosamprenavir indicate a pharmacokinetic interaction with saquinavir without low-dose ritonavir (decreased amprenavir concentrations; effect on saquinavir concentration is not well established).1 Concomitant use of ritonavir-boosted fosamprenavir and saquinavir has not been evaluated to date.1

Appropriate dosages for concomitant use of fosamprenavir and saquinavir with respect to safety and efficacy not established.1

Benzodiazepines

Midazolam, Triazolam

Concomitant use of fosamprenavir and midazolam or triazolam results in increased concentrations of the benzodiazepine.1

Concomitant use of fosamprenavir with midazolam or triazolam is contraindicated due to potential for serious and/or life-threatening adverse reactions (e.g., prolonged or increased sedation or respiratory depression).1

Alprazolam, Clorazepate, Diazepam, Flurazepam

Concomitant use of fosamprenavir and alprazolam, clorazepate, diazepam, or flurazepam results in increased benzodiazepine concentrations.1 The clinical importance of this pharmacokinetic interaction is unknown; reduction of benzodiazepine dosage may be necessary.1

Bosentan

Concomitant use of fosamprenavir and bosentan results in increased bosentan concentrations.1

In patients who have already been receiving fosamprenavir for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

In patients who have already been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating fosamprenavir; after at least 10 days of fosamprenavir therapy, bosentan can be resumed at a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

Calcium-channel Blocking Agents

Concomitant use of fosamprenavir and calcium-channel blocking agents (e.g., amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil) results in increased concentrations of the calcium-channel blocking agent.1 Use concomitantly with caution; clinical monitoring of the patient is recommended.1

Clarithromycin

Studies using amprenavir indicate possible pharmacokinetic interaction (slightly increased amprenavir concentrations, slightly decreased clarithromycin concentrations).1

Colchicine

Possible pharmacokinetic interaction (increased colchicine concentrations).1

Colchicine and ritonavir-boosted fosamprenavir should not be used concomitantly in patients with renal or hepatic impairment.1

When colchicine is used for treatment of gout flares in patients receiving ritonavir-boosted fosamprenavir, an initial colchicine dose of 0.6 mg should be given, followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.1 In those receiving fosamprenavir (without low-dose ritonavir), an initial colchicine dose of 1.2 mg should be used and a repeat dose given no earlier than 3 days later.1

When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-boosted fosamprenavir, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1 In those receiving fosamprenavir (without low-dose ritonavir), colchicine dosage should be decreased to 0.3 mg twice daily or 0.6 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once daily in those originally receiving 0.6 mg once daily.1

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted fosamprenavir, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.1 In those receiving fosamprenavir (without low-dose ritonavir), a maximum colchicine dosage of 1.2 mg daily (may be given as 0.6 mg twice daily) should be used.1

Corticosteroids

Fluticasone

Concomitant use of fluticasone (orally inhaled or intranasal) with fosamprenavir (with or without ritonavir) may result in increased concentrations of fluticasone.1

Use with caution; consider alternatives to fluticasone, especially when long-term use of the corticosteroid is anticipated.1 Concomitant use may cause significantly reduced serum cortisol concentrations; adrenal insufficiency and Cushing's syndrome have been reported in postmarketing experience.1

Coadministration of fluticasone and fosamprenavir with ritonavir is not recommended unless the potential benefits outweigh the risks of systemic corticosteroid adverse effects.1

Dexamethasone

Concomitant use of dexamethasone and fosamprenavir may result in decreased amprenavir concentrations and decreased antiretroviral efficacy.1 Use with caution.1

Ergot Derivatives

Concomitant use of fosamprenavir and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) results in increased concentrations of the ergot derivative.1

Concomitant use is contraindicated due to the potential for serious and/or life-threatening adverse reactions (e.g., acute ergot toxicity [manifested as peripheral vasospasm and ischemia of the extremities and other tissues]).1

Estrogens and Progestins

Concomitant use of ritonavir-boosted fosamprenavir and ethinyl estradiol with norethindrone results in decreased ethinyl estradiol concentrations.1 Concomitant use of unboosted fosamprenavir and ethinyl estradiol with norethindrone results in decreased amprenavir and ethinyl estradiol concentrations.1

Concomitant use may lead to loss of virologic response, and also results in increased risk of transaminase elevations.1 Use alternative methods of non-hormonal contraception.1 No data are available on the use of fosamprenavir plus ritonavir with other hormonal therapies such as hormone replacement therapy for postmenopausal women.1

Fentanyl

Concomitant use of fosamprenavir and fentanyl may increase fentanyl concentrations.1

Careful monitoring of therapeutic effects and adverse effects of fentanyl (e.g., potentially fatal respiratory depression) is recommended.1

GI Drugs

Antacids

Concomitant use of fosamprenavir and antacids (containing aluminum hydroxide/magnesium hydroxide) may decrease amprenavir concentrations, making fosamprenavir less effective.1

Use with caution when administered at the same time.1 Staggered coadministration of antacids and fosamprenavir has not been evaluated.1

Cisapride

Concomitant use of fosamprenavir and cisapride results in increased cisapride concentrations.1

Concomitant use is contraindicated due to potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias).1

Histamine H2-receptor Antagonists

Concomitant use of fosamprenavir (without ritonavir) and histamine H₂-receptor antagonists (cimetidine, famotidine, nizatidine) results in decreased amprenavir concentrations and thus possible decreased effectiveness of fosamprenavir.1 Interaction with ritonavir-boosted fosamprenavir and histamine H₂-receptor antagonists has not been evaluated.1 Use with caution.1

Proton-pump Inhibitors

Concomitant use of esomeprazole and fosamprenavir (without ritonavir) does not alter plasma concentrations of amprenavir, but increases the concentration of esomeprazole.1 Concomitant use of esomeprazole and ritonavir-boosted fosamprenavir is not expected to affect amprenavir or esomeprazole concentrations.1

Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) can be administered concomitantly with fosamprenavir with no change in amprenavir concentrations.1

HMG-CoA Reductase Inhibitors

Concomitant use of fosamprenavir and certain statins (atorvastatin, lovastatin, simvastatin) increases plasma concentrations of the statin.1

Atorvastatin

If atorvastatin is used concomitantly with fosamprenavir, titrate atorvastatin dosage carefully and use the lowest necessary dosage.1 Do not exceed an atorvastatin dosage of 20 mg daily.1

Lovastatin

Concomitant use of lovastatin with fosamprenavir is contraindicated due to potential for serious and/or life-threatening adverse effects (e.g., myopathy including rhabdomyolysis).1

Simvastatin

Concomitant use of simvastatin with fosamprenavir is contraindicated due to potential for serious and/or life-threatening adverse effects (e.g., myopathy including rhabdomyolysis).1

Immunosuppressive Agents

Concomitant use of fosamprenavir and cyclosporine, sirolimus, or tacrolimus results in increased concentrations of the immunosuppressive agent.1

Monitor therapeutic plasma concentrations of the immunosuppressive agent during concurrent use.1

Lomitapide

Concomitant use of fosamprenavir and lomitapide increases plasma lomitapide concentrations.1 Concomitant use is contraindicated due to potential for significantly increased transaminases.1

Methadone

Pharmacokinetic interaction is possible with methadone (decreased concentrations of methadone).1

Data suggest that the interaction is not clinically important; however, monitor patients for opiate withdrawal symptoms.1

Phosphodiesterase Type 5 Inhibitors

Concomitant use of fosamprenavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) is expected to result in substantially increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects (e.g., hypotension, visual disturbances, priapism, syncope) associated with these agents.1

Sildenafil

Concomitant use of fosamprenavir is contraindicated in patients receiving sildenafil (Revatio^®) for treatment of pulmonary arterial hypertension (PAH).1 Safe and effective dosages for concomitant use of the drugs have not been established.1

If sildenafil is used for treatment of erectile dysfunction in patients receiving fosamprenavir (with or without low-dose ritonavir), a sildenafil dosage of 25 mg once every 48 hours is recommended.1 Monitor closely for sildenafil-related adverse effects.1

Tadalafil

If tadalafil (Adcirca^®) is indicated for treatment of PAH in patients who have been receiving fosamprenavir (with or without low-dose ritonavir) for at least 1 week, tadalafil should be initiated at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1 Do not initiate fosamprenavir in patients receiving tadalafil for treatment of PAH; discontinue tadalafil therapy for ≥24 hours prior to initiating fosamprenavir.1 After at least 1 week of fosamprenavir therapy, tadalafil therapy may be resumed at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1

If tadalafil is used for treatment of erectile dysfunction in patients receiving fosamprenavir (with or without low-dose ritonavir), tadalafil dosage should not exceed 10 mg once every 72 hours.1 Monitor closely for tadalafil-related adverse effects.1

Vardenafil

If vardenafil is used for treatment of erectile dysfunction in patients receiving ritonavir-boosted fosamprenavir, do not exceed a vardenafil dosage of 2.5 mg once every 72 hours.1 Monitor closely for vardenafil-related adverse effects.1

If vardenafil is used for treatment of erectile dysfunction in patients receiving unboosted fosamprenavir, do not exceed a vardenafil dosage of 2.5 mg once every 24 hours.1 Monitor closely for vardenafil-related adverse effects.1

Salmeterol

Concomitant use of fosamprenavir and salmeterol results in increased salmeterol concentrations.1 Concomitant use of salmeterol and fosamprenavir is not recommended due to increased risk of salmeterol-associated adverse cardiovascular effects, including QT-interval prolongation, palpitations, and sinus tachycardia.1

Selective Serotonin-reuptake Inhibitors

Concomitant use of paroxetine and fosamprenavir results in decreased plasma concentrations of paroxetine.1 Adjust paroxetine dosage based on clinical response and tolerability.1

St. John's Wort ( Hypericum perforatum )

Concomitant use with St. John's wort ( Hypericum perforatum ) is contraindicated due to potential pharmacokinetic interaction (substantially decreased amprenavir concentrations); there is potential for loss of virologic response and possible resistance to amprenavir or other PIs.1

Trazodone

Concomitant use of trazodone and fosamprenavir may result in increased plasma concentrations of trazodone.1 Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.1 Caution is advised during concurrent use of trazodone and fosamprenavir; consider a lower trazodone dosage.1

Tricyclic Antidepressants

Concomitant use of fosamprenavir and amitriptyline or imipramine results in increased plasma concentrations of the tricyclic antidepressant.1 Monitor plasma concentrations of tricyclic antidepressants if used concomitantly with fosamprenavir.1

Warfarin

Potential pharmacokinetic interaction exists with warfarin (altered warfarin concentrations).1 If warfarin is used concomitantly with fosamprenavir, monitor the international normalized ratio (INR).1

Description

Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US) and has little or no antiviral activity until it is hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium.1 Amprenavir is an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease.1 During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes.1 By interfering with the formation of these essential proteins and enzymes, amprenavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions.1

HIV-1 strains with reduced susceptibility to amprenavir can be produced in vitro and strains with reduced susceptibility have emerged during fosamprenavir therapy.1 Varying degrees of cross-resistance among HIV protease inhibitors observed.1

The absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium has not been established.1 Peak amprenavir concentrations are attained 1.5-4 hours after administration of the prodrug.1 When a single 1.4-g dose of fosamprenavir is administered on an empty stomach as tablets or the oral suspension, amprenavir exposure (AUC) is similar, but peak amprenavir concentrations are 14.5% higher with the suspension compared with the tablet.1

Administration of fosamprenavir calcium tablets with food has no effect on bioavailability of amprenavir.1 Administration of fosamprenavir calcium suspension with food (i.e., standardized high-fat meal) reduces peak plasma concentrations of amprenavir by 46%, delays time to peak plasma concentration by 0.72 hours, and reduces the AUC by 28% compared with administration in the fasting state.1

In vitro studies indicate amprenavir is 90% bound to plasma proteins, primarily to α₁-acid glycoprotein.1 Following oral administration, fosamprenavir calcium is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate in the intestinal epithelium during absorption.1 Amprenavir is metabolized in the liver principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 Approximately 14% of an oral dose of fosamprenavir is excreted in urine and 75% is eliminated in feces as metabolites; only minimal amounts are eliminated unchanged in urine or feces.1 The plasma elimination half-life of amprenavir is approximately 7.7 hours.1

Advice to Patients

• Advise patients to read the patient information provided by the manufacturer.1
• Inform patients that fosamprenavir is used in conjunction with other antiretrovirals for the treatment of human immunodeficiency virus (HIV) infection.1
• If a dose is missed, instruct patients to take the dose as soon as it is remembered.1 Advise patients not to double their next dose or take more than the prescribed dose.1
• When the oral suspension is used, instruct patients to repeat the dose if vomiting occurs within 30 minutes of ingestion.1
• Advise adults to take fosamprenavir oral suspension on an empty stomach.1 Advise children to take the oral suspension with food.1 Advise patients that refrigeration of the suspension may improve the taste.1
• Advise patients to inform their clinician if they are allergic to sulfonamides.1 The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown.1
• Advise patients that skin reactions, including severe skin reactions, have been reported with fosamprenavir.1 Advise patients to discontinue fosamprenavir immediately if severe or life-threatening skin reactions, or moderate rashes with systemic symptoms, occur.1 Symptoms include hives or sores in the mouth; skin peeling and blisters; trouble swallowing or breathing; and/or swelling of the face, eyes, lips, tongue, or throat.1
• Advise patients that laboratory testing is recommended before and during treatment with fosamprenavir to assess for liver toxicity.1 Inform patients with underlying hepatitis B or C infection or significantly increased liver enzymes prior to treatment that they may be at increased risk of developing or worsening liver enzyme elevations during treatment, particularly at higher than recommended dosages that should not be used.1
• Risk of immune reconstitution syndrome.1 Advise patients to inform their clinician immediately of any signs or symptoms of infection since inflammation from previous infection may occur soon after fosamprenavir is started in combination with other antiretroviral agents.1
• Inform patients that an increase of body fat may occur, although the cause and long-term health effects of this are unknown at this time.1
• Advise patients that laboratory testing before and during therapy is recommended to assess for lipid elevations since increases in triglycerides and cholesterol have been observed with use of fosamprenavir.1
• Advise women to inform their clinician if they are or plan to become pregnant.1 Advise women that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy.1 Instruct patients using combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with fosamprenavir because hormonal levels may decrease and, if used in combination with fosamprenavir and ritonavir, transaminase elevations may occur.1
• Advise women to inform their clinician if they plan to breast-feed.1
• Fosamprenavir may interact with many drugs.1 Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John's wort), as well as any concomitant illnesses.1 Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at risk of PDE5 inhibitor-associated adverse effects, including hypotension, visual changes, and priapism, and should promptly report any symptoms to their clinician.1
• Advise patients of other precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ViiV Healthcare. Lexiva^® (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2020 Oct.

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