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Uses

Treatment of HIV Infection

Fosamprenavir is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and certain pediatric patients 4 weeks of age and older.

Fosamprenavir can be used with low-dose ritonavir (ritonavir-boosted fosamprenavir) or without low-dose ritonavir (unboosted fosamprenavir). Fosamprenavir (with or without low-dose ritonavir) usually is used in HIV protease inhibitor-based (PI-based) regimens that include 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that fosamprenavir (with or without low-dose ritonavir) is not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents. Regimens that include unboosted fosamprenavir may be associated with virologic failure and result in selection of mutations that confer resistance to fosamprenavir and darunavir; clinical trial data regarding use of ritonavir-boosted fosamprenavir are more limited compared with clinical trial data available for other ritonavir-boosted PIs.

Clinical Experience

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

In the NEAT study, 249 HIV-infected adults (mean age: 37 years; 69% male; 24% white; 32% black; 44% Hispanic; median baseline plasma HIV-1 RNA level: 4.83 log10 copies/mL; median baseline CD4 T-cell count: 212 cells/mm) were randomized to receive a 3-drug regimen that included either fosamprenavir (1.4 g twice daily) or nelfinavir (1250 mg twice daily) in conjunction with abacavir (300 mg twice daily) and lamivudine (150 mg twice daily). 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 less than 400 or 50 copies/mL, respectively; the median increase in CD4 T-cell count from baseline was 201/mm in patients receiving the fosamprenavir regimen and 216/mm in those receiving the nelfinavir regimen.

In the SOLO study, 649 HIV-infected adults (mean age: 37 years; 73% male; 53% white; 36% black; 8% Hispanic; median baseline plasma HIV-1 RNA level: 4.8 log10 copies/mL; median baseline CD4 T-cell count: 170 cells/mm) were randomized to receive a ritonavir-boosted regimen of fosamprenavir (1.4 g 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). 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 less than 400 or 50 copies/mL, respectively; the median increase in CD4 T-cell count from baseline was 203 cells/mm in patients receiving the ritonavir-boosted fosamprenavir regimen and 207 cells/mm in those receiving the nelfinavir regimen.

Antiretroviral-experienced Adults and Adolescents

The manufacturer advises that the following factors be considered when initiating ritonavir-boosted fosamprenavir in patients who have previously received a PI (PI-experienced patients). Data are insufficient to determine whether a regimen that includes ritonavir-boosted fosamprenavir is clinically equivalent to a regimen that includes the fixed-combination of lopinavir and ritonavir (lopinavir/ritonavir) in PI-experienced patients. Once-daily ritonavir-boosted fosamprenavir is not recommended in PI-experienced adults.

Clinical Experience

Fosamprenavir has been evaluated for use in HIV-infected adults who were antiretroviral-experienced (previously received therapy with PIs). In a randomized, open-label, multicenter study (study APV30003 [CONTEXT study]), 315 adults with HIV infection who had experienced virologic failure to 1 or 2 prior PI-containing regimens (mean age: 42 years; 85% male; 67% white; 24% black; 9% Hispanic; median baseline plasma HIV-1 RNA level: 4.14 log10 copies/mL; median baseline CD4 T-cell count: 263 cells/mm) 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 (1.4 g once daily with ritonavir 200 mg once daily), or lopinavir/ritonavir (400 mg of lopinavir and 100 mg of ritonavir twice daily). At 48 weeks, 58 or 46% of those receiving twice-daily ritonavir-boosted fosamprenavir, 50 or 37% of those receiving once-daily ritonavir-boosted fosamprenavir, and 61 or 50% of those receiving lopinavir/ritonavir had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively. In addition, the median increase in CD4 T-cell count from baseline was 81 cells/mm in patients receiving fosamprenavir and ritonavir twice daily and 91 cells/mm in those receiving lopinavir/ritonavir. 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. Furthermore, because the once-daily ritonavir-boosted fosamprenavir regimen appeared to be less effective than the twice-daily regimen or the regimen containing lopinavir/ritonavir, the manufacturer states that a once-daily regimen of ritonavir-boosted fosamprenavir is not recommended for use in patients who have previously received therapy with PIs.

Pediatric Patients

Fosamprenavir is used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in pediatric patients. In pediatric patients who have not previously received a PI (PI-naive pediatric patients), ritonavir-boosted fosamprenavir is used in those 4 weeks of age or older, and fosamprenavir (without low-dose ritonavir) is used in those 2 years of age or older. In PI-experienced pediatric patients, ritonavir-boosted fosamprenavir is used in those 6 months of age or older, and fosamprenavir (without low-dose ritonavir) is used in those 2 years of age or older.(See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

For initial treatment of HIV infection in pediatric patients who are antiretroviral-naive, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a ritonavir-boosted HIV PI, HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV integrase strand transfer inhibitor (INSTI) used in conjunction with 2 NRTIs (dual NRTIs). These experts state that regimens that include ritonavir-boosted fosamprenavir are not recommended for initial treatment in pediatric patients of any age because other more advantageous ritonavir-boosted PIs are available. These experts also state that a regimen that includes fosamprenavir (without low-dose ritonavir) is not recommended for use in pediatric patients of any age because of an inconvenient dosing regimen and the possibilities of selection of resistance mutations.

For further information on treatment of HIV infection in pediatric patients,

Clinical Experience

Safety and efficacy of fosamprenavir (with or without low-dose ritonavir) in conjunction with other antiretroviral agents has been evaluated in 3 open-label studies in PI-naive and PI-experienced pediatric patients 4 weeks to 18 years of age.

In one study (APV29005), 20 children 2-18 years of age (18 antiretroviral-naive, 2 antiretroviral-experienced) received a twice-daily regimen of fosamprenavir (oral suspension) without low-dose ritonavir in conjunction with other antiretrovirals. At 24 weeks, 65% of children had plasma HIV-1 RNA levels less than 400 copies/mL and the median increase from baseline in CD4 T-cell count was 350/mm. In addition, 89 children 2-18 years of age (49 PI-naive, 40 PI-experienced) received ritonavir-boosted fosamprenavir (oral suspension or tablet) twice daily. At 24 weeks, 71 or 55% of PI-naive or PI-experienced children had plasma HIV-1 RNA levels less than 400 copies/mL, respectively, and the median increase from baseline in CD4 T-cell count was 184/mm or 150/mm, respectively.

In a second study (APV20002), 54 children 4 weeks to less than 2 years of age (49 PI-naive, 5 PI-experienced) received a twice-daily regimen of fosamprenavir (oral suspension) with low-dose ritonavir (ritonavir-boosted fosamprenavir) in conjunction with other antiretrovirals. At 24 weeks, 72% had plasma HIV-1 RNA levels less than 400 copies/mL and the median increase from baseline in CD4 T-cell count was 400/mm in those 4 weeks to less than 6 months of age and 278/mm in those 6 months to 2 years of age.

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

Postexposure Prophylaxis following Occupational Exposure to HIV

Fosamprenavir (with or without low-dose ritonavir) is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

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). These experts state that fosamprenavir (with or without low-dose ritonavir) and 2 NRTIs can be considered an alternative regimen, but should be used for PEP only with expert consultation. The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

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. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Fosamprenavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals who have had exposure to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

CDC states that fosamprenavir is an alternative antiretroviral that can be used in nPEP regimens, but should be used in such regimens only with expert consultation.

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 if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Fosamprenavir calcium is administered orally as tablets or oral suspension.

Oral Suspension

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

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

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

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

Tablets

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

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

Dosage

Dosage of fosamprenavir calcium is expressed in terms of fosamprenavir.

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naive Adults

For initial treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive adults when a ritonavir-boosted regimen is used, the usual dosage is 1.4 g 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). Higher dosages of fosamprenavir and/or ritonavir are not recommended and are associated with increased serum transaminase concentrations.

If fosamprenavir is used without low-dose ritonavir in antiretroviral-naive adults, the usual dosage is 1.4 g of fosamprenavir twice daily.

Treatment of HIV Infection in Antiretroviral-experienced Adults

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

Once-daily ritonavir-boosted fosamprenavir regimens are not recommended in PI-experienced adults.(See Antiretroviral-experienced Adults under Uses: Treatment of HIV Infection.)

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 1.4 g once daily with ritonavir 100 mg once daily. Alternatively, fosamprenavir 1.4 g twice daily can be used without ritonavir. Fosamprenavir (with or without low-dose ritonavir) is used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

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.

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.

A once-daily regimen of fosamprenavir (with or without low-dose ritonavir) is not recommended in any pediatric patient.(See Pediatric Patients under Uses: Treatment of HIV Infection.)

A twice-daily regimen of ritonavir-boosted fosamprenavir should not be used in PI-experienced children younger than 6 months of age.

A twice-daily regimen of fosamprenavir (without low-dose ritonavir) should not be used in PI-naive or PI-experienced children younger than 2 years of age.

Treatment of HIV Infection in Antiretroviral-naive Pediatric Patients

For treatment of HIV-1 infection in PI-naive 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).(See Table 1.)

Table 1. Dosage of Ritonavir-boosted Fosamprenavir in PI-naive Pediatric Patients 4 Week of Age or Older[1 ]
Weight (kg) Fosamprenavir Dosage (Oral Suspension) Ritonavir Dosage
less than 11 45 mg/kg twice daily 7 mg/kg twice daily
11 to less than 15 30 mg/kg twice daily 3 mg/kg twice daily
15 to less than 20 23 mg/kg twice daily 3 mg/kg twice daily
20 or greater 18 mg/kg twice daily 3 mg/kg twice daily

Alternatively, PI-naive children weighing 39 kg or more can receive fosamprenavir tablets in a dosage of 700 mg twice daily (with ritonavir 100 mg twice daily).

If fosamprenavir is used without low-dose ritonavir in PI-naive children 2 years of age or older, fosamprenavir oral suspension can be given in a dosage of 30 mg/kg twice daily. Alternatively, PI-naive children 2 years of age or older weighing 47 kg or more can receive fosamprenavir tablets in a dosage of 1.4 g twice daily (without ritonavir).

Treatment of HIV Infection in Antiretroviral-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).(See Table 2.)

Table 2. Dosage of Ritonavir-boosted Fosamprenavir in PI-experienced Pediatric Patients 6 months of Age or Older[1 ]
Weight (kg) Fosamprenavir Dosage (Oral Suspension) Ritonavir Dosage
less than 11 45 mg/kg twice daily 7 mg/kg twice daily
11 to less than 15 30 mg/kg twice daily 3 mg/kg twice daily
15 to less than 20 23 mg/kg twice daily 3 mg/kg twice daily
20 or greater 18 mg/kg twice daily 3 mg/kg twice daily

Alternatively, PI-experienced children 6 months of age or older weighing 39 kg or more can receive fosamprenavir tablets in a dosage of 700 mg twice daily (with ritonavir 100 mg twice daily).

Alternatively, PI-experienced children 2 years of age or older weighing 47 kg or more can receive fosamprenavir tablets in a dosage of 1.4 g twice daily (without ritonavir).

Special Populations

Hepatic Impairment

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

Antiretroviral-naive 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). PI-experienced adults with mild hepatic impairment should receive fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily).

Antiretroviral-naive 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). PI-experienced adults with moderate hepatic impairment should receive fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily).

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

Renal Impairment

Dosage adjustments are not necessary in patients with renal impairment.

Geriatric Patients

In geriatric patients, dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions

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.

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 (e.g., alfuzosin, cisapride, ergot alkaloids, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], lovastatin, simvastatin, midazolam, triazolam).(See Drug Interactions.)

Concomitant use with drugs that may lead to loss of virologic response (e.g., rifampin, St. John's wort [Hypericum perforatum]).(See Drug Interactions.)

Concomitant use of ritonavir-boosted fosamprenavir and flecainide or propafenone.(See Drug Interactions: Antiarrhythmic Agents.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

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 occurred approximately 11 days after initiation of fosamprenavir and persisted for a median of 13 days. Severe or life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of patients receiving fosamprenavir in clinical studies.

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. Discontinue fosamprenavir if severe or life-threatening rash or moderate rash accompanied by systemic manifestations occurs.

Sulfonamide Sensitivity

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

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

Interactions

Concomitant use of fosamprenavir (with or without low-dose ritonavir) with certain drugs is contraindicated or requires particular caution.(See Contraindications and see Drug Interactions.)

When a ritonavir-boosted fosamprenavir regimen is used, the usual cautions, precautions, and contraindications associated with ritonavir should be considered.

Initiation of ritonavir-boosted fosamprenavir in patients receiving cytochrome P-450 (CYP) isoenzyme 3A4 substrates or initiation of CYP3A4 substrates in patients already receiving ritonavir-boosted fosamprenavir may increase plasma concentrations of such substrate drugs. Initiation of CYP3A4 inhibitors or inducers may increase or decrease plasma concentrations of ritonavir-boosted fosamprenavir, respectively. 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 could occur.

Potential drug interactions should be considered prior to and during ritonavir-boosted fosamprenavir therapy. Clinicians should review all drugs the patient is receiving and should monitor for adverse effects associated with other drugs used concomitantly with ritonavir-boosted fosamprenavir.(See Drug Interactions.)

Hepatic Effects

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

Liver function tests should be performed prior to initiating fosamprenavir, and patients should be closely monitored during treatment. HIV-infected 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 transaminase elevations.(See Hepatic Impairment under Cautions.)

Use of higher than recommended dosages of ritonavir-boosted fosamprenavir is associated with increased serum transaminase concentrations.

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV protease inhibitors (PIs); diabetic ketoacidosis has occurred. It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).

Immune Reconstitution Syndrome

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

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance have been reported in patients receiving antiretroviral therapy, including fosamprenavir. The mechanism and long-term consequences of fat redistribution are unknown; a causal relationship has not been established. Patients should be evaluated for physical signs of fat redistribution.

Lipid Effects

Increases in triglyceride and cholesterol concentrations have occurred in patients receiving ritonavir-boosted fosamprenavir. HIV infection itself is associated with lipid disorders. Serum triglyceride and cholesterol concentrations should be determined before initiating therapy with fosamprenavir and periodically monitored during therapy; manage lipid disorders as clinically appropriate.(See Drug Interactions: HMG-CoA Reductase Inhibitors.)

Hematologic Effects

Neutropenia has been reported in 3% of adults receiving fosamprenavir in clinical studies. Acute hemolytic anemia has been reported in at least one patient who received amprenavir (no longer commercially available in the US).

Hemophilia A and B

Spontaneous bleeding has been reported in patients with hemophilia A or B receiving HIV PIs; use caution in such patients. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.

Nephrolithiasis

Nephrolithiasis has been reported during postmarketing experience. If signs or symptoms of nephrolithiasis occur, consideration should be given to temporarily interrupting or discontinuing fosamprenavir.

HIV Resistance

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

Cardiovascular Effects

There have been postmarketing reports of myocardial infarction in patients receiving fosamprenavir. Findings from a case-control study suggest that an association exists between cumulative exposure to fosamprenavir or amprenavir (no longer commercially available in the US) and an increased risk of myocardial infarction. Further analysis of antiretroviral drug therapy classes found a higher relative risk of myocardial infarction with PIs compared with other antiretroviral drug classes; this may, in part, be due to the ability of PIs to elevate serum lipid concentrations. However, HIV infection itself is associated with ischemic heart disease.

Modifiable risk factors for cardiovascular disease (e.g., hypertension, diabetes, smoking) should be monitored and managed as clinically appropriate. Treatment should be individualized, with careful consideration given to the overall risks and benefits of continued treatment with antiretroviral therapy.

Specific Populations

Pregnancy

Category C.

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.apregistry.com.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that data are insufficient to recommend routine use of fosamprenavir for initial treatment in antiretroviral-naive pregnant women. If fosamprenavir is used in pregnant women, these experts state that the drug must be used with low-dose ritonavir (ritonavir-boosted fosamprenavir).

Lactation

Amprenavir is distributed into milk in rats. Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Safety and efficacy of fosamprenavir have not been established in PI-naive children younger than 4 weeks of age or in PI-experienced children younger than 6 months of age.

In PI-naive infants, fosamprenavir should only be used in those born at 38 weeks gestation or later who have attained a postnatal age of 28 days.

Once-daily regimens of fosamprenavir (with or without low-dose ritonavir) should not be used in pediatric patients.

Twice-daily regimens of fosamprenavir (without low-dose ritonavir) should not be used in pediatric patients younger than 2 years of age.

Some experts state that ritonavir-boosted fosamprenavir should be considered for initial treatment in pediatric patients only in those 6 months of age and older and only in special circumstances. These experts also state that fosamprenavir (without low-dose ritonavir) should not be used in pediatric patients of any age.(See Pediatric Patients under Uses: Treatment of HIV Infection.)

Adverse effects reported in pediatric patients have been similar to those reported in adults; vomiting and neutropenia were reported more frequently than in adults.

Geriatric Use

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

Hepatic Impairment

Fosamprenavir should be used with caution in patients with hepatic impairment since amprenavir concentrations are increased. Reduced dosage 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.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

HIV-infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy may be at increased risk for further elevations in hepatic enzyme concentrations.

Common Adverse Effects

The most common adverse effects in patients receiving fosamprenavir in conjunction with other antiretroviral agents are diarrhea, nausea, vomiting, headache, and rash.

Drug Interactions

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. Results of studies using fosamprenavir may not be predictive of the magnitude of interaction with ritonavir-boosted fosamprenavir. Drug interactions reported with low-dose ritonavir also should be considered.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

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.

Alfuzosin

Concomitant use of alfuzosin and fosamprenavir (with or without low-dose ritonavir) is contraindicated. Potential for increased alfuzosin concentrations that could result in hypotension.

Antiarrhythmic Agents

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

Pharmacokinetic interaction with amiodarone, systemic lidocaine, or quinidine (increased concentrations of the antiarrhythmic). Potential for serious and/or life-threatening adverse effects. The manufacturer of fosamprenavir states that these antiarrhythmic agents and fosamprenavir should be used concomitantly with caution and plasma concentrations of the antiarrhythmic agent should be monitored, if possible.

Some experts state that concomitant use of dronedarone and fosamprenavir (with or without low-dose ritonavir) is contraindicated.

Anticoagulants

Apixaban

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with apixaban (increased apixaban concentrations).

Concomitant use of fosamprenavir (with or without low-dose ritonavir) and apixaban should be avoided.

Dabigatran

Possible pharmacokinetic interaction if ritonavir-boosted fosamprenavir is used concomitantly with dabigatran (increased dabigatran concentrations).

Dosage adjustments are not needed in patients with creatinine clearances exceeding 50 mL/minute. Concomitant use of ritonavir-boosted fosamprenavir and dabigatran should be avoided in patients with creatinine clearances less than 50 mL/minute.

Edoxaban

Pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with edoxaban (increased edoxaban concentrations).

Concomitant use of fosamprenavir (with or without low-dose ritonavir) and edoxaban should be avoided.

Rivaroxaban

Pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with rivaroxaban (increased rivaroxaban concentrations).

Concomitant use of rivaroxaban and fosamprenavir (with or without low-dose ritonavir) should be avoided.

Warfarin

Potential pharmacokinetic interaction with warfarin (altered warfarin concentrations).

If warfarin is used concomitantly with fosamprenavir (with or without low-dose ritonavir), the international normalized ratio (INR) should be monitored, especially when the antiretroviral agent is initiated or discontinued; warfarin dosage should be adjusted as needed.

Anticonvulsants

Carbamazepine, Phenobarbital, Phenytoin

Concomitant use of fosamprenavir (without low-dose ritonavir) and some anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin) may decrease plasma amprenavir concentrations. Fosamprenavir (with or without low-dose ritonavir) should be used concomitantly with carbamazepine, phenobarbital, or phenytoin with caution. Some experts state that unboosted fosamprenavir should not be used concomitantly with these anticonvulsants and that alternative anticonvulsants or use of ritonavir-boosted fosamprenavir should be considered.

Concomitant use of ritonavir-boosted fosamprenavir and carbamazepine may increase carbamazepine concentrations and decrease concentrations of the PI; an alternative anticonvulsant should be considered or carbamazepine and amprenavir concentrations should be monitored and virologic response assessed.

Concomitant use of ritonavir-boosted fosamprenavir and phenytoin may decrease plasma concentrations and area under the concentration-time curve (AUC) of phenytoin and increase amprenavir concentrations. Usual dosages of ritonavir-boosted fosamprenavir may be used in patients receiving phenytoin, but phenytoin concentrations should be monitored and phenytoin dosage increased as needed.

Ethosuximide

Possible pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with ethosuximide (increased ethosuximide concentrations).

If fosamprenavir (with or without low-dose ritonavir) and ethosuximide are used concomitantly, the patient should be monitored for ethosuximide toxicity.

Lamotrigine

Possible pharmacokinetic interaction if ritonavir-boosted fosamprenavir is used concomitantly with lamotrigine (decreased lamotrigine concentrations).

If lamotrigine is used concomitantly with ritonavir-boosted fosamprenavir, increased lamotrigine dosage may be needed and lamotrigine concentration monitoring should be considered. Alternatively, use of a different anticonvulsant should be considered.

Antifungal Agents

Itraconazole

Concomitant use of itraconazole and fosamprenavir (with or without low-dose ritonavir) may result in increased concentrations of the antifungal and amprenavir.

In patients receiving fosamprenavir (with or without low-dose ritonavir), consider monitoring itraconazole concentrations to guide dosage adjustments. In those receiving fosamprenavir (without low-dose ritonavir), reduced antifungal dosage may be needed in those receiving itraconazole dosages exceeding 400 mg daily. In those receiving ritonavir-boosted fosamprenavir, itraconazole dosage should not exceed 200 mg daily unless plasma concentrations are used to guide dosage.

Isavuconazonium

Possible pharmacokinetic interaction if isavuconazonium sulfate (prodrug of isavuconazole) is used concomitantly with fosamprenavir (with or without low-dose ritonavir) (increased isavuconazole concentrations and altered fosamprenavir concentrations).

If fosamprenavir (with or without low-dose ritonavir) and isavuconazonium sulfate are used concomitantly, isavuconazole concentration monitoring should be considered and the patient should be monitored for fosamprenavir-associated adverse effects and virologic response.

Ketoconazole

Concomitant use of ketoconazole and fosamprenavir (with or without low-dose ritonavir) may result in increased concentrations of the antifungal.

In patients receiving fosamprenavir (without low-dose ritonavir), reduced antifungal dosage may be needed in those receiving ketoconazole dosages exceeding 400 mg daily. In those receiving ritonavir-boosted fosamprenavir, use caution and ketoconazole dosage should not exceed 200 mg daily.

Posaconazole

Concomitant use of posaconazole and fosamprenavir (without low-dose ritonavir) decreases the AUC of posaconazole and is expected to increase plasma concentrations of amprenavir. Concomitant use of posaconazole and ritonavir-boosted fosamprenavir may increase plasma concentrations of both posaconazole and amprenavir.

If fosamprenavir (without low-dose ritonavir) is used concomitantly with posaconazole, posaconazole concentrations should be monitored.

If ritonavir-boosted fosamprenavir is used concomitantly with posaconazole, posaconazole concentration monitoring should be considered and the patient should be monitored for fosamprenavir-associated adverse effects.

Voriconazole

Concomitant use of fosamprenavir and voriconazole may result in increased plasma concentrations of both drugs. Although specific data are not available on pharmacokinetic interactions between ritonavir-boosted fosamprenavir and voriconazole, studies using concomitant low-dose ritonavir and voriconazole indicate decreased voriconazole concentrations and AUC.

If fosamprenavir (without low-dose ritonavir) is used concomitantly with voriconazole, patients should be monitored frequently for toxicities.

Ritonavir-boosted fosamprenavir and voriconazole should not be used concomitantly unless potential benefits outweigh risks; if used concomitantly, monitoring voriconazole plasma concentrations should be considered and voriconazole dosage should be adjusted accordingly.

Antimycobacterial Agents

Bedaquiline

Possible pharmacokinetic interaction with ritonavir-boosted fosamprenavir (increased bedaquiline concentrations); clinical importance is unknown. If potential benefits outweigh risks, some experts state that bedaquiline and ritonavir-boosted fosamprenavir may be used concomitantly with caution; patients should be monitored for corrected QT (QTc) interval prolongation and liver dysfunction.

Rifabutin

Concomitant use of ritonavir-boosted fosamprenavir (fosamprenavir 700 mg and ritonavir 100 mg twice daily) with rifabutin (150 mg every other day) results in increased amprenavir concentrations and increased rifabutin metabolite (25-O-desacetylrifabutin) concentrations compared with rifabutin 300 mg daily alone.

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

Rifampin

Studies using amprenavir indicated pharmacokinetic interaction with rifampin (substantial [about 90%] decrease in amprenavir concentrations); possible decreased antiretroviral efficacy and increased risk of amprenavir resistance. Concomitant use of fosamprenavir and rifampin is contraindicated.

Rifapentine

Possible pharmacokinetic interaction with rifapentine (decreased amprenavir concentrations). Concomitant use of fosamprenavir and rifapentine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV-infected patients.

Antiplatelet Agents

Ticagrelor

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with ticagrelor (increased ticagrelor concentrations).

Concomitant use of fosamprenavir (with or without low-dose ritonavir) and ticagrelor should be avoided.

Vorapaxar

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with vorapaxar (increased vorapaxar concentrations).

Concomitant use of fosamprenavir (with or without low-dose ritonavir) and vorapaxar should be avoided.

Antipsychotic Agents

Lurasidone

Potential for serious and/or life-threatening adverse effects if used concomitantly with ritonavir-boosted fosamprenavir.

Concomitant use of ritonavir-boosted fosamprenavir and lurasidone is contraindicated.

If concomitant use of lurasidone and unboosted fosamprenavir is necessary, lurasidone dosage should be reduced.

Perphenazine, Risperidone, Thioridazine

Possible pharmacokinetic interaction if ritonavir-boosted fosamprenavir is used concomitantly with perphenazine, risperidone, or thioridazine (increased concentrations of the antipsychotic).

If used concomitantly with ritonavir-boosted fosamprenavir, the antipsychotic should be initiated at the lowest dosage and maintenance dosage should be adjusted. The patient should be monitored for toxicities associated with the antipsychotic.

Pimozide

Potential for serious and/or life-threatening adverse effects with pimozide (e.g., cardiac arrhythmias). Concomitant use of fosamprenavir and pimozide is contraindicated.

Quetiapine

Pharmacokinetic interaction with quetiapine expected (increased quetiapine concentrations).

In patients receiving fosamprenavir (with or without low-dose ritonavir), quetiapine should be initiated at the lowest dosage and titrated as needed. If fosamprenavir is initiated in a patient receiving a stable dosage of quetiapine, dosage of quetiapine should be reduced to one-sixth of the original dosage and the patient should be monitored for efficacy and adverse effects of the antipsychotic.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Pharmacokinetic interaction with maraviroc (increased plasma concentrations and AUC of maraviroc; decreased plasma concentrations and AUC of amprenavir). A maraviroc dosage of 150 mg twice daily should be used concomitantly with the usual dosage of ritonavir-boosted fosamprenavir. Unboosted fosamprenavir should not be used concomitantly with maraviroc.

No in vitro evidence of antagonistic antiretroviral effects with maraviroc.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of ritonavir-boosted fosamprenavir and dolutegravir decreases peak plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of fosamprenavir or ritonavir.

If ritonavir-boosted fosamprenavir is used concurrently with dolutegravir in adults who are antiretroviral-naive or antiretroviral-experienced but HIV integrase strand transfer inhibitor-naive (INSTI-naive), dolutegravir should be given in a dosage of 50 mg twice daily.

In patients who are INSTI-experienced and have documented or suspected INSTI resistance, an alternative to ritonavir-boosted fosamprenavir that is not a metabolic inducer should be used whenever possible.

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and amprenavir.

Elvitegravir

Possible pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used with cobicistat-boosted elvitegravir (altered concentrations of elvitegravir, cobicistat, and/or fosamprenavir).

Cobicistat-boosted elvitegravir should not be used concomitantly with fosamprenavir (with or without low-dose ritonavir).

Raltegravir

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

Appropriate dosages for concomitant use of raltegravir and fosamprenavir (with or without low-dose ritonavir) with respect to safety and efficacy not established. Some experts state that dosage adjustments are not necessary.

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) are synergistic against HIV-1.

Delavirdine

Studies using amprenavir indicate pharmacokinetic interaction with delavirdine (increased amprenavir concentrations, decreased delavirdine concentrations); potential for loss of virologic response and possible resistance to delavirdine. Concomitant use of fosamprenavir and delavirdine is contraindicated.

Efavirenz

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

Depending on the regimen of ritonavir-boosted fosamprenavir used, concomitant use with efavirenz may affect amprenavir concentrations. Concomitant use of efavirenz (600 mg once daily) with fosamprenavir 1.4 g once daily and ritonavir 200 mg once daily does not affect peak plasma amprenavir concentrations, but decreases the AUC and minimum plasma concentrations of amprenavir. When additional ritonavir is added to this regimen and efavirenz (600 mg once daily) is used concomitantly with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily, the AUC and peak plasma concentrations of amprenavir are increased slightly and minimum amprenavir plasma concentrations are not affected. When a twice-daily regimen of ritonavir-boosted fosamprenavir is used, concomitant use of efavirenz (600 mg once daily) with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily does not affect amprenavir AUC or peak plasma concentrations, but decreases minimum amprenavir plasma concentrations.

If ritonavir-boosted fosamprenavir is used in patients receiving efavirenz, the usual efavirenz dosage should be used with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily or, alternatively, fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily.

Etravirine

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

Etravirine and fosamprenavir (with or without low-dose ritonavir) should not be used concomitantly.

Nevirapine

Concomitant use of nevirapine and fosamprenavir (without low-dose ritonavir) results in a 33% decrease in the AUC of amprenavir and a 29% increase in the AUC of nevirapine. Concomitant use of nevirapine with a twice-daily regimen of ritonavir-boosted fosamprenavir results in an 11% decrease in amprenavir AUC and 14% increase in nevirapine AUC.

If nevirapine and a twice-daily regimen of ritonavir-boosted fosamprenavir are used concomitantly, usual nevirapine dosage should be used with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily. Concomitant administration of nevirapine with a once-daily regimen of ritonavir-boosted fosamprenavir has not been studied.

Concomitant use of nevirapine and fosamprenavir (without low-dose ritonavir) is not recommended.

Rilpivirine

Concomitant use of rilpivirine and fosamprenavir (with or without low-dose ritonavir) is expected to result in increased rilpivirine concentrations, but is not expected to affect amprenavir concentrations. Some experts state that dosage adjustments are not necessary.

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, stavudine, tenofovir, zidovudine) are synergistic.

Abacavir

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

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.

Tenofovir

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

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. 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.

HIV Protease Inhibitors (PIs)

In vitro evidence of synergistic antiretroviral effects with atazanavir and saquinavir and additive effects with indinavir, lopinavir, nelfinavir, and ritonavir.

Atazanavir

Pharmacokinetic interaction between atazanavir and ritonavir-boosted fosamprenavir (decreased plasma concentrations and AUC of atazanavir; no change in plasma concentrations or AUC of amprenavir). Data are not available regarding concomitant use of fosamprenavir (without low-dose ritonavir) and atazanavir.

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

Indinavir

Studies using amprenavir indicate that concomitant use of fosamprenavir (without low-dose ritonavir) and indinavir may result in pharmacokinetic interactions (increased plasma amprenavir concentrations and AUC; effect on indinavir concentrations not well established). Concomitant use of ritonavir-boosted fosamprenavir and indinavir has not been evaluated to date.

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

Lopinavir

Concomitant use of fosamprenavir (without low-dose ritonavir) with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) results in decreased amprenavir concentrations and AUC and unchanged lopinavir concentrations and AUC. Concomitant use of ritonavir-boosted fosamprenavir and lopinavir/ritonavir results in decreased amprenavir concentrations and AUC and altered lopinavir concentrations and AUC (decreased or increased). An increased incidence of adverse effects has been reported when the drugs were used concomitantly.

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

Nelfinavir

Studies using amprenavir indicate that concomitant use with nelfinavir may affect the pharmacokinetics of both drugs.

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

Ritonavir

Pharmacokinetic interaction with ritonavir (increased concentrations of amprenavir); concomitant low-dose ritonavir used for therapeutic advantage. Increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6.

Saquinavir

Studies using amprenavir indicate pharmacokinetic interaction with saquinavir (decreased amprenavir concentrations).

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

Tipranavir

Potential pharmacokinetic interaction with ritonavir-boosted tipranavir (decreased amprenavir concentrations).

Concomitant use of fosamprenavir and ritonavir-boosted tipranavir is not recommended.

β-Adrenergic Blocking Agents

Possible pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with certain β-adrenergic blocking agents (e.g., metoprolol, timolol) (increased β-adrenergic blocking agent concentrations).

If fosamprenavir (with or without low-dose ritonavir) is used concomitantly with a β-adrenergic blocking agent, dosage of the β-adrenergic blocking agent may need to be decreased and should be adjusted based on the patient's clinical response. Use of certain β-adrenergic blocking agents not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol) should be considered.

Benzodiazepines

Midazolam or Triazolam

Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).

Concomitant use of fosamprenavir with oral midazolam or triazolam is contraindicated. Some experts state that parenteral midazolam can be given in a single dose with caution in a monitored situation for procedural sedation in patients receiving fosamprenavir (with or without low-dose ritonavir).

Other Benzodiazepines

Potential pharmacokinetic interaction with alprazolam, clonazepam, clorazepate, diazepam, or flurazepam (increased benzodiazepine concentrations). Clinical importance unknown; reduction of benzodiazepine dosage may be necessary.

Although pharmacokinetic studies evaluating concomitant use with fosamprenavir are lacking, some experts recommend that use of benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) be considered since these drugs have less potential for interaction with PIs.

Bosentan

Possible pharmacokinetic interaction (increased bosentan concentrations).

In patients who have already been receiving fosamprenavir (with or without low-dose ritonavir) 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.

In patients who have already been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating fosamprenavir (with or without low-dose ritonavir); after at least 10 days of fosamprenavir therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

Buspirone

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with buspirone (increased buspirone concentrations).

When used concomitantly with fosamprenavir (with or without low-dose ritonavir), a low dosage of buspirone should be used with caution and should be titrated based on the patient's clinical response.

Calcium-channel Blocking Agents

Pharmacokinetic interaction with calcium-channel blocking agents (e.g., amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil) (increased concentrations of calcium-channel blocking agent). Use concomitantly with caution; clinical monitoring of the patient is recommended.

Colchicine

Possible pharmacokinetic interaction (increased colchicine concentrations).

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

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. 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.

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. 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.

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. 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.

Corticosteroids

Orally Inhaled or Intranasal Corticosteroids

Concomitant use of budesonide (orally inhaled or intranasal) or fluticasone (orally inhaled or intranasal) with fosamprenavir (with or without ritonavir) may result in increased concentrations of the corticosteroid; concomitant use with ritonavir-boosted fosamprenavir may result in adrenal insufficiency, including Cushing's syndrome.

Budesonide (orally inhaled or intranasal) and fluticasone (orally inhaled or intranasal) should not be used concomitantly with ritonavir-boosted fosamprenavir unless potential benefits of the inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects. An alternative corticosteroid (e.g., beclomethasone) should be considered, especially when long-term use of the corticosteroid is anticipated.

Some experts state that concomitant use of beclomethasone (inhaled or intranasal) and ritonavir-boosted PIs is not expected to result in clinically important pharmacokinetic interactions.

Local Injections of Corticosteroids

Concomitant use of intra-articular or other local injections of methylprednisolone, prednisolone, or triamcinolone with ritonavir-boosted fosamprenavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency, including Cushing's syndrome.

Ritonavir-boosted fosamprenavir should not be used concomitantly with local injections of methylprednisolone, prednisolone, or triamcinolone; other nonsteroidal therapies should be considered. If intra-articular corticosteroid therapy is required, an alternative antiretroviral that does not alter CYP3A4 activity should be considered (e.g., dolutegravir, raltegravir).

Systemic Corticosteroids

Concomitant use of systemic budesonide or prednisone may result in increased corticosteroid concentrations and may result in adrenal insufficiency, including Cushing's syndrome. Fosamprenavir (with or without low-dose ritonavir) should not be used concomitantly with systemic budesonide or prednisone unless potential benefits outweigh the risks of systemic corticosteroid adverse effects.

Concomitant use of systemic dexamethasone and fosamprenavir (with or without low-dose ritonavir) may result in decreased fosamprenavir concentrations and possible decreased antiretroviral efficacy. Systemic dexamethasone and fosamprenavir should be used concomitantly with caution; alternative corticosteroids should be considered for long-term use.

Eplerenone

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with eplerenone (increased eplerenone concentrations).

Some experts state that concomitant use of eplerenone and fosamprenavir (with or without low-dose ritonavir) is contraindicated.

Ergot Alkaloids

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) with ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine). Concomitant use with ergot alkaloids contraindicated.

If a woman receiving fosamprenavir or any other HIV protease inhibitor (PI) as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine) should be used for treatment of the hemorrhage only if alternative treatments (e.g., carboprost, misoprostol, oxytocin, dinoprostone) cannot be used and the potential benefits of the ergot alkaloid outweigh the risks. In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.

Estrogens and Progestins

Pharmacokinetic interaction with ritonavir-boosted fosamprenavir and a contraceptive preparation containing ethinyl estradiol 35 mcg with norethindrone 0.5 mg per tablet (decreased ethinyl estradiol and norethindrone concentrations). In addition, such concomitant use resulted in clinically important increases in serum transaminase concentrations. Pharmacodynamic interaction with fosamprenavir (without low-dose ritonavir) and oral contraceptives (loss of virologic response). Concomitant use of fosamprenavir and hormonal contraceptives is not recommended; alternative nonhormonal (e.g., barrier) method of contraception should be used.

Data are not available regarding concomitant use of fosamprenavir (with or without low-dose ritonavir) and subdermal implants containing etonogestrel. Alternative or additional methods of contraception or an alternative antiretroviral regimen should be considered.

Data are not available regarding concomitant use of fosamprenavir (with or without low-dose ritonavir) and transdermal systems containing ethinyl estradiol and norelgestromin. Alternative or additional methods of contraception or an alternative antiretroviral regimen should be considered.

Flibanserin

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with flibanserin (increased flibanserin concentrations).

Some experts state that concomitant use of fosamprenavir (with or without low-dose ritonavir) and flibanserin is contraindicated.

Fluvoxamine

Possible pharmacokinetic interaction if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with fluvoxamine (altered concentrations of fosamprenavir). Alternative antidepressant or alternative antiretroviral therapy should be considered.

GI Drugs

Antacids

Pharmacokinetic interaction with antacids (decreased amprenavir peak concentrations and AUC). The manufacturer of fosamprenavir states that this pharmacokinetic interaction is not clinically important and there are no restrictions for concomitant use of fosamprenavir and antacids. Some experts recommend that fosamprenavir be given simultaneously with or at least 2 hours before or 1 hour after antacids.

Cisapride

Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) when used concomitantly with cisapride. Concomitant use is contraindicated.

Histamine H2-receptor Antagonists

Pharmacokinetic interaction with histamine H2-receptor antagonists (decreased amprenavir concentrations, decreased ranitidine concentrations); potential for decreased antiretroviral efficacy.

Fosamprenavir should be used concomitantly with H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine) with caution; fosamprenavir (without low-dose ritonavir) should be administered at least 2 hours before the H2-receptor antagonist and use of ritonavir-boosted fosamprenavir should be considered.

Proton-pump Inhibitors

Concomitant use of esomeprazole and fosamprenavir does not alter plasma concentrations or AUC of amprenavir, but increases the AUC of esomeprazole. Concomitant use of esomeprazole and ritonavir-boosted fosamprenavir is not expected to affect amprenavir or esomeprazole concentrations.

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

Dosage adjustments are not necessary when fosamprenavir (with or without low-dose ritonavir) is used with a proton-pump inhibitor.

HCV Antivirals

HCV Protease Inhibitors

Simeprevir

Concomitant use of simeprevir and fosamprenavir (without low-dose ritonavir) may alter (increase or decrease) plasma concentrations of simeprevir due to CYP3A4 inhibition or induction by the HIV PIs. Concomitant use of simeprevir and ritonavir-boosted fosamprenavir is expected to increase simeprevir concentrations. No effect on amprenavir concentrations is expected when simeprevir and fosamprenavir (with or without low-dose ritonavir) are used concomitantly.

Concomitant use of simeprevir and fosamprenavir (with or without low-dose ritonavir) is not recommended.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir and fosamprenavir (with or without low-dose ritonavir) does not have a clinically important effect on daclatasvir concentrations.

Dosage adjustments are not necessary if fosamprenavir (with or without low-dose ritonavir) and daclatasvir are used concomitantly.

Elbasvir and Grazoprevir

Data are not available to date regarding the concomitant use of fosamprenavir (with or without low-dose ritonavir) and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir). Therefore, no dosage recommendations are available at this time.

Ledipasvir and Sofosbuvir

Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) with fosamprenavir (with or without low-dose ritonavir) is not expected to result in clinically important pharmacokinetic interactions. Dosage adjustments are not needed if ledipasvir/sofosbuvir is used concomitantly with fosamprenavir (with or without low-dose ritonavir).

Concomitant use of ledipasvir/sofosbuvir and an HIV antiretroviral regimen that includes ritonavir-boosted fosamprenavir and tenofovir DF may result in increased tenofovir concentrations. Safety of increased tenofovir concentrations in patients receiving ledipasvir/sofosbuvir and these antiretroviral regimens has not been established. Alternative HCV treatment or an alternative antiretroviral regimen should be considered to avoid increased tenofovir exposure. If concomitant use is necessary, the patient should be monitored for tenofovir-associated adverse effects.

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Concomitant use of fosamprenavir (without low-dose ritonavir) and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir may result in increased concentrations of paritaprevir and amprenavir. Concomitant use of ritonavir-boosted fosamprenavir and ombitasvir/paritaprevir/ritonavir with dasabuvir is expected to increase paritaprevir concentrations and may increase amprenavir concentrations.

Appropriate dosage adjustments have not been established. The manufacturer of fosamprenavir states that if fosamprenavir (without low-dose ritonavir) is used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, a dosage of fosamprenavir 1.4 g once daily may be considered. Concomitant use of ritonavir-boosted fosamprenavir and ombitasvir/paritaprevir/ritonavir with dasabuvir is not recommended.

HMG-CoA Reductase Inhibitors

Pharmacokinetic interactions with HMG-CoA reductase inhibitors (statins) metabolized by CYP3A isoenzyme. Concomitant use of fosamprenavir or ritonavir-boosted fosamprenavir and certain statins (e.g., atorvastatin, lovastatin, simvastatin) may increase plasma concentrations and AUC of the antilipemic agent and increase the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.

Atorvastatin

If atorvastatin is used concomitantly with fosamprenavir (with or without low-dose ritonavir), atorvastatin dosage should not exceed 20 mg daily. Atorvastatin dosage should be titrated carefully; the lowest necessary dosage should be used and the patient monitored for adverse effects.

Lovastatin

Concomitant use of lovastatin with fosamprenavir (with or without low-dose ritonavir) is contraindicated.

Pitavastatin

Dosage adjustments are not necessary if pitavastatin is used concomitantly with fosamprenavir (with or without low-dose ritonavir).

Rosuvastatin

Dosage adjustments are not necessary if rosuvastatin is used concomitantly with fosamprenavir (with or without low-dose ritonavir).

Simvastatin

Concomitant use of simvastatin with fosamprenavir (with or without low-dose ritonavir) is contraindicated.

Immunosuppressive Agents

Pharmacokinetic interaction with cyclosporine, everolimus, sirolimus, or tacrolimus expected (increased concentrations of the immunosuppressive agent).

If fosamprenavir (with or without low-dose ritonavir) is used concomitantly with cyclosporine, everolimus, sirolimus, or tacrolimus, plasma concentrations of the immunosuppressive agent should be monitored. Some experts state that the immunosuppressive agent should be initiated with an adjusted dosage to account for potential increased concentrations of the drug and the patient should be monitored for toxicities. A specialist should be consulted if necessary.

Ivabradine

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with ivabradine (increased ivabradine concentrations).

Some experts state that concomitant use of fosamprenavir (with or without low-dose ritonavir) and ivabradine is contraindicated.

Macrolides

Clarithromycin

Studies using amprenavir indicate possible pharmacokinetic interaction (slightly increased amprenavir concentrations and AUC, slightly decreased clarithromycin concentrations). Some experts state that dosage adjustments are not necessary if fosamprenavir (without low-dose ritonavir) is used concomitantly with clarithromycin.

Concomitant use of ritonavir-boosted fosamprenavir and clarithromycin may result in increased clarithromycin concentrations. An alternative macrolide (e.g., azithromycin) should be considered in patients receiving ritonavir-boosted fosamprenavir; if the drugs are used concomitantly, patients should be monitored for clarithromycin-related toxicities. If used concomitantly in patients with renal impairment, some experts state that clarithromycin dosage should be reduced by 50% in those with creatinine clearances of 30-60 mL/minute and reduced by 75% in those with a creatinine clearances less than 30 mL/minute.

Opiates and Opiate Partial Agonists

Buprenorphine

No clinically important pharmacokinetic interactions with buprenorphine.

Dosage adjustments are not necessary if buprenorphine is used concomitantly with ritonavir-boosted fosamprenavir, but clinical monitoring is recommended. If the route of buprenorphine administration is changed from transmucosal to subdermal implantation, the patient should be monitored to ensure that the effect of buprenorphine is adequate and not excessive.

Methadone

Studies using amprenavir indicate pharmacokinetic interaction with methadone (decreased concentrations of amprenavir and methadone).

Concomitant use of methadone with ritonavir-boosted fosamprenavir results in decreased plasma concentrations of methadone and no change in plasma concentrations of amprenavir. Opiate withdrawal is unlikely, but may occur. Patients should be monitored for opiate withdrawal and methadone dosage increased as clinically indicated.

Phosphodiesterase Type 5 Inhibitors

Concomitant use of fosamprenavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, 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.

Avanafil

If avanafil is used for treatment of erectile dysfunction in patients receiving fosamprenavir (without low-dose ritonavir), avanafil dosage should not exceed 50 mg once every 24 hours. Concomitant use of ritonavir-boosted fosamprenavir and avanafil is not recommended.

Sildenafil

Concomitant use of fosamprenavir (with or without low-dose ritonavir) is contraindicated in patients receiving sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH). Safe and effective dosages for concomitant use of the drugs have not been established.

If sildenafil is used for treatment of erectile dysfunction in patients receiving fosamprenavir (with or without low-dose ritonavir), sildenafil dosage should not exceed 25 mg once every 48 hours, and the patient should be closely monitored for adverse sildenafil-related effects.

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. Fosamprenavir (with or without low-dose ritonavir) should not be initiated in patients receiving tadalafil for treatment of PAH; tadalafil therapy should be discontinued for at least 24 hours prior to initiating fosamprenavir. 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.

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, and the patient should be closely monitored for tadalafil-related adverse effects.

If tadalafil is used for treatment of benign prostatic hyperplasia in patients receiving fosamprenavir (with or without low-dose ritonavir), tadalafil dosage should not exceed 2.5 mg once daily.

Vardenafil

If vardenafil is used for treatment of erectile dysfunction in patients receiving fosamprenavir (with or without low-dose ritonavir), vardenafil dosage should not exceed 2.5 mg once every 72 hours.

Salmeterol

Possible pharmacokinetic interaction if salmeterol is used concomitantly with fosamprenavir (increased salmeterol concentrations); increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia. Concomitant use of salmeterol and fosamprenavir is not recommended.

Selective Serotonin-reuptake Inhibitors

Concomitant use of paroxetine with ritonavir-boosted fosamprenavir results in decreased plasma concentrations of paroxetine. Dosage of the SSRI should be titrated based on clinical response and tolerability.

Suvorexant

Pharmacokinetic interaction expected if fosamprenavir (with or without low-dose ritonavir) is used concomitantly with suvorexant (increased suvorexant concentrations). Some experts state that concomitant use is not recommended.

Trazodone

Concomitant use of trazodone with fosamprenavir (with or without low-dose ritonavir) may result in increased plasma concentrations of trazodone. Caution is advised, and a lower trazodone dosage should be considered. Some experts recommend that the lowest effective dosage of trazodone be used and patients monitored for adverse CNS and cardiovascular effects.

Tricyclic Antidepressants

Potential pharmacokinetic interaction with amitriptyline, desipramine, imipramine, or nortriptyline (increased plasma concentrations of the tricyclic antidepressant). Plasma concentrations of these antidepressants should be monitored if used concomitantly with fosamprenavir.

Some experts recommend that the lowest possible dosage of tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) be used in patients receiving ritonavir-boosted fosamprenavir and that dosage of the antidepressant be titrated based on clinical assessment and/or plasma antidepressant concentrations.

Zolpidem

Potential pharmacokinetic interactions if zolpidem is used concomitantly with ritonavir-boosted fosamprenavir (increased zolpidem concentrations).

If zolpidem is used concomitantly with ritonavir-boosted fosamprenavir, some experts state that zolpidem should be initiated using a low dosage and dosage reduction may be needed.

Dietary and Herbal Supplements

St. John's Wort (Hypericum perforatum)

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

Pharmacokinetics

Absorption

Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US).

The absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium has not been established. Peak amprenavir concentrations are attained 1.5-4 hours after administration of the prodrug.

When a single 1.4-g dose of fosamprenavir is administered on an empty stomach as tablets or the oral suspension, amprenavir exposure (area under the concentration-time curve; AUC) is similar, but peak amprenavir concentrations are 14.5% higher with the suspension compared with the tablet.

Food

Administration of fosamprenavir calcium tablets with food has no effect on bioavailability of amprenavir.

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.

Distribution

Amprenavir crosses the placenta and is distributed into milk in animals. It is not known whether the drug crosses the human placenta or is distributed into human milk.

In vitro studies indicate amprenavir is 90% bound to plasma proteins, primarily to α1-acid glycoprotein.

Elimination

Following oral administration, fosamprenavir calcium is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate in the intestinal epithelium during absorption.

Amprenavir is metabolized in the liver principally by cytochrome P-450 (CYP) isoenzyme 3A4.

About 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.

The elimination half-life of amprenavir is approximately 7.7 hours.

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

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

The pharmacokinetics of fosamprenavir were studied in pediatric patients 2-5 years of age receiving fosamprenavir 30 mg/kg twice daily, in those 6-11 years of age receiving fosamprenavir 18 mg/kg and ritonavir 3 mg/kg twice daily, and in those 12-18 years of age receiving fosamprenavir 700 mg and ritonavir 100 mg twice daily.

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