Fosamprenavir Calcium (Monograph)

Brand name: Lexiva
Drug class: HIV Protease Inhibitors

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

Introduction

Antiretroviral; HIV protease inhibitor (PI).¹

Uses for Fosamprenavir Calcium

Treatment of HIV Infection

Treatment of HIV-1 infection; used in conjunction with other antiretrovirals in adult and pediatric patients.¹

Used in conjunction with low-dose ritonavir (ritonavir-boosted fosamprenavir) or without low-dose ritonavir (unboosted fosamprenavir).¹

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}

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Recommended as an alternative regimen in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and other individuals only after expert consultation.¹⁹⁹

USPHS recommends a 3-drug regimen of raltegravir and emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as preferred regimen for PEP following occupational exposures to HIV.¹⁹⁹ Fosamprenavir (with or without low-dose ritonavir) and 2 NRTIs can be considered an alternative regimen, but use for PEP only with expert consultation.¹⁹⁹ Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF; alternatives are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.¹⁹⁹

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.¹⁹⁹ Do not delay initiation of PEP while waiting for expert consultation.¹⁹⁹

Fosamprenavir Calcium Dosage and Administration

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

Administer orally with low-dose ritonavir (ritonavir-boosted fosamprenavir) or without low-dose ritonavir (unboosted fosamprenavir).¹

Administered as oral suspension or tablets.¹

Oral Suspension

Pediatric patients: Take with food.¹

Adults: Take without food.¹

If vomiting occurs soon after a dose of the oral suspension (within 30 minutes), repeat dose.¹

Taste of the suspension can be improved by refrigeration.¹

Shake vigorously prior to each dose.¹

Tablets

Take with or without food.¹

Dosage

Available as fosamprenavir calcium; dosage expressed in terms of fosamprenavir.¹

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

Pediatric Patients

Children 4 weeks to 18 years of age: Dosage is based on weight.¹ Do not exceed 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

Do not use once-daily regimens (with or without low-dose ritonavir) in pediatric patients.¹

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

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

Treatment of HIV Infection

Oral

PI-naïve infants and children ≥4 weeks of age (oral suspension): Twice-daily regimen with low-dose ritonavir.¹ See Table 1.

Alternatively, PI-naïve pediatric patients ≥2 years of age (oral suspension): 30 mg/kg twice daily (without low-dose ritonavir).¹

PI-naïve pediatric patients weighing ≥47 kg (tablets): 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

Oral

PI-experienced pediatric patients ≥6 months of age (oral suspension): Twice-daily regimen with low-dose ritonavir.¹ See Table 2.

PI-experienced pediatric patients weighing ≥47 kg (tablets): 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

Adults

Treatment of HIV Infection

Oral

Antiretroviral-naïve: 1400 mg twice daily (without low-dose ritonavir).¹

1400 mg once daily with low-dose ritonavir (100 or 200 mg once daily).¹

Alternatively, 700 mg twice daily with low-dose ritonavir (100 mg twice daily).¹

Oral

Protease inhibitor (PI)-experienced: 700 mg twice daily with low-dose ritonavir (100 mg twice daily).¹ Once-daily ritonavir-boosted fosamprenavir regimens not recommended.¹

Oral

Pregnant adults: 700 mg twice daily with low-dose ritonavir (100 mg twice daily).¹ Consider this regimen only in pregnant patients already on a stable twice-daily regimen of fosamprenavir 700 mg and ritonavir 100 mg prior to pregnancy who are virologically suppressed (HIV-1 RNA <50 copies per mL).¹

Closely monitor viral load to ensure viral suppression is maintained.¹

Postexposure Prophylaxis following Occupational Exposure to HIV† [off-label] (PEP)

Oral

1400 mg once daily with low-dose ritonavir (100 mg once daily).¹⁹⁹ Alternatively, 1400 mg twice daily (without low-dose ritonavir).¹⁹⁹

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.¹⁹⁹

Special Populations

Hepatic Impairment

Fosamprenavir (with or without low-dose ritonavir): Use with caution in patients with hepatic impairment.¹ Dosage reductions necessary in adults; data not available to support dosage recommendations for pediatric patients with hepatic impairment.¹

Mild hepatic impairment (Child-Pugh score 5–6): In antiretroviral-naïve adults, fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 700 mg twice daily (without ritonavir).¹ In PI-experienced adults, fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Moderate hepatic impairment (Child-Pugh score 7–9): In antiretroviral-naïve adults, fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 700 mg twice daily (without ritonavir).¹ In PI-experienced adults, fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Severe hepatic impairment (Child-Pugh score 10–15): In antiretroviral-naïve adults, fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily) or fosamprenavir 350 mg twice daily (without ritonavir).¹ In PI-experienced adults, fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Renal Impairment

No specific dosage recommendations at this time.¹

Geriatric Patients

No specific dosage recommendations at this time.¹ Select dosage with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Fosamprenavir Calcium

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 CYP3A4 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

Rash (usually maculopapular and of mild to moderate intensity, with or without pruritus) reported.¹ Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, reported rarely.¹

Discontinue fosamprenavir if severe or life-threatening rash or moderate rash accompanied by systemic symptoms occurs.¹

Sulfa Allergy

Because fosamprenavir contains a sulfonamide moiety, use with caution in patients with known sulfonamide allergy.¹ Potential for cross-sensitivity between sulfonamide drugs and fosamprenavir unknown.¹

Drug Interactions

When ritonavir-boosted fosamprenavir is used, the usual cautions, precautions, and contraindications associated with ritonavir should be considered.¹ Serious, life-threatening, or fatal drug interactions or loss of virologic effect and possible development of resistance can occur with drugs that inhibit or induce CYP3A.¹

Consider potential for drug interactions prior to and during ritonavir-boosted fosamprenavir therapy; review all drugs patient is receiving and monitor for adverse effects.¹

Hepatic Toxicity

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

HIV-infected patients with HBV or HCV coinfection or marked elevations in transaminases prior to fosamprenavir therapy may be at increased risk for developing or worsening of transaminase elevations.¹

Perform appropriate laboratory tests to evaluate hepatic function prior to initiating fosamprenavir and monitor patients closely during treatment.¹

Diabetes and Hyperglycemia

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of protease inhibitors (PIs); diabetic ketoacidosis also occurred in some cases.¹

Initiate or adjust dosage of insulin or oral hypoglycemic agents for treatment of these events as needed.¹

Causal relationships between therapy with PIs and these events not established.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to combination antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex, M. tuberculosis, cytomegalovirus, Pneumocystis jirovecii); this is called immune reconstitution syndrome and may necessitate further evaluation and treatment.¹

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution; however, 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 reported.¹ Mechanism and long-term consequences unknown; causal relationship not established.¹

Lipid Elevations

Increases in triglyceride and cholesterol concentrations have occurred with ritonavir-boosted fosamprenavir.¹

Determine serum triglyceride and cholesterol concentrations prior to initiating fosamprenavir and periodically monitor during therapy; manage lipid disorders as clinically appropriate.¹

Hemolytic Anemia

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

Hemophilia A and B

Spontaneous bleeding reported in some patients with hemophilia A or B treated with PIs; causal relationship not established.¹

Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.¹ Treatment with PIs continued or restarted in many of the reported cases.¹

Nephrolithiasis

Nephrolithiasis 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 in patients treated with fosamprenavir.¹ The possible effect of fosamprenavir therapy on subsequent therapy with other PIs unknown.¹

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry (APR) at 800-258-4263 or [Web].^{1 202}

Limited data on use of fosamprenavir in pregnancy.¹ Data insufficient to adequately assess risk of birth defects and miscarriage.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

Consider use of ritonavir-boosted fosamprenavir only in pregnant patients already on a stable twice-daily regimen of fosamprenavir 700 mg and ritonavir 100 mg prior to pregnancy who are virologically suppressed (HIV-1 RNA <50 copies per mL).¹ Closely monitor viral load to ensure viral suppression is maintained.¹

Safety, efficacy, and pharmacokinetics of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily studied in a clinical trial of pregnant women infected with HIV type 1 (HIV-1).¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Unknown whether affects human milk production or breast-fed infant.¹

Per HHS perinatal HIV transmission guideline, inform patients that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates postnatal HIV transmission risk to the infant.²⁰² Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces risk of breastfeeding HIV transmission to <1%, but not does not completely eliminate 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

May reduce the efficacy of combined hormonal contraceptives.¹ Advise patients to use an effective alternative contraceptive method or additional barrier method.¹

Pediatric Use

Studies have evaluated 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 not established in PI-naïve pediatric patients <4 weeks of age.¹ Treatment with fosamprenavir not recommended in PI-experienced pediatric patients <6 months of age.¹

Do notuse once-daily regimen (with or without low-dose ritonavir) in pediatric patients.¹

Do not use twice-daily regimen (without low-dose ritonavir) in pediatric patients <2 years of age.¹

Geriatric Use

Insufficient experience in those ≥65 years of age 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 concomitant disease and drug therapy.¹

Hepatic Impairment

Use with caution because amprenavir concentrations may be increased; assess hepatic function prior to and periodically during therapy.¹

Dosage reduction necessary in adults with hepatic impairment (Child-Pugh score of 5 or greater); data not available to support dosage recommendations for pediatric patients with hepatic impairment.¹

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

Renal Impairment

Pharmacokinetics not studied in in renal impairment; renal impairment not expected to have a clinically important effect on pharmacokinetics.¹

Common Adverse Effects

Most common adverse effects (incidence ≥4%) in adults: Diarrhea, nausea, vomiting, headache, rash.¹ Vomiting and neutropenia were reported more frequently in pediatric patients compared to adults.¹

Drug Interactions

Amprenavir (active metabolite of fosamprenavir) is metabolized by CYP3A4.¹

Amprenavir inhibits CYP3A4 and also may induce CYP3A4.¹

Amprenavir does not inhibit CYP2D6, 1A2, 2C9, 2C19, or 2E1, or uridine glucuronosyltransferase (UDPGT).¹

Some interaction studies have been performed using fosamprenavir.¹ These studies may not predict magnitude of interaction with ritonavir-boosted fosamprenavir.¹

Since fosamprenavir is metabolized to amprenavir, interactions reported with amprenavir (no longer commercially available in the US) also apply to fosamprenavir.¹

When fosamprenavir is used with low-dose ritonavir, consider interactions reported with low-dose ritonavir.¹ Refer to the full prescribing for ritonavir for specific information.

Ritonavir is a potent CYP2D6 inhibitor.¹ Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 with possible alteration in metabolism of amprenavir and/or the other drug.¹

Drugs Affecting or Affected by P-glycoprotein Transport

Amprenavir is a substrate of and an inducer of P-glycoprotein (P-gp) transport system.¹

Specific Drugs

Fosamprenavir Calcium Pharmacokinetics

Absorption

Bioavailability

Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US).¹

Absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium has not been established; peak amprenavir concentrations attained 1.5–4 hours after administration of the prodrug.¹

When a single 1.4-g dose 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

Food

Fosamprenavir tablets: Administration of with food has no effect on bioavailability of amprenavir.¹

Fosamprenavir suspension: Administration 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 AUC by 28% compared with administration in the fasting state.¹

Distribution

Extent

Amprenavir is distributed into milk in animals.¹ Not known whether drug is distributed into human milk.¹

Plasma Protein Binding

90% bound to plasma proteins, primarily to α₁-acid glycoprotein.¹

Elimination

Metabolism

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 liver principally by CYP3A4.¹

Elimination Route

About 14% of a single oral dose excreted in urine and 75% eliminated in feces as metabolites.¹ Only minimal amounts of unchanged amprenavir are eliminated in urine or feces.¹

Half-life

Amprenavir elimination half-life is approximately 7.7 hours.¹

Special Populations

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

Pharmacokinetics not studied to date in adults with impaired renal function, but renal impairment not expected to have a clinically important effect on pharmacokinetics.¹

Pharmacokinetics of fosamprenavir 700 mg twice daily in combination with ritonavir 100 mg twice daily studied in pregnant women; total amprenavir exposures (AUC) were lower during pregnancy compared with postpartum period.¹

Pharmacokinetics of fosamprenavir (with and without ritonavir) studied in PI-naïve and PI-experienced pediatric patients 4 weeks to <18 years of age and weighing ≥3 kg.¹

Stability

Storage

Oral

Suspension

5–30°C; avoid freezing.¹

Tablets

Tightly closed container at 25°C (excursions permitted to 15–30°C).¹

Actions

• Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US) and has little or no antiretroviral activity until hydrolyzed in vivo to amprenavir.¹

• Amprenavir, a protease inhibitor (PI), inhibits replication of HIV type 1 (HIV-1) by interfering with HIV protease.¹

• HIV-1 strains with reduced susceptibility to amprenavir were selected in vitro and have emerged during therapy with fosamprenavir.¹

• Varying degrees of cross-resistance occur among PIs; only limited data available to date regarding cross-resistance between amprenavir and other PIs.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 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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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