Fosamprenavir Calcium (Monograph)
Brand name: Lexiva
Drug class: HIV Protease Inhibitors
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.
Weight (kg) |
Fosamprenavir Dosage (Oral Suspension) |
Ritonavir Dosage |
---|---|---|
<11 |
45 mg/kg twice daily |
7 mg/kg twice daily |
11 to <15 |
30 mg/kg twice daily |
3 mg/kg twice daily |
15 to <20 |
23 mg/kg twice daily |
3 mg/kg twice daily |
≥20 |
18 mg/kg twice daily |
3 mg/kg twice daily |
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.
Weight (kg) |
Fosamprenavir Dosage (Oral Suspension) |
Ritonavir Dosage |
---|---|---|
<11 |
45 mg/kg twice daily |
7 mg/kg twice daily |
11 to <15 |
30 mg/kg twice daily |
3 mg/kg twice daily |
15 to <20 |
23 mg/kg twice daily |
3 mg/kg twice daily |
≥20 |
18 mg/kg twice daily |
3 mg/kg twice daily |
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
Drug |
Interaction |
Comments |
---|---|---|
Abacavir |
Studies using amprenavir indicate pharmacokinetic interaction unlikely1 No in vitro evidence of antagonistic antiretroviral effects1 |
|
Alfuzosin |
Potential for increased alfuzosin concentrations that could result in hypotension1 |
Concomitant use with fosamprenavir contraindicated1 |
Antacids containing aluminum hydroxide/ magnesium hydroxide |
Decreased amprenavir concentrations1 |
Use with caution when administered at the same time; staggered coadministration not evaluated1 |
Antiarrhythmic agents (amiodarone, disopyramide, flecainide, systemic lidocaine, propafenone, quinidine) |
Possible increased antiarrhythmic agent concentrations1 Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if ritonavir-boosted fosamprenavir used in patients receiving flecainide or propafenone1 |
In patients receiving ritonavir-boostedfosamprenavir, concomitant use with flecainide or propafenone contraindicated1 Caution if fosamprenavir used concomitantly with amiodarone, disopyramide, systemic lidocaine, or quinidine; antiarrhythmic concentration monitoring recommended, if available1 |
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) |
Carbamazepine, phenobarbital, phenytoin: Possible decreased amprenavir concentrations with unboosted fosamprenavir; potential for decreased fosamprenavir efficacy1 Phenytoin: Increased amprenavir concentrations and decreased phenytoin concentrations when used with ritonavir-boosted fosamprenavir1 |
Carbamazepine, phenobarbital, phenytoin: Use concomitantly with caution1 Phenytoin: Usual dosages of ritonavir-boosted fosamprenavir may be used, but monitor phenytoin concentrations and increase phenytoin dosage as needed1 |
Antifungals, azoles (itraconazole, ketoconazole) |
Itraconazole, ketoconazole: Possible increased antifungal concentrations1 |
Itraconazole, ketoconazole: Increase monitoring for adverse effects1 In patients receiving fosamprenavir (without low-dose ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of itraconazole or ketoconazole daily; in those receiving ritonavir-boosted fosamprenavir, high doses of itraconazole or ketoconazole (>200 mg daily) not recommended1 |
Antimycobacterials (rifabutin, rifampin) |
Rifabutin: 150 mg every other day with ritonavir-boosted fosamprenavir results in increased amprenavir concentrations and increased rifabutin metabolite concentrations compared with rifabutin 300 mg daily alone1 Rifampin: Studies using amprenavir indicate decreased amprenavir concentrations; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1 |
Rifabutin: If fosamprenavir (without low-dose ritonavir) used with rifabutin, reduce rifabutin dosage by at least 50% of the recommended dose; if ritonavir-boostedfosamprenavir used with rifabutin, reduce rifabutin dosage by at least 75% of the usual dosage of 300 mg daily (maximum dosage of 150 mg once every other day or 3 times weekly); monitor for neutropenia by performing CBCs weekly and as clinically indicated1 Rifampin: Concomitant use contraindicated (because of potential loss of virologic response and possible resistance to fosamprenavir or to other protease inhibitors [PIs])1 |
Antineoplastic agents (dasatinib, nilotinib, ibrutinib, vinblastine, everolimus) |
Dasatinib, nilotinib, ibrutinib, vinblastine, everolimus: Increased concentrations of the antineoplastic agent and potentially increased risk of adverse events1 |
If coadministration necessary, consult prescribing information for the antineoplastic drug1 |
Antipsychotics (lurasidone, pimozide, quetiapine) |
Lurasidone: Possible increased lurasidone concentrations; potential for serious and/or life-threatening adverse effects if used concomitantly with ritonavir-boosted fosamprenavir1 Pimozide: Possible increased pimozide concentrations; potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1 Quetiapine: Increased quetiapine concentrations expected1 |
Lurasidone: Concomitant use with ritonavir-boosted fosamprenavir contraindicated; if concomitant use with unboosted fosamprenavir necessary, reduce lurasidone dosage1 Pimozide: Concomitant use contraindicated1 Quetiapine: If possible, consider alternative antiretroviral therapy to avoid increases in quetiapine exposures; if initiating fosamprenavir (with ritonavir) in patient receiving quetiapine, reduce quetiapine to one-sixth of original dosage; monitor for adverse effects of quetiapine; if quetiapine is initiated in a patient taking fosamprenavir (with ritonavir), refer to the quetiapine prescribing information for initial dosage and titration1 |
Atazanavir |
Ritonavir-boosted fosamprenavir: Decreased atazanavir concentrations; no change in amprenavir concentrations1 Fosamprenavir (without low-dose ritonavir): No data1 In vitro evidence of synergistic antiretroviral effects1 |
Fosamprenavir (with or without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established1 |
Benzodiazepines (alprazolam, clorazepate, diazepam, flurazepam, midazolam, triazolam) |
Midazolam or triazolam: Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening adverse reactions (e.g., prolonged or increased sedation or respiratory depression)1 Alprazolam, clorazepate, diazepam, flurazepam: Possible increased benzodiazepine concentrations1 |
Midazolam or triazolam: Concomitant use contraindicated1 Alprazolam, clorazepate, diazepam, flurazepam: Clinical importance of pharmacokinetic interaction unknown; a decrease in benzodiazepine dosage may be needed1 |
Bosentan |
Increased bosentan concentrations1 |
In patients already receiving fosamprenavir for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 In patients already receiving bosentan, discontinue bosentan for ≥36 hours prior to initiating fosamprenavir; after ≥10 days of fosamprenavir, resume bosentan at a dosage of 62.5 mg once daily or every other day based on individual tolerability1 |
Calcium-channel blocking agents (diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine) |
Possible increased concentrations of calcium-channel blocking agent1 |
Use concomitantly with caution; clinical monitoring recommended1 |
Cisapride |
Possible increased cisapride concentrations; potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias)1 |
Concomitant use contraindicated1 |
Clarithromycin |
Studies using amprenavir indicate increased amprenavir concentrations and slightly decreased clarithromycin concentrations1 |
|
Colchicine |
Increased colchicine concentrations1 |
Patients with renal or hepatic impairment: Concomitant use of colchicine and ritonavir-boosted fosamprenavir not recommended1 Colchicine for treatment of gout flares: In those receiving ritonavir-boosted fosamprenavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later; in those receiving fosamprenavir (without low-dose ritonavir), use initial colchicine dose of 1.2 mg and repeat dose no earlier than 3 days later1 Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boostedfosamprenavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 once daily; in those receiving fosamprenavir (without low-dose ritonavir), decrease colchicine dosage to 0.3 mg twice daily or 0.6 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once daily in those originally receiving 0.6 mg once daily1 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted fosamprenavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily); in those receiving fosamprenavir (without low-dose ritonavir), use maximum colchicine dosage of 1.2 mg daily (may be given as 0.6 mg twice daily)1 |
Corticosteroids (dexamethasone, fluticasone) |
Fluticasone (orally inhaled, intranasal): Increased fluticasone concentrations1 Dexamethasone: Possible decreased amprenavir concentrations and decreased antiretroviral efficacy1 |
Fluticasone (orally inhaled, intranasal): May significantly reduce serum cortisol concentrations; adrenal insufficiency and Cushing's syndrome reported; do not use concomitantly unless potential benefits of inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects; consider alternative, especially when long-term corticosteroid use anticipated1 Dexamethasone (systemic): Use concomitantly with caution1 |
Delavirdine |
Increased amprenavir concentrations and decreased delavirdine concentrations; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1 No in vitro evidence of antagonistic antiretroviral effects1 |
Concomitant use contraindicated1 |
Didanosine |
No in vitro evidence of antagonistic antiretroviral effects1 |
Drug |
Interaction |
Comments |
---|---|---|
Dolutegravir |
Decreased dolutegravir concentrations1 |
Ritonavir-boosted fosamprenavir: Use dolutegravir 50 mg twice daily; in patients with documented or suspected integrase inhibitor (INSTI) resistance, consider alternative whenever possible1 |
Efavirenz |
Decreased amprenavir concentrations if used with fosamprenavir (with or without low-dose ritonavir)1 No in vitro evidence of antagonistic antiretroviral effects1 |
Fosamprenavir (without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established1 Ritonavir-boosted fosamprenavir once daily: An additional 100 mg per day of ritonavir (300 mg total) recommended with coadministration of efavirenz1 |
Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) |
Possible increased concentrations of ergot derivatives and potential for serious and/or life-threatening adverse reactions such as acute ergot toxicity (peripheral vasospasm and ischemia of the extremities and other tissues)1 |
Concomitant use contraindicated1 |
Estrogens/progestins |
Hormonal contraceptive containing ethinyl estradiol with norethindrone: Decreased ethinyl estradiol concentrations (with or without ritonavir); decreased amprenavir concentrations (with ritonavir-boosted fosamprenavir)1 Possible loss of virologic response; increased risk of transaminase elevations1 |
Hormonal contraceptives: Consider alternative methods of nonhormonal contraception1 |
Fentanyl |
Increased fentanyl concentrations1 |
Carefully monitor therapeutic effects and adverse effects of fentanyl (e.g., potentially fatal respiratory depression)1 |
Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine) |
Decreased amprenavir plasma concentrations when used concomitantly with unboosted fosamprenavir; possible decreased antiretroviral efficacy1 |
Use concomitantly with caution1 |
HMG-CoA reductase inhibitors (statins) |
Atorvastatin, lovastatin, simvastatin: Increased concentrations of the statin; increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 |
Atorvastatin: Do not exceed atorvastatin dosage of 20 mg daily; carefully titrate atorvastatin dosage; use lowest necessary dosage1 Lovastatin: Concomitant use with fosamprenavir contraindicated1 Simvastatin: Concomitant use with fosamprenavir contraindicated1 |
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus) |
Increased concentrations of immunosuppressive agent1 |
Monitor immunosuppressive agent concentrations1 |
Lamivudine |
Studies using amprenavir indicate no evidence of pharmacokinetic interaction1 No in vitro evidence of antagonistic antiretroviral effects1 |
|
Lomitapide |
Increased lomitapide concentrations1 |
Concomitant use contraindicated (potential for significantly increased transaminases)1 |
Lopinavir/ritonavir |
Decreased amprenavir and lopinavir concentrations; increased incidence of adverse effects reported1 In vitro evidence of additive antiretroviral effects1 |
Appropriate dosages for concomitant use with respect to safety and efficacy not established1 |
Maraviroc |
Increased maraviroc concentrations; decreased amprenavir concentrations1 |
Recommended maraviroc dosage during concurrent use is 150 mg twice daily with usual dosage of ritonavir-boosted fosamprenavir; do not use unboosted fosamprenavir1 |
Methadone |
Decreased methadone concentrations1 |
Data indicate interaction not clinically important; monitor for opiate withdrawal symptoms1 |
Nelfinavir |
Increased plasma amprenavir concentrations with concomitant use of fosamprenavir (without ritonavir) and nelfinavir; concomitant use of ritonavir-boostedfosamprenavir and nelfinavir not evaluated1 No in vitro evidence of antagonistic antiretroviral effects1 |
Appropriate dosages for concomitant use with respect to safety and efficacy not established1 |
Nevirapine |
Decreased amprenavir concentrations and increased nevirapine concentrations1 Ritonavir-boosted fosamprenavir (once-daily regimen): Concomitant use with nevirapine not studied1 No in vitro evidence of antagonistic antiretroviral effects1 |
Fosamprenavir (without low-dose ritonavir): Concomitant use not recommended1 No dosage adjustment required when nevirapine is administered with fosamprenavir plus ritonavir twice daily1 |
Paroxetine |
Decreased paroxetine concentrations1 |
Adjust paroxetine dosage based on clinical response and tolerability1 |
Drug |
Interaction |
Comments |
---|---|---|
Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) |
Esomeprazole: When used with fosamprenavir (without low-dose ritonavir), no change in amprenavir concentrations, and increased esomeprazole concentration; when used with ritonavir-boosted fosamprenavir, clinically important pharmacokinetic interaction unlikely1 |
Proton-pump inhibitors can be administered at the same time as fosamprenavir with no change in plasma amprenavir concentrations1 |
Raltegravir |
Fosamprenavir (with or without low-dose ritonavir): Decreased concentrations of raltegravir and amprenavir1 |
Fosamprenavir (with or without low-dose ritonavir): Appropriate dosage for concomitant use with respect to safety and efficacy not established1 |
St. John’s wort (Hypericum perforatum) |
Possible decreased amprenavir concentrations; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1 |
Concomitant use contraindicated1 |
Salmeterol |
Possible increased salmeterol concentrations and increased risk of salmeterol-associated adverse cardiovascular effects, including QT-interval prolongation, palpitations, and sinus tachycardia1 |
Concomitant use not recommended1 |
Saquinavir |
Decreased amprenavir concentrations with concomitant use of fosamprenavir (without ritonavir) and saquinavir; concomitant use of ritonavir-boosted fosamprenavir and saquinavir not evaluated1 No in vitro evidence of antagonistic antiretroviral effects1 |
Appropriate dosages for concomitant use with respect to safety and efficacy not established1 |
Sildenafil |
Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism)1 |
Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated; safe and effective dosages for concomitant use not established1 Sildenafil for treatment of erectile dysfunction: If used concomitantly with fosamprenavir (with or without low-dose ritonavir), a sildenafil dosage of 25 mg once every 48 hours is recommended; closely monitor for sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism)1 |
Tadalafil |
Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism)1 |
If tadalafil (Adcirca) is initiated for treatment of PAH in patients who have been receiving fosamprenavir (with or without low-dose ritonavir) for ≥1 week, use initial tadalafil dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily1 If fosamprenavir (with or without low-dose ritonavir) is indicated in patient already receiving tadalafil (Adcirca) for treatment of PAH, discontinue tadalafil for ≥24 hours prior to initiating fosamprenavir; after ≥1 week of the antiretroviral agent, resume tadalafil at dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily1 If tadalafil is used for treatment of erectile dysfunction in patients already receiving fosamprenavir (with or without low-dose ritonavir), do not exceed tadalafil dosage of 10 mg once every 72 hours and closely monitor for tadalafil-related adverse effects (e.g., hypotension, syncope, visual disturbances, priapism, syncope)1 |
Tenofovir |
No change in amprenavir concentrations with ritonavir-boosted fosamprenavir1 No in vitro evidence of antagonistic antiretroviral effects1 |
|
Trazodone |
Possible increased trazodone concentrations1 Increased risk of trazodone-associated adverse effects1 |
Use concomitantly with caution; consider reduced trazodone dosage1 |
Tricyclic antidepressants (amitriptyline, imipramine) |
Amitriptyline, imipramine: Possible increased concentrations of the tricyclic antidepressant1 |
Monitor plasma concentrations of the tricyclic antidepressant during concurrent use1 |
Vardenafil |
Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism)1 |
If ritonavir-boosted fosamprenavir is used in patients receiving vardenafil for treatment of erectile dysfunction, do not exceed vardenafil dosage of 2.5 mg once every 72 hours; if unboosted fosamprenavir is used in patients receiving vardenafil for treatment of erectile dysfunction, do not exceed vardenafil dosage of 2.5 mg once every 24 hours; closely monitor for vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism)1 |
Warfarin |
Possible altered warfarin concentrations1 |
Monitor INR1 |
Zidovudine |
Studies using amprenavir indicate possible increased amprenavir AUC; possible increased zidovudine plasma concentrations and AUC1 No in vitro evidence of antagonistic antiretroviral effects1 |
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
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Suspension |
50 mg (of fosamprenavir) per mL |
Lexiva |
Viiv |
Tablets, film-coated |
700 mg (of fosamprenavir)* |
Fosamprenavir Calcium Tablets |
||
Lexiva |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
1. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2020 Oct.
5. Rodriguez-French A, Boghossian J, Gray GE. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;35:22-32.
6. Gathe JC, I've P, Wood R. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. 2004;18:1529-37
186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2024 May 13. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm
199. Kuhar DT, Henderson DK, Struble KA. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013;34:875-92.
200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. https://clinicalinfo.hiv.gov/en/guidelines
201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov website. https://clinicalinfo.hiv.gov/en/guidelines
202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2024). Updates may be available at HIV.gov website. https://clinicalinfo.hiv.gov/en/guidelines
300. Fortuny C, Duiculescu D, Cheng K, et al. Pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old children. Pediatr Infect Dis J. 2014;33:50-56.
301. Cotton M, Cassim H, Pavia-Ruz N, et al. Pharmakinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 2 years—48-week study data. Pediatr Infect Dis J. 2014;33:57-62.
302. Eron J, Yeni P, Gathe J, et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet. 2006;368:476-482.
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