Fosamprenavir Calcium

Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: C-[(3S)-tetrahydro-3-furanyl] ester [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)-2-(phosphonooxy)propyl] carbamic acid disodium salt
Molecular Formula: C₂₅H₃₄N₃Na₂O₉PS
CAS Number: 226700-80-7
Brands: Lexiva

Introduction

Antiretroviral; HIV protease inhibitor (PI).¹

Uses for Fosamprenavir Calcium

Treatment of HIV Infection

Treatment of HIV infection in conjunction with other antiretrovirals.¹

Usually used in PI-based regimens that include a PI and 2 nucleoside reverse transcriptase inhibitors (NRTIs).^{1 3 4}

For initial treatment in HIV-infected adults and adolescents who are treatment-naive, some experts state that ritonavir-boosted fosamprenavir (given once or twice daily) is an alternative (not a preferred) PI for use in PI-based regimens in conjunction with 2 NRTIs.³ These experts state that fosamprenavir (without low-dose ritonavir) should be used with caution in PI-based regimens since such regimens may be associated with virologic failure and result in resistance mutations conferring resistance to other PIs (e.g., darunavir).³

When a PI-based regimen is used in children, some experts state that ritonavir-boosted fosamprenavir (given twice daily) in conjunction with 2 NRTIs is an alternative (not a preferred) regimen for initial treatment in treatment-naive children ≥6 years of age.⁴ These experts state that fosamprenavir (without low-dose ritonavir) in conjunction with 2 NRTIs can be considered for initial treatment in treatment-naive children ≥2 years of age in special circumstances when preferred or alternative PI-based regimens cannot be used.⁴

When selecting fosamprenavir for use in multiple-drug regimens, consider that data are insufficient to date to determine whether a regimen that includes ritonavir-boosted fosamprenavir is as effective as a regimen that includes the fixed-combination of lopinavir and ritonavir in adults who previously received PIs and that once-daily ritonavir-boosted fosamprenavir is not recommended in PI-experienced adults or in any pediatric patient.¹

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for transmission of the virus.¹¹ Used in conjunction with other antiretrovirals.¹¹

Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.¹⁰ Used in conjunction with other antiretrovirals.¹⁰

Fosamprenavir Calcium Dosage and Administration

Administration

Oral Administration

Tablets

Administer orally without regard to meals.¹

Suspension

Administer with food in children.¹ Administer on an empty stomach in adults.¹

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

Shake well prior to each dose.¹

The taste can be improved by refrigerating the suspension.¹

Dosage

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

Must be given in conjunction with other antiretrovirals.¹ If used with both ritonavir and efavirenz, dosage adjustment may be needed depending on frequency of administration.¹ (See Specific Drugs under Interactions.)

Pediatric Patients

Oral suspension is the preferred dosage form for young children because of suitability for providing the calculated dosage.¹

Children ≥2 years of age: Dosage is based on weight.¹ Do not exceed adult dosage.¹

Once-daily regimen (with or without low-dose ritonavir) is not recommended in pediatric patients.¹

Treatment of HIV Infection

Treatment-naive Pediatric Patients

Oral

Children 2–5 years of age (oral suspension): 30 mg/kg twice daily (without ritonavir).¹

Children ≥6 years of age (oral suspension): 30 mg/kg twice daily (without ritonavir).¹ If ritonavir-boosted regimen used, 18 mg/kg twice daily boosted with low-dose ritonavir (3 mg/kg twice daily).¹

Children weighing ≥39 kg (tablets): 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).^{1 4}

Children weighing ≥47 kg (tablets): 1.4 g twice daily (without ritonavir).^{1 4}

Treatment-experienced Pediatric Patients

Oral

Children 2–5 years of age: Data are insufficient for dosage recommendations.¹

Children ≥6 years of age (oral suspension): 18 mg/kg twice daily boosted with low-dose ritonavir (3 mg/kg twice daily).¹

Children weighing ≥39 kg (tablets): 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).^{1 4}

Adults

Treatment of HIV Infection

Treatment-naive Adults

Oral

1.4 g twice daily (without ritonavir).¹

1.4 g once daily boosted with low-dose ritonavir (100 or 200 mg once daily) or 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).¹

PI-experienced Adults

Oral

700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).¹ A once-daily regimen of ritonavir-boosted fosamprenavir not recommended in treatment-experienced patients.¹

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

1.4 g twice daily (without ritonavir).¹¹ Alternatively, 1.4 g once daily with low-dose ritonavir (200 mg once daily) or 700 mg twice daily with low-dose ritonavir (100 mg twice daily).¹¹

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.¹¹

Nonoccupational Exposure†

Oral

1.4 g twice daily (without ritonavir).¹⁰

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.¹⁰

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Maximum 1.4 g twice daily (without ritonavir) or 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Do not exceed adult dosage.¹

Adults

Treatment of HIV Infection

Treatment-naive Adults

Oral

Maximum 1.4 g once daily boosted with ritonavir (200 mg once daily) or 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Higher than recommended dosages of fosamprenavir and/or ritonavir associated with increased serum transaminase concentrations; higher dosages not recommended.¹

PI-experienced Adults

Oral

Maximum 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Higher than recommended dosages of fosamprenavir and/or ritonavir associated with increased serum transaminase concentrations; higher dosages not recommended.¹

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh score 5–6): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 700 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Moderate hepatic impairment (Child-Pugh score 7–9): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 700 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Severe hepatic impairment (Child-Pugh score 10–15): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 350 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Renal Impairment

Dosage adjustment not necessary.³

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Fosamprenavir Calcium

Contraindications

• Known hypersensitivity to fosamprenavir, amprenavir (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 (i.e., rifampin, ergot alkaloids, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, delavirdine, midazolam, triazolam).¹ (See Specific Drugs under Interactions.)

• Concomitant use of a ritonavir-boosted fosamprenavir regimen and flecainide or propafenone.¹ (See Antiarrhythmic Agents under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Hypersensitivity 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 if severe or life-threatening rash or moderate rash accompanied by systemic symptoms occurs.¹

Sulfonamide Sensitivity

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

Interactions

When a ritonavir-boosted fosamprenavir regimen is used, the usual cautions, precautions, and contrainfdications associated with ritonavir should be considered.¹

Serious and/or life-threatening drug interactions or loss of virologic effect can occur with some drugs.¹ (See Contraindications and Specific Drugs under Interactions.)

Hepatic Effects

Patients with coexisting hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or marked elevations in transaminase concentrations prior to fosamprenavir therapy may be at increased risk for developing transaminase elevations.¹

Perform appropriate laboratory tests to evaluate hepatic function prior to initiating fosamprenavir therapy and monitor patients closely during treatment.¹ (See Hepatic Impairment under Cautions.)

Use of fosamprenavir with ritonavir at higher than recommended dosages may result in elevated transaminase concentrations.¹

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.¹

Monitor blood glucose and initiate or adjust dosage of insulin or oral hypoglycemic agents as needed.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond 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 jiroveci [formerly P. carinii]);¹ this may necessitate further evaluation and treatment.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.¹ Evaluate patients for physical signs of fat redistribution.¹⁹

Lipid Effects

Increases in triglyceride and cholesterol concentrations have occurred with ritonavir-boosted fosamprenavir.^{1 19 21} HIV infection itself is associated with lipid disorders.¹⁹

Determine serum triglyceride and cholesterol concentrations prior to initiating fosamprenavir and periodically monitor during therapy; manage lipid disorders as clinically appropriate.^{1 19} (See HMG-CoA Reductase Inhibitors under Interactions.)

Hematologic Effects

Neutropenia has been reported with fosamprenavir;¹ acute hemolytic anemia has been reported in at least one patient who received amprenavir (no longer commercially available in the US).¹

Hemophilia A and B

Spontaneous bleeding reported with PIs;¹ causal relationship not established.¹

Use with caution in patients with hemophilia A or B.^{1 3} Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.¹

Nephrolithiasis

Nephrolithiasis reported in postmarketing surveillance.^{1 19} If signs or symptoms of nephrolithiasis occur, consider temporarily interrupting or discontinuing fosamprenavir.^{1 19}

HIV Resistance

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

Cardiovascular Effects

Postmarketing reports of myocardial infarction in patients receiving fosamprenavir.¹ Possible association between cumulative exposure to fosamprenavir/amprenavir and increased risk of myocardial infarction.¹⁹ Higher relative risk of myocardial infarction reported with PIs compared with other antiretroviral drug classes, possibly due to ability of PIs to elevate serum lipid concentrations.^{19 20} HIV infection itself is associated with ischemic heart disease.¹⁹

Monitor modifiable risk factors for cardiovascular disease (e.g., hypertension, diabetes, smoking) and manage as clinically appropriate.¹⁹ Individualize treatment, carefully considering risks and benefits of continued treatment.¹⁹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state safety and pharmacokinetic data insufficient to recommend routine use of fosamprenavir in pregnant women, but ritonavir-boosted fosamprenavir may be considered if other antiretroviral agents are not tolerated.¹²

Lactation

Distributed into milk in rats;¹ not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed^{1 12} because of risk of HIV transmission and risk of adverse effects in the infant.^{1 2}

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹

Once-daily regimen not recommended in pediatric patients.¹

Adverse effects in children 2–18 years of age similar to those reported in adults; vomiting reported more frequently in pediatric patients than in adults.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

Clearance decreased.¹

Use with caution; assess hepatic function prior to and periodically during therapy.¹

Dosage adjustments necessary in patients with hepatic impairment (Child-Pugh score 5–15).¹ (See Hepatic Impairment under Dosage and Administration.)

Increased risk for further elevations in hepatic enzyme concentrations in patients with chronic HBV or HCV infection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy.¹

Common Adverse Effects

Diarrhea, nausea, vomiting, headache, rash.¹

Interactions for Fosamprenavir Calcium

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 P2E1¹ 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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

Specific Drugs

Drug	Interaction	Comments
Abacavir	Studies using amprenavir indicate pharmacokinetic interaction unlikely1 In vitro evidence of synergistic antiretroviral effects1
Alfuzosin	Potential for increased alfuzosin concentrations that could result in hypotension1	Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated1
Antacids	Decreased amprenavir concentrations and AUC1	Not considered clinically important; manufacturer states there are no restrictions for concomitant use of fosamprenavir and antacids2
Antiarrhythmic agents (amiodarone, 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 Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if fosamprenavir used in conjunction with amiodarone, systemic lidocaine, or quinidine1	In patients receiving ritonavir-boosted fosamprenavir, concomitant use with flecainide or propafenone contraindicated1 Caution if fosamprenavir used concomitantly with amiodarone, systemic lidocaine, or quinidine; antiarrhythmic concentration monitoring recommended1
Anticoagulants, oral	Warfarin concentrations may be affected1	Monitor INR1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Fosamprenavir: Possible decreased amprenavir concentrations when used with carbamazepine, phenobarbital, or phenytoin;1 possible decreased antiretroviral efficacy1 Ritonavir-boosted fosamprenavir and phenytoin: Increased concentrations of amprenavir and decreased concentrations of phenytoin1	Fosamprenavir (without low-dose ritonavir): Use concomitantly with caution1 Ritonavir-boosted fosamprenavir: Monitor phenytoin concentrations; increase phenytoin dosage if indicated; no dosage adjustment recommended for ritonavir-boosted fosamprenavir 1
Antidepressants, tricyclics	Possible increased concentrations of tricyclic antidepressants (amitriptyline, imipramine) 1	Monitor tricyclic antidepressant concentrations1
Antifungals, azoles (itraconazole, ketoconazole, voriconazole)	Itraconazole: Possible increased antifungal and amprenavir concentrations1 3 Ketoconazole: Possible increased ketoconazole concentrations with fosamprenavir (with or without low-dose ritonavir)1 3 Voriconazole: Although specific data not available on interaction with ritonavir-boosted fosamprenavir, studies using low-dose ritonavir and voriconazole indicate decreased voriconazole concentrations;3 9 in addition, fosamprenavir (without ritonavir) possibly may result in increased concentrations of both drugs3	Itraconazole: In patients receiving fosamprenavir (with or without ritonavir), consider monitoring itraconazole concentrations to guide dosage adjustments; in those receiving fosamprenavir (without ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of itraconazole daily;1 3 in those receiving ritonavir-boosted fosamprenavir, itraconazole dosage >200 mg daily not recommended unless plasma concentrations are monitored1 3 Ketoconazole: In patients receiving fosamprenavir (without ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of ketoconazole daily;1 in those receiving ritonavir-boosted fosamprenavir, use caution and ketoconazole dosage >200 mg daily not recommended1 Voriconazole: Concomitant ritonavir-boosted fosamprenavir not recommended unless potential benefits outweigh risks; consider monitoring voriconazole plasma concentrations;3 9 if fosamprenavir (without ritonavir) is used, monitor frequently for toxicity3 9
Antimycobacterials (rifabutin, rifampin, rifapentine)	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;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Rifabutin: If fosamprenavir (without ritonavir) used with rifabutin, reduce rifabutin dosage by at least 50%1 (150 mg once daily or 300 mg 3 times weekly has been suggested);3 if ritonavir-boosted fosamprenavir used with rifabutin, reduce rifabutin dosage by at least 75% (maximum dosage of 150 mg once every other day or 3 times weekly);1 3 monitor for neutropenia by performing CBCs weekly and as clinically indicated1 Rifampin: Concomitant use contraindicated1 Rifapentine: Concomitant use not recommended3
Atazanavir	Decreased atazanavir concentrations; no change in amprenavir concentrations1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Benzodiazepines (alprazolam, clorazepate, diazepam, flurazepam, midazolam, triazolam)	Midazolam or triazolam: Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 Other benzodiazepines: Possible increased concentrations of alprazolam, clorazepate, diazepam, flurazepam1	Midazolam or triazolam: Manufacturer of fosamprenavir states that concomitant use is contraindicated;1 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation3 Other benzodiazepines: Clinical importance of pharmacokinetic interaction unknown; a decrease in benzodiazepine dosage may be needed1
Bosentan	Increased bosentan concentrations1	In patients already receiving fosamprenavir (with or without low-dose ritonavir) for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 3 In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating fosamprenavir (with or without low-dose ritonavir); after ≥10 days of fosamprenavir, resume bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 3
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 effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Clarithromycin	Studies using amprenavir indicate increased amprenavir concentrations and AUC1	Not considered clinically important;2 dosage adjustment not needed3
Colchicine	Increased colchicine concentrations1	Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted fosamprenavir1 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 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-boosted fosamprenavir, 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;1 in those receiving fosamprenavir (without 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);1 in those receiving fosamprenavir (without ritonavir), use maximum colchicine dosage of 1.2 mg daily (may be given as 0.6 mg twice daily)1
Corticosteroids (dexamethasone, fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with fosamprenavir (with or without low-dose ritonavir) resulting in decreased cortisol concentrations1 Dexamethasone: Possible decreased amprenavir concentrations; possible decreased antiretroviral efficacy1	Fluticasone nasal spray/oral inhalation: Consider alternative in patients receiving fosamprenavir (without ritonavir), especially when long-term corticosteroid therapy is anticipated; concomitant use with ritonavir-boosted fosamprenavir not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 Dexamethasone: Use concomitantly with caution1
Darunavir	Data not available regarding concomitant use of darunavir and fosamprenavir (with or without low-dose ritonavir)3
Delavirdine	Studies using amprenavir indicate possible increased amprenavir concentrations and AUC and possible decreased delavirdine plasma concentrations and AUC;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1 In vitro evidence of synergistic antiretroviral effects1	Concomitant use contraindicated1
Didanosine	In vitro evidence of synergistic antiretroviral effects1
Efavirenz	Substantially decreased amprenavir concentrations if used with fosamprenavir;1 additional pharmacokinetic interactions if ritonavir-boosted fosamprenavir used1 In vitro evidence of synergistic antiretroviral effects1	If fosamprenavir used with efavirenz, boosting with ritonavir required 1 2 3 When efavirenz used with ritonavir-boosted fosamprenavir, fosamprenavir 1.4 g once daily with ritonavir 300 mg once daily or fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily recommended1 3
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)	Possible increased concentrations of ergot alkaloids and potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm and ischemia of the extremities and other tissues)1	Concomitant use contraindicated1 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving fosamprenavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible12
Estrogens or Progestins	Hormonal contraceptive containing ethinyl estradiol 35 mcg with norethindrone 0.5 mg per tablet: Decreased ethinyl estradiol and norethindrone concentrations with ritonavir-boosted fosamprenavir; clinically important increase in serum transaminase concentrations1 Hormonal contraceptives: Possible loss of virologic response if used with fosamprenavir (without ritonavir)1 Hormone replacement therapy: Possible increase in serum transaminase concentrations with ritonavir-boosted fosamprenavir1	Hormonal contraceptives: Concomitant use not recommended;3 use alternative nonhormonal (e.g., barrier) contraceptives1 3
Etravirine	Fosamprenavir or ritonavir-boosted fosamprenavir: Substantially increased amprenavir concentrations17	Do not administer concomitantly;3 17 appropriate dosages for concomitant use with respect to safety and efficacy not established3 17
Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)	Decreased amprenavir plasma concentrations and AUC;1 possible decreased antiretroviral efficacy1	Use concomitantly with caution;1 administer at different times;3 consider using ritonavir-boosted fosamprenavir3
HMG-CoA reductase inhibitors (statins)	Possible decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors (e.g., atorvastatin, rosuvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1	Lovastatin or simvastatin: Concomitant use with fosamprenavir contraindicated1 Atorvastatin or rosuvastatin: Use lowest possible dosage of the HMG-CoA reductase inhibitor with careful monitoring1 Consider using HMG-CoA reductase inhibitors with low potential for interaction (e.g., fluvastatin, pravastatin)1
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1	Monitor concentrations of the immunosuppressive agent1
Indinavir	Studies using amprenavir indicate possible increased amprenavir plasma concentrations and AUC and decreased indinavir concentrations;1 concomitant use of ritonavir-boosted fosamprenavir not evaluated1 In vitro evidence of additive antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Lamivudine	Studies using amprenavir indicate no evidence of pharmacokinetic interaction1 In vitro evidence of synergistic antiretroviral effects1
Lopinavir	Fosamprenavir: Decreased amprenavir concentrations; no change in lopinavir concentrations 1 Ritonavir-boosted fosamprenavir: Decreased amprenavir concentrations; altered lopinavir concentrations1 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 established;1 3 concomitant use not recommended3
Maraviroc	Possible increased concentrations of maraviroc3	Recommended dosage of maraviroc is 150 mg twice daily3
Methadone	Decreased methadone concentrations1	Not considered clinically important; monitor for symptoms of opiate withdrawal and adjust methadone dosage if needed1 3
Nelfinavir	Studies using amprenavir indicate possible alterations in amprenavir and nelfinavir pharmacokinetics;1 concomitant use of ritonavir-boosted fosamprenavir and nelfinavir not evaluated1 In vitro evidence of additive antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1
Nevirapine	Decreased amprenavir concentrations and increased nevirapine concentrations with fosamprenavir (without ritonavir); clinically important interaction unlikely with ritonavir-boosted fosamprenavir1 In vitro evidence of additive antiretroviral effects1	Concomitant use of fosamprenavir (without ritonavir) with nevirapine not recommended1 Dosage adjustment not needed when ritonavir-boosted fosamprenavir is given twice daily with nevirapine; concomitant use with ritonavir-boosted fosamprenavir given once daily not studied1
Paroxetine	Decreased paroxetine concentrations with ritonavir-boosted fosamprenavir1	Monitor closely for antidepressant response;3 adjust paroxetine dosage based on clinical effects1 3
Pimozide	Possible increased pimozide concentrations;1 potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)	Esomeprazole: When used with fosamprenavir (without ritonavir), no change in amprenavir concentrations or AUC, and increased esomeprazole AUC;1 when used with ritonavir-boosted fosamprenavir, clinically important pharmacokinetic interaction unlikely1	Can be administered at the same time as proton-pump inhibitors with no change in plasma amprenavir concentrations1
Ritonavir	Increased plasma concentrations and AUC of amprenavir1 3 Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted fosamprenavir);1 increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D61 In vitro evidence of additive antiretroviral effects1	When ritonavir-boosted fosamprenavir is used in a once-daily regimen, recommended dosage is fosamprenavir 1.4 g once daily with ritonavir 100 or 200 mg once daily; when used in a twice-daily regimen, recommended dosage is fosamprenavir 700 mg twice with ritonavir 100 mg twice daily1 3 Once-daily regimen of ritonavir-boosted fosamprenavir not recommended in PI-experienced patients1
St. John’s wort (Hypericum perforatum)	Possible decreased amprenavir concentrations;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Concomitant use contraindicated1
Saquinavir	Decreased amprenavir concentrations1 In vitro evidence of synergistic antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1	Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated;1 3 fosamprenavir manufacturer states that a safe and effective dose for concomitant use not established1 Sildenafil for treatment of erectile dysfunction: If used concomitantly with fosamprenavir (with or without low-dose ritonavir), use reduced sildenafil dosage (25 mg repeated no more frequently than once every 48 hours) and monitor closely for adverse sildenafil effects1 3
Stavudine	In vitro evidence of synergistic antiretroviral effects1
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 3	If tadalafil (Adcirca) is initiated for treatment of PAH in patients already receiving fosamprenavir (with or without low-dose ritonavir) for ≥1 week, use an initial tadalafil dosage of 20 mg once daily and increase dosage to 40 mg once daily based on individual tolerability1 Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of fosamprenavir (with or without low-dose ritonavir) therapy;1 if fosamprenavir (with or without low-dose ritonavir) is indicated in a patient already receiving tadalafil (Adcirca) for treatment of PAH, discontinue tadalafil for at least 24 hours before starting fosamprenavir; tadalafil can be restarted after ≥1 week of fosamprenavir therapy using an initial tadalafil dosage of 20 mg once daily and increasing the dosage to 40 mg once daily based on individual tolerability1 If tadalafil is used for treatment of erectile dysfunction in patients already receiving fosamprenavir (with or without low-dose ritonavir), use reduced tadalafil dosage (10 mg repeated no more frequently than once every 72 hours) and monitor patient for adverse tadalafil effects1
Tenofovir	No change in amprenavir concentrations with ritonavir-boosted fosamprenavir1 In vitro evidence of synergistic antiretroviral effects1
Tipranavir	Possible decreased amprenavir concentrations3	Concomitant use not recommended;3 appropriate dosages for concomitant use with respect to safety and efficacy not established3
Trazodone	Possible increased trazodone concentrations with fosamprenavir (with or without low-dose ritonavir)1 Increased risk of trazodone-associated adverse effects1	Caution; reduced trazodone dosage may be needed1
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 3	If fosamprenavir (without ritonavir) is used in patients receiving vardenafil for treatment of erectile dysfunction, use reduced vardenafil dosage (2.5 mg given no more frequently than once every 24 hours) and monitor closely for adverse vardenafil effects1 If ritonavir-boosted fosamprenavir is used in patients receiving vardenafil for treatment of erectile dysfunction, use reduced vardenafil dosage (2.5 mg given no more frequently than once every 72 hours) and monitor for adverse vardenafil effects1
Zidovudine	Studies using amprenavir indicate possible increased amprenavir AUC;1 possible increased zidovudine plasma concentrations and AUC1 In vitro evidence of synergistic 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;¹ 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

Tablets: Administration of fosamprenavir calcium tablets with food has no effect on bioavailability of amprenavir.¹

Suspension: 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 AUC by 28% compared with administration in the fasting state.¹

Distribution

Extent

Amprenavir crosses the placenta and is distributed into milk in animals.¹ Not known whether drug crosses human placenta or 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 an oral dose excreted in urine and 75% eliminated in feces as metabolites.¹ Only minimal amounts eliminated unchanged in urine or feces.¹

Half-life

Amprenavir elimination half-life approximately 7.7 hours.¹

Special Populations

Following administration of ritonavir-boosted fosamprenavir, AUC of amprenavir increased 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 patients with impaired renal function,¹ but renal impairment not expected to have a clinically important effect on pharmacokinetics.¹

Pharmacokinetics studied in pediatric patients 2–5 years of age receiving fosamprenavir 30 mg/kg twice daily, patients 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.¹

Stability

Storage

Oral

Suspension

5–30°C; avoid freezing.¹

Tablets

Tight container at 25°C (may be exposed to 15–30°C).¹

ActionsActions

• 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 PI, inhibits replication of HIV-1 by interfering with HIV protease.¹

• HIV-1 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

• Importance of patient reading patient package insert provided by the manufacturer.¹

• Critical nature of compliance with HIV therapy.^{1 3} Importance of using fosamprenavir in conjunction with other antiretrovirals—not for monotherapy.^{1 3} Importance of informing patients to take fosamprenavir as prescribed and not to alter or discontinue fosamprenavir therapy without consulting their clinician.^{1 19}

• Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.^{1 3} HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.^{1 3}

• Importance of not missing a dose.¹ If a dose is missed by <4 hours, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time; if a dose is missed by >4 hours, omit the dose and take the next dose at the regularly scheduled time.¹

• Importance of informing patients about the clinical benefits and potential risks of fosamprenavir therapy and that the long-term effects of the drug are unknown.¹

• When the oral suspension is used, advise adults to take the preparation on an empty stomach.¹ Advise children to take the oral suspension with food.¹ Refrigeration of the suspension may improve the taste.¹

• When the oral suspension is used, repeat dose if vomiting occurs within 30 minutes of ingestion.¹

• Importance of patients informing their clinician if they are allergic to sulfonamides.¹

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.¹

• Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, priapism) and that any symptoms should be promptly reported to their clinician.¹

• Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Fosamprenavir Calcium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Suspension	50 mg (of fosamprenavir) per mL	Lexiva	GlaxoSmithKline
	Tablets, film-coated	700 mg (of fosamprenavir)	Lexiva	GlaxoSmithKline