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Fosamprenavir

Pronunciation

(FOS am pren a veer)

Index Terms

  • Fosamprenavir Calcium
  • GW433908G

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral, as calcium:

Lexiva: 50 mg/mL (225 mL) [contains methylparaben, polysorbate 80, propylene glycol, propylparaben; grape bubblegum peppermint flavor]

Tablet, Oral, as calcium:

Lexiva: 700 mg

Brand Names: U.S.

  • Lexiva

Pharmacologic Category

  • Antiretroviral, Protease Inhibitor (Anti-HIV)

Pharmacology

Fosamprenavir is rapidly and almost completely converted to amprenavir by cellular phosphatases in vivo. Amprenavir binds to the site of HIV-1 protease activity and inhibits cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV. This results in the formation of immature, noninfectious viral particles.

Absorption

63%

Metabolism

Fosamprenavir is rapidly and almost completely converted to amprenavir by cellular phosphatases in gut epithelium; amprenavir is hepatically metabolized via CYP isoenzymes (primarily CYP3A4); glucuronide conjugation of oxidized metabolites also occurs

Excretion

Minimal excretion of unchanged drug in urine (1%) and feces; 75% of dose excreted as metabolites via biliary tract into feces and 14% excreted as metabolites in urine

Time to Peak

1.5 to 4 hours (median: 2.5 hours)

Half-Life Elimination

~7.7 hours (amprenavir)

Protein Binding

~90% (to alpha1-acid glycoprotein); decreased in hepatic impairment

Special Populations: Hepatic Function Impairment

AUC of amprenavir was increased by ~22% in mild hepatic impairment, by ~70% in moderate hepatic impairment, and by ~80% in severe hepatic impairment. Protein binding also decreased.

Special Populations: Children

For children 2 to 18 years of age, the AUC is 31.4 to 93.4 mcg•h/mL, Cmax is 5 to 6.07 mcg/mL, and Cmin is 0.454 to 2.69 mcg/mL.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection, in combination with other antiretroviral agents

Contraindications

Clinically significant hypersensitivity (eg, Stevens-Johnson syndrome) to fosamprenavir, amprenavir, or any component of the formulation; coadministration with drugs highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, alfuzosin, rifampin, ergot derivatives [eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine], cisapride, St John wort, lovastatin, simvastatin, pimozide, delavirdine, sildenafil [when used for treatment of pulmonary arterial hypertension], midazolam, or triazolam); use of flecainide, lurasidone, or propafenone with concomitant ritonavir therapy.

Canadian labeling: Additional contraindications (not in US labeling): Coadministration with amiodarone, astemizole, diazepam, flurazepam, lidocaine (systemic), quetiapine, quinidine, terfenadine.

Dosing: Adult

HIV-1 infection: Oral:

Antiretroviral therapy-naive patients: Oral:

Unboosted regimen: 1,400 mg twice daily (without ritonavir); Note: This regimen is not recommended due to inferior potency compared to other protease inhibitor-based regimens and the potential for cross-resistance to darunavir (HHS [adults] 2015).

Ritonavir-boosted regimens:

Once-daily regimen: Fosamprenavir 1,400 mg once daily plus ritonavir 100 to 200 mg once daily

Twice-daily regimen: Fosamprenavir 700 twice daily plus ritonavir 100 mg twice daily

Protease inhibitor (PI)-experienced patients: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Note: Once-daily administration is not recommended in protease inhibitor-experienced patients.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection: Oral:

Infants ≥4 weeks, Children, and Adolescents <18 years: Note: Twice-daily dosing is recommended; once-daily dosing (without or without ritonavir) is not recommended in any pediatric patient.

Protease inhibitor (PI)-naive patients:

Ritonavir-boosted regimen: Infants ≥4 weeks, Children, and Adolescents: Note: Should not be administered to infants born <38 weeks' gestation and who have not attained a postnatal age of 28 days.

<11 kg: Fosamprenavir 45 mg/kg/dose twice daily plus ritonavir 7 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

11 to <15 kg: Fosamprenavir 30 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

15 to <20 kg: Fosamprenavir 23 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

≥20 kg: Fosamprenavir 18 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

Note: When combined with ritonavir, the adult regimen of fosamprenavir 700 mg plus ritonavir 100 mg twice daily can be used in children who weigh ≥39 kg; ritonavir capsules may be used for children who weigh ≥33 kg.

Unboosted regimen:

Children <2 years: Fosamprenavir without ritonavir is not recommended

Children and Adolescents ≥2 years and <47 kg: Fosamprenavir 30 mg/kg/dose twice daily (maximum: 1,400 mg twice daily)

Children and Adolescents ≥2 years and ≥47 kg: The adult regimen of fosamprenavir 1,400 mg twice daily may be used

Protease inhibitor (PI)-experienced patients:

Ritonavir-boosted regimen:

Infants <6 months: Not recommended in PI-experienced patients

Infants ≥6 months, Children, and Adolescents:

<11 kg: Fosamprenavir 45 mg/kg/dose twice daily plus ritonavir 7 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

11 to <15 kg: Fosamprenavir 30 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

15 to <20 kg: Fosamprenavir 23 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

≥20 kg: Fosamprenavir 18 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily (maximum: Fosamprenavir 700 mg/ritonavir 100 mg twice daily)

Note: When combined with ritonavir, the adult regimen of fosamprenavir 700 mg plus ritonavir 100 mg twice daily can be used in children who weigh ≥39 kg; ritonavir capsules may be used for children who weigh ≥33 kg.

Unboosted regimen: Note: No information provided in manufacturer’s labeling regarding unboosted fosamprenavir in PI-experienced pediatric patients except that fosamprenavir without ritonavir is not recommended in children <2 years of age and the adult unboosted regimen of 1,400 mg twice daily may be used for pediatric patients who weigh ≥47 kg.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, dosage adjustment unlikely due to minimal (eg, 1%) renal elimination of unchanged amprenavir.

Dosing: Hepatic Impairment

Adults:

Mild impairment (Child-Pugh class A): Reduce dosage of fosamprenavir to 700 mg twice daily without concurrent ritonavir (therapy naive) or fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily (therapy naive or PI experienced).

Moderate impairment (Child-Pugh class B): Reduce dosage of fosamprenavir to 700 mg twice daily without concurrent ritonavir (therapy naive) or fosamprenavir 450 mg twice daily plus ritonavir 100 mg once daily (therapy naive or PI experienced).

Severe impairment (Child-Pugh class C: Reduce dosage of fosamprenavir to 350 mg twice daily without concurrent ritonavir (therapy naive) or fosamprenavir 300 mg twice daily plus ritonavir 100 mg once daily (therapy naive or PI experienced).

Children: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

Oral suspension: Administer without food to adults; administer with food to pediatric patients. Readminister dose of suspension if emesis occurs within 30 minutes after dosing. Shake suspension vigorously prior to use.

Tablet: Administer with food in pediatric patients and in adult patients if taken with ritonavir. May be administered without regard to food in adult patients if not taken with ritonavir (HHS [adult] 2015).

Dietary Considerations

Tablets may be taken with or without food. Adults should take oral suspension without food; however, children should take oral suspension with food.

Storage

Lexiva: Store tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store oral suspension at 5°C to 30°C (41°F to 86°F). Do not freeze.

Telzir [Canadian product]: Store tablets 2°C to 30°C; do not freeze and discard 25 days after opening.

Drug Interactions

Abacavir: Protease Inhibitors may decrease the serum concentration of Abacavir. Monitor therapy

Alfuzosin: Protease Inhibitors may increase the serum concentration of Alfuzosin. Avoid combination

ALPRAZolam: Protease Inhibitors may increase the serum concentration of ALPRAZolam. Management: Seek alternatives to alprazolam in patients treated with HIV protease inhibitors. Concurrent use of alprazolam with indinavir is contraindicated. All patients receiving such a combination should be monitored closely for excessive response to alprazolam. Consider therapy modification

Amiodarone: Fosamprenavir may increase the serum concentration of Amiodarone. Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Protease Inhibitors may increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Boceprevir: May decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Boceprevir. Management: Some combinations are not recommended. See full drug interaction monograph for details. Consider therapy modification

Bosentan: May decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking fosamprenavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting fosamprenavir; wait at least 10 days before restarting bosentan. Consider therapy modification

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Consider therapy modification

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cisapride: Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Avoid combination

Clarithromycin: Protease Inhibitors may diminish the therapeutic effect of Clarithromycin. Specifically, certain protease inhibitors may decrease formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness vs. H. influenzae and other non-MAC infections. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed. Clarithromycin may increase the serum concentration of Protease Inhibitors. Management: Avoid clarithromycin adult doses greater than 1000 mg/day when used with a protease inhibitor. Further dose reductions may be needed in patients with impaired renal function. Consider alternative antimicrobial for any non-MAC infection. Consider therapy modification

Clorazepate: Fosamprenavir may increase the serum concentration of Clorazepate. Monitor therapy

Cobicistat: May increase the serum concentration of Fosamprenavir. However, the magnitude of this change is unclear, and dosing recommendations for this combination are not available. Avoid combination

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: Fosamprenavir may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are receiving ritonavir-boosted fosamprenavir. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Contraceptives (Estrogens): Protease Inhibitors may decrease the serum concentration of Contraceptives (Estrogens). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors. Consider therapy modification

Contraceptives (Progestins): May decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Cyclophosphamide: Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Monitor therapy

CycloSPORINE (Systemic): Protease Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Delavirdine: Fosamprenavir may decrease the serum concentration of Delavirdine. The active metabolite amprenavir is likely responsible for this effect. Delavirdine may increase the serum concentration of Fosamprenavir. Specifically, delavirdine may increase concentrations of the active metabolite amprenavir. Avoid combination

Dexamethasone (Systemic): May decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of Dexamethasone (Systemic). Monitor therapy

DiazePAM: Fosamprenavir may increase the serum concentration of DiazePAM. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: Fosamprenavir may decrease the serum concentration of Dolutegravir. Specifically, Fosamprenavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Fosamprenavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir to 50 mg twice daily in adults and pediatric patients (12 yrs or older and at least 40 kg). Seek alternatives to fosamprenavir/ritonavir in INSTI-experienced patients with suspected or certain INSTI resistance. Consider therapy modification

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Efavirenz: May decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Management: For once-daily fosamprenavir/ritonavir with efavirenz, an increased ritonavir dose to 300 mg/day is recommended in adult patients. No ritonavir dose adjustment is required if using twice-daily fosamprenavir/ritonavir. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Enfuvirtide: Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Nicergoline. Avoid combination

Etravirine: May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may increase. Avoid combination

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flecainide: Fosamprenavir may increase the serum concentration of Flecainide. Management: Concurrent use of ritonavir-boosted fosamprenavir with flecainide is contraindicated. The use of non-ritonavir-boosted fosamprenavir with flecainide is not specifically contraindicated but should only be undertaken with caution. Avoid combination

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Flurazepam: Fosamprenavir may increase the serum concentration of Flurazepam. Monitor therapy

Fosphenytoin: May increase the serum concentration of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Fosphenytoin. Monitor therapy

Garlic: May decrease the serum concentration of Protease Inhibitors. Management: Concurrent use of garlic supplements with protease inhibitors is not recommended. If this combination is used, monitor closely for altered serum concentrations/effects of protease inhibitors, and particularly for signs/symptoms of therapeutic failure. Consider therapy modification

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

H2-Antagonists: May decrease the serum concentration of Fosamprenavir. Cimetidine may also inhibit the metabolism of the active metabolite amprenavir, making its effects on fosamprenavir/amprenavir concentrations difficult to predict. Monitor therapy

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

HydrOXYzine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HydrOXYzine. Management: This combination is specifically contraindicated in some non-U.S. labeling. Consider therapy modification

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Itraconazole: May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be increased. Fosamprenavir may increase the serum concentration of Itraconazole. Management: Limit the adult maximum itraconazole dose to 200 mg/day with fosamprenavir/ritonavir. In patients receiving fosamprenavir without ritonavir, patients receiving greater than 400 mg/day itraconazole may also require dose reduction. Consider therapy modification

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumefantrine with a moderate CYP3A4 inhibitor. Consider therapy modification

Ketoconazole (Systemic): May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be increased. Fosamprenavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day with fosamprenavir/ritonavir. In patients receiving fosamprenavir without ritonavir, patients receiving greater than 400 mg/day ketoconazole may also require dose reduction. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Lopinavir: Fosamprenavir may decrease the serum concentration of Lopinavir. Specifically, amprenavir (the active metabolite of fosamprenavir) may decrease the serum concentration of lopinavir. Lopinavir may decrease the serum concentration of Fosamprenavir. Specifically, lopinavir/ritonavir may decrease the serum concentration of amprenavir (the active metabolite of fosamprenavir) Avoid combination

Lovastatin: Protease Inhibitors may increase the serum concentration of Lovastatin. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification

Meperidine: Protease Inhibitors may enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased. Consider therapy modification

Methadone: May decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be reduced. This effect has been demonstrated with Amprenavir alone but not with Fosamprenavir / Ritonavir. The potential impact on Fosamprenavir alone has not been investigated. Fosamprenavir may decrease the serum concentration of Methadone. Monitor therapy

Midazolam: Protease Inhibitors may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Avoid combination

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Nefazodone: Protease Inhibitors may increase the serum concentration of Nefazodone. Management: Consider alternatives to, or reduced doses of, nefazodone in patients treated with HIV protease inhibitors. Monitor patients receiving these combinations closely for toxic effects of nefazodone. Consider therapy modification

Nevirapine: May decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Management: Coadministration of nevirapine and fosamprenavir is not recommended without concurrent ritonavir. However, when nevirapine and fosamprenavir/ritonavir (twice daily) are used in combination, no dose adjustment is required. Consider therapy modification

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Management: Use of ritonavir-boosted fosamprenavir with ombitasvir/paritaprevir/ritonavir/dasabuvir is not recommended. Consider a reduced dose of fosamprenavir 1400 mg once daily (unboosted) when used with ombitasvir/paritaprevir/ritonavir/dasabuvir. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

PARoxetine: Fosamprenavir may decrease the serum concentration of PARoxetine. The active metabolite amprenavir is likely responsible for this effect. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: Fosamprenavir may decrease the serum concentration of Phenytoin. The active amprenavir metabolite is likely responsible for this effect. Phenytoin may increase the serum concentration of Fosamprenavir. Specifically, phenytoin may increase the concentration of the active metabolite amprenavir. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Protease Inhibitors may increase the serum concentration of Pimozide. Avoid combination

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Posaconazole: May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Posaconazole. Monitor therapy

Propafenone: Fosamprenavir may increase the serum concentration of Propafenone. Management: Concurrent use of ritonavir-boosted fosamprenavir with propafenone is contraindicated. The use of non-ritonavir-boosted fosamprenavir with propafenone is not specifically contraindicated but should only be undertaken with caution. Avoid combination

Protease Inhibitors: May increase the serum concentration of other Protease Inhibitors. Management: Atazanavir--indinavir combination contraindicated. Tipranavir/ritonavir or atazanavir/ritonavir not recommended with other protease inhibitors (PI). Darunavir/cobicistat not recommended with PI that require boosting.Other combos may require dose changes. Consider therapy modification

QuiNIDine: Fosamprenavir may increase the serum concentration of QuiNIDine. Monitor therapy

Raltegravir: Fosamprenavir may decrease the serum concentration of Raltegravir. Raltegravir may decrease the serum concentration of Fosamprenavir. Consider therapy modification

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Rifabutin: Fosamprenavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Rifabutin may increase the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of Rifabutin. Management: Reduce rifabutin doses. See full monograph for specific recommendations. Consider therapy modification

RifAMPin: May decrease the serum concentration of Fosamprenavir. Specifically, concentrations of amprenavir (active metabolite) may be decreased. Avoid combination

Riociguat: Protease Inhibitors may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

Rosuvastatin: Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: Protease Inhibitors may increase the serum concentration of Sildenafil. Management: Erectile dysfunction: sildenafil max = 25 mg/48 hrs with ritonavir, atazanavir, or darunavir; starting dose = 25 mg with other protease inhibitors (adult doses). Contraindicated if sildenafil being used for pulmonary arterial hypertension. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Simeprevir: Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. Avoid combination

Simvastatin: Protease Inhibitors may increase the serum concentration of Simvastatin. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May increase the metabolism of Protease Inhibitors. Avoid combination

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tacrolimus (Systemic): Protease Inhibitors may decrease the metabolism of Tacrolimus (Systemic). Consider therapy modification

Tacrolimus (Topical): Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Telaprevir: Fosamprenavir may decrease the serum concentration of Telaprevir. Telaprevir may decrease the serum concentration of Fosamprenavir. Avoid combination

Telithromycin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Telithromycin. Monitor therapy

Temsirolimus: Protease Inhibitors may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tipranavir: May decrease the serum concentration of Protease Inhibitors. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

TraZODone: Fosamprenavir may increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with fosamprenavir. Consider therapy modification

Triazolam: Protease Inhibitors may increase the serum concentration of Triazolam. Avoid combination

Tricyclic Antidepressants: Protease Inhibitors may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Valproate Products: Protease Inhibitors may decrease the serum concentration of Valproate Products. Monitor therapy

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Voriconazole: May increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be increased. Fosamprenavir may increase the serum concentration of Voriconazole. Monitor therapy

Warfarin: Fosamprenavir may increase the serum concentration of Warfarin. Monitor therapy

Zidovudine: Protease Inhibitors may decrease the serum concentration of Zidovudine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Skin rash (≤19%; onset: ~11 days; duration: ~13 days)

Endocrine & metabolic: Hypertriglyceridemia (>750 mg/dL: ≤11%)

Gastrointestinal: Diarrhea (5% to 13%; moderate-to-severe)

1% to 10%:

Central nervous system: Fatigue (2% to 4%; moderate-to-severe), headache (2% to 4%; moderate-to-severe)

Dermatologic: Pruritus (7% to 8%)

Endocrine & metabolic: Hyperglycemia (>251 mg/dL: ≤2%)

Gastrointestinal: Increased serum lipase (>2x ULN: 5% to 8%), nausea (3% to 7%; moderate-to-severe), vomiting (2% to 6%; moderate-to-severe), abdominal pain (≤2%; moderate-to-severe)

Hematologic & oncologic: Neutropenia (<750 cells/mm3: 3%)

Hepatic: Increased serum transaminases (>5x ULN: 4% to 8%)

<1% (Limited to important or life-threatening): Angioedema, cerebrovascular accident, hypercholesterolemia, myocardial infarction, nephrolithiasis, oral paresthesia, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hemolytic anemia: Acute hemolytic anemia has been reported in association with amprenavir use.

• Hepatic effects: May cause transaminase elevations, hepatitis, and/or exacerbate preexisting hepatic dysfunction; use with caution in patients with underlying hepatic disease, such as hepatitis B or C or cirrhosis. Dosage adjustment required in hepatic impairment.

• Hypersensitivity reactions: Protease inhibitors have been associated with a variety of hypersensitivity events (some severe), including rash, anaphylaxis (rare), angioedema, bronchospasm, erythema multiforme, and/or Stevens-Johnson syndrome (rare). It is generally recommended to discontinue treatment if severe rash or moderate symptoms accompanied by other systemic symptoms occur.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lipid elevations: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

• Nephrolithiasis: Cases have been reported in postmarketing surveillance; temporary or permanent discontinuation of therapy should be considered if symptoms develop.

• Sulfonamide allergy: Use with caution in patients with sulfonamide allergy. In clinical trials, the incidence of rash did not differ appreciably in patients with or without a history of sulfonamide allergy.

Disease-related concerns:

• Diabetes: Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, diabetic ketoacidosis, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors.

• Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding during protease inhibitor therapy has been reported.

Dosage forms specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Do not administer fosamprenavir (with or without ritonavir) to protease inhibitor-experienced pediatric patients <6 months of age. In addition, once-daily dosing of fosamprenavir (with or without ritonavir) is not recommended in any pediatric patient.

• Protease inhibitor-experienced adults: Once-daily fosamprenavir/ritonavir is not recommended in protease inhibitor–experienced adults.

Monitoring Parameters

Prior to initiation and periodically during therapy, monitor viral load, CD4 count, glucose; triglycerides and cholesterol; liver function tests (in patients with underlying hepatitis B or C)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Fosamprenavir has a low level of transfer across the human placenta. A small increased risk of preterm birth has been associated with maternal use of protease inhibitor-based combination antiretroviral (ARV) therapy during pregnancy; however, the benefits of use generally outweigh this risk and protease inhibitors (PIs) should not be withheld if otherwise recommended. Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with PIs; it is not clear if pregnancy increases this risk. The HHS Perinatal HIV Guidelines note there are insufficient data to recommend use during pregnancy. However, if used in women intolerant of other agents, fosamprenavir may be given as ritonavir-boosted twice-daily dosing. Unboosted fosamprenavir and once-daily dosing with ritonavir are not recommended. Dose adjustments are not needed during pregnancy.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in nonpregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience itching, headache or diarrhea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), angina, severe nausea, severe vomiting, side pain, polyuria, thirsty, weight loss, painful urination, back pain, abdominal pain, blood in urine, numbness or tingling of mouth, severe dizziness, passing out, shortness of breath, sweating a lot, severe loss of strength and energy, change in body fat, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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