indication

Indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. The use of fosamprenavir is pending revision due to a potential association between the drug and myocardial infarction and dyslipidemia in HIV infected adults.

pharmacology

Fosamprenavir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. It has little or no antiviral activity until it is hydrolyzed by cellular phosphatases into amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reducing the number of pills required versus standard amprenavir.

mechanism of action

Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. During HIV replication, HIV protease cleaves viral polypeptide products of the Gag and Gag-Pol genes to form structural proteins of the virion core and essential viral enzymes. Amprenavir interferes with this process by binding to the active site of HIV-1 protease, thereby preventing the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

biotransformation

In the gut epithelium during absorption, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system.

absorption

The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of a single 1,400 mg dose in the fasted state, fosamprenavir oral suspension (50 mg/mL) and fosamprenavir tablets (700 mg) provided similar amprenavir exposures (AUC), however, the C_max of amprenavir after administration of the suspension formulation was 14.5 % higher compared with the tablet.

half life

The plasma elimination half-life of amprenavir (the active metabolite) is approximately 7.7 hours.

route of elimination

Excretion of unchanged amprenavir in urine and feces is minimal. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir. Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system.

drug interactions

Abacavir: The serum concentration of Abacavir may be decreased by protease inhibitors such as Fosamprenavir. The antiviral response should be closely monitored.

Acenocoumarol: The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of acenocoumarol.

Alprazolam: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, alprazolam.

Aluminium: The antiacid decreases the absorption of amprenavir

Amiodarone: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of amiodarone.

Anisindione: The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of anisindione.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atorvastatin: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if fosamprenavir is initiated, discontinued or dose changed.

Bepridil: Amprenavir increases the effect and toxicity of bepridil

Bromazepam: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if fosamprenavir is initiated, discontinued or dose changed. Dosage adjustments may be required.

Calcium: The antiacid decreases the absorption of amprenavir

Cisapride: Amprenavir increases the effect and toxicity of cisapride

Clorazepate: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, clorazepate.

Cyclosporine: The protease inhibitor, fosamprenavir, may increase the effect of cyclosporine.

Dantrolene: Fosamprenavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if fosamprenavir is initiated, discontinued or dose changed.

Delavirdine: Decreased levels of delavirdine with increased levels of amprenavir

Diazepam: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, diazepam.

Dicumarol: The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of dicumarol.

Dihydroergotamine: Amprenavir increases the effect and toxicity of ergot derivative

Ergotamine: Amprenavir increases the effect and toxicity of ergot derivative

Fentanyl: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of fentanyl.

Flurazepam: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, flurazepam.

Fusidic Acid: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of fusidic acid.

Lovastatin: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the effect and toxicity of lovastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Magnesium: The antiacid decreases the absorption of amprenavir

Magnesium oxide: The antiacid decreases the absorption of amprenavir

Methadone: The protease inhibitor, fosamprenavir, may decrease the effect of methadone.

Midazolam: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, midazolam.

Pimozide: Amprenavir increases the effect and toxicity of pimozide

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifabutin: Amprenavir increases the effect and toxicity of rifabutin

Rifampin: Rifampin may decrease the effectiveness of fosamprenavir.

Sildenafil: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of sildenafil.

Simvastatin: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if fosamprenavir is initiated, discontinued or dose changed.

St. John's Wort: St. John's Wort decreases the effect of indinavir

Tacrolimus: The protease inhibitor, Fosamprenavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Fosamprenavir therapy is initiated, discontinued or altered.

Tadalafil: Fosamprenavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Fosmprenavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Tamsulosin: Fosamprenavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Fosamprenavir is initiated, discontinued, or dose changed.

Telithromycin: Fosamprevavir may increase the plasma concentration of Telithromycin. Consider alternate therapy or monitor therapeutic/adverse effects.

Temsirolimus: Fosamprenavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Fosamprenavir, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Fosamprenavir is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tiagabine: The strong CYP3A4 inhibitor, Fosamprenavir, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Fosamprenavir is initiated, discontinued or dose changed.

Tipranavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Fosamprenavir. Consider alternate therapy.

Tolterodine: Fosamprenavir may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Fosamprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The protease inhibitor, Fosamprenavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fosamprenavir is initiated, discontinued or dose changed.

Triazolam: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, triazolam.

Trimipramine: The strong CYP3A4 inhibitor, Fosamprenavir, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Fosamprenavir is initiated, discontinued or dose changed.

Vardenafil: Fosamprenavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Venlafaxine: Fosamprenavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Fosamprenavir is initiated, discontinued, or dose changed.

Verapamil: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Fosamprenavir is initiated, discontinued or dose changed.

Vinblastine: Fosamprenavir, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Fosamprenavir is initiated, discontinued or dose changed.

Vincristine: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Fosamprenavir is initiated, discontinued or dose changed.

Vinorelbine: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Fosamprenavir is initiated, discontinued or dose changed.

Voriconazole: Voriconazole may increase the serum concentration of fosamprenavir by decreasing its metabolism. Fosamprenavir may increase the serum concentration of voriconazole. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Warfarin: The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of warfarin.

Zolpidem: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if fosamprenavir is initiated, discontinued or dose changed.

Zonisamide: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if fosamprenavir is initiated, discontinued or dose changed.

Zopiclone: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if fosamprenavir is initiated, discontinued or dose changed.