Fosamprenavir

Indications

Fosamprenavir is used for:

Adult Dose

HIV Infection Therapy-naive patients 1400 mg PO q12hr (without ritonavir) 1400 mg PO qDay (with ritonavir 100-200 mg qDay) 700 mg PO q12hr (with ritonavir 100 mg q12hr) Protease inhibitor-experienced patients 700 mg PO q12hr (with ritonavir 100 mg q12hr) Coadministration with efavirenz 700 mg PO q12hr (with ritonavir 100 mg q12hr) plus 600 mg efavirenz qDay, or 1400 mg PO qDay (with ritonavir 300 mg qDay) plus 600 mg efavirenz qDay Combination with maraviroc 700 mg PO q12hr (with ritonavir 100 mg q12hr) plus maraviroc 150 mg PO q12hr Pregnant women on fosamprenavir plus ritonavir Indicated for pregnant women who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg before pregnancy and are virologically suppressed (HIV-1 RNA <50 copies/mL) 700 mg PO q12hr (with ritonavir 100 mg q12hr) Lower exposures of amprenavir (active moiety) observed during pregnancy; therefore, closely monitor viral load to ensure viral suppression is maintained Hepatic Impairment Mild (Child-Pugh 5-6): 700 mg PO q12hr without ritonavir (therapy-naive); OR 700 mg q12hr with ritonavir 100 mg qDay (therapy-naive or protease inhibitor-experienced) Moderate (Child-Pugh 7-9): 700 mg PO q12hr (therapy-naive) without ritonavir; OR 450 mg q12hr with ritonavir 100 mg qDay (therapy-naive or protease inhibitor-experienced) Severe (Child-Pugh 10-15): 350 mg PO q12hr without ritonavir (therapy-naive); OR 300 mg q12hr with ritonavir 100 mg qD (therapy-naive or protease-inhibitor experienced)

Child Dose

HIV Infection Protease inhibitor naïve patients <4 weeks: Safety and efficacy not established Indicated for protease inhibitor-naive pediatric patients aged 4 weeks or older, and for protease inhibitor-experienced children aged 6 months or older For infants, use only in those born at 38 weeks' gestation or greater and who have attained a postnatal age of 28 days <11 kg: 45 mg/kg PO q12hr plus ritonavir 7 mg/kg q12hr 11 to <15 kg: 30 mg/kg PO q12hr plus ritonavir 3 mg/kg q12hr 15 kg to <20 kg: 23 mg/kg PO q12hr plus ritonavir 3 mg/kg q12hr >20 kg: 18 mg/kg PO q12hr plus ritonavir 3 mg/kg q12hr NOTE: When dosing with ritonavir, do not exceed adult dose of 700 mg/ritonavir 100 mg q12hr Alternatively, protease inhibitor-naive children aged 2 yr or older may be administered 30 mg/kg PO q12hr (without ritonavir) Unboosted regimen <2 years: Not recommended without ritonavir >2 years and <47 kg: 30 mg/kg/dose PO q12hr; not to exceed 1400 mg PO q12hr >2 years and ?47 kg: 1400 mg PO q12hr Protease inhibitor experienced patients <6 months: Safety and efficacy not established >6 months <11 kg: 45 mg/kg/dose PO q12hr; not to exceed 700 mg fosamprenavir/100 mg ritonavir PO q12hr 11-15 kg: 30 mg/kg/dose PO q12hr plus 3 mg/kg/dose ritonavir PO q12hr; not to exceed 700 mg fosamprenavir/100 mg ritonavir PO q12hr 15 to <20 kg: 23 mg/kg/dose PO q12hr plus 3 mg/kg/dose ritonavir PO q12hr; not to exceed 700 mg fosamprenavir/100 mg ritonavir PO q12hr >20 kg: 18 mg/kg/dose PO q12hr plus 3 mg/kg/dose ritonavir PO q12hr; not to exceed 700 mg fosamprenavir/100 mg ritonavir PO q12hr

Renal Dose

Administration

Contra Indications

Hypersensitivity (eg, Stevens-Johnson syndrome) to fosamprenavir, amprenavir, or other component Concomitant use of drugs that depend heavily on CYP3A4 for clearance; metabolite amprenavir is a strong CYP3A4 inhibitor; use with ritonavir another strong CYP3A4 inhibitor may have additive inhibitory effects; check Drug Interactions Drugs that are contraindicated with fosamprenavir (with or without ritonavir) include lipid modifying agents (eg, lomitapide, lovastatin, simvastatin), alpha1-adrenoreptor agonists (eg, alfuzosin), antiarrhythmics (flecainide, propafenone), rifampin, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam

Precautions

New onset DM, exacerbation of pre-existing DM & hyperglycemia reported with unknown frequency/unknown causal relationship Sulfonamide allergy Monitor labs prior to and during treatment with Hepatitis B or C, or elevated transaminases Few reports of spontaneous bleeding in patients. with Hemophilia A and B During initial treatment, inflammatory response to indolent or residual opportunistic infections may occur and require treatment Fat redistribution with "cushingoid appearance" and "buffalo hump" may occur Increased risk for myocardial infarction (thought to be caused by protease inhibitors increasing risk of hyperlipidemia) Monitor triglycerides and cholesterol levels before initiating, then periodically; initiate clinical management of lipid disorders as required Combination treatment with ritonavir may lead to increased triglyceride level Unknown effect on activity of subsequently administered protease inhibitors Risk of immune reconstitution syndrome if used in combination with other antiretroviral drugs; autoimmune disorders (eg Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment Vomiting more common in children Cases of nephrolithiasis reported with fosamprenavir Acute hemolytic anemia reported with amprenavir Discontinue therapy if severe skin reactions including Stevens-Johnson syndrome occur

Pregnancy-Lactation

Pregnancy There are insufficient prospective pregnancy data from Antiretroviral Pregnancy Registry (APR) to adequately assess risk of adverse developmental outcomes; fosamprenavir use during pregnancy has been evaluated in a limited number of women as reported by the APR; available data from the APR show 2 birth defects in 109 first trimester exposures and 2 birth defects in 36 second and third trimester exposures compared with background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) Limited data are available for use in pregnancy; fosamprenavir 700 mg BID with ritonavir 100 mg BID should only be considered in pregnant patients who are already on a stable fosamprenavir/ritonavir regimen prior to pregnancy, and who are virologically suppressed (HIV-1 RNA <50 copies/mL) Contraception Fosamprenavir may reduce the efficacy of combined hormonal contraceptives; advise patients to use an effective alternative contraceptive method or an additional barrier method of contraception Lactation There is no information available on presence of amprenavir in human milk, the effects of the drug on breastfed infant, or effects of drug on milk production The CDC recommends that HIV1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection

Interactions

Adverse Effects

Side effects of Fosamprenavir : >10% Nausea (30-50%) Rash (16-20%) Fatigue (11-15%) Diarrhea (5-13%) Increased triglycerides (11%) 1-10% Increased serum lipase, ALT, AST (5-10%) in pts. treatment with concomitant ritonavir Vomiting (2-6%) Headache (2-4%) Pruritus (7-8%) Nausea (3-7%) Abdominal pain (≤ 2%) Increased hepatic transaminases (4-8%) <1% Stevens-Johnson syndrome Angioedema Myocardial infarction QT prolongation Nephrolithiasis Hypercholesterolemia Frequency Not Defined Spontaenous bleeding Acute hemolytic anemia Immune reconstitution syndrome Diabetes Mellitus Increase of body fat

Mechanism of Action

Prodrug converted to amprenavir (protease inhibitor) by cellular phosphatases in vivo; 700 mg fosamprenavir equivalent to 600 mg amprenavir Binds to active site of HIV-1 protease and thereby prevents processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature noninfectious viral particle