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Fosamprenavir (Lexiva, Telzir)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Interactions with Other Drugs
Resistance
Implications of fosamprenavir resistance for treatment with other antiretrovirals.
Implications of resistance to other antiretrovirals for fosamprenavir treatment
References
Related Resources
DHHS Guidelines
Characteristics of PIs
Drug Interactions with PIs
Interactions among PIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Fosamprenavir (Lexiva)
Class

Protease inhibitor

Background
U.S. Manufacturer

ViiV Healthcare

Approval

Fosamprenavir was approved by the U.S. Food and Drug Administration (FDA) in October 2003 for use in adults with HIV infection. In 2007, it was approved for treatment of children 2 years of age and older, and in 2012, approval was extended to children aged 4 weeks and older. Fosamprenavir is a prodrug of amprenavir, which was previously licensed for treatment of HIV infection. As of October 2007, fosamprenavir is the only amprenavir product available in the United States.

FDA approval was based on 3 Phase III studies, 2 in previously untreated patients and 1 in patients with prior protease inhibitor treatment. An open-label study compared fosamprenavir (without ritonavir boosting) with nelfinavir, each given twice daily with abacavir + lamivudine in previously untreated patients. At 48 weeks, higher rates of virologic suppression and CD4 T-lymphocyte increase were seen in the fosamprenavir treatment arm.(1) A second open-label study in previously untreated patients compared a once-daily combination of fosamprenavir + ritonavir with standard-dose nelfinavir, each in combination with twice-daily abacavir + lamivudine. Similar rates of virologic suppression and CD4 increase were observed in the 2 groups.(2)

In patients with prior virologic failure on 1 or 2 regimens containing a protease inhibitor, 2 combinations of ritonavir-boosted fosamprenavir were compared with lopinavir/ritonavir (Kaletra). Each regimen included 2 active nucleoside analogues. Through week 48, similar rates of virologic suppression and CD4 increase were seen in the twice-daily fosamprenavir + ritonavir group and in the lopinavir/ritonavir group; higher rates of virologic failure were seen in the third treatment group, in which fosamprenavir + ritonavir was given once daily.(3)

Formulation and Dosing

Fosamprenavir is available in tablet and oral suspension formulations. It is approved for twice-daily dosing; in adults, it also is approved for once-daily dosing when used in combination with ritonavir. For treatment-experienced patients, only the twice-daily combination of fosamprenavir + ritonavir is recommended.

Dosing of Fosamprenavir
Adult*Single PI

1,400 mg BID

Boosted

Fosamprenavir 700 mg BID + ritonavir 100 mg BID
Fosamprenavir 1,400 mg QD + ritonavir 200 mg QD
Fosamprenavir 1,400 mg QD + ritonavir 100 mg QD

PediatricAge <4 weeksNot FDA approved

Age ≥4 weeks (if no previous treatment with protease inhibitors) or age ≥6 months (if previous treatment with protease inhibitors)

<11 kg

11 kg to <15 kg

15 kg to <20 kg

≥20 kg

(Weight >39 kg: may give adult dosage, using tablet formulation of fosamprenavir)





Fosamprenavir 45 mg/kg (oral suspension) BID + ritonavir 7 mg/kg BID#
Fosamprenavir 30 mg/kg (oral suspension) BID + ritonavir 3 mg/kg BID#
Fosamprenavir 23 mg/kg (oral suspension) BID + ritonavir 3 mg/kg BID#
Fosamprenavir 18 mg/kg (oral suspension#) BID + ritonavir 3 mg/kg BID#

Unboosted PI option: age ≥2 years, no previous treatment with protease inhibitors

(Weight >47 kg: may give adult dosage, using tablet formulation of fosamprenavir)

30 mg/kg BID (oral suspension), not to exceed 1,400 mg BID

Abbreviations: BID = twice daily; PI = protease inhibitor; QD = once daily

* For protease inhibitor-experienced patients, adults and children, fosamprenavir is not recommended as a single PI; in these patients, only twice-daily dosing of fosamprenavir + ritonavir is recommended.

# Dosages should not exceed fosamprenavir 700 mg BID + ritonavir 100 mg BID.

There are no food restrictions.
Fosamprenavir interacts with a number of antiretroviral medications, including efavirenz, nevirapine, lopinavir/ritonavir, tipranavir, and other protease inhibitors; dose adjustments may be required and certain combinations are contraindicated. See Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for fosamprenavir with other antiretrovirals.
No dose adjustment is necessary in renal insufficiency.
Dosage adjustment is necessary in hepatic insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category C.
Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services state that fosamprenavir is "not recommended" in initial therapy.

In Phase III studies of initial therapy, fosamprenavir compared favorably with nelfinavir, both when used as a single protease inhibitor and when boosted with ritonavir. In the study (see "Approval") of twice-daily fosamprenavir + abacavir + lamivudine vs nelfinavir + abacavir + lamivudine, similar rates of viral suppression were seen through 48 weeks (by intent-to-treat analysis, viral load <50 copies/mL in 55% of fosamprenavir recipients and 41% of nelfinavir recipients; 95% confidence interval [CI]: 2%, 28%). In patients with baseline viral loads >100,000 copies/mL, the fosamprenavir arm appeared to achieve higher rates of viral suppression to <400 copies/mL. Median CD4 increases were 201-216 cells/µL.(1)

In the second comparison of fosamprenavir and nelfinavir in initial therapy, a once-daily combination of fosamprenavir boosted with low-dose ritonavir was used. Patients in both arms were also given twice-daily abacavir and lamivudine. Through week 48, by intent-to-treat analysis, comparable rates of viral suppression to <50 copies/mL were seen in the fosamprenavir + ritonavir group (55%) and the nelfinavir group (53%) (95% CI: -6%, 10%). In patients with baseline viral load >500,000 copies/mL, higher rates of viral suppression to <400 copies/mL were seen in the fosamprenavir + ritonavir group (73% vs 53%). Median CD4 increases were similar in the two groups (approximately 205 cells/µL).(2)

In a study evaluating ritonavir-boosted fosamprenavir and lopinavir/ritonavir in initial therapy, each boosted protease inhibitor was given twice daily in combination with once-daily abacavir + lamivudine. At 48 weeks, by intent-to-treat analysis, the proportion of subjects with viral suppression to <50 copies/mL was 66% in the fosamprenavir + ritonavir group and 65% in the lopinavir/ritonavir group. CD4 count increases were 176 cells/µL and 191 cells/µL, respectively.(4) In a small randomized comparison of fosamprenavir and atazanavir, each given once daily with ritonavir and tenofovir + emtricitabine , rates of HIV RNA <40 copies/mL at 48 weeks were 75% and 83%, respectively; p = .34.(5)

In patients with prior virologic failure on 1 or 2 protease inhibitors, a Phase III study compared 2 regimens containing fosamprenavir + ritonavir (a twice-daily combination and a once-daily combination) with fixed-dose lopinavir/ritonavir, each in combination with two active nucleoside analogues (dosed twice daily). At 48 weeks, lower rates of viral suppression to <50 copies/mL were seen in the fosamprenavir + ritonavir groups than in the lopinavir/ritonavir group (50% in the lopinavir/ritonavir group, 46% in the twice-daily fosamprenavir + ritonavir group); viral suppression was even less likely in the once-daily fosamprenavir + ritonavir arm.(3,6)

Potential Adverse Effects

Symptomatic adverse effects of fosamprenavir include rash, nausea, and diarrhea. Fosamprenavir contains a sulfonamide moiety and should be used cautiously in patients with sulfa allergy. Laboratory abnormalities include hyperlipidemia and increases in hepatic transaminase levels.

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with fosamprenavir is initiated.

Fosamprenavir has not been studied thoroughly in patients taking the drug during pregnancy; it is classified as an FDA Pregnancy Category C drug.

Interactions with Other Drugs

As with other antiretrovirals, fosamprenavir should be used only in combination regimens.

Amprenavir, the active metabolite of fosamprenavir, is metabolized by the cytochrome P450 3A4 (CYP3A4) isoenzyme, and may alter the concentrations of other drugs metabolized by this pathway, including rifabutin, hormonal contraceptives, ergot derivatives, certain benzodiazepines, antiarrhythmics, lipid-lowering agents, and others. Similarly, drugs or herbal preparations that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in amprenavir levels. For example, rifampin induces CYP3A4, and markedly decreases amprenavir levels.

Fosamprenavir has not been thoroughly studied in combination with nonnucleoside reverse transcriptase inhibitors or integrase inhibitors; in most cases, precise information on dosing in combination with other antiretrovirals is lacking. Coadministration of fosamprenavir with efavirenz has been shown to decrease amprenavir levels, but boosting with sufficient doses of ritonavir may maintain therapeutic amprenavir levels in the presence of efavirenz.(7) Fosamprenavir should not be used with etravirine or elvitegravir/cobicistat. Coadministration with dolutegravir requires dose adjustment of dolutegravir.

Information on drug interactions should be consulted, as dose adjustments are frequently required and some combinations are contraindicated.

Resistance

Resistance to fosamprenavir is associated with the selection of 1 or more of several resistance mutations.

Implications of fosamprenavir resistance for treatment with other antiretrovirals.

Mutations selected by fosamprenavir are also characteristic of amprenavir resistance, and include V32I, M46I, I47V, I50V, I54L/M, and I84V. Some mutations selected by fosamprenavir may confer significant cross-resistance to darunavir and other protease inhibitors. Resistance to fosamprenavir may develop more readily during treatment with unboosted fosamprenavir than during treatment containing ritonavir-boosted fosamprenavir.(8)

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing fosamprenavir.

Implications of resistance to other antiretrovirals for fosamprenavir treatment

Resistance mutations selected by other protease inhibitors may contribute to darunavir resistance. Mutations at protease codons 33, 46, 54, 82, 84, and others may confer cross-resistance to fosamprenavir.

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to fosamprenavir following failure of regimens containing other antiretrovirals, but further clinical studies are needed to clarify this question.

References
1.   Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE, Millard JM, Wannamaker PG. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):22-32.
2.   Gathe JC Jr, Ive P, Wood R, Schurmann D, Bellos NC, DeJesus E, Gladysz A, Garris C, Yeo J. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. 2004 Jul 23;18(11):1529-37.
3.  DeJesus E, LaMarca A, Sension M, Beltran C, Yeni P. The Context Study: Efficacy and Safety of GW433908/RTV in PI-experienced Subjects with Virological Failure (24 Week Results). 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 10-14, 2003. Abstract 178.
4.   Eron J Jr, Yeni P, Gathe J Jr, Estrada V, DeJesus E, Staszewski S, Lackey P, Katlama C, Young B, Yau L, Sutherland-Phillips D, Wannamaker P, Vavro C, Patel L, Yeo J, Shaefer M; KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet. 2006 Aug 5;368(9534):476-82.
5.   Smith KY, Weinberg WG, Dejesus E, Fischl MA, Liao Q, Ross LL, Pakes GE, Pappa KA, Lancaster CT; ALERT (COL103952) Study Team. Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS Res Ther. 2008 Mar 28;5:5.
6.  Elston RC, Yates P, Tisdale M, Richards N, White S, DeJesus E. GW433908 (908)/ritonavir (r): 48 week results in PI-experienced subjects: A retrospective analysis of virological response based on baseline genotype and phenotype. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract MoOrB1055.
7.   Wire MB, Ballow C, Preston SL, Hendrix CW, Piliero PJ, Lou Y, Stein DS. Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. AIDS. 2004 Apr 9;18(6):897-907.
8.   MacManus S, Yates PJ, Elston RC, White S, Richards N, Snowden W. GW433908/ritonavir once daily in antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks. AIDS. 2004 Mar 5;18(4):651-5.