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Fosamprenavir (Lexiva, Telzir)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
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

GlaxoSmithKline and Vertex Pharmaceuticals

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.(3,4)

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

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
Combinations

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 other protease inhibitors and nonnucleoside reverse transcriptase inhibitors; in most cases, precise information on dosing in combination with other antiretrovirals is lacking. Coadministration of fosamprenavir with lopinavir/ritonavir causes reductions in levels of both amprenavir and lopinavir; it appears that this adverse interaction cannot be overcome by increasing ritonavir levels.(5,6) Coadministration of amprenavir with tipranavir + ritonavir causes a decrease in amprenavir levels; the same effect would be expected to occur with fosamprenavir.(7) 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.(8)

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

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate ritonavir-boosted fosamprenavir (dosed once daily or twice daily), in combination with tenofovir/emtricitabine or abacavir/lamivudine, as "alternative" regimens for initial treatment of HIV infection. The guidelines categorize unboosted fosamprenavir as "not recommended" in initial therapy.

When used in initial therapy, fosamprenavir appears to compare favorably with nelfinavir, either when used as a single protease inhibitor or when boosted with ritonavir. In one Phase III 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 comparing ritonavir-boosted fosamprenavir with 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.(9)

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, similar rates of viral suppression to <400 copies/mL were seen in the fosamprenavir + ritonavir twice-daily group and the lopinavir/ritonavir group (58% and 61%, respectively; 95% CI for the difference: 16.6 -10.1), with comparable CD4 increases of approximately 85 cells/µL. In the once-daily fosamprenavir + ritonavir arm, patients had lower rates of viral suppression: 50% achieved HIV-1 RNA <400 copies/mL.(3,4,10)

Factors Affecting Adherence

Symptomatic adverse effects of fosamprenavir include rash, nausea, and diarrhea. Fosamprenavir appears to induce fewer gastrointestinal adverse effects than amprenavir. Laboratory abnormalities include hyperlipidemia and increases in hepatic transaminase levels. Fosamprenavir is associated with a low pill burden and simple dosing regimen; these factors may increase adherence. It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with fosamprenavir is initiated.

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 I50V, I54L/M, V32I, I47V, and M46I. These mutations do not appear to confer significant cross-resistance to other protease inhibitors. It appears that resistance to fosamprenavir may develop more readily during treatment with unboosted fosamprenavir than during treatment containing ritonavir-boosted fosamprenavir.(11)

Results from clinical studies are needed to elucidate fosamprenavir resistance and its implications for subsequent therapy. 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

Few data are available regarding the efficacy of fosamprenavir in individuals with HIV resistant to other protease inhibitors.

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.  Press release: Vertex Reports Preliminary 48-Week Data from Phase III Study of 433908, an Investigational HIV Protease Inhibitor. 7/24/03. http://www.vpharm.com/Pressreleases2003/pr072403.html
4.  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.
5.  Corbett AH, Davidson L, Park JJ, Patterson K, Eron JJ, Ngo L, Lim ML, Shelton M, Wire MB, and Kashuba ADM. Dose Separation Strategies to Overcome the Pharmacokinetic Interaction of a Triple Protease Inhibitor Regimen Containing Fosamprenavir, Lopinavir, and Ritonavir. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, Feburary 8-11, 2004. Abstract 611.
6.   Kashuba AD, Tierney C, Downey GF, Acosta EP, Vergis EN, Klingman K, Mellors JW, Eshleman SH, Scott TR, Collier AC. Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS. 2005 Jan 28;19(2):145-52.
7.  Walmsley S, Leith J, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone and in combination with saquinavir (SQV), amprenavir(APV), or lopinavir (LPV): Interim analysis of BI1182.51. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract WeOrB1236.
8.   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.
9.   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.
10.  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.
11.   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 March; 518(4):651-655.