Lexiva Information
Lexiva (Fosamprenavir calcium) Indications And Usage
Lexiva (Fosamprenavir calcium) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.
The following points should be considered when initiating therapy with Lexiva (Fosamprenavir calcium) plus ritonavir in protease inhibitor-experienced patients:
Lexiva (Fosamprenavir calcium) Dosage And Administration
Lexiva (Fosamprenavir calcium) Tablets may be taken with or without food.
Adults should take Lexiva (Fosamprenavir calcium) Oral Suspension without food. Pediatric patients should take Lexiva (Fosamprenavir calcium) Oral Suspension with food If emesis occurs within 30 minutes after dosing, re-dosing of Lexiva (Fosamprenavir calcium) Oral Suspension should occur.
Higher-than-approved dose combinations of Lexiva (Fosamprenavir calcium) plus ritonavir are not recommended due to an increased risk of transaminase elevations .
When Lexiva (Fosamprenavir calcium) is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.
Lexiva (Fosamprenavir calcium) Dosage Forms And Strengths
Lexiva (Fosamprenavir calcium) Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets with “GX LL7” debossed on one face.
Lexiva (Fosamprenavir calcium) Oral Suspension, 50 mg/mL, is a white to off-white suspension that has a characteristic grape-bubblegum-peppermint flavor.
Lexiva (Fosamprenavir calcium) Contraindications
Lexiva (Fosamprenavir calcium) is contraindicated:
Lexiva (Fosamprenavir calcium) Adverse Reactions
Adults
The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1 infected patients to Lexiva (Fosamprenavir calcium) Tablets, including 599 patients exposed to Lexiva (Fosamprenavir calcium) for greater than 24 weeks, and 409 patients exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these patients, 26% were female, 51% Caucasian, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received Lexiva (Fosamprenavir calcium) 1,400 mg once daily plus ritonavir 200 mg once daily, 24% received Lexiva (Fosamprenavir calcium) 1,400 mg twice daily, and 15% received Lexiva (Fosamprenavir calcium) 700 mg twice daily plus ritonavir 100 mg twice daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Selected adverse reactions reported during the clinical efficacy studies of Lexiva (Fosamprenavir calcium) are shown in Tables 2 and 3. Each table presents adverse reactions of moderate or severe intensity in patients treated with combination therapy for up to 48 weeks.
a
a
Skin rash (without regard to causality) occurred in approximately 19% of patients treated with Lexiva (Fosamprenavir calcium) in the pivotal efficacy studies. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had a median onset of 11 days after initiation of Lexiva (Fosamprenavir calcium) and had a median duration of 13 days. Skin rash led to discontinuation of Lexiva (Fosamprenavir calcium) in less than 1% of patients. In some patients with mild or moderate rash, dosing with Lexiva (Fosamprenavir calcium) was often continued without interruption; if interrupted, reintroduction of Lexiva (Fosamprenavir calcium) generally did not result in rash recurrence.
The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of Lexiva (Fosamprenavir calcium) are presented in Tables 4 and 5.
a
b
ULN = Upper limit of normal.
The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive patients who received Lexiva (Fosamprenavir calcium) in the pivotal studies was less than 1%.
a
b
c
ULN = Upper limit of normal.
Pediatric Patients:
All adverse events regardless of causality, all drug-related adverse events, and all laboratory events occurred with similar frequency in pediatrics compared with adults, with the exception of vomiting. Vomiting, regardless of causality, occurred more frequently among pediatric patients receiving Lexiva (Fosamprenavir calcium) twice daily with ritonavir ([30%] all aged between 2 and 18 years) and without ritonavir ([56%] all aged between 2 and 5 years) compared with adults receiving Lexiva (Fosamprenavir calcium) twice daily with ritonavir (10%) and without ritonavir (16%). The median duration of drug-related vomiting episodes was 1 day (range: 1 to 62 days). Vomiting required temporary dose interruptions in 4 pediatric patients and was treatment-limiting in 1 pediatric patient, all of whom were receiving Lexiva (Fosamprenavir calcium) twice daily with ritonavir.
In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of Lexiva (Fosamprenavir calcium) . Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Lexiva (Fosamprenavir calcium) .
Cardiac Disorders
Myocardial infarction.
Metabolism and Nutrition Disorders
Hypercholesterolemia.
Nervous System Disorders
Oral paresthesia.
Skin and Subcutaneous Tissue Disorders
Angioedema.
Urogenital
Nephrolithiasis.
Lexiva (Fosamprenavir calcium) Drug Interactions
If Lexiva (Fosamprenavir calcium) is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.
Lexiva (Fosamprenavir calcium) Use In Specific Populations
Pregnancy Category C. Embryo/fetal development studies were conducted in rats (dosed from day 6 to day 17 of gestation) and rabbits (dosed from day 7 to day 20 of gestation). Administration of fosamprenavir to pregnant rats and rabbits produced no major effects on embryo-fetal development; however, the incidence of abortion was increased in rabbits that were administered fosamprenavir. Systemic exposures (AUC) to amprenavir at these dosages were 0.8 (rabbits) to 2 (rats) times the exposures in humans following administration of the maximum recommended human dose (MRHD) of fosamprenavir alone or 0.3 (rabbits) to 0.7 (rats) times the exposures in humans following administration of the MRHD of fosamprenavir in combination with ritonavir. In contrast, administration of amprenavir was associated with abortions and an increased incidence of minor skeletal variations resulting from deficient ossification of the femur, humerus, and trochlea, in pregnant rabbits at the tested dose; approximately one-twentieth the exposure seen at the recommended human dose.
The mating and fertility of the F generation born to female rats given fosamprenavir was not different from control animals; however, fosamprenavir did cause a reduction in both pup survival and body weights. Surviving F female rats showed an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights compared with control animals. Systemic exposure (AUC) to amprenavir in the F pregnant rats was approximately 2 times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir.
There are no adequate and well-controlled studies in pregnant women. Lexiva (Fosamprenavir calcium) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to Lexiva (Fosamprenavir calcium) , an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
The safety, pharmacokinetic profile, and virologic response of Lexiva (Fosamprenavir calcium) Oral Suspension and Tablets were evaluated in pediatric patients aged 2 to 18 years in 2 open-label studies . No data are available for pediatric patients younger than 2 years.
The adverse reaction profile seen in pediatrics was similar to that seen in adults. Vomiting, regardless of causality, was more frequent in pediatrics than in adults .
Lexiva (Fosamprenavir calcium) Overdosage
In a healthy volunteer repeat-dose pharmacokinetic study evaluating high-dose combinations of Lexiva (Fosamprenavir calcium) plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 2.5 x ULN) was observed with Lexiva (Fosamprenavir calcium) 1,400 mg twice daily plus ritonavir 200 mg twice daily (4 of 25 subjects). Concurrent Grade 1/2 elevations in AST (greater than 1.25 x ULN) were noted in 3 of these 4 subjects. These transaminase elevations resolved following discontinuation of dosing.
There is no known antidote for Lexiva (Fosamprenavir calcium) . It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.
Lexiva (Fosamprenavir calcium) Description
Lexiva (Fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium is (3)-tetrahydrofuran-3-yl (1,2)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3)(1,2) configuration. It has a molecular formula of CHCaNOPS and a molecular weight of 623.7. It has the following structural formula:
Fosamprenavir calcium is a white to cream-colored solid with a solubility of approximately 0.31 mg/mL in water at 25°C.
Lexiva (Fosamprenavir calcium) Tablets are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir). Each 700-mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K30. The tablet film-coating contains the inactive ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.
Lexiva (Fosamprenavir calcium) Oral Suspension is available in a strength of 50 mg/mL of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir. Lexiva (Fosamprenavir calcium) Oral Suspension is a white to off-white suspension with a grape-bubblegum-peppermint flavor. Each one milliliter (1 mL) contains the inactive ingredients artificial grape-bubblegum flavor, calcium chloride dihydrate, hypromellose, methylparaben, natural peppermint flavor, polysorbate 80, propylene glycol, propylparaben, purified water, and sucralose.
Lexiva (Fosamprenavir calcium) Clinical Pharmacology
The pharmacokinetic properties of amprenavir after administration of Lexiva (Fosamprenavir calcium) , with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-infected patients; no substantial differences in steady-state amprenavir concentrations were observed between the 2 populations.
The pharmacokinetic parameters of amprenavir after administration of Lexiva (Fosamprenavir calcium) (with and without concomitant ritonavir) are shown in Table 7.
The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.
Absorption and Bioavailability
After administration of a single dose of Lexiva (Fosamprenavir calcium) to HIV-1-infected patients, the time to peak amprenavir concentration (T) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of Lexiva (Fosamprenavir calcium) in humans has not been established.
After administration of a single 1,400-mg dose in the fasted state, Lexiva (Fosamprenavir calcium) Oral Suspension (50 mg/mL) and Lexiva (Fosamprenavir calcium) Tablets (700 mg) provided similar amprenavir exposures (AUC), however, the C of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet.
Effects of Food on Oral Absorption
Administration of a single 1,400-mg dose of Lexiva (Fosamprenavir calcium) Tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir C, T, or AUC∞ .
Administration of a single 1,400-mg dose of Lexiva (Fosamprenavir calcium) Oral Suspension in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with a 46% reduction in C, a 0.72-hour delay in T, and a 28% reduction in amprenavir AUC∞.
Distribution
In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg/mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.
Metabolism
After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.
Amprenavir is both a substrate for and inducer of P-glycoprotein.
Elimination
Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.
Special Populations
Hepatic Impairment
The pharmacokinetics of amprenavir have been studied after the administration of Lexiva (Fosamprenavir calcium) in combination with ritonavir to adult HIV-1-infected patients with mild, moderate, and severe hepatic impairment. Following 2 weeks of dosing with Lexiva (Fosamprenavir calcium) plus ritonavir, the AUC of amprenavir was increased by approximately 22% in patients with mild hepatic impairment, by approximately 70% in patients with moderate hepatic impairment, and by approximately 80% in patients with severe hepatic impairment compared with HIV-1-infected patients with normal hepatic function. Protein binding of amprenavir was decreased in patients with hepatic impairment. The unbound fraction at 2 hours (approximate C) ranged between a decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (C) increased from 50% to 102%
The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE Capsules to adult patients with hepatic impairment. Following administration of a single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in patients with moderate cirrhosis and by approximately 4.5-fold in patients with severe cirrhosis compared with healthy volunteers .
Renal Impairment
The impact of renal impairment on amprenavir elimination in adult patients has not been studied. 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.
Pediatric Patients
The pharmacokinetics of amprenavir after administration of Lexiva (Fosamprenavir calcium) Oral Suspension and Lexiva (Fosamprenavir calcium) Tablets, with or without ritonavir, have been evaluated in 124 patients aged 2 to 18 years. Pharmacokinetic parameters for Lexiva (Fosamprenavir calcium) administered with food and with or without ritonavir in this patient population are provided in Tables 8 and 9 below.
Geriatric Patients
The pharmacokinetics of amprenavir after administration of Lexiva (Fosamprenavir calcium) to patients older than 65 years have not been studied .
Gender
The pharmacokinetics of amprenavir after administration of Lexiva (Fosamprenavir calcium) do not differ between males and females.
Race
The pharmacokinetics of amprenavir after administration of Lexiva (Fosamprenavir calcium) do not differ between blacks and non-blacks.
Drug Interactions
Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT).
Drug interaction studies were performed with Lexiva (Fosamprenavir calcium) and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, C, and C values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of Lexiva (Fosamprenavir calcium) on other drugs). In addition, since Lexiva (Fosamprenavir calcium) delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from studies with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, .
a
b
c
d
e
f
g
h
i
↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓ less than or equal to 10%), NA = Not applicable.
a
b
c
↑ = Increase; ↓ = Decrease; ↔ = No change (↑or ↓ less than 10%); NA = C not calculated for single-dose study.
Concomitant medication is also shown in this column where appropriate.
b
c
d
e
f
g
h
i
(0-48 hr)
↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓
a
b
↑ = Increase; ↓ = Decrease; ↔= No change (↑or ↓ less than 10%); NA = C not calculated for single-dose study; ND = Interaction cannot be determined as C was below the lower limit of quantitation.
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. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.
Antiviral Activity
Fosamprenavir has little or no antiviral activity in vitro. The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% effective concentration (EC) of amprenavir ranged from 0.012 to 0.08 μM in acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 mcg/mL). The median EC value of amprenavir against HIV-1 isolates from clades A to G was 0.00095 µM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC values for amprenavir against monocytes/macrophage tropic HIV-1 isolates (clade B) ranged from 0.003 to 0.075 µM in monocyte/macrophage cultures. The EC values of amprenavir against HIV-2 isolates grown in PBMCs were higher than those for HIV-1 isolates, and ranged from 0.003 to 0.11 µM. Amprenavir exhibited synergistic anti–HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz; and the protease inhibitors atazanavir and saquinavir. Amprenavir exhibited additive anti–HIV-1 activity in combination with the NNRTI nevirapine, the protease inhibitors indinavir, lopinavir, nelfinavir, and ritonavir; and the fusion inhibitor enfuvirtide. These drug combinations have not been adequately studied in humans.
Resistance
HIV-1 isolates with decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir. Genotypic analysis of isolates from treatment-naive patients failing amprenavir-containing regimens showed mutations in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as mutations in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated mutations have also been detected in HIV-1 isolates from antiretroviral-naive patients treated with Lexiva (Fosamprenavir calcium) . Of the 488 antiretroviral-naive patients treated with Lexiva (Fosamprenavir calcium) 1,400 mg twice daily or Lexiva (Fosamprenavir calcium) 1,400 mg plus ritonavir 200 mg once daily in studies APV30001 and APV30002, respectively, 61 patients (29 receiving Lexiva (Fosamprenavir calcium) and 32 receiving Lexiva (Fosamprenavir calcium) /ritonavir) with virologic failure (plasma HIV-1 RNA greater than 1,000 copies/mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive patients (17%) receiving Lexiva (Fosamprenavir calcium) without ritonavir in study APV30001 had evidence of genotypic resistance to amprenavir: I54L/M (n = 2), I54L + L33F (n = 1), V32I + I47V (n = 1), and M46I + I47V (n = 1). No amprenavir resistance-associated mutations were detected in antiretroviral-naive patients treated with Lexiva (Fosamprenavir calcium) /ritonavir for 48 weeks in study APV30002. However, the M46I and I50V mutations were detected in isolates from 1 virologic failure patient receiving Lexiva (Fosamprenavir calcium) /ritonavir once daily at Week 160 (HIV-1 RNA greater than 500 copies/mL). Upon retrospective analysis of stored samples using an ultrasensitive assay, these resistant mutants were traced back to Week 84 (76 weeks prior to clinical virologic failure).
Cross-Resistance
Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level less than 400 copies/mL) and protease inhibitor-resistance mutations detected in baseline HIV-1 isolates from protease inhibitor-experienced patients receiving Lexiva (Fosamprenavir calcium) /ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in study APV30003 is shown in Table 14. The majority of subjects had previously received either one (47%) or 2 protease inhibitors (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily Lexiva (Fosamprenavir calcium) /ritonavir, 54% (n = 55) had resistance to at least one protease inhibitor, with 98% (n = 54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (n = 58) had resistance to at least one protease inhibitor, with 97% (n = 56) of those having resistance to nelfinavir.
a
b
The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced patients responding to Lexiva (Fosamprenavir calcium) /ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for Lexiva (Fosamprenavir calcium) .
Isolates from 15 of the 20 patients receiving twice-daily Lexiva (Fosamprenavir calcium) /ritonavir up to Week 48 and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated mutations were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Isolates from 4 of the 16 patients continuing to receive twice-daily Lexiva (Fosamprenavir calcium) /ritonavir up to Week 96 who experienced virologic failure underwent genotypic analysis. Isolates from 2 patients contained amprenavir resistance-associated mutations: V32I, M46I, and I47V in 1 isolate and I84V in the other.
Lexiva (Fosamprenavir calcium) Clinical Studies
Study APV30001:
The mean age of the patients in this study was 37 years (range: 17 to 70 years), 69% of the patients were males, 20% were CDC Class C (AIDS), 24% were Caucasian, 32% were black, and 44% were Hispanic. At baseline, the median CD4+ cell count was 212 cells/mm (range: 2 to 1,136 cells/mm; 18% of patients had a CD4+ cell count of less than 50 cells/mm and 30% were in the range of 50 to less than 200 cells/mm). Baseline median HIV-1 RNA was 4.83 logcopies/mL (range: 1.69 to 7.41 logcopies/mL; 45% of patients had greater than 100,000 copies/mL).
The outcomes of randomized treatment are provided in Table 15.
a
b
Treatment response by viral load strata is shown in Table 16.
Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells/mmin the group receiving Lexiva (Fosamprenavir calcium) and 216 cells/mm in the nelfinavir group.
APV30002 was a randomized, open-label study, comparing treatment with Lexiva (Fosamprenavir calcium) Tablets (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir (1,250 mg twice daily) in 649 treatment-naive patients. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).
The mean age of the patients in this study was 37 years (range: 18 to 69 years), 73% of the patients were males, 22% were CDC Class C, 53% were Caucasian, 36% were black, and 8% were Hispanic. At baseline, the median CD4+ cell count was 170 cells/mm (range: 1 to 1,055 cells/mm; 20% of patients had a CD4+ cell count of less than 50 cells/mmand 35% were in the range of 50 to less than 200 cells/mm). Baseline median HIV-1 RNA was 4.81 logcopies/mL (range: 2.65 to 7.29 logcopies/mL; 43% of patients had greater than 100,000 copies/mL).
The outcomes of randomized treatment are provided in Table 17.
a
b
Treatment response by viral load strata is shown in Table 18.
Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells/mmin the group receiving Lexiva (Fosamprenavir calcium) and 207 cells/mm in the nelfinavir group.
APV30003 was a randomized, open-label, multicenter study comparing 2 different regimens of Lexiva (Fosamprenavir calcium) plus ritonavir (Lexiva (Fosamprenavir calcium) Tablets 700 mg twice daily plus ritonavir 100 mg twice daily or Lexiva (Fosamprenavir calcium) Tablets 1,400 mg once daily plus ritonavir 200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 patients who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens.
The mean age of the patients in this study was 42 years (range: 24 to 72 years), 85% were male, 33% were CDC Class C, 67% were Caucasian, 24% were black, and 9% were Hispanic. The median CD4+ cell count at baseline was 263 cells/mm (range: 2 to 1,171 cells/mm). Baseline median plasma HIV-1 RNA level was 4.14 log copies/mL (range: 1.69 to 6.41 log copies/mL).
The median durations of prior exposure to NRTIs were 257 weeks for patients receiving Lexiva (Fosamprenavir calcium) /ritonavir twice daily (79% had greater than or equal to 3 prior NRTIs) and 210 weeks for patients receiving lopinavir/ritonavir (64% had greater than or equal to 3 prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving Lexiva (Fosamprenavir calcium) /ritonavir twice daily (49% received greater than or equal to 2 prior protease inhibitors) and 130 weeks for patients receiving lopinavir/ritonavir (40% received greater than or equal to 2 prior protease inhibitors).
The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the study was powered) were -1.4 log copies/mL for twice-daily Lexiva (Fosamprenavir calcium) /ritonavir and -1.67 log copies/mL for the lopinavir/ritonavir group.
The proportions of patients who achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (secondary efficacy endpoint) were 58% with twice-daily Lexiva (Fosamprenavir calcium) /ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference: -16.6, 10.1). The proportions of patients with HIV-1 RNA less than 50 copies/mL with twice-daily Lexiva (Fosamprenavir calcium) /ritonavir and with lopinavir/ritonavir were 46% and 50%, respectively (95% CI for the difference: -18.3, 8.9). The proportions of patients who were virologic failures were 29% with twice-daily Lexiva (Fosamprenavir calcium) /ritonavir and 27% with lopinavir/ritonavir.
The frequency of discontinuations due to adverse events and other reasons, and deaths were similar between treatment arms.
Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 81 cells/mm with twice-daily Lexiva (Fosamprenavir calcium) /ritonavir and 91 cells/mm with lopinavir/ritonavir.
This study was not large enough to reach a definitive conclusion that Lexiva (Fosamprenavir calcium) /ritonavir and lopinavir/ritonavir are clinically equivalent.
Once-daily administration of Lexiva (Fosamprenavir calcium) plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of patients receiving Lexiva (Fosamprenavir calcium) 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL, respectively.
Two open-label studies in pediatric patients aged 2 to 18 years were conducted. In one study, twice-daily dosing regimens (Lexiva (Fosamprenavir calcium) with or without ritonavir) were evaluated in combination with other antiretroviral agents. A second study evaluated once-daily dosing of Lexiva (Fosamprenavir calcium) with ritonavir; the data from this study were insufficient to support a once-daily dosing regimen in any pediatric patient population.
Lexiva (Fosamprenavir calcium) : Eighteen (16 therapy-naive and 2 therapy-experienced) pediatric patients received Lexiva (Fosamprenavir calcium) Oral Suspension without ritonavir twice daily. At Week 24, 67% (12/18) achieved HIV-1 RNA less than 400 copies/mL, and the median increase from baseline in CD4+ cell count was 353 cells/mm.
Lexiva (Fosamprenavir calcium) plus ritonavir: Twenty-seven protease inhibitor-naive and 30 protease inhibitor-experienced pediatric patients received Lexiva (Fosamprenavir calcium) Oral Suspension or Tablets with ritonavir twice daily. At Week 24, 70% of protease inhibitor-naive (19/27) and 57% of protease inhibitor-experienced (17/30) patients achieved HIV-1 RNA less than 400 copies/mL; median increases from baseline in CD4+ cell counts were 131 cells/mm and 149 cells/mm in protease inhibitor-naive and experienced patients, respectively.
Lexiva (Fosamprenavir calcium) How Supplied/storage And Handling
Lexiva (Fosamprenavir calcium) Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets, with “GX LL7” debossed on one face.
Bottle of 60 with child-resistant closure (NDC 49702-207-18).
Store at controlled room temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Keep container tightly closed.
Lexiva (Fosamprenavir calcium) Oral Suspension, a white to off-white grape-bubblegum-peppermint-flavored suspension, contains 50 mg of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir in each 1 mL.
Bottle of 225 mL with child-resistant closure (NDC 49702-208-53).
This product does not require reconstitution.
Store at 5° to 30°C (41° to 86°F). Shake vigorously before using. Do not freeze.
Lexiva (Fosamprenavir calcium) Patient Counseling Information
See FDA-approved Patient Labeling (Patient Information).
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with Lexiva (Fosamprenavir calcium) .
Lexiva (Fosamprenavir calcium) may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, particularly St. John's wort.
Patients receiving PDE5 inhibitors should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism, and should promptly report any symptoms to their healthcare provider.
Patients receiving hormonal contraceptives should be instructed to use alternate contraceptive measures during therapy with Lexiva (Fosamprenavir calcium) because hormonal levels may be altered, and if used in combination with Lexiva (Fosamprenavir calcium) and ritonavir, liver enzyme elevations may occur.
Patients should be informed that Lexiva (Fosamprenavir calcium) is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of Lexiva (Fosamprenavir calcium) are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with Lexiva (Fosamprenavir calcium) can reduce the risk of transmitting HIV to others.
Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using Lexiva (Fosamprenavir calcium) . Patients should be advised to take Lexiva (Fosamprenavir calcium) every day as prescribed. Lexiva (Fosamprenavir calcium) must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.
Patients should be instructed to shake the bottle vigorously before each use and that refrigeration of the oral suspension may improve the taste for some patients.
Lexiva (Fosamprenavir calcium) and AGENERASE are registered trademarks of ViiV Healthcare.
The brands listed are trademarks of their respective owners and are not trademarks of ViiV Healthcare. The makers of these brands are not affiliated with and do not endorse ViiV Healthcare or its products.
Manufactured for:
by:
GlaxoSmithKline
Research Triangle Park, NC 27709
©2011, ViiV Healthcare. All rights reserved.
May 2011
LXV:13PI
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
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Lexiva (Fosamprenavir calcium)
Lexiva (Fosamprenavir calcium)
Lexiva (Fosamprenavir calcium)
