DESCRIPTION

LEXIVA (fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease. The chemical name of fosamprenavir calcium is (3 S )-tetrahydrofuran-3-yl (1 S ,2 R )-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3 S )(1 S ,2 R ) configuration. It has a molecular formula of C ₂₅ H ₃₄ CaN ₃ O ₉ PS and a molecular weight of 623.7.

Fosamprenavir calcium is a white to cream-colored solid with a solubility of approximately 0.31 mg/mL in water at 25°C.

LEXIVA 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 ingred-ients hypromellose, iron oxide red, titanium dioxide, and triacetin.

MICROBIOLOGY

Mechanism of Action:    Fosamprenavir is rapidly converted to amprenavir by cellular phosphatases in vivo. 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 in Vitro:    Fosamprenavir has little or no antiviral activity in vitro. The in vitro antiviral activity observed with fosamprenavir is not measurable due to trace amounts of amprenavir. 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% inhibitory concentration (IC ₅₀ ) 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). Amprenavir exhibited synergistic anti-HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, and zidovudine, and the protease inhibitor (PI) saquinavir, and additive anti-HIV-1 activity in combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine and PIs indinavir, lopinavir, nelfinavir, and ritonavir in vitro. These drug combinations have not been adequately studied in humans. The relationship between in vitro anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.

Resistance:    HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir. Genotypic analysis of isolates from amprenavir-treated patients 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. Of the 488 antiretroviral-naive patients treated with LEXIVA or LEXIVA/ritonavir in studies APV30001 and APV30002 respectively, 61 patients (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virological failure (plasma HIV-1 RNA >1,000 copies/mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive patients (17%) receiving LEXIVA 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-associated mutations were detected in antiretroviral-naive patients treated with LEXIVA/ritonavir in study APV30002.

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 <400 copies/mL) and PI-resistance mutations detected in baseline HIV-1 isolates from PI-experienced patients receiving LEXIVA/ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in study APV30003 is shown in Table 1. The majority of subjects had previously received either one (47%) or 2 PIs (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily LEXIVA/ritonavir, 54% (55) had resistance to at least one PI, with 98% (54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (58) had resistance to at least one PI, with 97% (56) of those having resistance to nelfinavir.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from PI-experienced patients responding to LEXIVA/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.

Isolates from 15 of the 20 patients receiving twice-daily LEXIVA/ritonavir 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.

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults:    Fosamprenavir is a prodrug, which is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed.

The pharmacokinetic properties of amprenavir after administration of LEXIVA, 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.

Absorption and Bioavailability:    After administration of a single dose of LEXIVA to HIV-1-infected patients, the time to peak amprenavir concentration (T _max ) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of LEXIVA in humans has not been established.

The pharmacokinetic parameters of amprenavir after administration of LEXIVA (with and without concomitant ritonavir) are shown in Table 2.

The median plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.

Effects of Food on Oral Absorption:    LEXIVA Tablets may be taken with or without food (see DOSAGE AND ADMINISTRATION ). Administration of a single 1,400-mg dose of LEXIVA in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared to the fasted state was associated with no significant changes in amprenavir C _max , T _max , or AUC _0-(infinity) .

Distribution:    In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha ₁ -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.

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 ¹⁴ C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for >90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Special Populations: Hepatic Insufficiency:    The pharmacokinetics of amprenavir after administration of LEXIVA have not been studied in patients with hepatic insufficiency.

The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE® Capsules to adult patients with impaired hepatic function using a single 600-mg oral dose. The AUC _0-(infinity) of amprenavir was significantly greater in patients with moderate cirrhosis (25.76 ± 14.68 mcg·hr/mL) compared with healthy volunteers (12.00 ± 4.38 mcg·hr/mL). The AUC _0-(infinity) and C _max were significantly greater in patients with severe cirrhosis (AUC _0-(infinity) : 38.66 ± 16.08 mcg·hr/mL; C _max : 9.43 ± 2.61 mcg/mL) compared with healthy volunteers (AUC _0-(infinity) : 12.00 ± 4.38 mcg·hr/mL; C _max : 4.90 ± 1.39 mcg/mL). Based on these data, patients with impaired hepatic function receiving LEXIVA without concurrent ritonavir may require dosage reduction. There are no data on the use of LEXIVA in combination with ritonavir in patients with any degree of hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Renal Insufficiency:    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 to pediatric patients are under investigation. There are insufficient data at this time to recommend a dose.

Geriatric Patients:    The pharmacokinetics of amprenavir after administration of LEXIVA to patients over 65 years of age have not been studied.

Gender:    The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females.

Race:    The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks.

Drug Interactions:    See also CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS : 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 and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, C _max , and C _min values are summarized in Table 3 (effect of other drugs on amprenavir) and Table 5 (effect of LEXIVA on other drugs). In addition, since LEXIVA delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from studies with AGENERASE are provided in Tables 4 and 6. For information regarding clinical recommendations, see PRECAUTIONS : Drug Interactions .

Nucleoside Reverse Transcriptase Inhibitors:    There was no clinically significant effect of amprenavir after administration of AGENERASE on abacavir in subjects receiving both agents based on historical data.

In a Phase III clinical trial (APV30003), plasma amprenavir trough concentrations were similar for subjects receiving tenofovir disoproxil fumarate in combination with LEXIVA and ritonavir as compared to subjects not receiving tenofovir.

HIV Protease Inhibitors:    In a 3-arm, randomized, cross-over study involving healthy volunteers, amprenavir pharmacokinetics were compared after administration of LEXIVA 1,400 mg twice daily plus lopinavir/ritonavir 533 mg/133 mg twice daily for 2 weeks versus LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks. Amprenavir concentrations were lower with the regimen containing lopinavir/ritonavir: C _max was 13% lower, AUC was 26% lower, and C _min was 42% lower. In the same study, lopinavir pharmacokinetics were compared after administration of LEXIVA 1,400 mg twice daily plus lopinavir/ritonavir 533 mg/133 mg twice daily for 2 weeks versus lopinavir/ritonavir 400 mg/100 mg twice daily for 2 weeks. Lopinavir concentrations were similar (less than 10% change in C _max , AUC, and C _min values) with these 2 regimens.

The effect of amprenavir after administration of AGENERASE Capsules on concentrations of other HIV protease inhibitors in subjects receiving both agents was evaluated using comparisons to historical data. Indinavir steady-state C _max , AUC, and C _min were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases in C _max and AUC were seen after the first dose. Saquinavir steady-state C _max , AUC, and C _min were increased 21%, decreased 19%, and decreased 48%, respectively, by concomitant amprenavir. Nelfinavir steady-state C _max , AUC, and C _min were increased by 12%, 15%, and 14%, respectively, by concomitant amprenavir.

Methadone:    Coadministration of amprenavir and methadone can decrease plasma levels of methadone.

Coadministration of amprenavir and methadone as compared to a non-matched historical control group resulted in a 30%, 27%, and 25% decrease in serum amprenavir AUC, C _max , and C _min , respectively.

INDICATIONS AND USAGE

LEXIVA is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.

The following points should be considered when initiating therapy with LEXIVA/ritonavir in protease inhibitor-experienced patients (see Description of Clinical Studies ).

• The protease inhibitor-experienced patient study was not large enough to reach a definitive conclusion that LEXIVA/ritonavir and lopinavir/ritonavir are clinically equivalent.
• Once-daily administration of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced patients.

Description of Clinical Studies:    Therapy-Naive Patients: Study APV30001: APV30001 was a randomized, open-label study, comparing treatment with LEXIVA Tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive patients. Both groups of patients 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 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 ³ (range: 2 to 1,136 cells/mm ³ ; 18% of patients had a CD4+ cell count of <50 cells/mm ³ and 30% were in the range of 50 to <200 cells/mm ³ ). Baseline median HIV-1 RNA was 4.83 log ₁₀ copies/mL (range: 1.69 to 7.41 log ₁₀ copies/mL; 45% of patients had >100,000 copies/mL).

The outcomes of randomized treatment are provided in Table 7.

Treatment response by viral load strata is shown in Table 8.

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells/mm ³ in the group receiving LEXIVA and 216 cells/mm ³ in the nelfinavir group.

Study APV30002:    APV30002 was a randomized, open-label study, comparing treatment with LEXIVA 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 ³ (range: 1 to 1,055 cells/mm ³ ; 20% of patients had a CD4+ cell count of <50 cells/mm ³ and 35% were in the range of 50 to <200 cells/mm ³ ). Baseline median HIV-1 RNA was 4.81 log ₁₀ copies/mL (range: 2.65 to 7.29 log ₁₀ copies/mL; 43% of patients had >100,000 copies/mL).

The outcomes of randomized treatment are provided in Table 9.

Treatment response by viral load strata is shown in Table 10.

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells/mm ³ in the group receiving LEXIVA and 207 cells/mm ³ in the nelfinavir group.

Protease Inhibitor-Experienced Patients: Study APV30003:    APV30003 was a randomized, open-label, multicenter study comparing 2 different regimens of LEXIVA plus ritonavir (LEXIVA Tablets 700 mg twice daily plus ritonavir 100 mg twice daily or LEXIVA 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 ³ (range: 2 to 1,171 cells/mm ³ ). Baseline median plasma HIV-1 RNA level was 4.14 log ₁₀ copies/mL (range: 1.69 to 6.41 log ₁₀ copies/mL).

The median durations of prior exposure to NRTIs were 257 weeks for patients receiving LEXIVA/ritonavir twice daily (79% had >/=3 prior NRTIs) and 210 weeks for patients receiving lopinavir/ritonavir (64% had >/=3 prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving LEXIVA/ritonavir twice daily (49% received >/=2 prior PIs) and 130 weeks for patients receiving lopinavir/ritonavir (40% received >/=2 prior PIs).

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 ₁₀ copies/mL for twice-daily LEXIVA/ritonavir and -1.67 log ₁₀ copies/mL for the lopinavir/ritonavir group.

The proportions of patients who achieved and maintained confirmed HIV-1 RNA <400 copies/mL (secondary efficacy endpoint) were 58% with twice-daily LEXIVA/ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference -16.6, 10.1). The proportions of patients with HIV-1 RNA <50 copies/mL with twice-daily LEXIVA/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/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 ³ with twice-daily LEXIVA/ritonavir and 91 cells/mm ³ with lopinavir/ritonavir.

This study was not large enough to reach a definitive conclusion that LEXIVA/ritonavir and lopinavir/ritonavir are clinically equivalent.

Once-daily administration of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of patients receiving LEXIVA/ritonavir once daily had plasma HIV-1 RNA <400 copies/mL and <50 copies/mL, respectively.

CONTRAINDICATIONS

LEXIVA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of this product or to amprenavir.

Coadministration of LEXIVA with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These drugs are listed in Table 11.

If LEXIVA is coadministered with ritonavir, the antiarrhythmic agents flecainide and propafenone are also contraindicated. Also, refer to the full prescribing information for NORVIR® (ritonavir) for other potential drug interactions.

WARNINGS

Serious and/or life-threatening drug interactions could occur between LEXIVA and amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine. Concentration monitoring of these agents is recommended if these agents are used concomitantly with LEXIVA (see CONTRAINDICATIONS ).

Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in patients treated with amprenavir (see ADVERSE REACTIONS ). Acute hemolytic anemia has been reported in a patient treated with amprenavir.

Rifampin should not be used in combination with LEXIVA because it reduces plasma concentrations of amprenavir by about 90%. The effect of rifampin on amprenavir concentrations when rifampin is administered with LEXIVA plus ritonavir is not known.

Concomitant use of LEXIVA and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of protease inhibitors, including LEXIVA, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in suboptimal levels of amprenavir and lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.

Concomitant use of LEXIVA with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including LEXIVA, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including LEXIVA, are used in combination with these drugs.

Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (e.g., sildenafil or vardenafil) in patients receiving protease inhibitors, including LEXIVA. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS : Drug Interactions and Information for Patients , and the complete specific PDE5 inhibitor prescribing information).

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.

PRECAUTIONS

Sulfa Allergy:    LEXIVA should be used with caution in patients with a known sulfonamide allergy. Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical study of LEXIVA used as the sole protease inhibitor, rash occurred in 2 of 10 patients (20%) with a history of sulfonamide allergy compared with 42 of 126 patients (33%) with no history of sulfonamide allergy. In 2 clinical studies of LEXIVA plus low-dose ritonavir, rash occurred in 8 of 50 patients (16%) with a history of sulfonamide allergy compared with 50 of 412 patients (12%) with no history of sulfonamide allergy.

Hepatic Impairment and Toxicity:    LEXIVA is principally metabolized by the liver; therefore, caution should be exercised when administering LEXIVA to patients with hepatic impairment because amprenavir concentrations may be increased (see CLINICAL PHARMACOLOGY : Special Populations: Hepatic Insufficiency ). Patients with impaired hepatic function receiving LEXIVA without concurrent ritonavir may require dose reduction (see DOSAGE AND ADMINISTRATION ). There are no data on the use of LEXIVA in combination with ritonavir in patients with any degree of hepatic impairment.

Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with LEXIVA and patients should be monitored closely during treatment.

Use of LEXIVA with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used (see OVERDOSAGE and DOSAGE AND ADMINISTRATION ).

Patients With Hemophilia:    There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Immune Reconstitution:    During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Fat Redistribution:    Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy, including LEXIVA. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Elevations:    Treatment with LEXIVA plus ritonavir has resulted in increases in the concentration of triglycerides (see Tables 16 and 17). Triglyceride and cholesterol testing should be performed prior to initiating therapy with LEXIVA and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. (See PRECAUTIONS : Table 12. Drugs That Should Not Be Coadministered with LEXIVA and Table 13: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with LEXIVA and HMG-CoA reductase inhibitors.)

Resistance/Cross-Resistance:    Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with LEXIVA will have on the activity of subsequently administered protease inhibitors. LEXIVA has been studied in patients who have experienced treatment failure with protease inhibitors (see INDICATIONS AND USAGE : Description of Clinical Studies ).

Information for Patients:    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. A Patient Information Sheet for LEXIVA Tablets is available for patient information.

Patients should be informed that LEXIVA 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 are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with LEXIVA 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. Patients should be advised to take LEXIVA every day as prescribed. LEXIVA 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 inform their healthcare provider if they have a sulfa allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown.

LEXIVA 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 because hormonal levels may be altered.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including LEXIVA, and that the cause and long-term health effects of these conditions are not known at this time.

Drug Interactions:    See also CONTRAINDICATIONS , WARNINGS , and CLINICAL PHARMACOLOGY : Drug Interactions .

Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of cytochrome P450 3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4.

Amprenavir is metabolized by CYP3A4. Coadministration of LEXIVA and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of LEXIVA and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects.

The potential for drug interactions with LEXIVA changes when LEXIVA is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when LEXIVA is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with LEXIVA plus ritonavir.

There are other agents that may result in serious and/or life-threatening drug interactions (see CONTRAINDICATIONS and WARNINGS ).

Carcinogenesis and Mutagenesis:    Carcinogenicity studies of fosamprenavir in rats and mice are in progress; however, results are available from carcinogenicity studies with amprenavir. Amprenavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in males of both species at the highest doses tested. Female mice and rats were not affected. These observations were made at systemic exposures equivalent to approximately 2 times (mice) and 4 times (rats) the human exposure (based on AUC _{0-24 hr} measurement) at the recommended dose of 1,200 mg twice daily. Administration of amprenavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Fosamprenavir and amprenavir were not mutagenic or genotoxic in a battery of in vitro and in vivo assays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes.

Impairment of Fertility:    The effects of fosamprenavir on fertility and general reproductive performance were investigated in male (treated for 4 weeks before mating) and female rats (treated for 2 weeks before mating through postpartum day 6). Systemic exposures (AUC _{0-24 hr} ) to amprenavir in these studies were 3 (males) to 4 (females) times higher than exposures in humans following administration of the maximum recommended human dose (MRHD) of fosamprenavir alone or similar to those seen in humans following administration of fosamprenavir in combination with ritonavir. Fosamprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats.

Pregnancy and Reproduction:    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 _{0-24 hr} ) to amprenavir at these dosages were 0.8 (rabbits) to 2 (rats) times the exposures in humans following administration of the 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 ₁ 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 ₁ 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 to control animals. Systemic exposure (AUC _{0-24 hr} ) to amprenavir in the F ₀ 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 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, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers:    The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known if amprenavir is excreted in human milk, amprenavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving LEXIVA.

Pediatric Use:    The safety and efficacy of LEXIVA Tablets have not been established in pediatric patients.

Geriatric Use:    Clinical studies of LEXIVA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adults. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

LEXIVA was studied in 700 patients in Phase III controlled clinical studies. The most common treatment-emergent adverse events in clinical studies of LEXIVA were diarrhea, nausea, vomiting, headache, and rash and were generally mild to moderate in severity. Treatment discontinuation due to adverse events occurred in 6.4% of patients receiving LEXIVA and in 5.9% of patients receiving comparator treatments.

Severe or life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 patients treated with LEXIVA, were reported in <1% of patients treated with LEXIVA in the clinical studies. Treatment with LEXIVA should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.

Skin rash (without regard to causality) occurred in approximately 19% of patients treated with LEXIVA 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 and had a median duration of 13 days. Skin rash led to discontinuation of LEXIVA in <1% of patients. In some patients with mild or moderate rash, dosing with LEXIVA was often continued without interruption; if interrupted, reintroduction of LEXIVA generally did not result in rash recurrence.

Selected adverse events reported during the clinical efficacy studies of LEXIVA are shown in Tables 14 and 15. Each table presents drug-related adverse events of moderate or severe intensity and adverse events of all grades regardless of causality in patients treated with combination therapy for up to 48 weeks.

The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of LEXIVA are presented in Tables 16 and 17.

The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive patients who received LEXIVA in the pivotal studies was <1%.

OVERDOSAGE

In a healthy volunteer repeat-dose pharmacokinetic study evaluating high-dose combinations of LEXIVA plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (>2.5 × ULN) was observed with LEXIVA 1,400 mg twice daily plus ritonavir 200 mg twice daily (4 of 25 subjects). Concurrent Grade 1/2 elevations in AST (>1.25 × ULN) were noted in 3 of these 4 subjects. These transaminase elevations resolved following discontinuation of dosing.

There is no known antidote for LEXIVA. 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.

DOSAGE AND ADMINISTRATION

LEXIVA Tablets may be taken with or without food.

The recommended oral dose of LEXIVA, alone or in combination with ritonavir, is as follows:

Therapy-Naive Patients:

• LEXIVA 1,400 mg twice daily (without ritonavir)
• LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily
• LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily

The twice-daily plus ritonavir dose is supported by pharmacokinetic and safety data (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).

Protease Inhibitor-Experienced Patients:

• LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily

Once-daily administration of LEXIVA plus ritonavir is not recommended in protease inhibitor-experienced patients (see Description of Clinical Studies ).

Adjustment of Ritonavir Dose When LEXIVA Plus Ritonavir are Administered With Efavirenz:    An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA plus ritonavir once daily (see Table 13. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction).

Prescribers should consult the full prescribing information for NORVIR (ritonavir) when using this agent.

High-Dose Combinations of LEXIVA Plus Ritonavir: Higher-than-approved dose combinations of LEXIVA plus ritonavir are not recommended for use (see PRECAUTIONS and OVERDOSAGE ).

Patients With Hepatic Impairment:    LEXIVA Tablets should be used with caution, at a reduced dosage of 700 mg twice daily in patients with mild or moderate hepatic impairment (Child-Pugh score ranging from 5 to 8) receiving LEXIVA without concurrent ritonavir (see CLINICAL PHARMACOLOGY : Hepatic Insufficiency ). LEXIVA should not be used in patients with severe hepatic impairment (Child-Pugh score ranging from 9 to 12) because the dose cannot be reduced below 700 mg. There are no data on the use of LEXIVA in combination with ritonavir in patients with any degree of hepatic impairment.

HOW SUPPLIED

LEXIVA Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets, with "GX LL7" debossed on one face.

Bottles of 60 with child-resistant closures (NDC 0173-0721-00).

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.

GlaxoSmithKline, Research Triangle Park, NC 27709

Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139

LEXIVA is a registered trademark of GlaxoSmithKline.

©2005, GlaxoSmithKline. All rights reserved.

June 2005/RL-2202

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