2.1 Adults

Therapy-Naive Adults

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

Dosing of LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)].

• LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
• Dosing of LEXIVA 700 mg twice daily plus 100 mg ritonavir twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)].

Protease Inhibitor-Experienced Adults

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

2.2 Pediatric Patients (2 to 18 years of age)

The recommended dosage of LEXIVA in patients ≥2 years of age should be calculated based on body weight (kg) and should not exceed the recommended adult dose. The data are insufficient to recommend: (1) once-daily dosing of LEXIVA alone or in combination with ritonavir, and (2) any dosing of LEXIVA in therapy-experienced patients 2 to 5 years of age.

Therapy-Naive 2 to 5 Years of Age

• LEXIVA Oral Suspension 30 mg/kg twice daily, not to exceed the adult dose of LEXIVA 1,400 mg twice daily.

Therapy-Naive ≥6 Years of Age

• Either LEXIVA Oral Suspension 30 mg/kg twice daily not to exceed the adult dose of LEXIVA 1,400 mg twice daily or LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg twice daily not to exceed the adult dose of LEXIVA 700 mg plus ritonavir 100 mg twice daily.

Therapy-Experienced ≥6 Years of Age

• LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.

Other Dosing Considerations

• When administered without ritonavir, the adult regimen of LEXIVA Tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.
• When administered in combination with ritonavir, LEXIVA Tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg.

2.3 Patients With Hepatic Impairment

See Clinical Pharmacology (12.3).Mild Hepatic Impairment (Child-Pugh score ranging from 5 to 6): LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

Moderate Hepatic Impairment (Child-Pugh score ranging from 7 to 9): LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive), or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

Severe Hepatic Impairment (Child-Pugh score ranging from 10 to 15): LEXIVA should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naive) or 300 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

5.1 Drug Interactions

See Table 1 for listings of drugs that are contraindicated due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity [see Contraindications (4), Drug Interactions (7.2)].

5.2 Skin Reactions

Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 patients treated with LEXIVA in clinical studies. Treatment with LEXIVA should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6)].

5.3 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.

5.4 Hepatic Toxicity

Use of LEXIVA with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2), Overdosage (10)]. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with LEXIVA and patients should be monitored closely during treatment.

5.5 Diabetes/Hyperglycemia

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.

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LEXIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

5.7 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.

5.8 Lipid Elevations

Treatment with LEXIVA plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol [see Adverse Reactions (6)]. 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 Drug Interactions (7)].

5.9 Hemolytic Anemia

Acute hemolytic anemia has been reported in a patient treated with amprenavir.

5.10 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.

5.11 Nephrolithiasis

Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving LEXIVA.Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

5.12 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 Clinical Studies (14.2)].

6.1 Clinical Trials

Adults

  The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1 infected patients to LEXIVA Tablets, including 599 patients exposed to LEXIVA for >24 weeks, and 409 patients exposed for >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 1,400 mg once daily plus ritonavir 200 mg once daily, 24% received LEXIVA 1,400 mg twice daily, and 15% received LEXIVA 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 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.

Table 2. Selected Moderate/Severe Clinical Adverse Reactions Reported in ≥2% of Antiretroviral-Naive Adult Patients

aAll patients also received abacavir and lamivudine twice daily.

Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in ≥2% of Protease Inhibitor-Experienced Adult Patients (Study APV30003)

aAll patients also received 2 reverse transcriptase inhibitors.

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.

The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of LEXIVA are presented in Tables 4 and 5.

Table 4. Grade 3/4 Laboratory Abnormalities Reported in ≥2% of Antiretroviral-Naive Adult Patients in Studies APV30001 and APV30002

aAll patients also received abacavir and lamivudine twice daily.

bFasting specimens.

ULN = Upper limit of normal.

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

Table 5. Grade 3/4 Laboratory Abnormalities Reported in ≥2% of Protease Inhibitor-Experienced Adult Patients in Study APV30003

aAll patients also received 2 reverse transcriptase inhibitors.

bFasting specimens.

cn = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir.

ULN = Upper limit of normal.

Pediatric Patients: LEXIVA with and without ritonavir was studied in 144 pediatric patients 2 to 18 years of age in 2 open-label studies. Safety information from 75 pediatric patients receiving LEXIVA twice daily with or without ritonavir follows.

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 twice daily with ritonavir ([30%] all between 2 and 18 years of age) and without ritonavir ([56%] all between 2 and 5 years of age) compared with adults receiving LEXIVA 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 twice daily with ritonavir.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of LEXIVA. 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. 

Cardiac Disorders

Myocardial infarction.

Metabolism and Nutrition Disorders

Hypercholesterolemia.

Nervous System Disorders

Oral paresthesia.

Skin and Subcutaneous Tissue Disorders

Angioedema.

Urogenital

Nephrolithiasis.

7.1 CYP Inhibitors and Inducers

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 (4)].

7.2 Drugs That Should Not Be Coadministered With LEXIVA

See Contraindications (4).

7.3 Established and Other Potentially Significant Drug Interactions

Table 6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.

Table 6. Established and Other Potentially Significant Drug Interactions

a  See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction.

8.1 Pregnancy

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 (AUC0-24 hr) 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 F1 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 F1 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 (AUC0-24 hr) to amprenavir in the F0 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.

8.3 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.

8.4 Pediatric Use

The safety, pharmacokinetic profile, and virologic response of LEXIVA Oral Suspension and Tablets were evaluated in pediatric patients 2 to 18 years of age in 2 open-label studies [see Clinical Studies (14.3)]. No data are available for pediatric patients <2 years of age.

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 [see Adverse Reactions (6.1)].

8.5 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.

8.6 Hepatic Impairment

  Amprenavir 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 (12.3)]. Patients with impaired hepatic function receiving LEXIVA with or without concurrent ritonavir require dose reduction [see Dosage and Administration (2.3)].

12.1 Mechanism of Action

Fosamprenavir is an antiviral agent [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

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.

The pharmacokinetic parameters of amprenavir after administration of LEXIVA (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.

Figure 1. Mean (±SD) Steady-State Plasma Amprenavir Concentrations and Mean IC50 Values Against HIV from Protease Inhibitor-Naive Patients (in the Absence of Human Serum)

Absorption and Bioavailability

After administration of a single dose of LEXIVA to HIV-1-infected patients, the time to peak amprenavir concentration (Tmax) 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.

After administration of a single 1,400-mg dose in the fasted state, LEXIVA Oral Suspension (50 mg/mL) and LEXIVA Tablets (700 mg) provided similar amprenavir exposures (AUC), however, the Cmax 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 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 Cmax, Tmax, or AUC0-∞ [see Dosage and Administration (2)].

Administration of a single 1,400-mg dose of LEXIVA 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 Cmax, a 0.72-hour delay in Tmax, and a 28% reduction in amprenavir AUC0-∞.

Distribution

In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-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 14C-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 Impairment

The pharmacokinetics of amprenavir have been studied after the administration of LEXIVA in combination with ritonavir to adult HIV-1-infected patients with mild, moderate, and severe hepatic impairment. Following 2 weeks of dosing with LEXIVA 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 Cmax) ranged between a decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (Cmin) increased from 50% to 102% [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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 Oral Suspension and LEXIVA Tablets, with or without ritonavir, have been evaluated in 124 patients 2 to 18 years of age. Pharmacokinetic parameters for LEXIVA 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 to patients over 65 years of age have not been studied [see Use in Specific Populations (8.5)].

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 Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7).]

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, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (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 11 and 13. For information regarding clinical recommendations, see Drug Interactions (7).

a Concomitant medication is also shown in this column where appropriate.

b Ritonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control.

c Compared with historical control.

d Patients were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.

e Compared with LEXIVA 700 mg/ritonavir 100 mg b.i.d. for 2 weeks.

f Patients were receiving nevirapine for at least 12 weeks prior to study.

g Compared with parallel control group.

↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓≤10%), NA = Not applicable.

a Compared with parallel control group.

b Median percent change; confidence interval not reported.

c Compared with historical data.

↑ = Increase; ↓ = Decrease; ↔= No change (↑or ↓<10%); NA = Cmin not calculated for single-dose study.

a Concomitant medication is also shown in this column where appropriate.

b Comparison arm of atazanavir 300 mg q.d. plus ritonavir 100 mg q.d. for 10 days.

c Administered as a combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg.

d Patients were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.

e Data represent lopinavir concentrations.

f Compared with lopinavir 400 mg/ritonavir 100 mg b.i.d. for 2 weeks.

g Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged.

h Patients were receiving nevirapine for at least 12 weeks prior to study.††Comparison arm of rifabutin 300 mg q.d. for 2 weeks. AUC is AUC(0-48 hr).

↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓<10%); ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

a Compared with historical data.

b Median percent change; confidence interval not reported.

↑ = Increase; ↓ = Decrease; ↔= No change (↑or ↓<10%); NA = Cmin not calculated for single-dose study; ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

12.4 Microbiology

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 (EC50) 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 EC50 value of amprenavir against HIV-1 isolates from clades A to G was 0.00095 µM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC50 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 EC50 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. Of the 488 antiretroviral-naive patients treated with LEXIVA 1,400 mg twice daily or LEXIVA 1,400 mg plus ritonavir 200 mg once daily in studies APV30001 and APV30002, respectively, 61 patients (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virologic 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 resistance-associated mutations were detected in antiretroviral-naive patients treated with LEXIVA/ritonavir for 48 weeks in study APV30002. However, the M46I and I50V mutations were detected in isolates from 1 virologic failure patient receiving LEXIVA/ritonavir once daily at Week 160 (HIV-1 RNA >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 <400 copies/mL) and protease inhibitor-resistance mutations detected in baseline HIV-1 isolates from protease inhibitor-experienced patients receiving LEXIVA/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/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.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-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 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/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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In long-term carcinogenicity studies, fosamprenavir was administered orally for up to 104 weeks at doses of 250, 400, or 600 mg/kg/day in mice and at doses of 300, 825, or 2,250 mg/kg/day in rats. Exposures at these doses were 0.3- to 0.7-fold (mice) and 0.7- to 1.4-fold (rats) those in humans given 1,400 mg twice daily of fosamprenavir alone, and 0.2- to 0.3-fold (mice) and 0.3- to 0.7-fold (rats) those in humans given 1,400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily. Exposures in the carcinogenicity studies were 0.1- to 0.3-fold (mice) and 0.3- to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. There was an increase in hepatocellular adenomas and hepatocellular carcinomas at all doses in male mice and at 600 mg/kg/day in female mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats, and at 835 mg/kg/day and 2,250 mg/kg/day in female rats. The relevance of the hepatocellular findings in the rodents for humans is uncertain. Repeat dose studies with fosamprenavir in rats produced effects consistent with enzyme induction, which predisposes rats, but not humans, to thyroid neoplasms. In addition, in rats only there was an increase in interstitial cell hyperplasia at 825 mg/kg/day and 2,250 mg/kg/day, and an increase in uterine endometrial adenocarcinoma at 2,250 mg/kg/day. The incidence of endometrial findings was slightly increased over concurrent controls, but was within background range for female rats. The relevance of the uterine endometrial adenocarcinoma findings in rats for humans is uncertain.

Fosamprenavir was 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.

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 (AUC0-24 hr) to amprenavir in these studies were 3 (males) to 4 (females) times higher than exposures in humans following administration of the 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.

14.1 Therapy-Naive Adult 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/mm3 (range: 2 to 1,136 cells/mm3; 18% of patients had a CD4+ cell count of <50 cells/mm3 and 30% were in the range of 50 to <200 cells/mm3). Baseline median HIV-1 RNA was 4.83 log10 copies/mL (range: 1.69 to 7.41 log10 copies/mL; 45% of patients had >100,000 copies/mL).

The outcomes of randomized treatment are provided in Table 15.

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/mm3 in the group receiving LEXIVA and 216 cells/mm3 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/mm3 (range: 1 to 1,055 cells/mm3; 20% of patients had a CD4+ cell count of <50 cells/mm3 and 35% were in the range of 50 to <200 cells/mm3). Baseline median HIV-1 RNA was 4.81 log10 copies/mL (range: 2.65 to 7.29 log10 copies/mL; 43% of patients had >100,000 copies/mL).

The outcomes of randomized treatment are provided in Table 17.

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/mm3 in the group receiving LEXIVA and 207 cells/mm3 in the nelfinavir group.

14.2 Protease Inhibitor-Experienced Adult 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/mm3 (range: 2 to 1,171 cells/mm3). Baseline median plasma HIV-1 RNA level was 4.14 log10 copies/mL (range: 1.69 to 6.41 log10 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 protease inhibitors) and 130 weeks for patients receiving lopinavir/ritonavir (40% received ≥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 log10 copies/mL for twice-daily LEXIVA/ritonavir and -1.67 log10 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/mm3 with twice-daily LEXIVA/ritonavir and 91 cells/mm3 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 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA <400 copies/mL and <50 copies/mL, respectively.

14.3 Pediatric Patients

Two open-label studies in pediatric patients 2 to 18 years of age were conducted. In one study, twice-daily dosing regimens (LEXIVA with or without ritonavir) were evaluated in combination with other antiretroviral agents. A second study evaluated once-daily dosing of LEXIVA with ritonavir; the data from this study were insufficient to support a once-daily dosing regimen in any pediatric patient population.

LEXIVA: Eighteen (16 therapy-naive and 2 therapy-experienced) pediatric patients received LEXIVA Oral Suspension without ritonavir twice daily. At Week 24, 67% (12/18) achieved HIV-1 RNA <400 copies/mL, and the median increase from baseline in CD4+ cell count was 353 cells/mm3.

LEXIVA plus ritonavir: Twenty-seven protease inhibitor-naive and 30 protease inhibitor-experienced pediatric patients received LEXIVA 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 <400 copies/mL; median increases from baseline in CD4+ cell counts were 131 cells/mm3 and 149 cells/mm3 in protease inhibitor-naive and experienced patients, respectively.

17.1 Drug Interactions

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.

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, and if used in combination with LEXIVA and ritonavir, liver enzyme elevations may occur.

17.2 Sulfa Allergy

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.

17.3 Redistribution/Accumulation of Body Fat

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.

17.4 Information About Therapy With LEXIVA

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.

17.5 Oral Suspension

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 and AGENERASE are registered trademarks of GlaxoSmithKline.

GlaxoSmithKline Vertex Pharmaceuticals Incorporated

Research Triangle Park, NC 27709 Cambridge, MA 02139

©2009, GlaxoSmithKline. All rights reserved.

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