FDA Label for Lexiva

1 Indications And Usage

LEXIVA^® 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 plus ritonavir in protease inhibitor-experienced patients:

• The protease inhibitor-experienced patient study was not large enough to reach a definitive conclusion that LEXIVA plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)].
• Once-daily administration of LEXIVA plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients.

2 Dosage And Administration

LEXIVA Tablets may be taken with or without food.

Adults should take LEXIVA Oral Suspension without food. Pediatric patients should take LEXIVA Oral Suspension with food [see Clinical Pharmacology (12.3)]. If emesis occurs within 30 minutes after dosing, re-dosing of LEXIVA Oral Suspension should occur.

Higher-than-approved dose combinations of LEXIVA plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)].

When LEXIVA is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.

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.

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).

3 Dosage Forms And Strengths

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

LEXIVA Oral Suspension, 50 mg/mL, is a white to off-white suspension that has a characteristic grape-bubblegum-peppermint flavor.

4 Contraindications

LEXIVA is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.
• when coadministered 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 (Table 1).

Table 1. Drugs Contraindicated With LEXIVA

Drug Class/Drug Name	Clinical Comment
Antiarrhythmics: Flecainide, propafenone	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics if LEXIVA is co-prescribed with ritonavir.
Antimycobacterials: Rifampina	May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	POTENTIAL for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agents: Cisapride	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal products: St. John’s wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.
HMG co-reductase inhibitors: Lovastatin, simvastatin	POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor: Delavirdinea	May lead to loss of virologic response and possible resistance to delavirdine.
Sedative/hypnotics: Midazolam, triazolam	POTENTIAL for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

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

• when coadministered with ritonavir in patients receiving the antiarrhythmic agents flecainide and propafenone. If LEXIVA is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications.

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 Adverse Reactions

• Severe or life-threatening skin reactions have been reported with the use of LEXIVA [see Warnings and Precautions (5.2)].
• The most common moderate to severe adverse reactions in clinical studies of LEXIVA were diarrhea, rash, nausea, vomiting, and headache.
• Treatment discontinuation due to adverse events occurred in 6.4% of patients receiving LEXIVA and in 5.9% of patients receiving comparator treatments. The most common adverse reactions leading to discontinuation of LEXIVA (incidence ≤1% of patients) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.

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 Drug Interactions

See also Contraindications (4), Clinical Pharmacology (12.3).

If LEXIVA is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.

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 (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 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 (AUC_0-24 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)].

10 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 x 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 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. 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.

11 Description

LEXIVA (fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C₂₅H₃₄CaN₃O₉PS and a molecular weight of 623.7. It has the following structural formula:

fosamprenavir calcium chemical structure - 26d3b057 5dd8 4bd5 8c05 2f9c28be35c4 01

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 ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.

LEXIVA Oral Suspension is available in a strength of 50 mg/mL of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir. LEXIVA 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.

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) - 26d3b057 5dd8 4bd5 8c05 2f9c28be35c4 02

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 (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 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.

14.3 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.

16 How Supplied/Storage And Handling

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

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 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.

This product does not require reconstitution.

Store at 5° to 30°C (41° to 86°F). Shake vigorously before using. Do not freeze.

This product is supplied by State of Florida DOH Central Pharmacy as follows:

17 Patient Counseling Information

See FDA-approved Patient Labeling

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.

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _