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 trial 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 [see Dosage and Administration (2.2, 2.3), Clinical Studies (14.2, 14.3)].
• •Dosing of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)].

2.1 General Dosing Information

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 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.
  • oDosing 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.
    • oDosing 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.
    
    

2.3 Pediatric Patients (Aged At Least 4 Weeks To 18 Years)

The recommended dosage of LEXIVA in patients aged at least 4 weeks to 18 years should be calculated based on body weight (kg) and should not exceed the recommended adult dose (Table 1).

^a When dosing with ritonavir, do not exceed the adult dose of LEXIVA 700 mg/ritonavir 100 mg twice-daily dose.

Alternatively, protease inhibitor-naive children aged 2 years and older can be administered LEXIVA (without ritonavir) 30 mg per kg twice daily.

LEXIVA should only be administered to infants born at 38 weeks’ gestation or greater and who have attained a post-natal age of 28 days.

For pediatric patients, pharmacokinetic and clinical data:

• •do not support once-daily dosing of LEXIVA alone or in combination with ritonavir [see Clinical Studies (14.3)].
• •do not support administration of LEXIVA alone or in combination with ritonavir for protease inhibitor‑experienced children younger than 6 months [see Clinical Pharmacology (12.3)].
• •do not support twice-daily dosing of LEXIVA without ritonavir in pediatric patients younger than 2 years [see Clinical Pharmacology (12.3)].

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.

2.4 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).

There are no data to support dosing recommendations for pediatric patients with hepatic impairment.

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 per 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 cytochrome P450 3A4 (CYP3A4) for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (Table 2).

Table 2. Drugs Contraindicated with LEXIVA (Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.)

Drug Class/Drug Name	Clinical Comment
Alpha 1-adrenoreceptor antagonists: Alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
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.
Antipsychotics: Lurasidone	POTENTIAL for serious and/or life-threatening reactions if LEXIVA is coadministered with ritonavir.
Pimozide	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
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 CoA-reductase inhibitors: Lovastatin, simvastatin	POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis.
Non-nucleoside reverse transcriptase inhibitor: Delavirdinea	May lead to loss of virologic response and possible resistance to delavirdine.
PDE5 inhibitors: Sildenafil (REVATIO) (for treatment of pulmonary arterial hypertension)	A safe and effective dose has not been established when used with LEXIVA. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
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 Risk Of Serious Adverse Reactions Due To Drug Interactions

Initiation of LEXIVA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving LEXIVA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of LEXIVA/ritonavir, respectively. These interactions may lead to:

• •Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
• •Clinically significant adverse reactions from greater exposures of LEXIVA/ritonavir.
• •Loss of therapeutic effect of LEXIVA/ritonavir and possible development of resistance.

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during therapy with LEXIVA/ritonavir; review concomitant medications during therapy with LEXIVA/ritonavir; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4), Drug Interactions (7)].

5.2 Skin Reactions

Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 subjects treated with LEXIVA in clinical trials. 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 trial of LEXIVA used as the sole protease inhibitor, rash occurred in 2 of 10 subjects (20%) with a history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy. In 2 clinical trials of LEXIVA plus low-dose ritonavir, rash occurred in 8 of 50 subjects (16%) with a history of sulfonamide allergy compared with 50 of 412 subjects (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-1-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 systems respond 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.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.7 Increase In Body Fat

Increase of body fat has been observed in patients receiving protease inhibitors, 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-1-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 trials of LEXIVA were diarrhea, rash, nausea, vomiting, and headache.
• •Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving LEXIVA and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of LEXIVA (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.

6.1 Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adult Trials

The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1–infected subjects to LEXIVA tablets, including 599 subjects exposed to LEXIVA for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these subjects, 26% were female, 51% white, 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.

Selected adverse reactions reported during the clinical efficacy trials of LEXIVA are shown in Tables 3 and 4. Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks.

^a All subjects also received abacavir and lamivudine twice daily.

^a All subjects also received 2 reverse transcriptase inhibitors.

Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with LEXIVA in the pivotal efficacy trials. 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 less than 1% of subjects. In some subjects 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 subjects with Grade 3 or 4 laboratory abnormalities in the clinical efficacy trials of LEXIVA are presented in Tables 5 and 6.

^a All subjects also received abacavir and lamivudine twice daily.

^b Fasting specimens.

ULN = Upper limit of normal.

The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received LEXIVA in the pivotal trials was less than 1%.

^a All subjects also received 2 reverse transcriptase inhibitors.

^b Fasting specimens.

^c n = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir.

ULN = Upper limit of normal.

Pediatric Trials

LEXIVA with and without ritonavir was studied in 237 HIV-1–infected pediatric subjects aged at least 4 weeks to 18 years in 3 open‑label trials; APV20002, APV20003, and APV29005 [see Clinical Studies (14.3)]. Vomiting and neutropenia occurred more frequently in pediatric subjects compared with adults. Other adverse events occurred with similar frequency in pediatric subjects compared with adults.

The frequency of vomiting among pediatric subjects receiving LEXIVA twice daily with ritonavir was 20% in subjects aged at least 4 weeks to younger than 2 years and 36% in subjects aged 2 to 18 years compared with 10% in adults. The frequency of vomiting among pediatric subjects receiving LEXIVA twice daily without ritonavir was 60% in subjects aged 2 to 5 years compared with 16% in adults.

The median duration of drug‑related vomiting episodes in APV29005 was 1 day (range: 1 to 3 days), in APV20003 was 16 days (range: 1 to 38 days), and in APV20002 was 9 days (range: 4 to 13 days). Vomiting was treatment limiting in 4 pediatric subjects across all 3 trials.

The incidence of Grade 3 or 4 neutropenia (neutrophils less than 750 cells per mm³) seen in pediatric subjects treated with LEXIVA with and without ritonavir was higher (15%) than the incidence seen in adult subjects (3%). Grade 3/4 neutropenia occurred in 10% (5 of 51) of subjects aged at least 4 weeks to younger than 2 years and 16% (28 of 170) of subjects aged 2 to 18 years.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of LEXIVA. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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 Cytochrome P450 Inhibitors And Inducers

Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 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

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.

Coadministration of ADCIRCA in patients on LEXIVA:

In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Coadministration of LEXIVA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

LEXIVA:

Sildenafil: 25 mg every 48 hours.

Tadalafil: no more than 10 mg every 72 hours.

Vardenafil: no more than 2.5 mg every 24 hours.

LEXIVA/ritonavir:

Sildenafil: 25 mg every 48 hours.

Tadalafil: no more than 10 mg every 72 hours.

Vardenafil: no more than 2.5 mg every 72 hours.

Use with increased monitoring for adverse events.

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

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXIVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

There are insufficient prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) to adequately assess the risk of adverse developmental outcomes. Fosamprenavir use during pregnancy has been evaluated in a limited number of women as reported by the APR. Available data from the APR show 2 birth defects in 109 first trimester exposures and 2 birth defects in 36 second and third trimester exposures compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The estimated rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population evaluates women and infants from a limited geographic area, and does not include birth defects in pregnancy outcomes for births that occurred at less than 20 weeks’ gestation.

In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to 2 times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir. In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD.

In the rat pre- and post-natal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately 2 times the exposure in humans at 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 (see Data).

Data

Human Data: Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens (including 109 live births exposed in the first trimester and 36 live births exposed in the second and third trimesters) there were 4 birth defects reported in live-born infants.

Animal Data: Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on gestation Days 6 to 17 and Days 7 to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC_{0-24 h}) approximately 2 times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir. However, increased incidence of abortion was observed in rabbits administered a maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In a study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on gestation Days 8 to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD.

In the rat pre- and post-natal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on gestation Day 6 to lactation/post-partum Day 20. Fosamprenavir caused a reduction in pup survival and body weights. In surviving female offspring from the high-dose group, 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 were observed. Systemic exposure (AUC_{0-24 h}) to amprenavir in rats was approximately 2 times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

There is no information available on the presence of amprenavir in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. When administered to lactating rats, amprenavir was present in milk (see Data). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving LEXIVA.

Data

Amprenavir was excreted into the milk of lactating rats following a single dose of amprenavir (100 mg per kg); a maximal milk concentration was achieved 2 hours post-administration at a milk concentration approximately 1.2 times that of maternal plasma concentrations.

8.3 Females And Males Of Reproductive Potential

Contraception

Use of LEXIVA may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)].

8.4 Pediatric Use

The safety, pharmacokinetic profile, virologic, and immunologic responses of LEXIVA with and without ritonavir were evaluated in protease inhibitor-naive and -experienced HIV-1–infected pediatric subjects aged at least 4 weeks to younger than 18 years and weighing at least 3 kg in 3 open-label trials [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.3)].

Treatment with LEXIVA is not recommended in protease inhibitor-experienced pediatric patients younger than 6 months. The pharmacokinetics, safety, tolerability, and efficacy of LEXIVA in pediatric patients younger than 4 weeks have not been established [see Clinical Pharmacology (12.3)]. Available pharmacokinetic and clinical data do not support once-daily dosing of LEXIVA alone or in combination with ritonavir for any pediatrics or twice-daily dosing without ritonavir in pediatric patients younger than 2 years [see Clinical Pharmacology (12.3), Clinical Studies (14.3)]. See Dosage and Administration (2.3) for dosing recommendations for pediatric patients.

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 (2.4)].

There are no data to support dosing recommendations for pediatric subjects with hepatic impairment.

10 Overdosage

In a healthy volunteer repeat-dose pharmacokinetic trial evaluating high-dose combinations of LEXIVA plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 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 (greater than 1.25 x ULN) were noted in 3 of these 4 subjects. These transaminase elevations resolved following discontinuation of dosing.

There is no known antidote for LEXIVA. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis, although it is unlikely as amprenavir is highly protein bound. 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 - lexiva spl graphic 01

Fosamprenavir calcium is a white to cream-colored solid with a solubility of approximately 0.31 mg per 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 per 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 antiretroviral agent [see Microbiology (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-1-infected subjects; 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 8.

^a Data shown are median (range).

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 EC₅₀ Values against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum)

Figure 1. - lexiva spl graphic 02

Absorption

After administration of a single dose of LEXIVA to HIV-1–infected subjects, 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.

After administration of a single 1,400-mg dose in the fasted state, LEXIVA oral suspension (50 mg per mL) and LEXIVA tablets (700 mg) provided similar amprenavir exposures (AUC); however, the C_max of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet.

Amprenavir is both a substrate for and inducer of P-glycoprotein.

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 C_max, T_max, or AUC_0-∞ [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 C_max, a 0.72-hour delay in T_max, and a 28% reduction in amprenavir AUC_0-∞.

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 per 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 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 greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Specific Populations

Patients with Hepatic Impairment: The pharmacokinetics of amprenavir have been studied after the administration of LEXIVA in combination with ritonavir to adult HIV-1–infected subjects 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 subjects with mild hepatic impairment, by approximately 70% in subjects with moderate hepatic impairment, and by approximately 80% in subjects with severe hepatic impairment compared with HIV-1–infected subjects with normal hepatic function. Protein binding of amprenavir was decreased in subjects with hepatic impairment. The unbound fraction at 2 hours (approximate C_max) ranged between a decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (C_min) increased from 50% to 102% [see Dosage and Administration (2.4)].

The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE capsules to adult subjects with hepatic impairment. Following administration of a single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in subjects with moderate cirrhosis and by approximately 4.5-fold in subjects with severe cirrhosis compared with healthy volunteers [see Dosage and Administration (2.4)].

Patients with Renal Impairment: The impact of renal impairment on amprenavir elimination in adults 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 following administration of LEXIVA oral suspension and LEXIVA tablets, with or without ritonavir, have been studied in a total of 212 HIV-1–infected pediatric subjects enrolled in 3 trials. LEXIVA without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged 2 to 5 years. LEXIVA with ritonavir was administered as LEXIVA 30 mg per kg plus ritonavir 6 mg per kg once daily to children aged 2 to 18 years and as LEXIVA 18 to 60 mg per kg plus ritonavir 3 to 10 mg per kg twice daily to children aged at least 4 weeks to 18 years; body weights ranged from 3 to 103 kg.

Amprenavir apparent clearance decreased with increasing weight. Weight-adjusted apparent clearance was higher in children younger than 4 years, suggesting that younger children require higher mg-per-kg dosing of LEXIVA.

The pharmacokinetics of LEXIVA oral suspension in protease inhibitor-naive infants younger than 6 months (n = 9) receiving LEXIVA 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC₁₂ and C_min than adults receiving twice-daily LEXIVA 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC₁₂, C_max, and C_min were 26.6 mcg•hour per mL, 6.25 mcg per mL, and 0.86 mcg per mL, respectively. Because of expected low amprenavir exposure and a requirement for large volume of drug, twice-daily dosing of LEXIVA alone (without ritonavir) in pediatric subjects younger than 2 years was not studied.

Pharmacokinetic parameters for LEXIVA administered with food and with ritonavir in this patient population at the recommended weight-band–based dosage regimens are provided in Table 9.

^a Recommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis.

Subjects aged 2 to younger than 6 years receiving LEXIVA 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir C_max (n = 9), AUC₁₂ (n = 9), and C_min (n = 19) of 7.15 (5.05, 10.1), 22.3 (15.3, 32.6), and 0.513 (0.384, 0.686), respectively.

Geriatric Patients: The pharmacokinetics of amprenavir after administration of LEXIVA to patients older than 65 years have not been studied [see Use in Specific Populations (8.5)].

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

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

Drug Interaction Studies

[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). Amprenavir is both a substrate for and inducer of P-glycoprotein.

Drug interaction trials 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 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 trials 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 C_max, AUC, and C_min increased by 63%, 45%, and 13%, respectively, compared with historical control.

^c Compared with historical control.

^d Subjects 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 Subjects were receiving nevirapine for at least 12 weeks prior to trial.

^g C_last (C_{12 h} or C_{24 h}).

^h Doses of LEXIVA and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days.

ⁱ Compared with parallel control group.

↑= Increase; ↓= Decrease; ↔ = No change (↑ or ↓ less than or equal to 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 ↓ less than 10%); NA = C_min not calculated for single‑dose trial.

^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 Subjects 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 Subjects were receiving nevirapine for at least 12 weeks prior to trial.

ⁱ Comparison arm of rifabutin 300 mg q.d. for 2 weeks. AUC is AUC_(0-48 h).

↑ = Increase; ↓= Decrease; ↔ = No change (↑ or ↓less than 10%); ND = Interaction cannot be determined as C_min 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 ↓ less than 10%); NA = C_min not calculated for single-dose trial; ND = Interaction cannot be determined as C_min 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 cell culture. The 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 in cell culture. The 50% effective concentration (EC₅₀) of amprenavir ranged from 0.012 to 0.08 microM in acutely infected cells and was 0.41 microM in chronically infected cells (1 microM = 0.50 mcg per mL). The median EC₅₀ value of amprenavir against HIV-1 isolates from clades A to G was 0.00095 microM 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 microM 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 microM. The anti–HIV-1 activity of amprenavir was not antagonistic in combination with the nucleoside reverse transcriptase inhibitors (NRTIs); abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, efavirenz, and nevirapine; the protease inhibitors (PIs) atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir; and the gp41 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 cell culture and obtained from subjects treated with fosamprenavir. Genotypic analysis of isolates from treatment-naive subjects failing amprenavir-containing regimens showed substitutions in the HIV-1 protease resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as substitutions in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated substitutions have also been detected in HIV-1 isolates from antiretroviral-naive subjects treated with LEXIVA. Of the 488 antiretroviral-naive subjects treated with LEXIVA 1,400 mg twice daily or LEXIVA 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, isolates from 61 subjects (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virologic failure (plasma HIV-1 RNA greater than 1,000 copies per mL on 2 occasions on or after Week 12) were genotyped. Isolates from 5 of the 29 antiretroviral-naive subjects (17%) receiving LEXIVA without ritonavir in Trial 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 substitutions were detected in isolates from antiretroviral-naive subjects treated with LEXIVA/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from 1 virologic failure subject receiving LEXIVA/ritonavir once daily at Week 160 (HIV-1 RNA greater than 500 copies per mL). Upon retrospective analysis of stored samples using an ultrasensitive assay, these resistant substitutions were traced back to Week 84 (76 weeks prior to clinical virologic failure).

Cross-Resistance

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level less than 400 copies per mL) and protease inhibitor-resistance substitutions detected in baseline HIV-1 isolates from protease inhibitor-experienced subjects receiving LEXIVA/ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in Trial 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.

^a Results should be interpreted with caution because the subgroups were small.

^b Most subjects had greater than 1 protease inhibitor resistance-associated substitution at baseline.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects 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 subjects 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 substitutions were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Isolates from 4 of the 16 subjects continuing to receive twice-daily LEXIVA/ritonavir up to Week 96 who experienced virologic failure underwent genotypic analysis. Isolates from 2 subjects contained amprenavir resistance-associated substitutions: 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 per kg per day in mice and at doses of 300, 825, or 2,250 mg per kg per 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 per kg per day in female mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats, and at 825 mg per kg per day and 2,250 mg per kg per 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 per kg per day and 2,250 mg per kg per day, and an increase in uterine endometrial adenocarcinoma at 2,250 mg per kg per 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) that received doses of 300, 820, or 2,240 mg per kg per day. Systemic exposures (AUC_{0-24 h}) 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 Trials

APV30001

A randomized, open-label trial evaluated treatment with LEXIVA tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive subjects. Both groups of subjects also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 17 to 70 years); 69% of the subjects were male, 20% were CDC Class C (AIDS), 24% were white, 32% were black, and 44% were Hispanic. At baseline, the median CD4+ cell count was 212 cells per mm³ (range: 2 to 1,136 cells per mm³; 18% of subjects had a CD4+ cell count of less than 50 cells per mm³ and 30% were in the range of 50 to less than 200 cells per mm³). Baseline median HIV-1 RNA was 4.83 log₁₀ copies per mL (range: 1.69 to 7.41 log₁₀ copies per mL; 45% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 15.

^a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).

^b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

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 per mm³ in the group receiving LEXIVA and 216 cells per mm³ in the nelfinavir group.

APV30002

A randomized, open-label trial evaluated 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 subjects. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 18 to 69 years); 73% of the subjects were male, 22% were CDC Class C, 53% were white, 36% were black, and 8% were Hispanic. At baseline, the median CD4+ cell count was 170 cells per mm³ (range: 1 to 1,055 cells per mm³; 20% of subjects had a CD4+ cell count of less than 50 cells per mm³ and 35% were in the range of 50 to less than 200 cells per mm³). Baseline median HIV-1 RNA was 4.81 log₁₀ copies per mL (range: 2.65 to 7.29 log₁₀ copies per mL; 43% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 17.

^a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).

^b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

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

14.2 Protease Inhibitor-Experienced Adult Trials

APV30003

A randomized, open-label, multicenter trial evaluated 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 subjects who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens.

The mean age of the subjects in this trial was 42 years (range: 24 to 72 years); 85% were male, 33% were CDC Class C, 67% were white, 24% were black, and 9% were Hispanic. The median CD4+ cell count at baseline was 263 cells per mm³ (range: 2 to 1,171 cells per mm³). Baseline median plasma HIV-1 RNA level was 4.14 log₁₀ copies per mL (range: 1.69 to 6.41 log₁₀ copies per mL).

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

The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the trial was powered) were -1.4 log₁₀ copies per mL for twice-daily LEXIVA/ritonavir and -1.67 log₁₀ copies per mL for the lopinavir/ritonavir group.

The proportions of subjects who achieved and maintained confirmed HIV-1 RNA less than 400 copies per 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 subjects with HIV-1 RNA less than 50 copies per 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 subjects 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 per mm³ with twice-daily LEXIVA/ritonavir and 91 cells per mm³ with lopinavir/ritonavir.

This trial 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 subjects receiving LEXIVA 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA less than 400 copies per mL and less than 50 copies per mL, respectively.

14.3 Pediatric Trials

Three open-label trials in pediatric subjects aged at least 4 weeks to 18 years were conducted. In one trial (APV29005), twice-daily dosing regimens (LEXIVA with or without ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged 2 to 18 years. In a second trial (APV20002), twice-daily dosing regimens (LEXIVA with ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged at least 4 weeks to younger than 2 years. A third trial (APV20003) evaluated once-daily dosing of LEXIVA with ritonavir; the pharmacokinetic data from this trial did not support a once-daily dosing regimen in any pediatric patient population.

APV29005

LEXIVA: Twenty (18 therapy-naive and 2 therapy-experienced) pediatric subjects received LEXIVA oral suspension without ritonavir twice daily. At Week 24, 65% (13 of 20) achieved HIV-1 RNA less than 400 copies per mL, and the median increase from baseline in CD4+ cell count was 350 cells per mm³.

LEXIVA plus Ritonavir: Forty-nine protease inhibitor-naive and 40 protease inhibitor-experienced pediatric subjects received LEXIVA oral suspension or tablets with ritonavir twice daily. At Week 24, 71% of protease inhibitor-naive (35 of 49) and 55% of protease inhibitor-experienced (22 of 40) subjects achieved HIV-1 RNA less than 400 copies per mL; median increases from baseline in CD4+ cell counts were 184 cells per mm³ and 150 cells per mm³ in protease inhibitor-naive and experienced subjects, respectively.

APV20002

Fifty-four pediatric subjects (49 protease inhibitor-naive and 5 protease inhibitor-experienced) received LEXIVA oral suspension with ritonavir twice daily. At Week 24, 72% of subjects achieved HIV-1 RNA less than 400 copies per mL. The median increases from baseline in CD4+ cell counts were 400 cells per mm³ in subjects aged at least 4 weeks to younger than 6 months and 278 cells per mm³ in subjects aged 6 months to 2 years.

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.

Bottle of 60 with child-resistant closure (NDC 49702-207-18).

Store at controlled room temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Keep container tightly closed.

LEXIVA oral suspension, a white to off-white grape-bubblegum-peppermint–flavored suspension, contains 50 mg of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir in each 1 mL.

Bottle of 225 mL with child-resistant closure (NDC 49702-208-53).

This product does not require reconstitution.

Store in refrigerator or at room temperature (5° to 30°C; 41° to 86°F). Shake vigorously before using. Do not freeze.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, particularly St. John’s wort.

Advise patients receiving PDE5 inhibitors 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 [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7)].

Contraception

Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with LEXIVA because hormonal levels may decrease, and if used in combination with LEXIVA and ritonavir, liver enzyme elevations may occur [see Drug Interactions (7.3), Use in Specific Populations (8.3)].

Severe Skin Reactions

Advise patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, have been reported with LEXIVA. Advise patients to discontinue LEXIVA immediately for severe or life-threatening skin reactions or for moderate rashes accompanied by systemic symptoms [see Warnings and Precautions (5.2), Adverse Reactions (6)].

Sulfa Allergy

Advise patients to 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 [see Warnings and Precautions (5.3)].

Hepatic Toxicity

Advise patients that it is recommended to have laboratory testing before and during therapy as patients with underlying hepatitis B or C or marked elevations of transaminases prior to treatment may be at increased risk for developing or worsening transaminase elevations with use of LEXIVA, particularly at higher than recommended doses which should not be used. [see Warnings and Precautions (5.4)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including LEXIVA is started [see Warnings and Precautions (5.6)].

Increase in Body Fat

Inform patients that an increase of body fat may occur in patients receiving protease inhibitors, including LEXIVA, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)].

Lipid Elevations

Advise patients that it is recommended to have laboratory testing before and during therapy as increases in the concentration of triglycerides and cholesterol have been reported with use of LEXIVA [see Warnings and Precautions (5.8), Adverse Reactions (6)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXIVA during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients that if they miss a dose of LEXIVA, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].

Oral Suspension

Instruct patients to shake the bottle vigorously before each use and inform them that refrigeration of the oral suspension may improve the taste for some patients [see How Supplied/Storage and Handling (16)].

LEXIVA and AGENERASE are trademarks owned by or licensed to the ViiV Healthcare group of companies.

ADCIRCA is a registered trademark owned by Eli Lilly and Company.

The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

Manufactured for:

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 ViiV Healthcare group of companies or its licensor.

LXV:23PI

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

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

Spl Patient Package Insert

If you are taking LEXIVA with ritonavir, do not take the following medicines:

Pregnancy Registry. There is a pregnancy registry for women who take LEXIVA during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with LEXIVA.

Especially tell your healthcare provider if you take:

You can ask your healthcare provider or pharmacist for a list of medicines that interact with LEXIVA. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take LEXIVA with other medicines.

The most common side effects of LEXIVA in adults include:

Keep LEXIVA and all medicines out of the reach of children.

Package Label.Principal Display Panel

PRINCIPAL DISPLAY PANEL

NDC 49702-208-53

LEXIVA^®

(fosamprenavir calcium)

Oral Suspension

50 mg/mL

SHAKE VIGOROUSLY BEFORE USING.

ALERT: Find out about medicines that should NOT be taken with LEXIVA.

225 mL

R_x only

Do not use if shrinkband on bottle is broken or missing.

LEXlVA is a registered trademark of the ViiV Healthcare group of companies

Licensed from

Vertex Pharmaceuticals Incorporated

Cambridge, MA 02139

Made in Canada

©2015, the ViiV Healthcare group of companies

•  10000000136223 Rev. 7/15

Lexiva Oral Suspension 50 mg per mL 225 mL carton - lexiva spl graphic 03

PRINCIPAL DISPLAY PANEL

NDC 49702-207-18

LEXIVA^®

(fosamprenavir calcium)

TABLETS

700 mg

60 Tablets

ALERT: Find out about medicines that should NOT be taken with LEXIVA.

Note to Pharmacist: Do not cover ALERT box with pharmacy label.

R_x only

For use in combination regimens with or without ritonavir.

Each tablet contains 700 mg of fosamprenavir as fosamprenavir calcium. 

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 bottle tightly closed. 

See prescribing information for dosage information. 

LEXIVA is a trademark of ViiV Healthcare. 

Licensed from Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139 

Manufactured for:  

ViiV Healthcare  

Research Triangle Park, NC 27709 

by: 

GlaxoSmithKline 

Research Triangle Park, NC 27709 

Made in Belgium

Rev. 12/16

10000000143789