Lexiva

Overdose

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 ½ 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.

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.
Antipsychotics: 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

Undesirable effects

• Severe or life-threatening skin reactions have been reported with the use of LEXIVA.
• 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.

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.

Table 3: Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects

Adverse Reaction	APV300001a	APV30002a
LEXIVA 1,400 mg b.i.d. (n=661)	Nelfinavir 1,250 mg b.i.d. (n=83)	LEXIVA 1,400 mg q.d./ Ritonavir200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n=327)
Gastrointestinal
Diarrhea	5%	18%	10%	18%
Nausea	7%	4%	7%	5%
Vomiting	2%	4%	6%	4%
Abdominal pain	1%	0%	2%	2%
Skin
Rash	8%	2%	3%	2%
General disorders
Fatigue	2%	1%	4%	2%
Nervous system
Headache	2%	4%	3%	3%
a All subjects also received abacavir and lamivudine twice daily.

Table 4: Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003)

Adverse Reaction	LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 106)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Gastrointestinal
Diarrhea	13%	11%
Nausea	3%	9%
Vomiting	3%	5%
Abdominal pain	<1%	2%
Skin
Rash	3%	0%
Nervous system
Headache	4%	2%
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.

Table 5: Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002

Laboratory Abnormality	APV30001a	APV30002a
LEXIVA 1,400 mg b.i.d. (n = 166)	Nelfinavir 1,250 mg b.i.d. (n = 83)	LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n = 327)
ALT (>5 x ULN)	6%	5%	8%	8%
AST (>5 x ULN)	6%	6%	6%	7%
Serum lipase (>2 x ULN)	8%	4%	6%	4%
Triglyceridesb(>750 mg/dL)	0%	1%	6%	2%
Neutrophil count, absolute (<750 cells/mm³)	3%	6%	3%	4%
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%.

Table 6: Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003

Laboratory Abnormality	LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 104)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Triglyceridesb (>750 mg/dL)	11%c	6%c
Serum lipase (>2 x ULN)	5%	12%
ALT (>5 x ULN)	4%	4%
AST (>5 x ULN)	4%	2%
Glucose (>251 mg/dL)	2%c	2%c
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. 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.

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.

Therapeutic indications

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.
• Once-daily administration of LEXIVA plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients.
• Dosing of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months.

Pharmacokinetic properties

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.

Table 8: Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Adults

Regimen	Cmax (mcg/mL)	Tmax (hours)a	AUC24 (mcg•h/mL)	Cmin (mcg/mL)
LEXIVA 1,400 mg b.i.d.	4.82 (4.06-5.72)	1.3 (0.8-4.0)	33.0 (27.6-39.2)	0.35 (0.27-0.46)
LEXIVA 1,400 mg q.d. plus Ritonavir 200 mg q.d.	7.24 (6.32-8.28)	2.1 (0.8-5.0)	69.4 (59.7-80.8)	1.45 (1.16-1.81)
LEXIVA 1,400 mg q.d. plus Ritonavir 100 mg q.d.	7.93 (7.25-8.68)	1.5 (0.75-5.0)	66.4 (61.1-72.1)	0.86 (0.74-1.01)
LEXIVA 700 mg b.i.d. plus Ritonavir 100 mg b.i.d.	6.08 (5.38-6.86)	1.5 (0.75-5.0)	79.2 (69.0-90.6)	2.12 (1.77-2.54)
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)

Absorption

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

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

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 Cmax, Tmax, or AUC0-∞.

Administration of a single 1,400-mg dose of LEXIVA oral suspension in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with a 46% reduction in Cmax, a 0.72-hour delay in Tmax, and a 28% reduction in amprenavir AUC0-∞.

Distribution

In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg 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.

Date of revision of the text

Dec 2017

Name of the medicinal product

Lexiva

Fertility, pregnancy and lactation

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 (AUC0-24 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 (AUC0-24 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.

Qualitative and quantitative composition

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.

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.

Manufactured for: ViiV Healthcare, Vertex Pharmaceuticals Incorporated, Research Triangle Park, NC 27709, Cambridge, MA 02139. by: GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Dec 2017

Special warnings and precautions for use

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS 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. 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.

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.

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.

Hepatic Toxicity

Use of LEXIVA with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used. 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.

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.

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.

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.

Lipid Elevations

Treatment with LEXIVA plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol. 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.

Hemolytic Anemia

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

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.

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.

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.

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.

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.

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.

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.

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..

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.

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.

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.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXIVA during pregnancy.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

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.

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.

Nonclinical Toxicology 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 (AUC0-24 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.

Use In Specific Populations 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 (AUC0-24 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 (AUC0-24 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.

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.

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.

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.

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. 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 DOSAGE AND ADMINISTRATION for dosing recommendations for pediatric patients.

Geriatric Use

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

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. Patients with impaired hepatic function receiving LEXIVA with or without concurrent ritonavir require dose reduction.

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

Dosage (Posology) and method of administration

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. 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.

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

Adults Therapy-Naive Adults

• LEXIVA 1,400 mg twice daily (without ritonavir).
• LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily.
• LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily.
  • Dosing of LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data.
• LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
  • Dosing of LEXIVA 700 mg twice daily plus 100 mg ritonavir twice daily is supported by pharmacokinetic and safety data.

Protease Inhibitor-Experienced Adults

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

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).

Table 1: Twice-Daily Dosage Regimens by Weight for Protease Inhibitor-Naive Pediatric Patients (Aged 4 Weeks and Older) and for Protease Inhibitor-Experienced Pediatric Patients (Aged 6 Months and Older) Using LEXIVA Oral Suspension with Concurrent Ritonavir

Weight	Twice-Daily Dosage Regimen
<11 kg	LEXIVA 45 mg/kg plus ritonavir 7 mg/kga
11 kg - <15 kg	LEXIVA 30 mg/kg plus ritonavir 3 mg/kga
15 kg - <20 kg	LEXIVA 23 mg/kg plus ritonavir 3 mg/kga
≥20 kg	LEXIVA 18 mg/kg plus ritonavir 3 mg/kga
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.
• do not support administration of LEXIVA alone or in combination with ritonavir for protease inhibitor-experienced children younger than 6 months.
• do not support twice-daily dosing of LEXIVA without ritonavir in pediatric patients younger than 2 years.

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.

Patients With Hepatic Impairment

See CLINICAL PHARMACOLOGY).

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.

Interaction with other medicinal products and other forms of interaction

SIDE EFFECTS

• Severe or life-threatening skin reactions have been reported with the use of LEXIVA.
• 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.

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.

Table 3: Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects

Adverse Reaction	APV300001a	APV30002a
LEXIVA 1,400 mg b.i.d. (n=661)	Nelfinavir 1,250 mg b.i.d. (n=83)	LEXIVA 1,400 mg q.d./ Ritonavir200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n=327)
Gastrointestinal
Diarrhea	5%	18%	10%	18%
Nausea	7%	4%	7%	5%
Vomiting	2%	4%	6%	4%
Abdominal pain	1%	0%	2%	2%
Skin
Rash	8%	2%	3%	2%
General disorders
Fatigue	2%	1%	4%	2%
Nervous system
Headache	2%	4%	3%	3%
a All subjects also received abacavir and lamivudine twice daily.

Table 4: Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003)

Adverse Reaction	LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 106)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Gastrointestinal
Diarrhea	13%	11%
Nausea	3%	9%
Vomiting	3%	5%
Abdominal pain	<1%	2%
Skin
Rash	3%	0%
Nervous system
Headache	4%	2%
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.

Table 5: Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002

Laboratory Abnormality	APV30001a	APV30002a
LEXIVA 1,400 mg b.i.d. (n = 166)	Nelfinavir 1,250 mg b.i.d. (n = 83)	LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n = 327)
ALT (>5 x ULN)	6%	5%	8%	8%
AST (>5 x ULN)	6%	6%	6%	7%
Serum lipase (>2 x ULN)	8%	4%	6%	4%
Triglyceridesb(>750 mg/dL)	0%	1%	6%	2%
Neutrophil count, absolute (<750 cells/mm³)	3%	6%	3%	4%
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%.

Table 6: Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003

Laboratory Abnormality	LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 104)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Triglyceridesb (>750 mg/dL)	11%c	6%c
Serum lipase (>2 x ULN)	5%	12%
ALT (>5 x ULN)	4%	4%
AST (>5 x ULN)	4%	2%
Glucose (>251 mg/dL)	2%c	2%c
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. 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.

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.

DRUG INTERACTIONS

See also CONTRAINDICATIONS, CLINICAL PHARMACOLOGY.

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

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.

Drugs That Should Not Be Coadministered With LEXIVA

See CONTRAINDICATIONS.

Established And Other Potentially Significant Drug Interactions

Table 7 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 7: Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir	LEXIVA: ↓Amprenavir (predicted) ↔or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir	LEXIVA: ↔Amprenavir (predicted)↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑ Simeprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)	LEXIVA: ↑ Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted)	Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	For contraindicated NNRTIs (delavirdine),. Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	For contraindicated NNRTIs (delavirdine),. Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira	LEXIVA:↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravira	LEXIVA/ritonavir: ↓Dolutegravir	The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroca	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine	↑Antiarrhythmics	For contraindicated antiarrhythmics (flecainide, propafenone),. Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↑Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine	Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy).
	↑Trazodone	Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina	↑Rifabutin and rifabutin metabolite	For contraindicated antimycobacterials (rifampin),. A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine Lurasidone	LEXIVA/ritonavir: ↑Quetiapine	For contraindicated antipsychotics (lurasidone, pimozide),. Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
	↑Lurasidone	Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	For contraindicated sedative/hypnotics (midazolam, triazolam),. Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina	↑Atorvastatin	For contraindicated HMG-CoA reductase inhibitors (lovastatin, simvastatin),. Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑ Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/ norethindronea	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	For contraindicated PDE5 inhibitors [sildenafil (REVATIO)],. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: 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.
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.
a See CLINICAL PHARMACOLOGY Tables 10, 11, 12, or 13 for magnitude of interaction.