FDA Label for Fosamprenavir Calcium

1 Indications And Usage

Fosamprenavir calcium tablets are 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 fosamprenavir calcium tablets plus ritonavir in protease inhibitor-experienced patients:

• •The protease inhibitor-experienced patient trial was not large enough to reach a definitive conclusion that fosamprenavir plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)].
• •Once-daily administration of fosamprenavir plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.1, 2.2), Clinical Studies (14.2, 14.3)].
• •Dosing of fosamprenavir plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)].

2 Dosage And Administration

Fosamprenavir calcium tablets may be taken with or without food.

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

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

Therapy-Naive Adults

• •Fosamprenavir 1,400 mg twice daily (without ritonavir).
• •Fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily.
• •Fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily.
  • •Dosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)].
  • •Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily.
    • •Dosing of fosamprenavir 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

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

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

The recommended dosage of fosamprenavir 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).

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

Fosamprenavir 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 fosamprenavir alone or in combination with ritonavir [see Clinical Studies (14.3)].
• •do not support administration of fosamprenavir 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 fosamprenavir 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 fosamprenavir calcium tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.
• •When administered in combination with ritonavir, fosamprenavir calcium tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg.

2.3 Patients With Hepatic Impairment

See Clinical Pharmacology (12.3).

Mild Hepatic Impairment (Child-Pugh Score Ranging From 5 To 6)

Fosamprenavir 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)

Fosamprenavir 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)

Fosamprenavir 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

Fosamprenavir Calcium Tablets are available containing 700 mg of fosamprenavir as fosamprenavir calcium.

• •The 700 mg tablets are pink, film-coated, modified capsule shaped, unscored tablets debossed with M on one side of the tablet and FT7 on the other side.

4 Contraindications

Fosamprenavir calcium tablets are 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 Fosamprenavir (Information in the table applies to fosamprenavir with or without ritonavir, unless otherwise indicated.)

Drug Class/Drug Name	Clinical Comment
Alpha 1-adrenoreceptor antagonist: 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 fosamprenavir is co-prescribed with ritonavir.
Antimycobacterials: Rifampin See Clinical Pharmacology (12.3)Tables 10, 11, 12, or 13 for magnitude of interaction.	May lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors.
Antipsychotics: Lurasidone	POTENTIAL for serious and/or life-threatening reactions if fosamprenavir 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 fosamprenavir or to the class of protease inhibitors.
HMG co-reductase inhibitors: Lovastatin, simvastatin	POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis.
Non-nucleoside reverse transcriptase inhibitor: Delavirdine	May lead to loss of virologic response and possible resistance to delavirdine.
PDE5 inhibitor: Sildenafil (REVATIO®) (for treatment of pulmonary arterial hypertension)	A safe and effective dose has not been established when used with fosamprenavir. 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.

 

• •when coadministered with ritonavir in patients receiving the antiarrhythmic agents, flecainide and propafenone. If fosamprenavir 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 fosamprenavir/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of fosamprenavir/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 fosamprenavir/ritonavir.
• •Loss of therapeutic effect of fosamprenavir/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 fosamprenavir/ritonavir therapy; review concomitant medications during fosamprenavir/ritonavir therapy; 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 fosamprenavir in clinical trials. Treatment with fosamprenavir 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

Fosamprenavir 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir. 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 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy, including fosamprenavir. 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir. 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 fosamprenavir will have on the activity of subsequently administered protease inhibitors. Fosamprenavir 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 fosamprenavir [see Warnings and Precautions (5.2)].
• •The most common moderate to severe adverse reactions in clinical trials of fosamprenavir were diarrhea, rash, nausea, vomiting, and headache.
• •Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir (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 fosamprenavir calcium tablets, including 599 subjects exposed to fosamprenavir 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 fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir 1,400 mg twice daily; and 15% received fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily.

Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir 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.

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

The percentages of subjects with Grade 3 or 4 laboratory abnormalities in the clinical efficacy trials of fosamprenavir are presented in Tables 5 and 6.

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

Pediatric Trials

Fosamprenavir 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir 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 fosamprenavir. 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 fosamprenavir.

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

The potential for drug interactions with fosamprenavir changes when fosamprenavir 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 fosamprenavir is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir 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 Fosamprenavir

See Contraindications (4).

7.3 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 fosamprenavir with or without ritonavir, unless otherwise indicated.

Use of PDE5 inhibitors for erectile dysfunction:

Fosamprenavir:

Fosamprenavir/ritonavir:

Use with increased monitoring for adverse events.

Pregnancy Category C

Embryo/fetal development studies were conducted in rats (dosed from Day 6 to Day 17 of gestation) and rabbits (dosed from Day 7 to Day 20 of gestation). Administration of fosamprenavir to pregnant rats and rabbits produced no major effects on embryo-fetal development; however, the incidence of abortion was increased in rabbits that were administered fosamprenavir. Systemic exposures (AUC_{0-24 h}) to amprenavir at these dosages were 0.8 (rabbits) to 2 (rats) times the exposures in humans following administration of the maximum recommended human dose (MRHD) of fosamprenavir alone or 0.3 (rabbits) to 0.7 (rats) times the exposures in humans following administration of the MRHD of fosamprenavir in combination with ritonavir. In contrast, administration of amprenavir was associated with abortions and an increased incidence of minor skeletal variations resulting from deficient ossification of the femur, humerus, and trochlea, in pregnant rabbits at the tested dose approximately one-twentieth the exposure seen at the recommended human dose.

The mating and fertility of the F₁ generation born to female rats given fosamprenavir was not different from control animals; however, fosamprenavir did cause a reduction in both pup survival and body weights. Surviving F₁ female rats showed an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights compared with control animals. Systemic exposure (AUC_{0-24 h}) to amprenavir in the F₀ pregnant rats was approximately 2 times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir.

There are no adequate and well-controlled studies in pregnant women. Fosamprenavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to fosamprenavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Although it is not known if amprenavir is excreted in human milk, amprenavir is secreted into the milk of lactating rats. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving fosamprenavir.

8.4 Pediatric Use

The safety, pharmacokinetic profile, virologic, and immunologic responses of fosamprenavir 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 fosamprenavir is not recommended in protease inhibitor-experienced pediatric patients younger than 6 months. The pharmacokinetics, safety, tolerability, and efficacy of fosamprenavir 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 fosamprenavir 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 (2.2) for dosing recommendations for pediatric patients.

8.5 Geriatric Use

Clinical studies of fosamprenavir 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 fosamprenavir to patients with hepatic impairment because amprenavir concentrations may be increased [see Clinical Pharmacology (12.3)]. Patients with impaired hepatic function receiving fosamprenavir with or without concurrent ritonavir require dose reduction [see Dosage and Administration (2.3)].

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 fosamprenavir plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 2.5 x ULN) was observed with fosamprenavir 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 fosamprenavir. 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

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 623.67. It has the following structural formula:

Fosamprenavir Structural Formula - image 01

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

Fosamprenavir calcium 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, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, silicified microcrystalline cellulose, titanium dioxide and triacetin.

12.1 Mechanism Of Action

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

12.3 Pharmacokinetics

The pharmacokinetic properties of amprenavir after administration of fosamprenavir, 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 fosamprenavir (with and without concomitant ritonavir) are shown in Table 8.

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) - image 02

Absorption And Bioavailability

After administration of a single dose of fosamprenavir 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 fosamprenavir in humans has not been established.

After administration of a single 1,400 mg dose in the fasted state, fosamprenavir calcium oral suspension (50 mg per mL) and fosamprenavir calcium 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 fosamprenavir calcium 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)].

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.

Hepatic Impairment

The pharmacokinetics of amprenavir have been studied after the administration of fosamprenavir in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following 2 weeks of dosing with fosamprenavir 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 (2.3)].

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 (2.3)].

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 fosamprenavir calcium oral suspension and fosamprenavir calcium tablets, with or without ritonavir, have been studied in a total of 212 HIV-1-infected pediatric subjects enrolled in 3 trials. Fosamprenavir without ritonavir was administered as 30 mg per kg or 40 mg per kg twice daily to children aged 2 to 5 years. Fosamprenavir with ritonavir was administered as fosamprenavir 30 mg per kg plus ritonavir 6 mg per kg once daily to children aged 2 to 18 years and as fosamprenavir 18 mg per kg to 60 mg per kg plus ritonavir 3 mg per kg to 10 mg per kg twice daily to children aged at least 4 weeks to 18 years; body weights ranged from 3 kg 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 fosamprenavir.

The pharmacokinetics of fosamprenavir calcium oral suspension in protease inhibitor-naive infants younger than 6 months (n = 9) receiving fosamprenavir 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC₁₂ and C_min than adults receiving twice-daily fosamprenavir 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 fosamprenavir alone (without ritonavir) in pediatric subjects younger than 2 years was not studied.

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

Subjects aged 2 to younger than 6 years receiving fosamprenavir 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 fosamprenavir to patients older than 65 years have not been studied [see Use in Specific Populations (8.5)].

Gender

The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between males and females.

Race

The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between blacks and non-blacks.

Drug Interactions

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

Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Amprenavir is both a substrate for and inducer of P-glycoprotein.

Drug interaction trials were performed with fosamprenavir 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 fosamprenavir on other drugs). In addition, since fosamprenavir 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)].

Table 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE

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. Amprenavir exhibited synergistic anti-HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz; and the protease inhibitors atazanavir and saquinavir. Amprenavir exhibited additive anti-HIV-1 activity in combination with the NNRTI nevirapine, the protease inhibitors indinavir, lopinavir, nelfinavir, and ritonavir; and the fusion inhibitor enfuvirtide. These drug combinations have not been adequately studied in humans.

Resistance

HIV-1 isolates with decreased susceptibility to amprenavir have been selected in 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 gene 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 fosamprenavir. Of the 488 antiretroviral-naive subjects treated with fosamprenavir 1,400 mg twice daily or fosamprenavir 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, 61 subjects (29 receiving fosamprenavir and 32 receiving fosamprenavir/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. Five of the 29 antiretroviral-naive subjects (17%) receiving fosamprenavir 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 antiretroviral-naive subjects treated with fosamprenavir/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from 1 virologic failure subject receiving fosamprenavir/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 fosamprenavir/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 1 (47%) or 2 protease inhibitors (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily fosamprenavir/ritonavir, 54% (n = 55) had resistance to at least 1 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 1 protease inhibitor, with 97% (n = 56) of those having resistance to nelfinavir.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects responding to fosamprenavir/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 fosamprenavir.

Isolates from 15 of the 20 subjects receiving twice-daily fosamprenavir/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 fosamprenavir/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 mg per kg per day, 400 mg per kg per day, or 600 mg per kg per day in mice and at doses of 300 mg per kg per day, 825 mg per kg per day, 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 835 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). 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.

Apv30001

A randomized, open-label trial evaluated treatment with fosamprenavir calcium 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.

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 fosamprenavir and 216 cells per mm³ in the nelfinavir group.

Apv30002

A randomized, open-label trial evaluated treatment with fosamprenavir calcium 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.

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 fosamprenavir and 207 cells per mm³ in the nelfinavir group.

Apv30003

A randomized, open-label, multicenter trial evaluated 2 different regimens of fosamprenavir plus ritonavir (fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily or fosamprenavir calcium 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 fosamprenavir/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 fosamprenavir/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 fosamprenavir/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 fosamprenavir/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 fosamprenavir/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 fosamprenavir/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 fosamprenavir/ritonavir and 91 cells per mm³ with lopinavir/ritonavir.

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

Once-daily administration of fosamprenavir plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of subjects receiving fosamprenavir 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 1 trial (APV29005), twice-daily dosing regimens (fosamprenavir 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 (fosamprenavir 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 fosamprenavir with ritonavir; the pharmacokinetic data from this trial did not support a once-daily dosing regimen in any pediatric patient population.

Fosamprenavir

Twenty (18 therapy-naive and 2 therapy-experienced) pediatric subjects received fosamprenavir calcium 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.

Fosamprenavir Plus Ritonavir

Forty-nine protease inhibitor-naive and 40 protease inhibitor-experienced pediatric subjects received fosamprenavir calcium 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 fosamprenavir calcium 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

Fosamprenavir Calcium Tablets are available containing 700 mg of fosamprenavir as fosamprenavir calcium.

The 700 mg tablets are pink, film-coated, modified capsule shaped, unscored tablets debossed with M on one side of the tablet and FT7 on the other side. They are available as follows:

NDC 0378-3520-91
bottles of 60 tablets

NDC 0378-3520-80
bottles of 180 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Keep container tightly closed.

Dispense in original container.

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 Fosamprenavir Calcium Tablets.

Fosamprenavir calcium tablets 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.

Instruct patients receiving hormonal contraceptives to use alternate contraceptive measures during therapy with fosamprenavir calcium tablets because hormonal levels may be altered, and if used in combination with fosamprenavir calcium tablets and ritonavir, liver enzyme elevations may occur.

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.

Redistribution/Accumulation of Body Fat: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including fosamprenavir calcium tablets, and that the cause and long-term health effects of these conditions are not known at this time.

Information about HIV-1 Infection: Fosamprenavir calcium tablets are not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-1-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death.

Advise patients to remain under the care of a physician when using fosamprenavir calcium tablets.

Advise patients to take all HIV medications exactly as prescribed.

Advise patients to avoid doing things that can spread HIV-1 infection to others.

Advise patients not to re-use or share needles or other injection equipment.

Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Female patients should be advised not to breastfeed because it is not known if fosamprenavir can be passed to your baby in your breast milk and whether it could harm your baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Fosamprenavir calcium tablets must always be used in combination with other antiretroviral drugs. Inform patients not to alter the dose or discontinue therapy without consulting their physician. Physicians should instruct their patients that if they miss a dose, they should take it as soon as possible and then return to their normal schedule. Patients should not double their next dose or take more than the prescribed dose.

Patient Information

Fosamprenavir Calcium Tablets
(fos″ am pren′ a vir kal′ see um)

Important: Fosamprenavir calcium tablets can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with fosamprenavir calcium tablets. See the section “Who should not take fosamprenavir calcium tablets?”

Read this Patient Information before you start taking fosamprenavir calcium tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What are fosamprenavir calcium tablets?

Fosamprenavir calcium tablets are a prescription anti-HIV medicine used with other anti-HIV medicines to treat human immunodeficiency (HIV-1) infections in adults and children 4 weeks of age and older. Fosamprenavir calcium tablets are a type of anti-HIV medicine called a protease inhibitor. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

When used with other anti-HIV medicines, fosamprenavir calcium tablets may help:

• 1.Reduce the amount of HIV-1 in your blood. This is called “viral load”.
• 2.Increase the number of white blood cells called CD4 (T) cells, which help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4 (T) cell count may improve your immune system. This may reduce your risk of death or infections that can happen when your immune system is weak (opportunistic infections).

It is not known if fosamprenavir is safe and effective in children younger than 4 weeks of age.

Fosamprenavir calcium tablets do not cure HIV-1 infection or AIDS. People taking fosamprenavir calcium tablets may develop infections or other conditions associated with HIV-1 infection, including opportunistic infections (for example, pneumonia and herpes virus infections).

You should remain under the care of your healthcare provider when using fosamprenavir calcium tablets.

Avoid doing things that can spread HIV-1 infection to others.

• •Do not re-use or share needles or other injection equipment.
• •Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• •Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions on how to prevent passing HIV to other people.

Who should not take fosamprenavir calcium tablets?

Do not take fosamprenavir calcium tablets if you take any of the following medicines:

• •alfuzosin (UROXATRAL^®)
• •flecainide
• •propafenone (RYTHMOL SR^®)
• •rifampin (RIFADIN^®, RIFAMATE^®, RIFATER^®, RIMACTANE^®)
• •ergot including:
  • •dihydroergotamine mesylate (D.H.E. 45^®, MIGRANAL^®)
  • •ergotamine tartrate (CAFERGOT^®, MIGERGOT^®, ERGOMAR^®, MEDIHALER ERGOTAMINE^®)
  • •methylergonovine (METHERGINE^®)
  • •St. John’s wort (Hypericum perforatum)
  • •lovastatin (ADVICOR^®, ALTOPREV^®)
  • •simvastatin (ZOCOR^®, VYTORIN^®, SIMCOR^®)
  • •pimozide (ORAP^®)
  • •delavirdine mesylate (RESCRIPTOR^®)
  • •sildenafil (REVATIO^®), for treatment of pulmonary arterial hypertension
  • •triazolam (HALCION^®)
  • •lurasidone (LATUDA^®)

  Serious problems can happen if you or your child take any of the medicines listed above with fosamprenavir calcium tablets.

  Do not take fosamprenavir calcium tablets if you are allergic to AGENERASE^® (amprenavir), fosamprenavir calcium, or any of the ingredients in fosamprenavir calcium tablets. See the end of this leaflet for a complete list of ingredients in fosamprenavir calcium tablets.

  What should I tell my healthcare provider before taking fosamprenavir calcium tablets?

  Before taking fosamprenavir calcium tablets, tell your healthcare provider if you:

  • •are allergic to medicines that contain sulfa
  • •have liver problems, including hepatitis B or C
  • •have kidney problems
  • •have high blood sugar (diabetes)
  • •have hemophilia
  • •have any other medical condition
  • •are pregnant or plan to become pregnant. It is not known if fosamprenavir will harm your unborn baby.
  •  Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines 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.
  • •Do not breastfeed. We do not know if fosamprenavir can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

  Tell your healthcare provider about all prescription and over-the-counter medicines you take. Also tell your healthcare provider about any vitamins, herbal supplements, and dietary supplements you are taking.

  Taking fosamprenavir calcium tablets with certain other medicines may cause serious side effects. Fosamprenavir calcium tablets may affect the way other medicines work, and other medicines may affect how fosamprenavir calcium tablets work.

  Especially tell your healthcare provider if you take:

  • •quetiapine (SEROQUEL^®)
  • •estrogen-based contraceptives (birth control pills). Fosamprenavir calcium tablets may reduce effectiveness of estrogen-based contraceptives. During treatment with fosamprenavir calcium tablets, you should use a different contraceptive method.
  • •medicines to treat liver problems, including hepatitis C infection.

  Know all the medicines that you take. Keep a list of them with you to show healthcare providers and pharmacists when you get a new medicine.

  How should I take fosamprenavir calcium tablets?

  • •Stay under the care of a healthcare provider while taking fosamprenavir calcium tablets.
  • •Take fosamprenavir calcium tablets exactly as prescribed by your healthcare provider.
  • •Do not change your dose or stop taking fosamprenavir calcium tablets without talking with your healthcare provider.
  • •If your child is taking fosamprenavir, your child’s healthcare provider will decide the right dose based on your child’s weight.
  • •You can take fosamprenavir calcium tablets with or without food.
  • •If you miss a dose of fosamprenavir calcium tablets, take the next dose as soon as possible and then take your next dose at the regular time. Do not double the next dose. If you take too many fosamprenavir calcium tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

  What are the possible side effects of fosamprenavir calcium tablets?

  Fosamprenavir calcium tablets may cause serious side effects including:

  • •Severe skin rash. Fosamprenavir calcium tablets may cause severe or life-threatening skin reactions or rash.
     
    If you get a rash with any of the following symptoms, stop taking fosamprenavir calcium tablets and call your healthcare provider or get medical help right away:
    • •hives or sores in your mouth, or your skin blisters and peels
    • •trouble swallowing or breathing
    • •swelling of your face, eyes, lips, tongue, or throat
    • •Liver problems. Your healthcare provider should do blood tests before and during your treatment with fosamprenavir calcium tablets to check your liver function. Some people with liver problems, including hepatitis B or C, may have an increased risk of developing worsening liver problem during treatment with fosamprenavir calcium tablets.
    • •Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors, including fosamprenavir calcium tablets, can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often while taking fosamprenavir calcium tablets.
    • •Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV medicine.
    • •Changes in body fat. These changes can happen in people who take antiretroviral therapy. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
    • •Changes in blood tests. Some people have changes in blood tests while taking fosamprenavir calcium tablets. These include increases seen in liver function tests, blood fat levels, and decreases in white blood cells. Your healthcare provider should do regular blood tests before and during your treatment with fosamprenavir calcium tablets.
    • •Increased bleeding problems in some people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors, including fosamprenavir calcium tablets.
    • •Kidney stones. Some people have developed kidney stones while taking fosamprenavir calcium tablets. Tell your healthcare provider right away if you develop signs or symptoms of kidney stones:
      • •pain in your side
      • •blood in your urine
      • •pain when you urinate

      The most common side effects of fosamprenavir calcium tablets in adults include:

      • •nausea
      • •vomiting
      • •diarrhea
      • •headache

      Vomiting is the most common side effect in children when taking fosamprenavir calcium tablets.

      Tell your healthcare provider about any side effect that bothers you or that does not go away.

      These are not all the possible side effects of fosamprenavir calcium tablets. For more information, ask your healthcare provider or pharmacist.

      Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

      How should I store fosamprenavir calcium tablets?

      • •Store fosamprenavir calcium tablets at room temperature between 20° to 25°C (68° to 77°F).
      • •Keep the bottle of fosamprenavir calcium tablets tightly closed.

      Keep fosamprenavir calcium tablets and all medicines out of the reach of children.

      General information about fosamprenavir calcium tablets

      Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use fosamprenavir calcium tablets for a condition for which they were not prescribed. Do not give fosamprenavir calcium tablets to other people, even if they have the same symptoms you have. They may harm them.

      This leaflet summarizes the most important information about fosamprenavir calcium tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about fosamprenavir calcium tablets that is written for health professionals.

      For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

      What are the ingredients in fosamprenavir calcium tablets?

      Active ingredient: fosamprenavir calcium

      Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, silicified microcrystalline cellulose, titanium dioxide and triacetin.

      This Patient Information has been approved by the U.S. Food and Drug Administration.

      The brand names listed are trademarks of their respective owners.

      Manufactured for:
      Mylan Pharmaceuticals Inc.
      Morgantown, WV 26505 U.S.A.

      Manufactured by:
      Mylan Laboratories Limited
      Hyderabad — 500 034, India
      Code No.: MH/DRUGS/25/NKD/89

      75056335

      Revised: 1/2017
      MX:FOSM:R5

      
      

Principal Display Panel – 700 Mg

NDC 0378-3520-91

Fosamprenavir
Calcium
Tablets
700 mg

ALERT: Find out about medicines that should NOT
be taken with Fosamprenavir Calcium Tablets.

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

Rx only     60 Tablets

Each film-coated tablet contains
700 mg of fosamprenavir as
fosamprenavir calcium.

Usual Dosage: See accompanying
prescribing information.

For use in combination regimens with
or without ritonavir.

Keep this and all medication out of the
reach of children.

Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Mylan.com

RMX3520D2

Dispense in original container.

Keep container tightly closed.

Code No.: MH/DRUGS/25/NKD/89

Fosamprenavir Calcium Tablets 700 mg Bottle Label - image 03