Fosamprenavir Drug Information

General Dosing Information

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

Adults 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. o Dosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data. • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. o Dosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data. Protease Inhibitor-Experienced Adults • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy • Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. o Dosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL).

Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained. Data regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available.

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). 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 Fosamprenavir Calcium Oral Suspension with Concurrent Ritonavir 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 postnatal 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. • do not support administration of fosamprenavir alone or in combination with ritonavir for protease inhibitor-experienced children younger than 6 months. • do not support twice-daily dosing of fosamprenavir without ritonavir in pediatric patients younger than 2 years. 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.

Patients with Hepatic Impairment See Clinical Pharmacology. 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.

Clinical Trials Experience

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. The population age ranged from 17 to 72 years. Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir are shown in Tables 2 and 3.

Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks. Table 2. Selected Moderate/Severe Clinical Table 3.

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

Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received fosamprenavir in the pivotal trials was less than 1%. Table 5. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003 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.

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. Vomiting was treatment limiting in 4 pediatric subjects across all 3 trials.

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.

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. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other enzymes, including glucuronosyl transferase.

There are other agents that may result in serious and/or life-threatening drug interactions.

Established and Other Potentially Significant Drug Interactions If fosamprenavir is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions. Table 6 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.

Table 6. Fosamprenavir: ↑ Amprenavir ↓ Delavirdine Fosamprenavir/ ritonavir: ↑ Amprenavir ↓ Delavirdine Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine. Coadministration is contraindicated due to potential hypotension.

Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir is co-prescribed with ritonavir. Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors. Fosamprenavir/ritonavir: Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions.

Coadministration is contraindicated due to 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 agent: Cisapride ↑ Cisapride Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Herbal product: St.

Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). • The following dose adjustments are recommended for use of tadalafil (ADCIRCA ® ) with fosamprenavir: Coadministration of ADCIRCA in patients on fosamprenavir: In patients receiving fosamprenavir for at least one week, start ADCIRCA at 20 mg once daily. Proton pump inhibitors: Esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Fosamprenavir: ↔ Amprenavir ↑ Esomeprazole Fosamprenavir/ ritonavir: ↔ Amprenavir ↔ Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of fosamprenavir with no change in plasma amprenavir concentrations.

Sedative/hypnotics: Midazolam, triazolam ↑ Midazolam ↑ Triazolam Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Tricyclic antidepressants: Amitriptyline, imipramine ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Limited data are available for use of fosamprenavir in pregnancy.

Fosamprenavir 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data ). There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy.

The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data ). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.

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 postnatal 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 ). Clinical Considerations Virologic Monitoring During Pregnancy and the Postpartum Period Based on limited data on the use of fosamprenavir during pregnancy, no dosage adjustments are required for pregnant patients who are already on a stable twice-daily regimen of fosamprenavir 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). In a clinical trial of 10 HIV-1–infected pregnant women treated with fosamprenvir 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period.

Therefore, viral load should be monitored closely to ensure viral suppression is maintained. Pregnancy data with other dosage regimens of fosamprenavir (with or without ritonavir) are not available. Data Human Data Fosamprenavir 700 mg taken with ritonavir 100 mg twice daily in combination with a background regimen was evaluated in a clinical trial of 10 HIV-1–infected pregnant women during the second and third trimesters and postpartum.

Subjects initiated fosamprenavir/ritonavir during pregnancy at a median of 19 weeks’ gestation; 4 had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation. Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n = 6) or third trimester (n = 9) and postpartum (n = 9). Pregnancy outcomes were available for all 10 subjects, among which 1 twin pregnancy was included.

Compared to the postpartum period, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration n =. All 11 infants born had test results that were negative for HIV-1 at the time of delivery and through 12 months postpartum.

There were no new safety findings compared with the known safety profile of fosamprenavir/ritonavir in HIV-1–infected adults. Prospective reports from the APR of overall major birth defects in pregnancies exposed to fosamprenavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group.

Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC 0-24 h ) approximately 2 times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir. However, increased incidence of abortion was observed in rabbits administered a maternally toxic dose of fosamprenavir (672.8 mg per kg per day).

In a study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on Gestation Days 8 to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD. Fosamprenavir caused a reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed.

Systemic exposure (AUC 0-24 h ) to amprenavir in rats was approximately 2 times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.

Pediatric Use The safety, pharmacokinetic profile, and 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. 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.

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 Dosage and Administration for dosing recommendations for pediatric patients.

• 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.
• Fosamprenavir calcium tablets are contraindicated when coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of fosamprenavir and possible resistance) are listed below. The list of contraindicated drugs applies to the use of fosamprenavir with or without ritonavir, unless otherwise indicated. If fosamprenavir is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications.
• Fosamprenivir is contraindicated when coadministered with the following drugs: o Alpha 1-adrenoreceptor antagonist: Alfuzosin o Antiarrhythmics: Flecainide (with ritonavir ), propafenone (with ritonavir ) o Antimycobacterial: Rifampin o Antipsychotic: Lurasidone (with ritonavir ), pimozide o Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine o GI motility agent: Cisapride o Herbal product: St. John’s wort ( Hypericum perforatum ) o Lipid modifying agents: Lomitapide, lovastatin, simvastatin o Non-nucleoside reverse transcriptase inhibitor: Delavirdine o PDE5 inhibitor: Sildenafil (REVATIO ® ) (for treatment of pulmonary arterial hypertension) o Sedative/hypnotics: Midazolam, triazolam
• Hypersensitivity to fosamprenavir or amprenavir (e.g., Stevens-Johnson syndrome).
• Drugs highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma levels may result in serious and/or life-threatening events.
• Review ritonavir contraindications when used in combination.

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.