Fosamprenavir Calcium

FDA Drug Information • Also known as: Fosamprenavir Calcium

Brand Names: Fosamprenavir Calcium
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Fosamprenavir calcium, USP is a prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium, USP is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium, USP is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H34CaN3O9PS and a molecular weight of 623.7. It has the following structural formula: Fosamprenavir calcium, USP is a white to cream color solid which is soluble in methanol. Fosamprenavir calcium tablets, USP are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium, USP (equivalent to approximately 600 mg of amprenavir). Each 700 mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone. The tablet coating contains the inactive ingredients ethylcellulose, ferric oxide red, hypromellose, talc, and titanium dioxide. The imprinting ink contains the inactive ingredients ferric oxide black, propylene glycol, and shellac. FDA approved dissolution test specifications differ from USP. Structure

What Is Fosamprenavir Calcium Used For?

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 calcium tablets plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)] . Once-daily administration of fosamprenavir calcium tablets plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.2, 2.3), Clinical Studies (14.2, 14.3)] . Dosing of fosamprenavir calcium tablets plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)] . Fosamprenavir calcium tablets are HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Therapy-Naive Adults: Fosamprenavir calcium tablets 1,400 mg twice daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) Protease Inhibitor-Experienced Adults: Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) Pregnant Patients: Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in women who are already on a stable twice-daily regimen of fosamprenavir calcium /ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). (2.2) Pediatric Patients (aged at least 4 weeks to 18 years): Dosage should be calculated based on body weight (kg) and should not exceed adult dose. (2.3) Hepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. (2.4) Dosing Considerations Fosamprenavir calcium tablets may be taken with or without food. (2.1) Fosamprenavir Calcium Oral Suspension: Adults should take without food; pediatric patients should take with food. (2.1) 2.1 General Dosing Information Fosamprenavir calcium tablets may be taken with or without food. Adults should take fosamprenavir calcium oral suspension without food. Pediatric patients should take fosamprenavir calcium oral suspension with food [see Clinical Pharmacology (12.3)] . If emesis occurs within 30 minutes after dosing, re-dosing of fosamprenavir calcium oral suspension should occur. Higher-than-approved dose combinations of fosamprenavir calcium tablets plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)] . When fosamprenavir calcium tablets are used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir. 2.2 Adults Therapy-Naive Adults Fosamprenavir calcium tablets 1,400 mg twice daily (without ritonavir). Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily. Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)] . Dosing of fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)] . Protease Inhibitor-Experienced Adults Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 700 mg...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS Severe or life-threatening skin reactions have been reported with the use of fosamprenavir calcium [see Warnings and Precautions (5.2)]. The most common moderate to severe adverse reactions in clinical trials of fosamprenavir calcium were diarrhea, rash, nausea, vomiting, and headache. Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir calcium and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir calcium (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash. In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. (6.1) Vomiting and neutropenia were more frequent in pediatrics than in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 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 calcium 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 calcium 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir calcium 1,400 mg twice daily; and 15% received fosamprenavir calcium 700 mg twice daily plus ritonavir 100 mg twice daily. Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir calcium 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 Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects Adverse Reaction APV30001 a APV30002 a Fosamprenavir Calcium 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir Calcium 1,400 mg and Ritonavir 200 mg Once Daily (n = 322) Nelfinavir 1,250 mg Twice Daily (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 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003) Adverse Reaction Fosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily a (n = 106) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily 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 fosamprenavir calcium 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 calcium and had a median duration of 13 days. Skin rash led to discontinuation of fosamprenavir calcium in less than 1% of subjects. In some subjects with mild or moderate rash,...

Drug Interactions

7 DRUG INTERACTIONS Coadministration of fosamprenavir calcium with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3) Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3) Coadministration of fosamprenavir calcium or fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7) Coadministration of fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. (7) 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 calcium and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir calcium and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. The potential for drug interactions with fosamprenavir calcium changes when fosamprenavir calcium 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 calcium is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir calcium 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 [see Contraindications (4)] . 7.2 Established and Other Potentially Significant Drug Interactions If fosamprenavir calcium is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions [see Contraindications (4), Clinical Pharmacology (12.3)] . Table 6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to fosamprenavir calcium with or without ritonavir, unless otherwise indicated. Table 6. 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 Fosamprenavir calcium: ↓ Amprenavir (predicted) ↔ or ↓ Boceprevir (predicted) Fosamprenavir calcium /ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)...

Contraindications

4 CONTRAINDICATIONS Fosamprenavir calcium 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. Fosamprenavir calcium is 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 calcium and possible resistance) are listed below [see Drug Interactions (7), Clinical Pharmacology (12.3)] . The list of contraindicated drugs applies to the use of fosamprenavir calcium with or without ritonavir, unless otherwise indicated. If fosamprenavir calcium is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. Fosamprenavir calcium is contraindicated when coadministered with the following drugs: Alpha 1-adrenoreceptor antagonist: Alfuzosin Antiarrhythmics: Flecainide (with ritonavir ), propafenone (with ritonavir ) Antimycobacterial: Rifampin Antipsychotic: Lurasidone (with ritonavir ), pimozide Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agent: Cisapride Herbal product: St. John’s wort ( Hypericum perforatum ) Lipid modifying agents: Lomitapide, lovastatin, simvastatin Non-nucleoside reverse transcriptase inhibitor: Delavirdine PDE5 inhibitor: Sildenafil (Revatio) (for treatment of pulmonary arterial hypertension) Sedative/hypnotics: Midazolam, triazolam Hypersensitivity to fosamprenavir calcium or amprenavir (e.g., Stevens-Johnson syndrome). (4) 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. (4) Review ritonavir contraindications when used in...

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir calcium 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 calcium in pregnancy. fosamprenavir calcium 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 calcium/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...

Overdosage

10 OVERDOSAGE In a healthy volunteer repeat-dose pharmacokinetic trial evaluating high-dose combinations of fosamprenavir calcium plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 2.5 x ULN) was observed with fosamprenavir calcium 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 calcium. 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Fosamprenavir calcium tablets, USP, 700 mg, are pink colored, coated, oval-shaped tablets with “RJ47” imprinted on one side with black ink and plain on the other side. They are supplied as follows- NDC 63304-583-30 Bottles of 30 with child-resistant closure NDC 63304-583-60 Bottles of 60 with child-resistant closure NDC 63304-583-01 Bottles of 100 Store at 20° C to 25° C (68° F to 77° F) [See USP Controlled Room Temperature]. Keep bottle tightly closed. Protect from moisture.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.