FOSAMPRENAVIR CALCIUM

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

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)

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 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 calcium /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 [see Use in Specific Populations (8.1), Clinical Pharmacology (12.3)]. Data regarding use of other regimens of fosamprenavir calcium tablets (with or without ritonavir) in pregnancy are not available. 2.3 Pediatric Patients (Aged at Least 4 Weeks to 18 Years) The recommended dosage of fosamprenavir calcium 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 Weight Twice-Daily Dosage Regimen < 11 kg Fosamprenavir Calcium 45 mg/kg plus ritonavir 7 mg/kg a 11 kg - < 15 kg Fosamprenavir Calcium 30 mg/kg plus ritonavir 3 mg/kg a 15 kg - < 20 kg Fosamprenavir Calcium 23 mg/kg plus ritonavir 3 mg/kg a ≥ 20 kg Fosamprenavir Calcium 18 mg/kg plus ritonavir 3 mg/kg a a When dosing with ritonavir, do not exceed the adult dose of fosamprenavir calcium 700 mg/ritonavir 100 mg twice-daily dose. Alternatively, protease inhibitor-naive children aged 2 years and older can be administered fosamprenavir calcium (without ritonavir) 30 mg per kg twice daily. Fosamprenavir calcium 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 calcium alone or in combination with ritonavir [see Clinical Studies (14.3)] . do not support administration of fosamprenavir calcium 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 calcium 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. 2.4 Patients with Hepatic Impairment See Clinical Pharmacology (12.3) . Mild Hepatic Impairment (Child-Pugh Score Ranging from 5 to 6) Fosamprenavir calcium tablets 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 calcium tablets 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 calcium tablets 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.

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 combination. (4)

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, dosing with fosamprenavir calcium was often continued without interruption; if interrupted, reintroduction of fosamprenavir calcium 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 calcium are presented in Tables 4 and 5. Table 4. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002 Laboratory Abnormality 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) ALT (> 5 x ULN) 6% 5% 8% 8% AST (> 5 x ULN) 6% 6% 6% 7% Serum lipase (> 2 x ULN) 8% 4% 6% 4% Triglycerides b (> 750 mg/dL) 0% 1% 6% 2% Neutrophil count, absolute (< 750 cells/mm 3 ) 3% 6% 3% 4% a All subjects also received abacavir and lamivudine twice daily. b Fasting specimens. ULN = Upper limit of normal. The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received fosamprenavir calcium 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 Laboratory Abnormality Fosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily a (n = 104) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily a (n = 103) Triglycerides b (> 750 mg/dL) 11% c 6% c Serum lipase (> 2 x ULN) 5% 12% ALT (> 5 x ULN) 4% 4% AST (> 5 x ULN) 4% 2% Glucose (> 251 mg/dL) 2% c 2% c a All subjects also received 2 reverse transcriptase inhibitors. b Fasting specimens. c n = 100 for fosamprenavir calcium plus ritonavir, n = 98 for lopinavir plus ritonavir. ULN = Upper limit of normal. Pediatric Trials Fosamprenavir calcium 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 calcium 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 calcium 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 mm 3 ) seen in pediatric subjects treated with fosamprenavir calcium 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 calcium. 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 calcium. Cardiac Disorders Myocardial infarction. Metabolism and Nutrition Disorders Hypercholesterolemia. Nervous System Disorders Oral paresthesia. Skin and Subcutaneous Tissue Disorders Angioedema. Urogenital Nephrolithiasis.

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) Coadministration of fosamprenavir calcium or fosamprenavir calcium/ ritonavir and boceprevir is not recommended. HCV protease inhibitor: Simeprevir Fosamprenavir calcium: ↔ Amprenavir (predicted) ↑ or ↓ Simeprevir (predicted) Fosamprenavir calcium /ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted) Coadministration of fosamprenavir calcium or fosamprenavir calcium/ritonavir and simeprevir is not recommended. HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) Fosamprenavir calcium: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) Fosamprenavir calcium /ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavircalcium 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of Fosamprenavircalcium /ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Delavirdine a Fosamprenavir calcium: ↑ Amprenavir ↓ Delavirdine Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine [see Contraindications (4)] . Fosamprenavir calcium/ritonavir: ↑ Amprenavir ↓Delavirdine Non-nucleoside reverse transcriptase inhibitor: Efavirenz a Fosamprenavir calcium: ↓ Amprenavir Fosamprenavir calcium/ritonavir: ↓ Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir calcium /ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with Fosamprenavir calcium plus ritonavir twice daily. Non-nucleoside reverse transcriptase inhibitor: Nevirapine a Fosamprenavir calcium: ↓ Amprenavir ↑ Nevirapine Coadministration of nevirapine and fosamprenavir calcium without ritonavir is not recommended. Fosamprenavir calcium/ritonavir: ↓ Amprenavir ↑ Nevirapine No dosage adjustment required when nevirapine is administered with fosamprenavir calcium/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir calcium/ritonavir once-daily regimen has not been studied. HIV protease inhibitor: Atazanavir a Fosamprenavir calcium: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir calcium/ritonavir: ↓ Atazanavir ↔ Amprenavir HIV protease inhibitors: Indinavir a , nelfinavir a Fosamprenavir calcium: ↑ Amprenavir Effect on indinavir and nelfinavir is not well established. Fosamprenavir calcium/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Lopinavir/ritonavir a ↓ Amprenavir ↓ Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitor: Saquinavir a Fosamprenavir calcium: ↓ Amprenavir Effect on saquinavir is not well established. Fosamprenavir calcium/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor: Raltegravir a Fosamprenavir calcium: ↓ Amprenavir ↓ Raltegravir Fosamprenavir calcium/ritonavir: ↓ Amprenavir ↓ Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor: Dolutegravir a Fosamprenavir calcium /ritonavir: ↓Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with Fosamprenavircalcium /ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance. HIV CCR5 co-receptor antagonist: Maraviroc a Fosamprenavir calcium/ritonavir: ↓ Amprenavir ↑ Maraviroc No dosage adjustment required for fosamprenavir calcium /ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with fosamprenavir calcium/ritonavir. Fosamprenavir calcium should be given with ritonavir when coadministered with maraviroc. Other Agents Alpha 1-adrenoreceptor antagonist: Alfuzosin ↑Alfuzosin Coadministration is contraindicated due to potential hypotension [see Contraindications (4)] . Antacid: MAALOX TC ↓Amprenavir Use with caution when administered at the same time. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations. Staggered coadministration of antacids and fosamprenavir calcium has not been evaluated. Antiarrhythmics: Amiodarone, disopyramide, lidocaine (systemic), and quinidine Flecainide, propafenone ↑ Antiarrhythmics ↑Antiarrhythmics Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir calcium is co-prescribed with ritonavir [see Contraindications (4)] . Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Fosamprenavir calcium: ↓ Amprenavir Use with caution. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Phenytoin a Fosamprenavir calcium/ritonavir: ↑ Amprenavir ↓ Phenytoin Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in fosamprenavir calcium/ritonavir dose is recommended. Antidepressant: Paroxetine, trazodone ↓ Paroxetine Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). ↑ Trazodone Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as fosamprenavir calcium, the combination should be used with caution and a lower dose of trazodone should be considered. Antifungals: Ketoconazole a , itraconazole ↑ Ketoconazole ↑ Itraconazole Increase monitoring for adverse events. Fosamprenavir calcium: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Fosamprenavir calcium/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended. Anti-gout: Colchicine ↑ Colchicine Patients with renal or hepatic impairment should not be given colchicine with fosamprenavir calcium/ritonavir. Fosamprenavir calcium/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Fosamprenavir calcium and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares : If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day). Antimycobacterial: Rifabutin a ↑ Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. Fosamprenavir calcium: A dosage reduction of rifabutin by at least half the recommended dose is required. Fosamprenavir calcium/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week). Antimycobacterial: Rifampin a ↓Amprenavir Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to Fosamprenavir calcium or to the class of protease inhibitors [see Contraindications (4)]. Antineoplastics: Dasatinib, nilotinib, ibrutinib, vinblastine, everolimus ↑Antineoplastics Fosamprenavir calcium or fosamprenavir calcium /ritonavir may increase plasma concentrations of antineoplastics metabolized by CYP3A, potentially increasing the risk of adverse events typically associated with these medications. In case of coadministration, please refer to relevant prescribing information for these medications. Antipsychotics: Lurasidone Pimozide Quetiapine ↑Lurasidone ↑Pimozide ↑Quetiapine Fosamprenavir calcium: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. Fosamprenavir calcium /ritonavir: Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)] . Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] . Fosamprenavir calcium /ritonavir: Initiation of fosamprenavir calcium with ritonavir in patients taking quetiapine : Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking fosamprenavir calcium with ritonavir : Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑ Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed. Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑ Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended. Corticosteroid: Dexamethasone ↓ Amprenavir Use with caution. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations. Endothelin-receptor antagonist: Bosentan ↑ Bosentan Coadministration of bosentan in patients on fosamprenavir calcium: In patients who have been receiving fosamprenavir calcium for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of fosamprenavir calcium in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of fosamprenavir calcium.After at least 10 days following the initiation of fosamprenavir calcium, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine ↑Ergot derivatives 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 [see Contraindications (4)] . GI motility agent: Cisapride ↑Cisapride Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Herbal product: St. John’s wort (Hypericum perforatum) ↓Amprenavir Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to Fosamprenavir calcium or to the class of protease inhibitors [see Contraindications (4)] . Histamine H 2 -receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine a Fosamprenavir calcium: ↓ Amprenavir Fosamprenavir calcium/ritonavir: Interaction not evaluated Use with caution. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus ↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents. Inhaled beta-agonist: Salmeterol ↑ Salmeterol Concurrent administration of salmeterol with fosamprenavir calcium is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: Fluticasone Fosamprenavir calcium: ↑ Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. Fosamprenavir calcium/ritonavir: ↑ Fluticasone May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and fosamprenavir calcium/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Lipid Modifying Agents: HMG-CoA reductase inhibitors : Atorvastatin a Lovastatin, simvastatin Other lipid modifying agents : Lomitapide ↑Atorvastatin ↑Lovastatin ↑Simvastatin ↑Lomitapide Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day. Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see Contraindications (4)] . Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases. Narcotic analgesic: Methadone Fentanyl ↓ Methadone ↑Fentanyl Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. Careful monitoring of therapeutic effects and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended. Oral contraceptives: Ethinyl estradiol/norethindrone a Alternative methods of non-hormonal contraception are recommended. Fosamprenavir calcium: ↓ Amprenavir ↓ Ethinyl estradiol May lead to loss of virologic response. a Fosamprenavir calcium/ritonavir: ↓ Ethinyl estradiol Increased risk of transaminase elevations. No data are available on the use of fosamprenavir calcium/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women. PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑ Sildenafil ↑ Tadalafil ↑ Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): •Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH. A safe and effective dose has not been established when used with fosamprenavir calcium. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope) [see Contraindications (4)]. • The following dose adjustments are recommended for use of tadalafil (ADCIRCA ® ) with fosamprenavir calcium: Coadministration of ADCIRCA in patients on fosamprenavir calcium: In patients receiving fosamprenavir calcium for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of fosamprenavir calcium in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of fosamprenavir calcium. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir calcium. After at least one week following the initiation of fosamprenavir calcium, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Fosamprenavir calcium: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. Fosamprenavir calcium/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events. Proton pump inhibitors: Esomeprazole a , lansoprazole, omeprazole, pantoprazole, rabeprazole Fosamprenavir calcium: ↔ Amprenavir ↑ Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of fosamprenavir calcium with no change in plasma amprenavir concentrations. Fosamprenavir calcium/ritonavir: ↔ Amprenavir ↔ Esomeprazole 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 [see Contraindications (4)]. Tricyclic antidepressants: Amitriptyline, imipramine ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants. a See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction.