Fosamprenavir Drug Information

• 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.
• 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 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 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 All subjects also received abacavir and lamivudine twice daily. APV30002 Fosamprenavir 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir 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% 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 700 mg and Ritonavir 100 mg Twice Daily All subjects also received 2 reverse transcriptase inhibitors. (n = 106) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily (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% 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 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 ULN = Upper limit of normal. Laboratory Abnormality APV30001 All subjects also received abacavir and lamivudine twice daily. APV30002 Fosamprenavir 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir 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 Fasting specimens. (> 750 mg/dL) 0% 1% 6% 2% Neutrophil count, absolute (< 750 cells/mm 3 ) 3% 6% 3% 4% 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 ULN = Upper limit of normal. Laboratory Abnormality Fosamprenavir 700 mg and Ritonavir 100 mg Twice Daily. All subjects also received 2 reverse transcriptase inhibitors. (n = 104) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily (n = 103) Triglycerides Fasting specimens. (> 750 mg/dL) 11% n = 100 for fosamprenavir plus ritonavir, n = 98 for lopinavir plus ritonavir. 6% Serum lipase (> 2 x ULN) 5% 12% ALT (> 5 x ULN) 4% 4% AST (> 5 x ULN) 4% 2% Glucose (> 251 mg/dL) 2% 2% 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 mm 3 ) 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.

• Coadministration of fosamprenavir 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 or fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. ( 7 )
• Coadministration of fosamprenavir 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 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 [see Contraindications (4) ] . 7.2 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 [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 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: ↓ Amprenavir (predicted) ↔ or ↓ Boceprevir (predicted) Fosamprenavir/ ritonavir: ↓ Amprenavir (predicted) ↓ Boceprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and boceprevir is not recommended. HCV protease inhibitor: Simeprevir Fosamprenavir: ↔ Amprenavir (predicted) ↑ or ↓ Simeprevir (predicted) Fosamprenavir/ ritonavir: ↔ Amprenavir (predicted) ↑ Simeprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and simeprevir is not recommended. HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) Fosamprenavir: ↑ Amprenavir (predicted) ↑ or ↔ Paritaprevir (predicted) Fosamprenavir/ ritonavir: ↑ or ↔ Amprenavir (predicted) ↑ Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/dasabuvir. Coadministration of fosamprenavir/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Delavirdine See Clinical Pharmacology (12.3) Tables 10 , 11 , 12 , or 13 for magnitude of interaction. Fosamprenavir: ↑ Amprenavir ↓ Delavirdine Fosamprenavir/ ritonavir: ↑ Amprenavir ↓ Delavirdine Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine [see Contraindications (4) ] . Non-nucleoside reverse transcriptase inhibitor: Efavirenz Fosamprenavir: ↓ Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ ritonavir: ↓ Amprenavir An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Non-nucleoside reverse transcriptase inhibitor: Nevirapine Fosamprenavir: ↓ Amprenavir ↑ Nevirapine Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/ ritonavir: ↓ Amprenavir ↑ Nevirapine No dosage adjustment required when nevirapine is administered with fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once-daily regimen has not been studied. HIV protease inhibitor: Atazanavir Fosamprenavir: Interaction has not been evaluated. Fosamprenavir/ ritonavir: ↓ Atazanavir ↔ Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Indinavir , nelfinavir Fosamprenavir: ↑ Amprenavir Effect on indinavir and nelfinavir is not well established. Fosamprenavir/ 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 ↓ 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 Fosamprenavir: ↓ Amprenavir Effect on saquinavir is not well established. Fosamprenavir/ 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 Fosamprenavir: ↓ Amprenavir ↓ Raltegravir Fosamprenavir/ ritonavir: ↓ Amprenavir ↓ Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor: Dolutegravir Fosamprenavir/ ritonavir: ↓ Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with fosamprenavir/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance. HIV CCR5 co-receptor antagonist: Maraviroc Fosamprenavir/ ritonavir: ↓ Amprenavir ↑ Maraviroc No dosage adjustment required for fosamprenavir/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with fosamprenavir/ritonavir. Fosamprenavir 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 may be less effective due to decreased amprenavir plasma concentrations. Staggered coadministration of antacids and fosamprenavir has not been evaluated. Antiarrhythmics: Amiodarone, disopyramide, lidocaine (systemic), and quinidine ↑ Antiarrhythmics Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. Antiarrhythmics: Flecainide, propafenone ↑ Antiarrhythmics Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir 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: ↓ Amprenavir Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Phenytoin Fosamprenavir/ ritonavir: ↑ Amprenavir ↓ Phenytoin Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in fosamprenavir/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, the combination should be used with caution and a lower dose of trazodone should be considered. Antifungals: Ketoconazole , itraconazole ↑ Ketoconazole ↑ Itraconazole Increase monitoring for adverse events. Fosamprenavir: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Fosamprenavir/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/ritonavir. Fosamprenavir/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 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 ↑ Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. Fosamprenavir: A dosage reduction of rifabutin by at least half the recommended dose is required. Fosamprenavir/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 or to the class of protease inhibitors [see Contraindications (4)] . Antineoplastics: Dasatinib, nilotinib, ibrutinib, vinblastine, everolimus ↑ Antineoplastics Fosamprenavir or fosamprenavir/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 ↑ Lurasidone Fosamprenavir: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. Fosamprenavir/ritonavir: Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] . Pimozide ↑ Pimozide Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Quetiapine ↑ Quetiapine Fosamprenavir/ritonavir: Initiation of fosamprenavir 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 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 may be less effective due to decreased amprenavir plasma concentrations. Endothelin-receptor antagonist: Bosentan ↑ Bosentan Coadministration of bosentan in patients on fosamprenavir: In patients who have been receiving fosamprenavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of fosamprenavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of fosamprenavir. After at least 10 days following the initiation of fosamprenavir, 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 or to the class of protease inhibitors [see Contraindications (4) ] . Histamine H 2 -receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine Fosamprenavir: ↓ Amprenavir Fosamprenavir/ ritonavir: Interaction not evaluated Use with caution. Fosamprenavir 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 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: ↑ Fluticasone Fosamprenavir/ ritonavir: ↑ Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and fosamprenavir/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 ↑ Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day. Lovastatin, simvastatin ↑ Lovastatin ↑ Simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see Contraindications (4) ] . Other lipid modifying agents: Lomitapide ↑ Lomitapide Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases. Narcotic analgesic: Methadone ↓ Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. Fentanyl ↑ Fentanyl Careful monitoring of therapeutic effects and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended. Oral contraceptives: Ethinyl estradiol/norethindrone Fosamprenavir: ↓ Amprenavir ↓ Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. Fosamprenavir/ ritonavir: ↓ Ethinyl estradiol Increased risk of transaminase elevations. No data are available on the use of fosamprenavir/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. 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: Coadministration of ADCIRCA in patients on fosamprenavir: In patients receiving fosamprenavir 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 in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of fosamprenavir. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir. After at least one week following the initiation of fosamprenavir, 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: 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/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 , 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 [see Contraindications (4) ] . 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 = 7) was 0.27 (0.24 to 0.30). At delivery, 9 subjects had HIV-1 viral load less than 50 copies/mL, and 1 subject had a viral load of 111 copies/mL. 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.

Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens, there were 2 birth defects reported in 109 first trimester exposures and 2 birth defects reported in 36 second and third trimester exposures. The background rate for major birth defects is 2.7% in a U.S. reference population of the MACDP. 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. Animal Data Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on Gestation Days 6 to 17 and Days 7 to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (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. In the rat pre- and postnatal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on Gestation Day 6 to Lactation/Postpartum Day 20. Fosamprenavir caused a reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed. Systemic exposure (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 [see Drug Interactions (7), Clinical Pharmacology (12.3)]. 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). ( 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 )

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.