Fosamprenavir Calcium

Pronunciation: FOS-am-PREN-a-vir KAL-see-um
Class: Protease inhibitor

Trade Names

Lexiva
- Tablets 700 mg (equivalent to approximately amprenavir 600 mg)
- Suspension, oral 50 mg/mL (equivalent to approximately amprenavir 43 mg/mL)

Telzir (Canada)

Pharmacology

Fosamprenavir is a prodrug of amprenavir that inhibits HIV-1 protease, the enzyme required to form functional proteins in HIV-infected patients.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

As fosamprenavir is absorbed, it is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium. T max is between 1.5 and 4 h. Unboosted fosamprenavir C max is about 4.82 mcg/mL. AUC is approximately 33 mcg•h/mL, and C min is approximately 0.35 mcg/mL. Administration of fosamprenavir tablets in the fed state compared with the fasted state was not associated with significant changes in C max , T max , or AUC. Administration of fosamprenavir oral suspension in the fed state compared with the fasted was associated with a 46% decrease in C max , 0.72 h delay in T max , and 28% decrease in AUC.

Distribution

Approximately 90% protein bound, primarily to alpha-1 acid glycoprotein.

Metabolism

After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir, which is metabolized in the liver by CYP3A4.

Elimination

Approximately 1% excreted unchanged in the urine. Approximately 14% and 75% (with more than 90% as metabolites) of an administered dose of amprenavir excreted in the urine and feces, respectively. The half-life of amprenavir is approximately 7.7 h.

Special Populations

Renal Function Impairment

Renal function impairment is not expected to impact elimination.

Hepatic Function Impairment

AUC of amprenavir was increased by approximately 22% in mild hepatic impairment, by approximately 70% in moderate hepatic impairment, and by approximately 80% in severe hepatic impairment. Protein binding also decreased.

Elderly

Pharmacokinetics not studied in patients older than 65 yr of age.

Children

For children 2 to 18 yr of age, the AUC is 31.4 to 93.4 mcg•h/mL, C max is 5 to 6.07 mcg/mL, and C min is 0.454 to 2.69 mcg/mL.

Gender

Gender does not appear to affect the pharmacokinetics.

Race

Race does not appear to affect the pharmacokinetics.

Indications and Usage

Treatment of HIV infection in combination with other antiretroviral agents.

Contraindications

Coadministration with drugs highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, cisapride, delavirdine, dihydroergotamine, ergonovine, ergotamine, lovastatin, methylergonovine, midazolam, pimozide, rifampin, simvastatin, St. John's wort, triazolam); coadministration with flecainide or propafenone when administered with ritonavir; hypersensitivity to any component of the product or to amprenavir.

Dosage and Administration

Therapy-Naive Patients
Adults

PO 1,400 mg twice daily without ritonavir; 1,400 mg plus ritonavir 200 mg once daily; 1,400 mg once daily plus ritonavir 100 mg once daily; or 700 mg twice daily plus ritonavir 100 mg twice daily.

Children

PO

2 to 5 yr of age

30 mg/kg of oral suspension twice daily (max, 1,400 mg twice daily).

6 yr of age and older

30 mg/kg of oral suspension twice daily (max, 1,400 mg twice daily) or 18 mg/kg of oral suspension plus ritonavir 3 mg/kg twice daily (max, fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily). When administered without ritonavir, the adult regimen of fosamprenavir 1,400 mg twice daily may be used for children weighing at least 47 kg. When administered with ritonavir, fosamprenavir tablets may be used for children weighing at least 39 kg; ritonavir capsules may be used for children weighing at least 33 kg.

Protease Inhibitor–Experienced Patients
Adults

PO 700 mg twice daily plus ritonavir 100 mg twice daily. Once-daily administration of fosamprenavir plus ritonavir is not recommended in protease inhibitor–experienced patients.

Therapy-Experienced Patients
Children 6 yr of age and older

PO 18 mg/kg of oral suspension plus ritonavir 3 mg/kg twice daily (max, fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily). When administered with ritonavir, fosamprenavir tablets may be used for children weighing at least 39 kg; ritonavir capsules may be used for children weighing at least 33 kg.

Hepatic Function Impairment
Adults

PO

Mild hepatic function impairment (Child-Pugh score 5 to 6)

Reduce dosage to 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 function impairment (Child-Pugh score 7 to 9)

Reduce dosage to 700 mg twice daily (therapy-naive) without ritonavir (therapy-naive) or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor–experienced).

Severe hepatic function impairment (Child-Pugh score 10 to 15)

Reduce dosage to 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).

General Advice

  • Administer tablets without regard to meals; administer with food if GI upset occurs.
  • Adults should take the oral suspension without food; children should take the oral suspension with food.
  • If vomiting occurs within 30 min after dosing, redosing of the oral suspension should occur.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Keep tightly capped. Store oral suspension at 41° to 86°F. Shake vigorously before using. Do not freeze.

Drug Interactions

Amprenavir is the active metabolite of fosamprenavir.

Amiodarone, bepridil, quinidine, systemic lidocaine, tricyclic antidepressants (eg, amitriptyline)

Plasma levels of these agents may be increased, resulting in serious and/or life-threatening drug interactions. Use with caution and monitor plasma concentrations. Adjust the drug dosage as needed.

Anticholinergic agents (eg, fesoterodine, darifenacin, solifenacin, tolterodine)

Plasma concentrations of the anticholinergic agent may be elevated, increasing the pharmacologic effects and risk of adverse reactions. When coadministered with fosamprenavir, the daily dose of darifenacin should not exceed 7.5 mg, the daily dose of solifenacin should not exceed 5 mg, the daily dose of tolterodine should not exceed 2 mg, and the daily dose of fesoterodine should not exceed 4 mg.

Aripiprazole

Aripiprazole plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the patient and adjust the aripiprazole dose as needed.

Atazanavir, paroxetine, phenytoin

Plasma levels of these agents may be reduced, resulting in a decrease in pharmacologic response. Monitor drug concentrations and the response of the patient. Adjust the drug dosage as needed.

Atorvastatin, rosuvastatin

Coadministration may increase the risk of myopathy, including rhabdomyolysis. Use the lowest possible dose of atorvastatin or rosuvastatin. Carefully monitor the patient. Consider use of fluvastatin or pravastatin as an alternative agent.

Benzodiazepines (eg, alprazolam, clorazepate, diazepam, flurazepam), calcium channel blockers (eg, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil), cyclosporine, rapamycin, tacrolimus, trazodone

Plasma levels of these agents may be elevated by fosamprenavir, increasing the risk of adverse reactions. Use with caution. Monitor the response of the patient. Lower doses of these agents may be needed.

Carbamazepine

Amprenavir plasma levels may be reduced, leading to a decrease in virologic response. Carbamazepine concentrations may be elevated, increasing the risk of toxicity. Use with caution. Monitor plasma concentrations and adjust dosage as needed.

Colchicine

Colchicine plasma concentrations may be increased. Life-threatening and fatal colchicine toxicity may occur. Avoid coadministration in patients with hepatic or renal impairment. In patients with normal renal and hepatic function, coadministration of fosamprenavir and colchicine should be undertaken using a maximum colchicine dosage of 0.3 mg twice daily with careful monitoring for colchicine-related adverse effects.

Contraceptives, hormonal

Amprenavir and hormonal contraceptive concentrations may be reduced, resulting in a loss of efficacy. Alternative methods of nonhormonal contraception are recommended.

Corticosteroids (eg, dexamethasone), histamine H 2 -receptor antagonists (eg, cimetidine), lopinavir/ritonavir combination, phenobarbital, proton pump inhibitors (eg, omeprazole)

Amprenavir plasma levels may be reduced, leading to a decrease in virologic response. Use with caution.

Corticosteroids (eg, nasal fluticasone, oral prednisone)

Corticosteroid metabolism (CYP3A4) may be inhibited, increasing the risk for toxicity. Coadministration of fluticasone and fosamprenavir plus ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid adverse reactions.

CYP3A4 inhibitors (eg, clarithromycin)

Coadministration of fosamprenavir with inhibitors of CYP3A4 may lead to increased amprenavir concentrations. Use with caution.

Delavirdine

May lead to loss of virologic response and possible resistance to delavirdine. Amprenavir concentrations may be elevated. Coadministration is contraindicated.

Dronedarone

Dronedarone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Avoid coadministration.

Drugs highly dependent on CYP3A4 metabolism (eg, cisapride, dihydroergotamine, ergonovine, ergotamine, lovastatin, methylergonovine, midazolam, pimozide, ranolazine, simvastatin, triazolam)

Coadministration of these agents with fosamprenavir is contraindicated because of the potential for serious and/or life-threatening reactions.

Efavirenz

Coadministration may decrease amprenavir concentrations. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir plus ritonavir once daily.

Eplerenone

Eplerenone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Close clinical monitoring is indicated when eplerenone is coadministered with fosamprenavir. Adjust the eplerenone dose as needed.

Erythromycin

Erythromycin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions such as cardiac arrhythmias. Avoid coadministration.

Esomeprazole

Esomeprazole exposure may be increased. Monitor for adverse reactions and adjust the esomeprazole dose as needed.

Eszopiclone

Eszopiclone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Close clinical monitoring is indicated when eszopiclone is coadministered with fosamprenavir. Adjust the eszopiclone dose as needed.

Flecainide, propafenone

These agents are contraindicated when fosamprenavir is administered with ritonavir.

Food

Administration of a single dose of fosamprenavir 1,400 mg oral suspension in the fed state (standardized high-fat meal: 967 kcal, 67 g of fat, 33 g of protein, 58 g of carbohydrate) compared with the fasted state was associated with a 46% reduction in C max , a 0.72-hour delay in T max , and a 28% reduction in amprenavir AUC. Grapefruit juice may increase plasma concentrations of amprenavir. If grapefruit juice cannot be avoided, closely monitor the patient and adjust the fosamprenavir dose as needed. Garlic ingestion may reduce amprenavir plasma concentrations, decreasing the pharmacologic effects. Avoid garlic ingestion.

Indinavir, nelfinavir

Amprenavir plasma levels may be elevated, leading to an increase in adverse reactions. Monitor amprenavir plasma concentrations and observe the response of the patient. Adjust the fosamprenavir dose as needed.

Itraconazole, ketoconazole

Plasma levels of these agents as well as those of amprenavir may be elevated, increasing the risk of adverse reactions. Monitor patients for an increase in adverse reactions and adjust dosages as needed.

Ixabepilone

Ixabepilone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration. If fosamprenavir must be given with ixabepilone, ixabepilone dosage adjustment may be needed.

Lopinavir/Ritonavir

Coadministration of lopinavir plus ritonavir with fosamprenavir may decrease amprenavir C max and AUC. Coadministration may increase lopinavir plus ritonavir C max and AUC. An increased rate of adverse reactions has been observed with coadministration of these agents. Appropriate dosages of the combinations with respect to safety and efficacy have not been established.

Mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus)

mTOR plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration. If coadministration of fosamprenavir is necessary, monitor the clinical response of the patient and adjust the mTOR dose as needed.

Maraviroc

Maraviroc plasma concentrations may be elevated, increasing the pharmacologic effects and of risk adverse reactions. Monitor the response of the patient and adjust the maraviroc dose as needed.

Methadone

Amprenavir and methadone plasma concentrations may be reduced, decreasing the efficacy. Monitor the patient for a loss in efficacy, including opioid withdrawal. Adjust therapy as needed.

Nevirapine

Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. Amprenavir concentrations may be reduced, leading to a decrease in virologic response. Nevirapine concentrations may be elevated.

Nilotinib

Nilotinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions such as cardiac arrhythmias. Avoid coadministration. If coadministration of fosamprenavir is necessary, it is recommended that therapy with nilotinib be interrupted. If fosamprenavir must be given with nilotinib, nilotinib dosage adjustment may be needed.

Opioid analgesics (eg, alfentanil, buprenorphine, fentanyl, sufentanil)

Opioid analgesic plasma concentrations may be increased and the half-life prolonged, increasing the risk of adverse reactions. Monitor respiratory function and adjust the opioid dose as needed.

Phenytoin

Fosamprenavir plus ritonavir may decrease phenytoin concentrations. Monitor phenytoin concentrations and increase phenytoin dose as appropriate.

Phosphodiesterase type 5 inhibitors (PDE5) (eg, sildenafil, tadalafil, vardenafil)

Plasma levels may be increased by amprenavir, increasing the risk of adverse reactions. Dose limitation of PDE5 inhibitors is needed.

Protein-tyrosine kinase inhibitors (eg, dasatinib, sunitinib, sorafenib)

Protein-tyrosine kinase inhibitor plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the response of the patient and adjust the protein-tyrosine kinase inhibitor dose as needed.

Quetiapine

Quetiapine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the response of the patient and adjust the quetiapine dose as needed.

Rifabutin

Rifabutin and amprenavir concentrations may be elevated. Dose reduction in rifabutin is needed. Monitor for neutropenia.

Rifampin, St. John's wort

Coadministration is contraindicated. Amprenavir plasma concentrations may be reduced, decreasing the efficacy, which may lead to loss of virologic response and possible resistance to amprenavir or to the class of protease inhibitors.

Saquinavir

Coadministration may decrease amprenavir levels. Appropriate dosages have not been established.

Vasopressin receptor antagonists (eg, conivaptan, tolvaptan)

Vasopressin receptor antagonist plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Warfarin

Because warfarin concentrations may be altered, monitoring of INR is recommended.

Zidovudine

Coadministration may increase amprenavir AUC and may increase zidovudine exposure. Monitor the patient for adverse reactions and adjust the zidovudine dose as needed.

Adverse Reactions

Cardiovascular

MI (postmarketing).

CNS

Fatigue, headache (2%); oral paresthesia (postmarketing).

Dermatologic

Rash (8%); Stevens-Johnson syndrome (postmarketing).

GI

Nausea (7%); diarrhea (5%); vomiting (2%); abdominal pain (1%).

Genitourinary

Nephrolithiasis (postmarketing).

Hematologic-Lymphatic

Acute hemolytic anemia.

Lab Tests

Increased serum lipase (8%); increased ALT, increased AST (6%); decreased absolute neutrophil count (3%).

Metabolic-Nutritional

Hypercholesterolemia (postmarketing).

Miscellaneous

Angioedema (postmarketing).

Precautions

Monitor

Perform triglyceride and cholesterol testing prior to initiating treatment and at periodic intervals during treatment. Monitor LFTs prior to initiating treatment and periodically thereafter.


Pregnancy

Category C .

Lactation

Undetermined. HIV-infected women should not breast-feed infants.

Children

Safety and efficacy not established in children younger than 2 yr of age.

Elderly

Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidity.

Hepatic Function

Because patients with hepatic function impairment may require dosage reduction, use with caution.

Diabetes mellitus/hyperglycemia

New-onset and exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported. Monitor blood sugar in patients with diabetes when drug is started or dose is changed.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, have been observed in patients receiving antiretroviral therapy, including fosamprenavir. A causal relationship has not been established.

Hemolytic anemia

Has been reported with amprenavir.

Hemophilia

Spontaneous bleeding has been reported in patients with hemophilia A and B treated with protease inhibitors.

Hepatic toxicity

Patients with hepatitis B or C or marked elevations in transaminase levels may be at increased risk of developing or worsening of transaminase elevations. Monitor closely.

Immune reconstitution syndrome

Has been reported in patients receiving combination antiretroviral therapy.

Lipid elevations

Increased triglyceride concentrations have been reported in patients receiving fosamprenavir plus ritonavir.

Nephrolithiasis

Has been reported. Consider temporary interruption or discontinuation of therapy if signs or symptoms occur.

Resistance/Cross-resistance

It is not known what effect fosamprenavir therapy will have on the subsequent administration of protease inhibitors.

Skin reactions

Severe and life-threatening skin reactions (eg, Stevens -Johnson syndrome) have been reported.

Sulfa allergy

Because fosamprenavir contains a sulfonamide moiety, use with caution in patients with sulfa allergy.

Overdosage

Symptoms

Elevated ALT and AST.

Patient Information

  • Advise patient to read the patient information leaflet before starting therapy and with each refill.
  • Warn patient that this drug is not to be used by itself but is combined with other antiviral agents, and not to change the dose or stop taking any of the antiviral agents unless advised by health care provider.
  • Advise adult patients to take tablets without regard to food; however, adults should take the oral suspension without food.
  • Advise caregivers to give the oral suspension with food to children.
  • Advise patient that if a dose is missed by more than 4 h, to wait and take the next dose at the regular time. If a dose is missed by less than 4 h, advise patient to take missed dose right away and then take next dose at the regular time. If a dose is skipped, caution patient not to double the dose to catch up, but to continue with normal schedule.
  • Instruct patient to immediately report persistent diarrhea, nausea, vomiting, rash, or any unusual symptom to health care provider.
  • Inform patient that the drug does not completely eliminate HIV virus and, therefore, does not reduce risk of transmitting HIV to others. Advise patient that appropriate precautions must still be taken.
  • Advise patient that the drug is not a cure for HIV infection and that illnesses associated with HIV infection (including opportunistic infections) may continue to be acquired. Instruct patients to remain under health care provider's care.
  • Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
  • Instruct patients to inform health care provider if they have a sulfa allergy.
  • Inform patients that redistribution or accumulation of body fat may occur.
  • Instruct patients receiving the oral suspension to shake product vigorously before each use.
  • Instruct patients that refrigeration of the oral suspension may improve the taste.
  • Advise HIV-infected mothers not to breast-feed infants to avoid risk of HIV transmission to the infant.
  • Instruct patients taking hormonal contraceptives to use alternate contraceptive measures during therapy with fosamprenavir because hormonal levels may be altered.
  • Warn patient not to take any prescription or OTC drugs, herbal preparations (especially St. John's wort), or dietary supplements without consulting health care provider.
  • Advise patients receiving PDE5 inhibitors that they may be at an increased risk of PDE5 inhibitor–associated adverse reactions, including hypotension, priapism, and visual changes, and to promptly report any symptoms to their health care provider.

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