Fosamprenavir Calcium

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

Pharmacology

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

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. C _max is about 4.82 mcg/mL. AUC is approximately 33 mcg•h/mL. C _min is approximately 0.35 mcg/mL.

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. About 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 is approximately 7.7 h.

Special Populations

Renal function impairment is not expected to impact elimination.

AUC of amprenavir was increased 2.5-fold in patients with moderate cirrhosis and 4.5-fold in patients with severe cirrhosis.

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

Gender and race do 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 Cl and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, cisapride, delavirdine, dihydroergotamine, ergonovine, ergotamine, flecainide, lovastatin, methylergonovine, midazolam, pimozide, propafenone, rifampin, simvastatin, St. John's wort, triazolam); when administered with ritonavir in patients receiving flecainide and propafenone; hypersensitivity to any component of the product or to amprenavir.

Dosage and Administration

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.

PO

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

Oral suspension 30 mg/kg twice daily (max, 1,400 mg twice daily) or oral suspension 18 mg/kg plus ritonavir 3 mg/kg twice daily (max, fosamprenavir 700 mg plus ritonavir 100 mg twice daily).

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.

PO Oral suspension 18 mg/kg 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 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.

PO

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).

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

Reduce dosage to 350 mg twice daily without ritonavir (therapy-naive).

General Advice

• Administer without regard to meals; administer with food if GI upset occurs.
• When administered in combination with ritonavir, fosamprenavir tablets may be used for children weighing at least 39 kg, and ritonavir capsules may be used for children weighing at least 33 kg.
• Once-daily administration of fosamprenavir plus ritonavir is not recommended for protease inhibitor–experienced adults or children.
• Adults should take the oral suspension without food; children should take the oral suspension with food.
• If vomiting occurs within 30 minutes after dosing, re-dosing 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

Plasma levels of these drugs may be increased, resulting in serious and/or life-threatening drug interactions.

Plasma levels of these agents may be reduced, resulting in a decrease in pharmacologic response.

Plasma levels of these agents may be elevated by fosamprenavir, increasing the risk of adverse reactions.

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

Alternative methods of nonhormonal contraception are recommended.

May lead to loss of virologic response and possible resistance to delavirdine.

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

These agents are contraindicated when fosamprenavir is administered with ritonavir.

Amprenavir plasma levels may be elevated, leading to an increase in adverse reactions.

Plasma levels of these agents may be elevated by fosamprenavir, increasing the risk of adverse events. Dose reduction in ketoconazole or itraconazole is needed.

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.

Plasma levels may be increased by amprenavir, increasing the risk of adverse reactions. Dose limitation of phosphodiesterase type 5 inhibitors is needed.

Dose reduction in rifabutin is needed. Monitor for neutropenia.

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

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

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Fatigue, headache (2%).

Dermatologic

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

GI

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

Hematologic-Lymphatic

Acute hemolytic anemia.

Lab Tests

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

Precautions

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.

Crossresistance/resistance

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

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 and accumulation of body fat have been observed in patients receiving 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.

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.

Skin reactions

Severe and life-threatening skin reactions (eg, Steven-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 adults to take prescribed dose without regard to meals but to take with food if GI upset occurs. Advise caregivers to give dose with food for 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, or 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.
• Caution women using hormonal contraceptives to use alternative contraceptive measures during therapy because hormonal contraceptive effectiveness may be altered.
• 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.
• Caution HIV-infected woman that breast-feeding can cause HIV infection in the baby.
• 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.

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