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Trade Names:
Lexiva
- Tablets 700 mg (equivalent to 600 mg amprenavir)

Mechanism of Action

Pharmacology

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 t _½ is approximately 7.7 h.

Special Populations

Moderate cirrhosis increases AUC, while severe cirrhosis increases AUC and C _max . Patients with impaired hepatic function may require dosage reduction.

Indications and Usage

Treatment of HIV infections 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, ergot derivatives [eg, ergonovine]), GI motility agent, neuroleptic agent (eg, pimozide), and sedative/hypnotics (eg, midazolam, triazolam); when administered with ritonavir, flecainide and propafenone are contraindicated; hypersensitivity to any component of this product or to amprenavir.

Dosage and Administration

PO 1,400 mg twice daily without ritonavir; 1,400 mg every day plus 200 mg ritonavir every day; 700 mg twice daily 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 In patients with mild or moderate hepatic impairment receiving fosamprenavir without ritonavir reduce dosage to 700 mg twice daily. Do not use in patients with severe hepatic impairment.

General Advice

• Administer without regard to meals. Administer with food if GI upset occurs.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Keep tightly capped.

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 elevated by fosamprenavir, increasing the risk of adverse reactions.

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

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

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

These agents are contraindicated when fosamprenavir is administered with ritonavir.

Coadministration is not recommended because the risk of myopathy, including rhabdomyolysis, may be increased.

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

Plasma levels may be reduced by fosamprenavir, resulting in a loss of pharmacologic response.

Plasma levels may be increased by amprenavir, increasing the risk of side effects.

Because amprenavir plasma levels may be reduced about 90%, avoid coadministration.

Amprenavir plasma concentrations may be reduced by St. John's wort, decreasing the clinical efficacy; 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 international normalized ratio is recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Headache (19%); depressive/mood disorders (8%); paresthesia (2%).

Dermatologic

Rash (35%); pruritus (7%); Stevens-Johnson syndrome.

GI

Nausea (39%); diarrhea (34%); vomiting (16%); abdominal pain (5%).

Hematologic-Lymphatic

Neutropenia (3%); acute hemolytic anemia.

Lab Tests

Increased serum lipase (8%); increased ALT and AST (6%).

Miscellaneous

Fatigue (10%).

Precautions

Pregnancy

Category C .

Lactation

HIV-infected mothers should not breast-feed their infants.

Children

Safety and efficacy not established.

Elderly

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

Hepatic Function

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

Cross-resistance/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 diabetic patient 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.

Hemophilia

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

Sulfa allergy

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

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 patient to take prescribed dose without regard to meals but to take with food if GI upset occurs.
• 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, take the missed dose right away and then take the 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 report the following symptoms immediately to health care provider: rash; persistent nausea, vomiting, or diarrhea; any unusual symptom.
• Inform patient that the drug does not completely eliminate HIV virus and therefore does not reduce risk of transmitting HIV to others. 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. Patients should remain under a physician's care.
• Instruct diabetic patient 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 reduced.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breastfeeding. Caution HIV-infected mother that breastfeeding can cause HIV infection in the baby.