Amprenavir

New Dosing Recommendations for Amprenavir and Ritonavir Used as Combination Therapy

On February 5, 2002, the Food and Drug Administration (FDA) approved new labeling for amprenavir and ritonavir when the agents are used in combination. The new dosage recommendations are in recognition of the pharmacokinetic impact of concurrent therapy. In addition, changes in serum lipids associated with concurrent therapy have been added to the product labeling.

Pronunciation (am PREN a veer)

• Antiretroviral Agents
• Antiretroviral Therapy for HIV Infection

U.S. Brand Names Agenerase®

Generic Available No

Canadian Brand Names Agenerase®

Pharmacologic Category Antiretroviral Agent, Protease Inhibitor

Use Treatment of HIV infections in combination with at least two other antiretroviral agents; oral solution should only be used when capsules or other protease inhibitors are not therapeutic options

Pregnancy Risk Factor C

Pregnancy Implications It is not known if amprenavir crosses the human placenta and there are no clinical studies currently underway to evaluate its use in pregnant women. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263).

Lactation Excretion in breast milk unknown/contraindicated

Contraindications Hypersensitivity to amprenavir or any component of the formulation; concurrent therapy with rifampin, astemizole, bepridil, cisapride, ergot derivatives, midazolam, pimozide, triazolam, lovastatin, simvastatin, and hormonal contraceptives; severe previous allergic reaction to sulfonamides; oral solution is contraindicated in infants or children <4 years of age, pregnant women, patients with renal or hepatic failure, and patients receiving concurrent metronidazole or disulfiram

Warnings/Precautions Because of hepatic metabolism and effect on cytochrome P450 enzymes, amprenavir should be used with caution in combination with other agents metabolized by this system (see Contraindications and Drug Interactions). Avoid concurrent use of St John's wort (may lead to loss of virologic response and/or resistance). Use with caution in patients with diabetes mellitus, sulfonamide allergy, hepatic impairment, or hemophilia. Redistribution of fat may occur (eg, buffalo hump, peripheral wasting, cushingoid appearance). Additional vitamin E supplements should be avoided. Concurrent use of sildenafil should be avoided. Certain ethnic populations (Asians, Eskimos, Native Americans) may be at increased risk of propylene glycol-associated adverse effects; use of the oral solution of amprenavir should be avoided. Use oral solution only when capsules or other protease inhibitors are not options. Dosage adjustment is required for combination therapy with amprenavir and ritonavir; in addition, the risk of hyperlipidemia may be increased during concurrent therapy.

Adverse Reactions Protease inhibitors cause dyslipidemia which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause "protease paunch," buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

>10%:

1% to 10%:

Overdosage/Toxicology Monitor for signs and symptoms of propylene glycol toxicity if the oral solution is administered.

Drug Interactions Substrate of CYP2C8/9, 3A4; Inhibits CYP2C19, 3A4

Antiarrhythmics: Amprenavir may increase serum concentrations/toxicity of several antiarrhythmic agents. Use extreme caution with amiodarone, bepridil, lidocaine, and quinidine.

Anticonvulsants (phenytoin, phenobarbital, carbamazepine): May decrease serum concentrations of amprenavir.

Benzodiazepines (alprazolam, clorazepate, diazepam, flurazepam midazolam, triazolam) toxicity may be increased; concurrent use of midazolam and triazolam is specifically contraindicated.

Calcium channel blockers: Amprenavir may increase serum concentrations/effects.

Cisapride: Amprenavir may increase serum concentrations of cisapride, increasing the risk of malignant arrhythmias; use is contraindicated.

Clarithromycin: May increase serum concentrations of amprenavir.

Dexamethasone: The effect of amprenavir may be decreased by dexamethasone; use caution.

Didanosine (buffered formulation): May decrease serum concentrations of amprenavir. Take amprenavir 1 hour before or after didanosine.

Disulfiram: Concurrent use with amprenavir oral solution is contraindicated due to risk of propylene glycol toxicity.

Efavirenz: May decrease serum concentrations of amprenavir.

Ergot alkaloids (dihydroergotamine, ergotamine, ergonovine, methylergonovine): Toxicity (peripheral ischemia, vasospasm) is increased by amprenavir; concurrent use is contraindicated.

HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, simvastatin) serum concentrations may be increased by amprenavir, increasing the risk of myopathy/rhabdomyolysis. Lovastatin and simvastatin are contraindicated. Use lowest possible dose of atorvastatin. Fluvastatin and pravastatin may be safer alternatives.

Immunosuppressants (cyclosporine, tacrolimus): Amprenavir may increase serum concentrations of immunosuppressive agents.

Methadone: Effect of amprenavir may be diminished (consider alternative antiretroviral). In addition, the effect of methadone may be reduced (dosage increase may be required).

Metronidazole: Concurrent use with amprenavir oral solution is contraindicated due to risk of propylene glycol toxicity.

Nelfinavir: May increase serum concentrations of amprenavir.

Nevirapine: May decrease serum concentrations of amprenavir.

Oral contraceptives: Concurrent use of ethinyl estradiol/norethindrone may lead to decreased effect of amprenavir; avoid use. Nonhormonal contraception is recommended.

Pimozide: Toxicity is significantly increased by amprenavir; concurrent use is contraindicated.

Rifampin/rifabutin: May decrease serum concentrations of amprenavir. Concurrent use of rifampin is contraindicated. Serum concentrations of rifabutin may be increased by amprenavir; dosage adjustment required.

Ritonavir: The serum concentrations of ritonavir may be increased by amprenavir. In addition, the risk of cholesterol/triglyceride elevations may be increased, specific dosing has been recommended for both agents.

Sildenafil: Serum concentrations may be increased by amprenavir; when used concurrently, do not exceed a maximum sildenafil dose of 25 mg in a 48-hour period.

St John's wort: May decrease serum concentrations of amprenavir. Use is contraindicated.

Tricyclic antidepressants: Amprenavir may increase serum concentrations/toxicity, potentially leading to serious arrhythmias.

Warfarin: Effect may be increased by amprenavir. Monitor INR.

Note: Amprenavir may also increase the effect/toxicity of other drugs metabolized by CYP3A4.

Ethanol: Avoid ethanol with amprenavir oral solution.

Food: Levels increased sixfold with high-fat meals.

Herb/Nutraceutical: Amprenavir serum concentration may be decreased by St John's wort; avoid concurrent use. Formulations contain vitamin E; avoid additional supplements.

Mechanism of Action Binds to the protease activity site and inhibits the activity of the enzyme. HIV protease is required for the cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Inhibition prevents cleavage of these polyproteins, resulting in the formation of immature, noninfectious viral particles.

Absorption: 63%

Distribution: 430 L

Protein binding: 90%

Metabolism: Hepatic via CYP (primarily CYP3A4)

Bioavailability: Not established; increased sixfold with high-fat meal

Half-life elimination: 7.1-10.6 hours

Time to peak: 1-2 hours

Excretion: Feces (75%); urine (14% as metabolites)

Dosage Oral: Note: Capsule and oral solution are not interchangeable on a mg-per-mg basis.

Capsule:

Solution:

Dosage adjustment in renal impairment: Oral solution is contraindicated in renal failure.

Dosage adjustment in hepatic impairment:

Dietary Considerations May be taken with or without food; do not take with high-fat meal.

Patient Information Amprenavir is not a cure for HIV, nor has it been found to reduce transmission of HIV. Take as directed, with or without food. Maintain adequate fluid intake (2-3 L/day of fluids unless instructed to restrict fluid intake) and adequate nutritional intake (small, frequent meals may help). Do not take additional vitamin E supplements. Do not take St John's wort. You will be more susceptible to infection (avoid crowds or exposure to contagious diseases or infection). You may experience headache or confusion (use caution when driving or engaging in tasks requiring alertness until response to drug in known); headache (mild analgesic may help); nausea, vomiting, or increase flatulence (small frequent meals, may help); diarrhea (boiled milk, yogurt, or buttermilk may help). Inform prescriber if you experience muscle numbness or tingling; unresolved persistent vomiting, diarrhea, or abdominal pain; difficulty breathing or chest pain; unusual skin rash; or change in color of stool or urine. Avoid alcohol if taking oral solution. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Additional Information Capsules contain 109 int. units of vitamin E per capsule; oral solution contains 46 int. units of vitamin E per mL. Propylene glycol is included in the oral solution; a dose of 22.5 mg/kg twice daily corresponds to an intake of 1650 mg/kg of propylene glycol. Capsule and oral solution are not interchangeable on a mg-per-mg basis.

Anesthesia and Critical Care Concerns/Other Considerations Propylene glycol is included in the oral solution. A dose of 22.5 mg/kg twice daily corresponds to an intake of 1650 mg/kg of propylene glycol. Capsule and oral solution are not interchangeable on a mg-per-mg basis.

Dental Health: Effects on Dental Treatment 10%: Perioral tingling/numbness, taste disorders

Dental Health: Vasoconstrictor/Local Anesthetic Precautions No information available to require special precautions

Dental Comment Propylene glycol is included in the oral solution; a dose of 22.5 mg/kg twice daily corresponds to an intake of 1650 mg/kg of propylene glycol.

Mental Health: Effects on Mental Status Depression is common; may cause headache and fatigue

Mental Health: Effects on Psychiatric Treatment Contraindicated with midazolam and triazolam. Concurrent use with vitamin E and sildenafil should be avoided. May increase concentrations of alprazolam, clorazepate, diazepam, flurazepam, sildenafil, carbamazepine, and pimozide. May increase adverse effects of TCAs (monitor serum levels).

Capsule: 50 mg, 150 mg

Solution, oral [use only when there are no other options]: 15 mg/mL (240 mL) [contains propylene glycol 550 mg/mL and vitamin E 46 int. units/mL; grape-bubblegum-peppermint flavor]

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," February 5, 2001. Available at: http://www.hivatis.org. Accessed February 14, 2001.

Kaul DR, Cinti SK, Carver PL, et al, "HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications,"Pharmacotherapy, 1999, 19(3):281-98.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States, Perinatal HIV Guidelines Working Group," January 24, 2001. Available at: http://www.hivatis.org. Accessed February 14, 2001.

International Brand Names Agenerase® (CA, FR, DE, NO, CH); Prozei® (JP)