Amprenavir

Pronunciation

(am PREN a veer)

U.S. Brand Names

Agenerase®

Generic Available

Canadian Brand Names

Agenerase®

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

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. Use of oral solution is contraindicated during pregnancy. 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 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to amprenavir or any component of the formulation; concurrent therapy with cisapride, ergot derivatives, midazolam, pimozide, and triazolam; 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 use of lovastatin or simvastatin (risk of rhabdomyolysis may be increased). Avoid concurrent use of hormonal contraceptives, rifampin, and/or 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. 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 increased abdominal girth, buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

>10%:

Central nervous system: Paresthesia (peripheral 10% to 14%)

Dermatologic: Rash (22%)

Endocrine & metabolic: Hyperglycemia (>160 mg/dL: 37% to 41%), hypertriglyceridemia (>399 mg/dL: 36% to 47%; >750 mg/dL: 8% to 13%)

Gastrointestinal: Nausea (43% to 74%), vomiting (24% to 34%), diarrhea (39% to 60%), abdominal symptoms

Miscellaneous: Perioral tingling/numbness (26% to 31%)

1% to 10%:

Central nervous system: Depression (4% to 15%), headache, fatigue, depression, mood disorder

Dermatologic: Stevens-Johnson syndrome (1% of total, 4% of patients who develop a rash)

Endocrine & metabolic: Hyperglycemia (>251 mg/dL: 2% to 3%)

Gastrointestinal: Taste disorders (2% to 10%)

Hepatic: AST increased (3% to 5%), ALT increased (4%), amylase increased (3% to 4%)

Overdosage/Toxicology

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

Drug Interactions

Substrate of CYP2C8/9 (minor), 3A4 (major); Inhibits CYP2C19 (weak), 3A4 (strong)

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.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amprenavir. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Amprenavir may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Delavirdine: Amprenavir decreases the serum concentrations of delavirdine; may lead to loss of virologic response and possible resistance to delavirdine. Concomitant use is not recommended.

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 not recommended. 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 not recommended. Serum concentrations of rifabutin may be increased by amprenavir; dosage adjustment required.

Ritonavir: The serum concentrations of amprenavir may be increased by ritonavir. In addition, the risk of cholesterol/triglyceride elevations may be increased, specific dosing has been recommended for both agents. Concurrent use of amprenavir oral solution with ritonavir oral solution is not recommended (due to competition for metabolic elimination between propylene glycol and ethanol in these formulations).

Sildenafil, tadalafil, vardenafil: Serum concentrations may be increased by amprenavir. When used concurrently with sildenafil, do not exceed a maximum sildenafil dose of 25 mg in a 48-hour period. When used concurrently with tadalafil, do not exceed a maximum tadalafil dose of 10 mg in a 72-hour period. When used concurrently with vardenafil, do not exceed vardenafil dose of 2.5 mg in a 24-hour period (2.5 mg in a 72-hour period if used with ritonavir).

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

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

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

Ethanol/Nutrition/Herb Interactions

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.

Pharmacodynamics/Kinetics

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:

Children 4-12 years and older (<50 kg): 20 mg/kg twice daily or 15 mg/kg 3 times daily; maximum: 2400 mg/day

Children >13 years (>50 kg) and Adults: 1200 mg twice daily

Note: Dosage adjustments for amprenavir when administered in combination therapy:

Efavirenz: Adjustments necessary for both agents:

Amprenavir 1200 mg 3 times/day (single protease inhibitor) or

Amprenavir 1200 mg twice daily plus ritonavir 200 mg twice daily

Ritonavir: Adjustments necessary for both agents:

Amprenavir 1200 mg plus ritonavir 200 mg once daily or

Amprenavir 600 mg plus ritonavir 100 mg twice daily

Solution:

Children 4-12 years or older (up to 16 years weighing <50 kg): 22.5 mg/kg twice daily or 17 mg/kg 3 times daily; maximum: 2800 mg/day

Children 13-16 years (weighing at least 50 kg) or >16 years and Adults: 1400 mg twice daily

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

Dosage adjustment in hepatic impairment:

Child-Pugh score between 5-8:

Capsule: 450 mg twice daily

Solution: 513 mg twice daily; contraindicated in hepatic failure

Child-Pugh score between 9-12:

Capsule: 300 mg twice daily

Solution: 342 mg twice daily; contraindicated in hepatic failure

Dietary Considerations

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

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug is not a cure for HIV, nor has it been found to reduce transmission. Take as directed, at regular intervals around-the-clock. May take with light meal (eg, dry toast, skim milk, corn flakes) to reduce GI upset. Avoid alcohol. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Amprenavir may be prescribed with a combination of other medications; time these medications as directed by prescriber. You may be advised to check your glucose levels (this drug can cause exacerbation or new-onset diabetes). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations unless approved by prescriber). May cause body changes due to redistribution of body fat, facial atrophy, or breast enlargement (normal effects of drug); nausea, vomiting, or flatulence (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); muscle weakness or flank pain (consult prescriber for approved analgesic); headache or insomnia (consult prescriber for medication); or diarrhea (boiled milk, buttermilk, or yogurt may help). Inform prescriber if you experience muscle numbness or tingling; unresolved persistent vomiting, diarrhea, or abdominal pain; respiratory difficulty or chest pain; unusual skin rash; or change in color of stool or urine. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant and do not get pregnant while taking this medicine. This drug decreases the effect of oral contraceptives; consult prescriber for use of appropriate barrier contraceptives. Do not breast-feed.

Additional Information

The 150 mg 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

The 150 mg 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.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Perioral tingling/numbness and taste disorder.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

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). Concomitant use of amprenavir and St John's wort is not recommended. Coadministration of protease inhibitors (amprenavir) with St John's wort is expected to substantially decrease protease inhibitor serum concentrations leading to a loss of virologic response and possible resistance to amprenavir or to the class of protease inhibitors.

Dosage Forms

[DSC] = Discontinued product

Capsule: 50 mg, 150 mg [DSC]

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-bubble gum-peppermint flavor]

References

"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.aidsinfo.nih.gov. 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," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

International Brand Names

Agenerase® (AR, AT, BE, BR, CA, CH, DE, DK, ES, FI, FR, GB, IE, IL, IT, MX, NO, NZ, PL, PT, RO, SE, SI, TR)

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