Agenerase

Generic Name: Amprenavir
Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: [3S - [3R*(1R*,2S*)]] - [3 - [[(4 - Aminophenyl)sulfonyl] - (2 - methylpropyl)amino] - 2 - hydroxy - 1 - (phenylmethyl)propyl] tetrahydro-3-furanyl carbamate
Molecular Formula: C₂₅H₃₅N₃O₆S
CAS Number: 161814-49-9

• 
  

  Because of potential risk of toxicity from the large amount of propylene glycol contained in amprenavir oral solution, the oral solution is contraindicated in infants and children <4 years of age, pregnant women, patients with hepatic or renal failure, and those receiving metronidazole or disulfiram and should be used with caution in others.^{1 46} (See Contraindications and see Propylene Glycol-associated Toxicity under Cautions.)

  
  


• 
  

  Amprenavir oral solution should only be used when amprenavir capsules or other HIV protease inhibitors (PIs) cannot be used.⁴⁶

  
  

Introduction

Antiretroviral; HIV protease inhibitor (PI).^{1 46}

Uses for Agenerase

Treatment of HIV Infection

In August 2007, the manufacturer of amprenavir announced that sales of the drug would be discontinued as of October 2007.⁷¹ This action was taken because demand for amprenavir had declined substantially and because of the availability of other treatment options (e.g., fosamprenavir oral suspension for the treatment of HIV-1 infection in children).⁷¹ Patients receiving amprenavir should be evaluated for alternative treatment (e.g., an alternative PI or a different antiretroviral regimen).⁷¹

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 14 15 16 46}

When selecting a PI-based regimen for initial therapy in adults, fosamprenavir (with or without low-dose ritonavir) recommended instead of amprenavir (lower pill burden, once-daily regimen possible, better GI tolerance).¹⁴

If selecting amprenavir for use in multiple-drug regimens, consider that amprenavir is less effective than indinavir in PI-naive patients, that mild to moderate adverse GI effects have led to discontinuance of amprenavir during the first 12 weeks of therapy, and that data are limited regarding response to amprenavir in PI-experienced patients.^{1 46}

Agenerase Dosage and Administration

Administration

Oral Administration

Administer orally.¹ May be given without regard to meals, but avoid high-fat meals since absorption of the drug may be decreased.^{1 14 46}

The liquid-filled capsules and oral solution are not bioequivalent and are not interchangeable on a mg-per-mg basis.^{1 46}

Oral solution should be used only when amprenavir capsules or other PIs cannot be used; switch patients from the oral solution as soon as they are able to take capsules.^{1 46}

Dosage

Must be given in conjunction with other antiretrovirals.^{1 46} If used with ritonavir capsules, dosage adjustment recommended and additional drug interactions must be considered (see Specific Drugs under Interactions.).^{1 46}

Pediatric Patients

Treatment of HIV Infection

Oral

Pediatric Dosage for Treatment of HIV

Age and Weight (kg)	Dosage for Liquid-filled Capsules	Dosage for Oral Solution
4–12 years of age weighing <50 kg	20 mg/kg twice daily or 15 mg/kg 3 times daily (maximum 2.4 g daily)1 15	22.5 mg/kg (1.5 mL/kg) twice daily or 17 mg/kg (1.1 mL/kg) 3 times daily (maximum 2.8 g daily)15 46
13–16 years of age weighing <50 kg	20 mg/kg twice daily or 15 mg/kg 3 times daily (maximum 2.4 g daily)1 15	22.5 mg/kg (1.5 mL/kg) twice daily or 17 mg/kg (1.1 mL/kg) 3 times daily (maximum 2.8 g daily) 15 46
13–16 years of age weighing ≥50 kg	1.2 g twice daily1	1.4 g twice daily14 46
>16 years of age	1.2 g twice daily1	1.4 g twice daily46

Adults

Treatment of HIV Infection

Oral

Liquid-filled Capsules: 1.2 g twice daily.^{1 14}

If used in conjunction with low-dose ritonavir, manufacturer recommends amprenavir 1.2 g once daily with ritonavir 200 mg once daily or amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.¹

Oral Solution: 1.4 g twice daily.^{14 46}

Special Populations

Hepatic Impairment

Dosage recommendations not available for children with hepatic impairment since the drug has not been evaluated in these patients.^{1 46}

Dosage adjustments necessary in adults with hepatic impairment based on Child-Pugh scores; oral solution contraindicated in those with hepatic failure.^{1 46 49}

Liquid-filled Capsules: 450 mg twice daily in adults with Child-Pugh scores 5–8 and 300 mg twice daily in those with Child-Pugh scores 9–12.^{1 49}

Oral Solution: 513 mg (34 mL) twice daily in adults with Child-Pugh scores 5–8 and 342 mg (23 mL) twice daily in those with Child-Pugh scores 9–12.⁴⁶

Renal Impairment

Dosage adjustments not needed.¹

Use oral solution with caution in patients with renal impairment;⁴⁶ oral solution contraindicated in those with renal failure.⁴⁶

Geriatric Patients

Cautious dosage selection; pharmacokinetics have not been studied in this age group.^{1 46}

Cautions for Agenerase

Contraindications

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  Known hypersensitivity to amprenavir or any ingredient in the formulation.^{1 46}

  
  


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  Use of oral solution in infants and children <4 years of age, pregnant women, patients with hepatic or renal failure, and patients receiving disulfiram or metronidazole due to the potential risk of propylene glycol-associated toxicity.^{1 46} (See Specific Drugs under Interactions.)

  
  


• 
  

  Concomitant use with drugs highly dependent on CYP3A4 for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., cisapride, ergot derivatives, pimozide, midazolam, triazolam).^{1 46} (See Specific Drugs under Interactions.)

  
  


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  Concomitant use of ritonavir-boosted amprenavir with flecainide or propafenone.^{1 46} (See Specific Drugs under Interactions.)

  
  

Warnings/Precautions

Warnings

Interactions

Concomitant use with certain drugs is not recommended (e.g., rifampin, lovastatin, simvastatin, St. John’s wort, fluticasone) or requires particular caution (e.g., sildenafil, tadalafil, vardenafil).¹ (See Specific Drugs under Interactions.)

Propylene Glycol-Associated Toxicity

Possible toxicity from the large amount of propylene glycol in the oral solution;⁴⁶ only limited information available regarding chronic exposure to large amounts of propylene glycol.⁴⁶

Infants and children <4 years of age, women, and certain ethnic populations (Asians, Native Alaskans, Native Americans) may be at increased risk.⁴⁶ (See Contraindications under Cautions.)

Use oral solution only when amprenavir liquid-filled capsules and other PIs cannot be used.⁴⁶ Switch to amprenavir capsules as soon as patient is able to take capsules.^{1 46}

If oral solution is used, monitor for propylene glycol-associated adverse events (e.g., seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, hemolysis).⁴⁶

Concomitant use of amprenavir oral solution and ritonavir oral solution not recommended because the large amount of propylene glycol in the amprenavir preparation and alcohol in the ritonavir preparation may compete for the same metabolic elimination pathway.⁴⁶

If accidental overdosage of the oral solution occurs, consider the large amount of propylene glycol in the preparation.^{1 46} Monitor for toxicity and manage acid-base abnormalities;^{1 46} propylene glycol can be removed by hemodialysis.⁴⁶

Hyperglycemic and Diabetogenic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.^{1 36 46}

Monitor blood glucose and initiate or adjust dosage of insulin or oral hypoglycemic agents as needed.^{1 46}

Dermatologic Reactions

Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred.^{1 46}

Discontinue if severe or life-threatening rash or moderate rash accompanied by systemic symptoms occurs.^{1 46}

Sensitivity Reactions

Sulfonamide Hypersensitivity

Because amprenavir is a sulfonamide derivative, use with caution in patients with known sulfonamide allergy.^{1 46}

General Precautions

HIV Resistance

Possibility of HIV resistant to amprenavir and possible cross-resistance to other PIs.^{1 46} Effect of amprenavir therapy on subsequent therapy with other PIs unknown.^{1 46}

Hemophilia A and B

Spontaneous bleeding reported with PIs;^{1 37 41 46} causal relationship not established.^{1 46}

Use with caution in patients with a history of hemophilia type A or B.^{1 37 46} Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.^{1 46}

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance.^{1 27 46}

Lipid Effects

Increases in total serum cholesterol and triglyceride concentrations have occurred with amprenavir with or without ritonavir.^{1 46}

Determine serum triglycerides and cholesterol concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.^{1 46} (See HMG-CoA Reductase Inhibitors under Interactions.)

Vitamin E Content

Each 50-mg amprenavir capsule contains 36 units and each mL of the oral solution contains 46 units of vitamin E.^{41 46} Vitamin E content of usual dosages of these formulations exceeds recommended daily intake.^{1 46}

Supplemental vitamin E should not be taken during amprenavir therapy.^{1 46}

The high vitamin E content of the capsules and oral solution may exacerbate vitamin K deficiency caused by anticoagulant therapy or malabsorption.^{1 46}

Effects of long-term, high-dose vitamin E not well characterized and not specifically studied in HIV-infected individuals.^{1 46}

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

The oral solution contraindicated during pregnancy because of potential risk to the fetus from the high propylene glycol content.^{1 46 58} Some experts state safety and pharmacokinetic data insufficient to recommend amprenavir liquid-filled capsules in pregnant women.⁵⁸

Lactation

Distributed into milk in rats;^{1 46} not known whether distributed into human milk.^{1 46}

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.^{1 46}

Pediatric Use

Safety and efficacy not established in children <4 years of age.^{1 15 46}

The oral solution contraindicated in infants and children <4 years of age because of potential risk of toxicity from the high propylene glycol content.^{1 46}

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.^{1 46}

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 46}

Hepatic Impairment

Clearance may be decreased;^{1 46} dosage adjustments necessary.^{1 46 49} (See Hepatic Impairment under Dosage and Administration.)

Use with caution; assess hepatic function prior to and periodically during therapy.^{1 46}

Oral solution contraindicated in those with hepatic failure because of increased risk of propylene glycol-associated adverse events.^{1 46}

Renal Impairment

Effects on amprenavir pharmacokinetics not studied.^{1 46}

Because of increased risk of propylene glycol-associated adverse events, oral solution should be used with caution in those with renal impairment and is contraindicated in those with renal failure.⁴⁶

Common Adverse Effects

Nausea, vomiting, diarrhea, abdominal pain/discomfort, taste disorder, rash, paresthesia (oral/perioral).^{1 27 46}

Interactions for Agenerase

Amprenavir is metabolized by CYP3A4 and also is an inhibitor of CYP3A4.^{1 46}

Does not inhibit CYP2D6, 1A2, 2C9, 2C19, or P2E1.^{1 46}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors or substrates of CYP3A4 with possible alteration in metabolism of amprenavir and/or the other drug.^{1 4 46}

Specific Drugs

Drug	Interaction	Comments
Abacavir	Possible increased amprenavir plasma concentrations and AUC;1 46 no effect on abacavir pharmacokinetics1 46 In vitro evidence of synergistic antiretroviral effects1 46	No dosage adjustments recommended41
Alcohol	Increased risk of propylene glycol-associated adverse effects in those receiving oral solution46	Alcoholic beverages should not be consumed while receiving amprenavir oral solution46
Antacids	Possible decreased amprenavir concentrations1 46	Take amprenavir at least 1 hour before or after antacids1 46
Antiarrhythmic agents (amiodarone, systemic lidocaine, quinidine)	Possible increased antiarrhythmic agent concentrations;1 46 potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias) with certain agents1 46	Use concomitantly with caution; antiarrhythmic concentration monitoring recommended1 46
Anticoagulants, oral	Warfarin concentrations affected1 46 High vitamin E content of amprenavir preparations may exacerbate blood coagulation defect of vitamin K deficiency caused by anticoagulants1	Monitor INR1 46
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased amprenavir concentrations;1 46 possible decreased effectiveness of the antiretroviral1 46	Use concomitantly with caution1 46
Antidepressants, tricyclics	Possible increased concentrations of tricyclic antidepressants (amitriptyline, imipramine) and potential for serious and/or life-threatening effects1 46	Monitor tricyclic antidepressant concentrations1 46
Antifungals, azoles (itraconazole, ketoconazole, voriconazole)	Itraconazole or ketoconazole: Possible increased antifungal concentrations;1 46 possible effect on amprenavir pharmacokinetics1 46 Voriconazole: Possible inhibition of amprenavir metabolism and/or voriconazole metabolism68	Itraconazole or ketoconazole: Monitor for adverse effects of the antifungal;1 46 reduction in antifungal dosage may be needed in those receiving itraconazole or ketoconazole dosages >400 mg daily1 46 Voriconazole: Monitor for toxicities related to voriconazole and/or the PI68
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)	Rifabutin: Decreased amprenavir concentrations; increased concentrations of rifabutin and rifabutin metabolite1 50 46 Rifampin: Decreased amprenavir concentrations;1 46 possible loss of virologic response and possible resistance to the antiretroviral1 46	Rifabutin: Reduce rifabutin dosage to ≥50% of usually recommended dosage; monitor for neutropenia by performing weekly CBC as clinically indicated1 46 Rifampin: Concomitant use contraindicated1 45 46 63 Rifapentine: Concomitant use not recommended14
Benzodiazepines	Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 46 Possible increased concentrations of alprazolam, clorazepate, diazepam, flurazepam1 46	Concomitant use with midazolam or triazolam contraindicated1 46 Clinical importance of interaction with other benzodiazepines unknown; a decrease in benzodiazepine dosage may be needed1 46
Calcium-channel blocking agents (diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine)	Possible increased concentrations of calcium-channel blocking agent1 46	Use concomitantly with caution; clinical monitoring recommended1 46
Cisapride	Possible increased cisapride concentrations; potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1 46	Concomitant use contraindicated1 14 46
Clarithromycin	Increased amprenavir concentrations and AUC;1 24 46 possible decreased clarithromycin concentrations and decreased 14-hydroxyclarithromycin concentrations and AUC24	No dosage adjustments recommended1 24 41
Corticosteroids (dexamethasone, fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with amprenavir (with or without low-dose ritonavir) resulting in decreased cortisol concentrations1 46 Dexamethasone: Possible decreased amprenavir concentrations; possible loss of virologic response1 46	Fluticasone nasal spray/oral inhalation: Consider alternative in patients receiving amprenavir (without ritonavir), especially when long-term corticosteroid therapy is anticipated; concomitant use with ritonavir-boosted amprenavir not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 46 Dexamethasone: Use with caution1 46
Darunavir		Concomitant use of ritonavir-boosted darunavir and amprenavir not recommended pending further accumulation of data70
Delavirdine	Possible increased amprenavir concentrations and AUC1 46 Possible decreased delavirdine concentrations and AUC;1 46 possible loss of virologic response and possible resistance to delavirdine1 46	Should not be used concomitantly1 46
Didanosine	Possible decreased amprenavir concentrations with buffered didanosine preparations1 46 In vitro evidence of synergistic antiretroviral effects1 46	Administer amprenavir at least 1 hour before or after buffered didanosine (pediatric oral solution admixed with antacid)1 46
Disulfiram	Potential risk of toxicity if used concomitantly with amprenavir oral solution because of the large amount of propylene glycol in the solution1 46	Concomitant use of disulfiram and amprenavir oral solution contraindicated1 46
Efavirenz	Possible decreased amprenavir concentrations and AUC;1 43 46 possible increased efavirenz AUC43	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsb
Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Possible increased concentrations of ergot alkaloids and potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm and ischemia of the extremities and other tissues)1 46	Concomitant use contraindicated1 14 46 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving amprenavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible58
Estrogens/Progestins	Hormonal contraceptives: Possible decreased amprenavir concentrations with ethinyl estradiol and norethindrone;1 46 possible loss of virologic response and possible resistance to the antiretroviral1 46	Hormonal contraceptives: Use alternative nonhormonal contraceptives1 46
Fosamprenavir	Possible increased toxicity14	Do not use concomitantly; fosamprenavir is a prodrug of amprenavir14
HMG-CoA reductase inhibitors	Possible decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors with potential for increased risk of myopathy (including rhabdomyolysis)1 46	Concomitant use with lovastatin or simvastatin not recommended;1 46 caution if used with other HMG-CoA reductase inhibitors1 46 If used with atorvastatin, use lowest possible initial atorvastatin dosage with careful monitoring1 46 Consider using HMG-COA reductase inhibitors with low potential for interaction (e.g., pravastatin, fluvastatin, rosuvastatin)1 46 59 60 69
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1 46	Monitor concentrations of the immunosuppressive agent1 46
Indinavir	Increased plasma concentrations and AUC of amprenavir; decreased plasma concentrations and AUC of indinavir1 46 In vitro evidence of additive antiretroviral effects1 46	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Lamivudine	No evidence of pharmacokinetic interaction1 46	No dosage adjustments recommended41
Lopinavir	Pharmacokinetic interaction may affect both drugs1 46 62	Once-daily lopinavir regimen not recommended with amprenavir62 For treatment-naive adults, manufacturer of lopinavir recommends 400 mg of lopinavir and 100 mg of ritonavir (2 tablets) twice daily; consider a dosage increase to 600 mg of lopinavir and 150 mg of ritonavir (3 tablets) twice daily for treatment-experienced adults when reduced susceptibility to lopinavir is suspected62 Manufacturer of lopinavir recommends that adults receive 533 mg of lopinavir and 133 mg of ritonavir (6.7 mL of the oral solution) twice daily62 For pediatric patients 6 months to 12 years of age, manufacturer of lopinavir recommends that those weighing 7 to <15 kg receive a dosage of 13 mg/kg of lopinavir and 3.25 mg/kg of ritonavir twice daily and those weighing 15–45 kg receive 11 mg/kg of lopinavir and 2.75 mg/kg of ritonavir twice daily; those weighing >45 kg should receive 533 mg of lopinavir and 133 mg of ritonavir (6.7 mL oral solution) twice daily or 400 mg of lopinavir and 100 mg of ritonavir (2 tablets) twice daily62 Pediatric patients ≥12 years of age may receive recommended adult dosage62
Methadone	Decreased amprenavir concentrations and AUC; possible decreased effectiveness of the antiretroviral1 46 Decreased methadone concentrations1 46	Consider alternative antiretroviral agents1 46 If used with amprenavir, monitor and consider possible need to increase methadone dosage1 46
Metronidazole	Potential risk of toxicity if used concomitantly with amprenavir oral solution because of the large amount of propylene glycol in the solution 46	Concomitant use contraindicated46
Nelfinavir	Increased plasma concentrations and AUC of amprenavir1 46 In vitro evidence of additive antiretroviral effects1 46	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Nevirapine	Possible decreased amprenavir concentrations1 46	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Pimozide	Possible increased pimozide concentrations;1 46 potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1 46	Concomitant use contraindicated1 14 46
Ritonavir	Increased amprenavir plasma concentrations and AUC;1 46 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted amprenavir1 Potential for the large amount of propylene glycol in amprenavir oral solution and alcohol in ritonavir oral solution to compete for the same metabolic elimination pathway46 In vitro evidence of additive antiretroviral effects1 46	Reduce amprenavir dosage when used concomitantly with ritonavir; if amprenavir capsules used in adults, use amprenavir 1.2 g once daily with ritonavir 200 mg once daily or amprenavir 600 mg twice daily with ritonavir 100 mg twice daily1 46 Appropriate pediatric dosage of amprenavir capsules used concomitantly with ritonavir not established1 Concomitant use of amprenavir oral solution and ritonavir oral solution not recommended46 If ritonavir and amprenavir used concomitantly, concomitant use of flecainide or propafenone contraindicated1 46
St. John’s wort (Hypericum perforatum)	Possible decreased amprenavir concentrations;1 46 54 55 possible loss of virologic response and possible resistance to the antiretroviral1 46 54 55	Concomitant use not recommended1 14 46 54 55
Saquinavir	Decreased amprenavir concentrations1 46 In vitro evidence of synergistic antiretroviral effects1 46	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Sildenafil	Increased sildenafil concentrations; increased risk of sildenafil-associated adverse effects1 46	Use caution and reduced sildenafil dosage (do not exceed 25 mg every 48 hours); monitor closely for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 46
Tadalafil	Increased tadalafil concentrations; increased risk of tadalafil-associated adverse effects66	Use initial tadalafil dosage of 5 mg and do not exceed a single dose of 10 mg in 72 hours66
Tenofovir	In vitro evidence of additive or synergistic antiretroviral effectsc
Tipranavir	Possible decreased amprenavir concentrations with ritonavir-boosted tipranavir67	Concomitant use not recommended67
Trazodone	Possible increased trazodone concentrations1 46	Use with caution; consider decreased trazodone dosage1 46
Vardenafil	Possible increased vardenafil concentrations and possible increase in vardenafil-associated adverse effects65	Use initial vardenafil dosage of 2.5 mg and do not exceed a single dose of 2.5 mg in 24 hours65
Vitamin E	Possible excessive vitamin E dosage because of high vitamin E content of amprenavir preparations1 46 High vitamin E doses may exacerbate blood coagulation defect of vitamin K deficiency caused by anticoagulant therapy or malabsorption1	Supplemental vitamin E not recommended1 46
Zidovudine	Possible increased amprenavir AUC;1 46 possible increased zidovudine concentrations and AUC1 46 In vitro evidence of synergistic antiretroviral effects1 46	No dosage adjustments recommended41

Agenerase Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability has not been established.^{1 46}

Amprenavir not appreciably absorbed from GI tract when given alone;^{40 41} amprenavir formulated with vitamin E rapidly absorbed following oral administration.^{1 48}

Peak amprenavir plasma concentrations attained 1–2 hours after oral administration of capsules or oral solution formulated with vitamin E.^{1 48 46}

Amprenavir liquid-filled capsules and oral solution not bioequivalent; oral solution about 14% less bioavailable compared with capsules.^{1 46}

Food

Oral bioavailability of amprenavir may be decreased if administered with a high-fat meal.^{1 46}

Distribution

Extent

Animal studies indicate distribution into various tissues.²

CSF concentrations <1% of plasma concentrations.⁴¹

Amprenavir crosses the placenta and is distributed into milk in animals.⁴¹ Not known whether drug crosses human placenta or is distributed into human milk.¹⁴

Plasma Protein Binding

90% bound to plasma or serum proteins, principally to α₁-acid glycoprotein.^{1 23 46}

Elimination

Metabolism

Metabolized in liver principally by CYP3A4.^{1 4 46}

Elimination Route

About 14% of an oral dose excreted in urine and 75% eliminated in feces.^{1 41 46} Only minimal amounts eliminated unchanged in urine or feces.^{1 46}

Half-life

7.1–10.6 hours in HIV-infected adults with normal renal and hepatic function.^{1 2 41 46 48}

Special Populations

Peak plasma concentrations and AUC may be increased in patients with hepatic impairment.^{1 46 49}

Pharmacokinetics not studied to date in patients with renal impairment; decreased clearance not expected.^{1 46}

Stability

Storage

Oral

Liquid-filled Capsules

25°C.¹

Solution

25°C.⁴⁶

Actions and SpectrumActions

• 
  

  Pharmacologically related to, but structurally different from, other PIs (e.g., atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) and other currently available antiretrovirals.^{11 21}

  
  


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  Active against HIV-1 and, to a lesser extent, HIV-2.^{1 7 11 46}

  
  


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  Inhibits replication of HIV-1 and HIV-2 by interfering with HIV protease.^{1 7 11 46}

  
  


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  HIV-1 with reduced susceptibility to amprenavir have been selected in vitro and have emerged during therapy with the drug.^{1 2 5 6 7 8 19 20 46}

  
  


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  Varying degrees of cross-resistance occur among PIs; only limited data available to date regarding cross-resistance between amprenavir and other PIs.¹