DrugindexOnline^{2nd edition}

Generic Name: amprenavir
Dosage Form: Capsules

Agenerase Description

Agenerase (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H35N3O6S and a molecular weight of 505.64. It has the following structural formula:

Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C.

Agenerase Capsules are available for oral administration. Each 50-mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50-mg Agenerase Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily adult dose of Agenerase is 1,744 IU.

MICROBIOLOGY

Mechanism of Action

Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

Antiviral Activity in Vitro

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 μM in acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 mcg/mL). Amprenavir exhibited synergistic anti−HIV-1 activity incombination with abacavir, zidovudine, didanosine, or saquinavir, and additive anti−HIV-1 activity in combination with indinavir, nelfinavir, and ritonavir in vitro. These drug combinations have not been adequately studied in humans. The relationship between in vitro anti−HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.

Resistance

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with amprenavir. Genotypic analysis of isolates from amprenavir-treated patients showed mutations in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V as well as mutations in the p7/p1 and p1/p6 gag cleavage sites. Phenotypic analysis of HIV-1 isolates from 21 nucleoside reverse transcriptase inhibitor- (NRTI-) experienced, protease inhibitor-naive patients treated with amprenavir in combination with NRTIs for 16 to 48 weeks identified isolates from 15 patients who exhibited a 4­- to 17-fold decrease in susceptibility to amprenavir in vitro compared to wild-type virus. Clinical isolates that exhibited a decrease in amprenavir susceptibility harbored one or more amprenavir-associated mutations. The clinical relevance of the genotypic and phenotypic changes associated with amprenavir therapy is under evaluation.

Cross-Resistance

Varying degrees ofHIV-1 cross-resistance among protease inhibitors have been observed. Five of 15 amprenavir-resistant isolates exhibited 4- to 8-fold decrease in susceptibility to ritonavir. However, amprenavir-resistant isolates were susceptible to either indinavir or saquinavir.

Agenerase - Clinical Pharmacology

Pharmacokinetics in Adults

The pharmacokinetic properties of amprenavir have been studied in asymptomatic, HIV-infected adult patients after administration of single oral doses of 150 to 1,200 mg and multiple oral doses of 300 to 1,200 mg twice daily.

Absorption and Bioavailability

Amprenavir was rapidly absorbed after oral administration in HIV-1-infected patients with a time to peak concentration (Tmax) typically between 1 and 2 hours after a single oral dose. The absolute oral bioavailability of amprenavir in humans has not been established.

Increases in the area under the plasma concentration versus time curve (AUC) after single oral doses between 150 and 1,200 mg were slightly greater than dose proportional. Increases in AUC were dose proportional after 3 weeks of dosing with doses from 300 to 1,200 mg twice daily. The pharmacokinetic parameters after administration of amprenavir 1,200 mg twice daily for 3 weeks to HIV-infected subjects are shown in Table 1.

Table 1. Average (%CV) Pharmacokinetic Parameters After 1,200 mg Twice Daily of Amprenavir Capsules (n = 54)

Cmax (mcg/mL)	Tmax (hours)	AUC0-12 (mcg•hr/mL)	Cavg (mcg/mL)	Cmin (mcg/mL)	CL/F (mL/min/kg)
7.66 (54%)	1.0 (42%)	17.7 (47%)	1.48 (47%)	0.32 (77%)	19.5 (46%)

The relative bioavailability of Agenerase Capsules and Oral Solution was assessed in healthy adults. Agenerase Oral Solution was 14% less bioavailable compared to the capsules.

Effects of Food on Oral Absorption: The relative bioavailability of Agenerase Capsules was assessed in the fasting and fed states in healthy volunteers (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate). Administration of a single 1,200-mg dose of amprenavir in the fed state compared to the fasted state was associated with changes in Cmax (fed: 6.18 ± 2.92 mcg/mL, fasted: 9.72 ± 2.75 mcg/mL), Tmax (fed: 1.51 ± 0.68, fasted: 1.05 ± 0.63), and AUC0-∞ (fed: 22.06 ± 11.6 mcg•hr/mL, fasted: 28.05 ± 10.1 mcg•hr/mL). Agenerase may be taken with or without food, but should not be taken with a high-fat meal (see DOSAGE AND ADMINISTRATION).

Distribution: The apparent volume of distribution (Vz/F) is approximately 430 L in healthy adult subjects. In vitro binding is approximately 90% to plasma proteins. The high affinity binding protein for amprenavir is alpha1-acid glycoprotein (AAG). The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism: Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.

Elimination: Excretion of unchanged amprenavir in urine and feces is minimal. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as radiocarbon in urine and feces, respectively. Two metabolites accounted for >90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir ranged from 7.1 to 10.6 hours.

Special Populations

Hepatic Insufficiency: Agenerase has been studied in adult patients with impaired hepatic function using a single 600-mg oral dose. The AUC0-∞ was significantly greater in patients with moderate cirrhosis (25.76 ± 14.68 mcg•hr/mL) compared with healthy volunteers (12.00 ± 4.38 mcg•hr/mL). The AUC0-∞ and Cmax were significantly greater in patients with severe cirrhosis (AUC0-∞: 38.66 ± 16.08 mcg•hr/mL; Cmax: 9.43 ± 2.61 mcg/mL) compared with healthy volunteers (AUC0-∞: 12.00 ± 4.38 mcg•hr/mL; Cmax: 4.90 ± 1.39 mcg/mL). Patients with impaired hepatic function require dosage adjustment (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The impact of renal impairment on amprenavir elimination in adult patients has not been studied. The renal elimination of unchanged amprenavir represents <3% of the administered dose.

Pediatric Patients: The pharmacokinetics of amprenavir have been studied after either single or repeat doses of Agenerase Capsules or Oral Solution in 84 pediatric patients. Twenty HIV−1-infected children ranging in age from 4 to 12 years received single doses from 5 mg/kg to 20 mg/kg using 25-mg or 150-mg capsules. The Cmax of amprenavir increased less than proportionally with dose. The AUC0-∞ increased proportionally at doses between 5 and 20 mg/kg. Amprenavir is 14% less bioavailable from the liquid formulation than from the capsules; therefore Agenerase Capsules and Agenerase Oral Solution are not interchangeable on a milligram-per-milligram basis.

Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years due to the potential risk of toxicity from the large amount of the excipient, propylene glycol. Please see the complete prescribing information for Agenerase Oral Solution for full information.

Table 2. Average (%CV) Pharmacokinetic Parameters in Children Ages 4 to 12 Years Receiving 20 mg/kg Twice Daily or 15 mg/kg Three Times Daily of Agenerase Oral Solution

Dose	n	Cmax(mcg/mL)	Tmax (hours)	AUCss* (mcg•hr/mL)	Cavg (mcg/mL)	Cmin (mcg/mL)	CL/F (mL/min/kg)
20 mg/kg b.i.d.	20	6.77 (51%)	1.1 (21%)	15.46 (59%)	1.29 (59%)	0.24 (98%)	29 (58%)
15 mg/kg t.i.d.	17	3.99 (37%)	1.4 (90%)	8.73 (36%)	1.09 (36%)	0.27 (95%)	32 (34%)

* AUC is 0 to 12 hours for b.i.d. and 0 to 8 hours for t.i.d., therefore the Cavg is a better comparison of the exposures.

Geriatric Patients: The pharmacokinetics of amprenavir have not been studied in patients over 65 years of age.

Gender: The pharmacokinetics of amprenavir do not differ between males and females.

Race: The pharmacokinetics of amprenavir do not differ between blacks and non-blacks.

Drug Interactions

See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.

Amprenavir is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT).

Drug interaction studies were performed with amprenavir capsules and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of amprenavir on the AUC, Cmax, and Cmin are summarized in Table 3 (effect of other drugs on amprenavir) and Table 4 (effect of amprenavir on other drugs). For information regarding clinical recommendations, see PRECAUTIONS.

Table 3. Drug Interactions: Pharmacokinetic Parameters for Amprenavir in the Presence of the Coadministered Drug

Co-administered Drug	Dose of Coadministered Drug	Dose of Agenerase	n	% Change in Amprenavir Pharmacokinetic Parameters* (90% CI)
				Cmax	AUC	Cmin
Abacavir	300 mg b.i.d. for 3 weeks	900 mg b.i.d. for 3 weeks	4	↑47 (↓15 to ↑154)	↑29 (↓18 to ↑103)	↑27 (↓46 to ↑197)
Clarithromycin	500 mg b.i.d. for 4 days	1,200 mg b.i.d. for 4 days	12	↑15 (↑1 to ↑31)	↑18 (↑8 to ↑29)	↑39 (↑31 to ↑47)
Delavirdine	600 mg b.i.d. for 10 days	600 mg b.i.d. for 10 days	9	↑40‡	↑130‡	↑125‡
Ethinyl estradiol/ Norethindrone	0.035 mg/1 mg for 1 cycle	1,200 mg b.i.d. for 28 days	10	↔ (↓20 to ↑3)	↓22 (↓35 to ↓8)	↓20 (↓41 to ↑8)
Indinavir	800 mg t.i.d. for 2 weeks (fasted)	750 or 800 mg t.i.d. for 2 weeks (fasted)	9	↑18 (↓13 to ↑58)	↑33 (↑2 to ↑73)	↑25 (↓27 to ↑116)
Ketoconazole	400 mg single dose	1,200 mg single dose	12	↓16 (↓25 to ↓6)	↑31 (↑20 to ↑42)	NA
Lamivudine	150 mg single dose	600 mg single dose	11	↔ (↓17 to ↑9)	↔ (↓15 to ↑14)	NA
Nelfinavir	750 mg t.i.d. for 2 weeks (fed)	750 or 800 mg t.i.d. for 2 weeks (fed)	6	↓14 (↓38 to ↑20)	↔ (↓19 to ↑47)	↑189 (↑52 to ↑448)
Rifabutin	300 mg q.d. for 10 days	1,200 mg b.i.d. for 10 days	5	↔ (↓21 to ↑10)	↓15 (↓28 to 0)	↓15 (↓38 to ↑17)
Rifampin	300 mg q.d. for 4 days	1,200 mg b.i.d. for 4 days	11	↓70 (↓76 to ↓62)	↓82 (↓84 to ↓78)	↓92 (↓95 to ↓89)
Ritonavir	100 mg b.i.d. for 2 to 4 weeks	600 mg b.i.d.	18	↓30† (↓44 to ↓14)	↑64† (↑37 to ↑97)	↑508† (↑394 to ↑649)
Ritonavir	200 mg q.d. for 2 to 4 weeks	1,200 mg q.d.	12	↔† (↓17 to ↑30)	↑62† (↑35 to ↑94)	↑319† (↑190 to ↑508)
Saquinavir	800 mg t.i.d. for 2 weeks (fed)	750 or 800 mg t.i.d. for 2 weeks (fed)	7	↓37 (↓54 to ↓14)	↓32 (↓49 to ↓9)	↓14 (↓52 to ↑54)
Zidovudine	300 mg single dose	600 mg single dose	12	↔ (↓5 to ↑24)	↑13 (↓2 to ↑31)	NA

* Based on total-drug concentrations.

†Compared to amprenavir 1,200 mg b.i.d. in the same patients.

‡Median percent change; confidence interval not reported.

↑= Increase; ↓ = Decrease; ↔ = No change (↑or ↓<10%); NA = Cmin not calculated for single-dose study.

Table 4. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir

Co-administered Drug	Dose of Coadministered Drug	Dose of Agenerase	n	% Change inPharmacokinetic Parameters of Coadministered Drug (90% CI)
				Cmax	AUC	Cmin
Clarithromycin	500 mg b.i.d. for 4 days	1,200 mg b.i.d. for 4 days	12	↓10 (↓24 to ↑7)	↔ (↓17 to ↑11)	↔ (↓13 to ↑20)
Delavirdine	600 mg b.i.d. for 10 days	600 mg b.i.d. for 10 days	9	↓47*	↓61*	↓88*
Ethinyl estradiol	0.035 mg for 1 cycle	1,200 mg b.i.d for 28 days	10	↔ (↓25 to ↑15)	↔ (↓14 to ↑38)	↑32 (↓3 to ↑79)
Norethindrone	1.0 mg for 1 cycle	1,200 mg b.i.d. for 28 days	10	↔ (↓20 to ↑18)	↑18 (↑1 to ↑38)	↑45 (↑13 to ↑88)
Ketoconazole	400 mg single dose	1,200 mg single dose	12	↑19 (↑8 to ↑33)	↑44 (↑31 to ↑59)	NA
Lamivudine	150 mg single dose	600 mg single dose	11	↔ (↓17 to ↑3)	↔ (↓11 to 0)	NA
Methadone	44 to 100 mg q.d. for >30 days	1,200 mg b.i.d. for 10 days	16	R-Methadone (active)
				↓25 (↓32 to ↓18)	↓13 (↓21 to ↓5)	↓21 (↓32 to ↓9)
				S-Methadone (inactive)
				↓48 (↓55 to ↓40)	↓40 (↓46 to ↓32)	↓53 (↓60 to ↓43)
Rifabutin	300 mg q.d. for 10 days	1,200 mg b.i.d. for 10 days	5	↑119 (↑82 to ↑164)	↑193 (↑156 to ↑235)	↑271 (↑171 to ↑409)
Rifampin	300 mg q.d. for 4 days	1,200 mg b.i.d. for 4 days	11	↔ (↓13 to ↑12)	↔ (↓10 to ↑13)	ND
Zidovudine	300 mg single dose	600 mg single dose	12	↑40 (↑14 to ↑71)	↑31 (↑19 to ↑45)	NA

*Median percent change; confidence interval not reported.

↑ = Increase; ↓ = Decrease;↔= No change (↑ or ↓<10%); NA = Cmin not calculated for single-dose study; ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

There was no effect of amprenavir on abacavir in subjects receiving both agents based on historical data.

HIV Protease Inhibitors

The effect of amprenavir on total drug concentrations of other HIV protease inhibitors in subjects receiving both agents was evaluated using comparisons to historical data. Indinavir steady-state Cmax, AUC, and Cmin were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases in Cmax and AUC were seen after the first dose. Saquinavir steady-state Cmax, AUC, and Cmin were increased 21%, decreased 19%, and decreased 48%, respectively, by concomitant amprenavir. Nelfinavir steady-state Cmax, AUC, and Cmin were increased by 12%, 15%, and 14%, respectively, by concomitant amprenavir.

Methadone

Coadministration of amprenavir and methadone can decrease plasma levels of methadone.

Coadministration of amprenavir and methadone as compared to a non-matched historical control group resulted in a 30%, 27%, and 25% decrease in serum amprenavir AUC, Cmax, and Cmin, respectively.

For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions.

Indications and Usage for Agenerase

Agenerase (amprenavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

The following points should be considered when initiating therapy with Agenerase:

In a study of NRTI-experienced, protease inhibitor-naive patients, Agenerase was found to be significantly less effective than indinavir (see Description of Clinical Studies).

Mild to moderate gastrointestinal adverse events led to discontinuation of Agenerase primarily during the first 12 weeks of therapy (see ADVERSE REACTIONS).

There are no data on response to therapy with Agenerase in protease inhibitor-experienced patients.

Description of Clinical Studies

Therapy-Naive Adults

PROAB3001, a randomized, double-blind, placebo-controlled, multicenter study, compared treatment with Agenerase Capsules (1,200 mg twice daily) plus lamivudine (150 mg twice daily) plus zidovudine (300 mg twice daily) versus lamivudine (150 mg twice daily) plus zidovudine (300 mg twice daily) in 232 patients. Through 24 weeks of therapy, 53% of patients assigned to Agenerase/zidovudine/lamivudine achieved HIV-1 RNA <400 copies/mL. Through week 48, the antiviral response was 41%. Through 24 weeks of therapy, 11% of patients assigned to zidovudine/lamivudine achieved HIV-1 RNA <400 copies/mL. Antiviral response beyond week 24 is not interpretable because the majority of patients discontinued or changed their antiretroviral therapy.

NRTI-Experienced Adults

PROAB3006, a randomized, open-label multicenter study, compared treatment with Agenerase Capsules (1,200 mg twice daily) plus NRTIs versus indinavir (800 mg every 8 hours) plus NRTIs in 504 NRTI-experienced, protease inhibitor-naive patients, median age 37 years (range 20 to 71 years), 72% Caucasian, 80% male, with a median CD4 cell count of 404 cells/mm3 (range 9 to 1,706 cells/mm3) and a median plasma HIV-1 RNA level of 3.93 log10 copies/mL (range 2.60 to 7.01 log10 copies/mL) at baseline. Through 48 weeks of therapy, the median CD4 cell count increase from baseline in the amprenavir group was significantly lower than in the indinavir group, 97 cells/mm3 versus 144 cells/mm3, respectively. There was also a significant difference in the proportions of patients with plasma HIV-1 RNA levels <400 copies/mL through 48 weeks (see Figure 1 and Table 5).

Figure 1. Virologic Response Through Week 48, PROAB3006*,†

HIV-1 RNA status and reasons for discontinuation of randomized treatment at 48 weeks are summarized (Table 5).

Table 5. Outcomes of Randomized Treatment Through Week 48 (PROAB3006)

Outcome	Agenerase (n = 254)	Indinavir (n = 250)
HIV-1 RNA <400 copies/mL*	30%	49%
HIV-1 RNA ≥400 copies/mL†,‡	38%	26%
Discontinued due to adverse events*,‡	16%	12%
Discontinued due to other reasons‡,§	16%	13%

* Corresponds to rates at Week 48 in Figure 1.

†Virological failures at or before Week 48.

‡Considered to be treatment failure in the analysis.

§Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Contraindications

Coadministration of Agenerase is contraindicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 6.

Table 6. Drugs That Are Contraindicated With Agenerase

Drug Class	Drugs Within Class That Are CONTRAINDICATED with Agenerase
Ergot derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI motility agent	Cisapride
Neuroleptic	Pimozide
Sedatives/hypnotics	Midazolam, triazolam

If Agenerase is coadministered with ritonavir, the antiarrhythmic agents flecainide and propafenone are also contraindicated.

Because of the potential toxicity from the large amount of the excipient, propylene glycol, contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the complete prescribing information for Agenerase Oral Solution for full information.

Ageneraseis contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of this product.

Warnings

ALERT

Find out about medicines that should not be taken with Agenerase.

Serious and/or life-threatening drug interactions could occur between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine. Concentration monitoring of these agents is recommended if these agents are used concomitantly with Agenerase (see CONTRAINDICATIONS).

Rifampin should not be used in combination with amprenavir because it reduces plasma concentrations and AUC of amprenavir by about 90%.

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of Agenerase with ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing’s syndrome and adrenalsuppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and Agenerase/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS: Drug Interactions).

Concomitant use of Agenerase and St. John's wort (hypericum perforatum) or products containing St. John’s wort is not recommended. Coadministration of protease inhibitors, including Agenerase, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in suboptimal levels of amprenavir and lead to loss of virologic response and possible resistance to Agenerase or to the class of protease inhibitors.

Concomitant use of Agenerase with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Agenerase, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including amprenavir, are used in combination with these drugs.

Particular caution should be used when prescribing sildenafil in patients receiving amprenavir. Coadministration of Agenerase with sildenafil is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS: Drug Interactions and Information for Patients, and the complete prescribing information for sildenafil).

Because of the potential toxicity from the large amount of the excipient, propylene glycol, contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the complete prescribing information for Agenerase Oral Solution for full information.

Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in patients treated with Agenerase (see ADVERSE REACTIONS). Acute hemolytic anemia has been reported in a patient treated with Agenerase.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.

Precautions

General

Agenerase Capsules and Agenerase Oral Solution are not interchangeable on a milligram-per-milligram basis(see CLINICAL PHARMACOLOGY: Pediatric Patients).

Amprenavir is a sulfonamide. The potential for cross-sensitivity between drugs in the sulfonamide class and amprenavir is unknown. Agenerase should be used with caution in patients with a known sulfonamide allergy.

Agenerase is principally metabolized by the liver. Agenerase, when used alone and in combination with low-dose ritonavir, has been associated with elevations of SGOT (AST) and SGPT (ALT) in some patients. Caution should be exercised when administering Agenerase to patients with hepatic impairment (see DOSAGE AND ADMINISTRATION). Appropriate laboratory testing should be conducted prior to initiating therapy with Agenerase and at periodic intervals during treatment.

Formulations of Agenerase provide high daily doses of vitamin E (see Information for Patients, DESCRIPTION, and DOSAGE AND ADMINISTRATION). The effects of long-term, high-dose vitamin E administration in humans is not well characterized and has not been specifically studied in HIV-infected individuals. High vitamin E doses may exacerbate the blood coagulation defect of vitamin K deficiency caused by anticoagulant therapy or malabsorption.

Patients with Hemophilia

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Agenerase. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently