Agenerase

Capsule: 50 and 150 mg; Solution: 15 mg/ml

Capsules and oral solution should be stored at room temperature, 20 C to 25 C (68 F to 77 F).

• Glaxo SmithKline Pharmaceuticals

Tell your healthcare provider if you are breastfeeding. You should not breastfeed if you are HIV-positive because of the chance of passing the HIV virus to your baby through your milk. Also, it is not known if Agenerase can pass into your breast milk and if it can harm your baby. If you are a woman who has or will have a baby, talk with your healthcare provider about the best way to feed your baby.

If you take too much Agenerase, call your healthcare provider or poison control center right away.

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.

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.

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.

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.

* 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.

* 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.

*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.

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

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.

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.

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

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.

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).

* 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.

There is no known antidote for Agenerase. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.

Agenerase Capsules, 50 mg, are oblong, opaque, off-white to cream-colored soft gelatin capsules printed with “GX CC1” on one side.

Bottles of 480 with child-resistant closures (NDC 0173-0679-00).

Store at controlled room temperature of 25°C (77°F) (see USP).

Agenerase Capsules are manufactured by

R.P. Scherer

Beinheim, France

for

Licensed from

GlaxoSmithKline Vertex Pharmaceuticals Incorporated

Research Triangle Park, NC 27709 Cambridge, MA 02139

Agenerase is a registered trademark of GlaxoSmithKline.

©2005, GlaxoSmithKline. All rights reserved.

May 2005 RL-2194

PHARMACISTDETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _