Agenerase Oral Solution

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Agenerase


Generic Name: amprenavir
Dosage Form: Oral solution

Because of the potential risk of toxicity from the large amount of the excipient, propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CONTRAINDICATIONS AND WARNINGS).

Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options.

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 Oral Solution is for oral administration. One milliliter (1 mL) of Agenerase Oral Solution contains 15 mg of amprenavir in solution and the inactive ingredients acesulfame potassium, artificial grape bubblegum flavor, citric acid (anhydrous), d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), menthol, natural peppermint flavor, polyethylene glycol 400 (PEG 400) (170 mg), propylene glycol (550 mg), saccharin sodium, sodium chloride, and sodium citrate (dihydrate). Solutions of sodium hydroxide and/or diluted hydrochloric acid may have been added to adjust pH. Each mL of Agenerase Oral Solution contains 46 IU vitamin E in the form of TPGS. Propylene glycol is in the formulation to achieve adequate solubility of amprenavir. The recommended daily dose of Agenerase Oral Solution of 22.5 mg/kg twice daily corresponds to a propylene glycol intake of 1,650 mg/kg/day. Acceptable intake of propylene glycol for pharmaceuticals has not been established.

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 of HIV-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.

Agenerase Oral Solution contains a large amount of propylene glycol, which is hepatically metabolized by the alcohol and aldehyde dehydrogenase enzyme pathway. Alcohol dehydrogenase (ADH) is present in the human fetal liver at 2 months of gestational age, but at only 3% of adult activity. Although the data are limited, it appears that by 12 to 30 months of postnatal age, ADH activity is equal to or greater than that observed in adults. Additionally, certain patient groups (females, Asians, Eskimos, Native Americans) may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol (see CLINICAL PHARMACOLOGY: Special Populations: Gender and Race).

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 Oral Solution is contraindicated in patients with hepatic failure.

Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see WARNINGS). Agenerase Oral Solution should be used with caution in patients with hepatic impairment. Agenerase Capsules have 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

Agenerase Oral Solution is contraindicated in patients with renal failure.

Patients with renal impairment are at increased risk of propylene glycol-associated adverse events. Additionally, because metabolites of the excipient, propylene glycol, in Agenerase Oral Solution may alter acid-base balance, patients with renal impairment should be monitored for potential adverse events (see WARNINGS). Agenerase Oral Solution should be used with caution in patients with renal impairment. The impact of renal impairment on amprenavir elimination has not been studied. The renal elimination of unchanged amprenavir represents <3% of the administered dose.

Pediatric Patients

Agenerase Oral Solution is contraindicated in infants and children below 4 years of age (see CONTRAINDICATIONS and WARNINGS).

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.

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. Females may have a lower amount of alcohol dehydrogenase compared with males and may be at increased risk of propylene glycol-associated adverse events; no data are available on propylene glycol metabolism in females.

Race

The pharmacokinetics of amprenavir do not differ between blacks and non-blacks. Certain ethnic populations (Asians, Eskimos, and Native Americans) may be at increased risk of propylene glycol-associated adverse events because of alcohol dehydrogenase polymorphisms; no data are available on propylene glycol metabolism in these groups.

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 capsules 1,200 mg b.i.d. in the same patients.

Median percent change; confidence interval not reported.

[Symbol_Wingdings_225] = Increase; [Symbol_Wingdings_226] = Decrease; ⇔ = No change ([Symbol_Wingdings_225] or [Symbol_Wingdings_226]<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.

[Symbol_Wingdings_225] = Increase; [Symbol_Wingdings_226] = Decrease; ⇔ = No change ([Symbol_Wingdings_225] or [Symbol_Wingdings_226]<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: Concurrent use of Agenerase Oral Solution and NORVIR® (ritonavir) Oral Solution is not recommended because the large amount of propylene glycol in Agenerase Oral Solution and ethanol in NORVIR Oral Solution may compete for the same metabolic pathway for elimination. This combination has not been studied in pediatric patients.

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.

Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options.

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

Because of the potential risk of toxicity from the large amount of the excipient, propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see WARNINGS and PRECAUTIONS).

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 Oral Solution

Drug Class

Drugs Within Class That Are CONTRAINDICATED with Agenerase

Alcohol-dependence treatment

Disulfiram

Antibiotic

Metronidazole

Ergot derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agent

Cisapride

Neuroleptic

Pimozide

Sedatives/hypnotics

Midazolam, triazolam

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

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.

Because of the potential risk of toxicity from the large amount of the excipient, propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and PRECAUTIONS).

Because of the possible toxicity associated with the large amount of propylene glycol and the lack of information on chronic exposure to large amounts of propylene glycol, Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options. Certain ethnic populations (Asians, Eskimos, Native Americans) and women may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol; no data are available on propylene glycol metabolism in these groups (see CLINICAL PHARMACOLOGY: Special Populations: Gender and Race).

If patients require treatment with Agenerase Oral Solution, they should bemonitored closely for propylene glycol-associated adverse events, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Patients should be switched from Agenerase Oral Solution to Agenerase Capsules as soon as they are able to take the capsule formulation.

Concurrent use of Agenerase Oral Solution and NORVIR (ritonavir) Oral Solution is not recommended because the large amount of propylene glycol in Agenerase Oral Solution and ethanol in NORVIR Oral Solution may compete for the same metabolic pathway for elimination.

Use of alcoholic beverages is not recommended in patients treated with Agenerase Oral Solution.

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 adrenal suppression 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).

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 and CONTRAINDICATIONS).

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 unknown. A causal relationship has not been established.

Lipid Elevations

Treatment with Agenerase alone or in combination with ritonavir capsules has resulted in increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiation of therapy with Agenerase and at periodic intervals during treatment. Lipid disorders should be managed as clinically appropriate. See PRECAUTIONS Table 8: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with Agenerase and HMG-CoA reductase inhibitors.

Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect amprenavir therapy will have on the activity of subsequently administered protease inhibitors. It is also unknown what effect previous treatment with other protease inhibitors will have on the activity of amprenavir (see MICROBIOLOGY).

Information for Patients

A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with Agenerase. A Patient Package Insert (PPI) for Agenerase Oral Solution is available for patient information.

Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole. Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options.

Patients treated with Agenerase Capsules should be cautioned against switching to Agenerase Oral Solution because of the increased risk of adverse events from the large amount of propylene glycol in Agenerase Oral Solution.

Women, Asians, Eskimos, or Native Americans, as well as patients who have hepatic or renal insufficiency, should be informed that they may be at increased risk of adverse events from the large amount of propylene glycol in Agenerase Oral Solution.

Patients should be informed that Agenerase is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of Agenerase (amprenavir) are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with Agenerase can reduce the risk of transmitting HIV to others through sexual contact.

Patients should remain under the care of a physician while using Agenerase. Patients should be advised to take Agenerase every day as prescribed. Agenerase must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.

Patients should inform their doctor if they have a sulfa allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and amprenavir is unknown.

Agenerase may interact with many drugs; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products, particularly St. John"s wort.

Patients taking antacids (or the buffered formulation of didanosine) should take Agenerase at least 1 hour before or after antacid (or the buffered formulation of didanosine) use.

Patients should be advised that drinking alcoholic beverages is not recommended while taking Agenerase Oral Solution.

Patients receiving sildenafil should be advised that they may be at an increased risk of sildenafil-associated adverse events including hypotension, visual changes, and priapism, and should promptly report any symptoms to their doctor.

Patients taking Agenerase should be instructed not to use hormonal contraceptives because some birth control pills (those containing ethinyl estradiol/norethindrone) have been found to decrease the concentration of amprenavir. Therefore, patients receiving hormonal contraceptives should be instructed to use alternate contraceptive measures during therapy with Agenerase.

High-fat meals may decrease the absorption of Agenerase and should be avoided. Agenerase may be taken with meals of normal fat content.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Adult and pediatric patients should be advised not to take supplemental vitamin E since the vitamin E content of Agenerase exceeds the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).

Laboratory Tests

The combination of Agenerase and low-dose ritonavir has been associated with elevations of cholesterol and triglycerides, SGOT (AST), and SGPT (ALT) in some patients. Appropriate laboratory testing should be considered prior to initiating combination therapy with Agenerase and ritonavir capsules and at periodic intervals or if any clinical signs or symptoms of hyperlipidemia or elevated liver function tests occur during therapy. For comprehensive information concerning laboratory test alterations associated with ritonavir, physicians should refer to the complete prescribing information for NORVIR (ritonavir).

Drug Interactions

See also CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Drug Interactions.

Agenerase is an inhibitor of cytochrome P450 3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. There are other agents that may result in serious and/or life-threatening drug interactions (see CONTRAINDICATIONS and WARNINGS).

Use of alcoholic beverages is not recommended in patients treated with Agenerase Oral Solution.

Table 7. Drugs That Should Not Be Coadministered With Agenerase Oral Solution

Drug Class/Drug Name

Clinical Comment

Alcohol-dependence treatment:

Disulfiram

CONTRAINDICATED due to potential risk of toxicity from the large amount of the excipient, propylene glycol, in Agenerase Oral Solution.

Antibiotic:

Metronidazole

CONTRAINDICATED due to potential risk of toxicity from the large amount of the excipient, propylene glycol, in Agenerase Oral Solution.

Antimycobacterials:

Rifampin*

May lead to loss of virologic response and possible resistance to Agenerase or to the class of protease inhibitors.

Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI motility agents:

Cisapride

CONTRAINDICATED due topotential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Herbal products:

St. John’s wort (hypericum perforatum)

May lead to loss of virologic response and possible resistance to Agenerase or to the class of protease inhibitors.

HIV protease inhibitor:

Ritonavir oral solution

Concurrent use of Agenerase Oral Solution and NORVIR (ritonavir) Oral Solution is not recommended because the large amount of propylene glycol in Agenerase Oral Solution and ethanol in NORVIR Oral Solution may compete for the same metabolic pathway for elimination.

HMG co-reductase inhibitors:

Lovastatin, simvastatin

Potential for serious reactions such as risk of myopathy including rhabdomyolysis.

Neuroleptic:

Pimozide

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Non-nucleoside reverse transcriptase inhibitor:

Delavirdine*

May lead to loss of virologic response and possible resistance to delavirdine.

Oral contraceptives:

Ethinyl estradiol/norethindrone

May lead to loss of virologic response and possible resistance to Agenerase. Alternative methods of non-hormonal contraception are recommended.

Sedative/hypnotics:

Midazolam, triazolam

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 3 and 4.

Table 8. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name

Effect on Concentration of Amprenavir or Concomitant Drug

Clinical Comment

HIV-Antiviral Agents

Non-nucleoside reverse transcriptase inhibitors:

Efavirenz, nevirapine

↓Amprenavir

Appropriate doses of the combinations with respect to safety and efficacy have not been established.

Nucleoside reverse transcriptase inhibitor:

Didanosine (buffered formulation only)

↓Amprenavir

Take Agenerase at least 1 hour before or after the buffered formulation of didanosine.

HIV protease inhibitors:

Indinavir*, lopinavir/ritonavir, nelfinavir*

↑Amprenavir

Amprenavir’s effect on other protease inhibitors is not well established.

Appropriate doses of the combinations with respect to safety and efficacy have not been established.

HIV protease inhibitor:

Ritonavir Capsules*

↑Amprenavir

The dose of amprenavir should be reduced when used in combination with ritonavir capsules (see Dosage and Administration). Also, see the full prescribing information for NORVIR for additional drug interaction information.

Concurrent use of Agenerase Oral Solution and NORVIR (ritonavir) Oral Solution is not recommended because the large amount of propylene glycol in Agenerase Oral Solution and ethanol in NORVIR Oral Solution may compete for the same metabolic pathway for elimination.

HIV protease inhibitor:

Saquinavir*

↓Amprenavir

Amprenavir’s effect on saquinavir is not well established.

Appropriate doses of the combination with respect to safety and efficacy have not been established.

Other Agents

Antacids

↓Amprenavir

Take Agenerase at least 1 hour before or after antacids.

Antiarrhythmics:

Amiodarone, lidocaine (systemic), and quinidine

↑Antiarrhythmics

Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with Agenerase, if available.

Antiarrhythmic:

Bepridil

↑Bepridil

Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.

Anticoagulant:

Warfarin

Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.

Anticonvulsants:

Carbamazepine, phenobarbital, phenytoin

↓Amprenavir

Use with caution. Agenerase may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitant



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