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AGENERASE (amprenavir) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression 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 CONTRAINDICATIONS AND ). AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options. |
AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3 S )-tetrahydro-3-furyl N -[(1 S ,2 R )-3-(4-amino- N -isobutylbenzenesulfonamido)-1-benzyl-2- hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3 S )(1 S ,2 R ) configuration. It has a molecular formula of C 25 H 35 N 3 O 6 S and a molecular weight of 505.64.
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, polythylene 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 d-alpha tocopheryl polyethylene glycol 1000 succinate. 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 1650 mg/kg per day. Acceptable intake of propylene glycol for pharmaceuticals has not been established.
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 (IC 50 ) 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 in combination 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 were also 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 M46I/L, I47V, I50V, I54L/V, and I84V as well as mutations in the viral protease p1/p6 cleavage site. Phenotypic analysis of HIV-1 isolates from some patients on amprenavir monotherapy for 8 to 12 weeks showed a 5- to 10-fold decrease in susceptibility to amprenavir in vitro compared to baseline. Phenotypic analysis of HIV-1 isolate from 28 patients treated with amprenavir in combination with zidovudine and lamivudine for 16 to 36 weeks identified isolates from 6 patients that exhibited a 5- to 11-fold decrease in susceptibility to amprenavir in vitro compared to wild-type virus. Clinical isolates that exhibited a decrease in amprenavir susceptibility harbored amprenavir-associated mutations. The clinical relevance of the genotypic and phenotypic changes associated with amprenavir therapy has not been established.
Cross-Resistance: Varying degrees of HIV-1 cross-resistance among protease inhibitors have been observed. The potential for protease inhibitor cross-resistance in HIV-1 isolates from amprenavir-treated patients has not been fully evaluated.
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 1200 mg and multiple oral doses of 300 to 1200 mg twice daily.
Absorption and Bioavailability: Amprenavir was rapidly absorbed after oral administration in HIV-1-infected patients with a time to peak concentration (t max ) 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 1200 mg were slightly greater than dose-proportional. Increases in AUC were dose-proportional after 3 weeks of dosing with doses from 300 to 1200 mg twice daily. The pharmacokinetic parameters after administration of amprenavir 1200 mg b.i.d. for 3 weeks to HIV-infected subjects are shown in Table 1.
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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, 6 grams fat, 33 grams protein, 58 grams carbohydrate). Administration of a single 1200-mg dose of amprenavir in the fed state compared to the fasted state was associated with changes in C max (fed: 6.18 ± 2.92 mcg/mL, fasted: 9.72 ± 2.75 mcg/mL), t max (fed: 1.51 ± 0.68, fasted: 1.05 ± 0.63), and AUC 0-(infinity) (fed: 22.06 ± 11.6 mcg·h/mL, fasted: 28.05 ± 10.1 mcg·h/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 (V z /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 alpha 1 -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 CYP3A4 enzyme system. The two 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 : 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 14 C-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 ). 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 AUC 0-(infinity) was significantly greater in patients with moderate cirrhosis (25.76 ± 14.68 mcg·h/mL) compared with healthy volunteers (12.00 ± 4.38 mcg·h/mL). The AUC 0-(infinity) and C max were significantly greater in patients with severe cirrhosis (AUC 0-(infinity) : 38.66 ± 16.08 mcg·h/mL; C max : 9.43 ± 2.61 mcg/mL) compared with healthy volunteers (AUC 0-(infinity) : 12.00 ± 4.38 mcg·h/mL; C max : 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 ). 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 ).
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 C max of amprenavir increased less than proportionally with dose. The AUC 0-(infinity) 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.
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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 , , 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, C max , and C min 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 .
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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 C max , AUC, and C min were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases in C max and AUC were seen after the first dose. Saquinavir steady-state C max , AUC, and C min were increased 21%, decreased 19%, and decreased 48%, respectively, by concomitant amprenavir. Nelfinavir steady-state C max , AUC, and C min were increased by 12%, 15%, and 14%, respectively, by concomitant amprenavir.
For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions .
AGENERASE (amprenavir) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression with AGENERASE .
AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options.
Clinical Studies: Therapy-Naive Adults: PROAB3001, an ongoing, randomized, double-blind, placebo-controlled, multicenter study, compared treatment with AGENERASE Capsules (1200 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, median age 37 years (range 18 to 63 years), 75% Caucasian, 89% male, with a median CD4 cell count of 416 cells/mm 3 (range 138 to 1800 cells/mm 3 ) and a median plasma HIV-1 RNA of 4.67 log 10 copies/mL (range 3.06 to 6.31 log 10 copies/mL) at baseline. Through 24 weeks of therapy, there was no significant difference in the median CD4 cell count between the treatment arms. Figure 1 shows the proportions of patients with plasma HIV-1 RNA levels <400 copies/mL through 24 weeks.
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HIV-1 RNA status and reasons for discontinuation of randomized treatment at 24 weeks are summarized (Table 5).
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Therapy-Experienced Adults: PROAB3006, an ongoing, randomized, open-label multicenter study, compared treatment with AGENERASE Capsules (1200 mg twice daily) plus NRTIs versus indinavir (800 mg every 8 hours) plus NRTIs in 504 NRTI- and non-nucleoside reverse transcriptase inhibitor- (NNRTI) 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 399 cells/mm 3 (range 9 to 1706 cells/mm 3 ) and a median plasma HIV-1 RNA level of 3.93 log 10 copies/mL (range 2.60 to 7.01 log 10 copies/mL) at baseline. Through 24 weeks of therapy, there was a smaller increase in median CD4 cell count from baseline for the amprenavir group than for the indinavir group. Figure 2 shows the proportions of patients with plasma HIV-1 RNA levels <400 copies/mL through 24 weeks.
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HIV-1 RNA status and reasons for discontinuation of randomized treatment at 24 weeks are summarized (Table 6).
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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 and PRECAUTIONS ).
AGENERASE also should not be administered concurrently with astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, midazolam, and triazolam. Although these drugs have not been specifically studied, coadministration may result in competitive inhibition of metabolism of these products and may cause serious or life-threatening adverse events. (See for agents whose coadministration may result in competitive inhibition of metabolism but for which concentration monitoring is recommended.)
AGENERASE is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of this product.
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 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 be monitored 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.
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%.
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 or cerivastatin). 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.
General: AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable on a milligram per milligram basis .
Amprenavir is a sulfonamide. The potential for cross-sensitivity between drugs in the sulfonamide class and amprenavir is unknown. Patients with a known sulfonamide allergy should be treated with caution.
AGENERASE is principally metabolized by the liver; therefore caution should be exercised when administering this drug to patients with hepatic impairment .
Formulations of AGENERASE provide high daily doses of vitamin E . 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.
Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Resistance/Cross-Resistance: Because of 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 (see MICROBIOLOGY ).
Information for Patients: 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. AGNERASE 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.
Some drugs should not be used with AGENERASE. Therefore, patients should be advised that they must report to their doctor the use of any other prescription or nonprescription medication.
Patients taking antacids (or didanosine) should take AGENERASE at least 1 hour before or after antacid (or 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 receiving hormonal contraceptives should be instructed that alternate contraceptive measures should be used 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 protease inhibitors 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).
Drug Interactions: See also CONTRAINDICATIONS , , and : Drug Interactions .
AGENERASE is an inhibitor of cytochrome P450 CYP3A4 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 ).
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Antimycobacterials: Rifampin: Rifampin should not be used in combination with amprenavir since it reduces plasma concentrations and AUC of amprenavir by about 90%.
Rifabutin: Coadministration of amprenavir with rifabutin results in a 15% decrease in amprenavir plasma AUC and a 193% increase in rifabutin plasma AUC. A dosage reduction of rifabutin to at least half the recommended dose is required when AGENERASE and rifabutin are coadministered (see : Drug Interactions ). A complete blood count should be performed weekly and as clinically indicated in order to monitor for neutropenia in patients receiving amprenavir and rifabutin.
Other Potentially Significant Drug Interactions: Other medications that interact at CYP3A4, either as substrates, inhibitors, or inducers of the enzyme, could have potential interactions when used concomitantly. The clinical significance of these potential interactions is unknown and has not been studied.
Antibiotics: Dapsone and erythromycin may have their plasma concentrations increased by AGENERASE. Erythromycin may also increase amprenavir serum concentrations.
Antifungals: Itraconazole may have its plasma concentrations increased by AGENERASE. Itraconazole may increase serum concentrations of amprenavir.
Benzodiazepines: Alprazolam, clorazepate, diazepam, and flurazepam may have their serum concentrations increased by AGENERASE, which could increase their activity.
Calcium Channel Blockers: Diltiazem, nicardipine, nifedipine, and nimodipine may have their serum concentrations increased by AGENERASE, which could increase their activity.
Cholesterol-Lowering Agents: Atorvastatin, cerivastatin, lovastatin, pravastatin, and simvastatin may have their serum concentration increased by AGENERASE, which could increase their activity or toxicity. 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 or cerivastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including amprenavir, are used in combination with these drugs.
Erectile Dysfunction Agents: Particular caution should be used when prescribing sildenafil in patients receiving amprenavir. Because amprenavir is a cytochrome P4503A4 inhibitor, coadministration of AGENERASE with sildenafil is likely to result in an increase of sildenafil concentrations by competitive inhibition of metabolism. The magnitude of this interaction has not been determined. Results from drug interaction studies in healthy volunteers indicate that coadministration of saquinavir soft gelatin capsules (1200 mg t.i.d.) increases sildenafil (100 mg single dose) AUC by 210% (3.1-fold) and coadministration of ritonavir (500 mg b.i.d.) increases sildenafil (100 mg single dose) AUC by 1000% (11-fold). Providers should consult the sildenafil prescribing information for dose reductions of sildenafil in patients receiving ritonavir. Patients receiving amprenavir and sildenafil should be advised that they may be at an increased risk for sildenafil-associated adverse events, including hypotension, visual changes, and priapism, and should report these symptoms promptly to their doctor.
NNRTIs: NNRTIs have the potential to increase (delavirdine) or decrease (efavirenz, nevirapine) serum concentrations of amprenavir.
Steroids: Estrogens, progestogens, and some glucocorticoids may have an interaction with AGENERASE, but there is insufficient information to predict the nature of the interaction. Because of this potential for metabolic interactions with amprenavir, the efficacy of hormonal contraceptives may be reduced. Alternate or additional reliable barrier methods of contraception are recommended for women of childbearing potential.
Other Agents: There are other agents that may have their plasma concentrations increased by AGENERASE, and include, but are not limited to: clozapin, carbamazepine, loratadine, pimozide, and warfarin.
Cimetidine and ritonavir may increase amprenavir plasma concentrations.
Antacids (and didanosine secondary to the antacid content) have not been specifically studied. Based upon data with other protease inhibitors, it is advisable that antacids not be taken at the same time as AGENERASE because of potential interference with absorption. It is recommended that their administration be separated by at least an hour.
Use of alcoholic beverages is not recommended in patients treated with AGENERASE Oral Solution.
Carcinogenesis and Mutagenesis: Long-term carcinogenicity studies of amprenavir in rodents are in progress. Amprenavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes.
Fertility: The effects of amprenavir on fertility and general reproductive performance were investigated in male rats (treated for 28 days before mating, at doses producing up to twice the expected clinical exposure based on AUC comparisons) and female rats (treated for 15 days before mating through day 17 of gestation at doses producing up to 2 times the expected clinical exposure). Amprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats. The reproductive performance of the F1 generation born to female rats given amprenavir was not different from control animals.
Pregnancy and Reproduction: AGENERASE Oral Solution is contraindicated during pregnancy due to the potential risk of toxicity to the fetus from the high propylene glycol content. Therefore, if AGENERASE is used in pregnant women, the AGENERASE Capsules formulation should be used (see complete prescribing information for AGENERASE Capsules).
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to AGENERASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known if amprenavir is excreted in human milk, amprenavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and any possible adverse effects of amprenavir, mothers should be instructed not to breastfeed if they are receiving AGENERASE.
Pediatric Use: AGENERASE Oral Solution is contraindicated in infants and children below the age of 4 years due to the potential risk of toxicity from the excipient propylene glycol (see CONTRAINDICATIONS and ). Alcohol dehydrogenase (ADH), which metabolizes propylene glycol, 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.
One hundred eighteen patients 4 to 17 years of age have received amprenavir as single or multiple doses in studies. An adverse event profile similar to that seen in adults was seen in pediatric patients.
Geriatric Use: Clinical studies of AGENERASE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adults. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Rates of discontinuation of randomized therapy due to adverse events were 15% in amprenavir vs 3% in placebo recipients from Study 3001, and 16% in amprenavir vs 8% in indinavir recipients from Study 3006. In these studies, adverse events leading to amprenavir discontinuation included gastrointestinal events (11%), rash (3%), and paresthesias (<1%).
Most gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain) that led to amprenavir discontinuation were graded as mild or moderate in severity.
In all multidose studies in HIV-infected patients, skin rash occurred in 28% of patients treated with amprenavir. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rashes had onsets ranging from 7 to 73 days (median: 10 days) after amprenavir initiation. With mild or moderate rash, amprenavir dose was often continued without interruption; if interrupted, reintroduction of amprenavir generally did not result in rash recurrence (Phase 3 studies).
Severe or life-threatening rash, including Stevens-Johnson syndrome, occurred in 1% of recipients of AGENERASE (4% of recipients who developed rash) (see ). Amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.
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In Phase 3 studies, 1 patient experienced diabetes mellitus de novo , and another developed a dorsocervical fat enlargement (buffalo hump).
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In studies 3001 and 3006, no increased frequency of Grade 3 or 4 AST, ALT, amylase, or bilirubin elevations was seen compared to controls.
Pediatric Patients: An adverse event profile similar to that seen in adults was seen in pediatric patients.
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 Oral Solution contains large amounts of propylene glycol. In the event of overdosage, monitoring and management of acid-base abnormalities is recommended. Propylene glycol can be removed by hemodialysis.
AGENERASE may be taken with or without food; however, a high-fat meal decreases the absorption of amprenavir and should be avoided . Adult and pediatric patients should be advised not to take supplemental vitamin E since the vitamin E content of AGENERASE Oral Solution exceeds the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
The recommended dose of AGENERASE Oral Solution based on body weight and age is shown in Table 10. Consideration should be given to switching patients from AGENERASE Oral Solution to AGENERASE Capsules as soon as they are able to take the capsule formulation (see ).
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Patients with Hepatic Impairment: AGENERASE Oral Solution is contraindicated in patients with hepatic failure (see CONTRAINDICATIONS ).
Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see ). AGENERASE Oral Solution should be used with caution in patients with hepatic impairment. Based on a study with AGENERASE Capsules, adult patients with a Child-Pugh score ranging from 5 to 8 should receive a reduced dose of AGENERASE Oral Solution of 513 mg (34 mL) twice daily, and adult patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of AGENERASE Oral Solution of 342 mg (23 mL) twice daily (see : Hepatic Insufficiency ).
AGENERASE Oral Solution has not been studied in children with hepatic impairment.
Renal Insufficiency: AGENERASE Oral Solution is contraindicated in patients with renal failure (see CONTRAINDICATIONS ).
Patients with renal impairment are at increased risk of propylene glycol-associated adverse events. AGENERASE Oral Solution should be used with caution in patients with renal impairment (see ).
AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable on a milligram per milligram basis (see CLINICAL PHARMACOLOGY ).
AGENERASE Oral Solution, a clear, pale yellow to yellow, grape bubblegum-peppermint-flavored liquid, contains 15 mg of amprenavir in each 1 mL.
Bottles of 240 mL with child-resistant closures (NDC 0173-0687-00). This product does not require reconstitution.
Store at controlled room temperature of 25°C (77°F) (see USP).
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AGENERASE® (amprenavir) Oral Solution
Please read this information before you start taking AGENERASE (pronounced ah-GEN-er-ase) Oral Solution, and re-read it each time you receive your prescription, just in case something has changed. Remember that this information does not take the place of careful discussions with your doctor when you start this medication and at checkups. You should not change or stop your anti-HIV treatment without first talking with your doctor. You should tell your doctor about any drug you are taking or planning to take because taking AGENERASE Oral Solution with some medications can result in serious or life-threatening problems.
AGENERASE Oral Solution is a medication used to treat HIV infection. HIV is the virus that causes AIDS (acquired immune deficiency syndrome). AGENERASE Oral Solution is taken by mouth as an oral solution. It belongs to a class of anti-HIV medicines called protease inhibitors.
AGENERASE Oral Solution should not be used in infants and children below the age of 4 years, pregnant women, patients with liver or kidney failure, and patients receiving disulfiram (ANTABUSE®) or metronidazole (FLAGYL®).
AGENERASE Oral Solution contains a large amount of propylene glycol, a liquid needed to dissolve amprenavir. Because of the possible side effects of the large amount of propylene glycol, AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not options. You should not switch from AGENERASE Capsules to AGENERASE Oral Solution without talking to your doctor.
If you are a woman or an Asian, Eskimo, or Native American, or if you have liver or kidney disease, you may be at increased risk of side effects from the large amount of propylene glycol in AGENERASE Oral Solution.
AGENERASE Oral Solution is used only in combination with other anti-HIV medicines. When used in combination therapy, AGENERASE Oral Solution may help lower the amount of HIV found in your blood, raise CD4 (T) cell count, and keep your immune system as healthy as possible so that it can help fight infection. However, AGENERASE Oral Solution does not have these effects in all patients.
Common side effects of AGENERASE Oral Solution are nausea, vomiting, diarrhea, rash, and a tingling sensation around the mouth. Severe or life-threatening rash has been reported.
Possible side effects from the large amount of propylene glycol in AGENERASE Oral Solution include seizures, drowsiness, fast heart rate, and kidney and blood abnormalities.
Contact your doctor if you have nausea, vomiting, diarrhea, or rash. Your doctor may be able to help you manage these symptoms. Your doctor will advise you whether your symptoms can be managed on therapy or whether AGENERASE Oral Solution should be stopped.
This list of side effects is not complete. Your doctor or pharmacist can discuss with you a more complete list of possible side effects with AGENERASE Oral Solution. Talk to your doctor promptly about any side effects you have.
Take AGENERASE Oral Solution exactly as your doctor prescribes it. AGENERASE Oral Solution can be taken with or without food. However, you should not take AGENERASE with a high-fat meal because this could reduce the effectiveness of AGENERASE Oral Solution.
To help make sure that your anti-HIV therapy is as effective as possible, be very careful to take all of your medication exactly as your doctor prescribed it and do not skip any doses.
If you miss a dose of AGENERASE Oral Solution by more than 4 hours, wait and take the next dose at the regularly scheduled time. However, if you miss a dose by fewer than 4 hours, take your missed dose immediately. Then take your next dose at the regularly scheduled time. Do not take more or less than your prescribed dose of AGENERASE Oral Solution at any one time.
When your supply of AGENERASE Oral Solution or other anti-HIV drugs starts to run low, arrange to get more from your doctor or pharmacy. It is very important that you take anti-HIV drugs as prescribed by your doctor because the amount of virus in your blood may increase if one or more of the drugs is stopped, even for a short time.
Protease inhibitors, including AGENERASE, may interact with other drugs, including those you take without a prescription. Before you take AGENERASE, tell your doctor about any drugs that you are taking or are planning to take, including non-prescription drugs.
AGENERASE Oral Solution does not cure HIV infection or AIDS. At this time we do not know if AGENERASE will help you live longer or have fewer of the medical problems (opportunistic infections) that are associated with HIV infection or AIDS. Because of this, you must be sure to be seen regularly by your healthcare professional.
No. AGENERASE Oral Solution, as well as other anti-HIV medications, has not been shown to reduce the risk of passing HIV to others through sexual contact or blood contamination. Continue to practice safe sex and do not use or share dirty needles.
AGENERASE Oral Solution should not be used in infants and children below 4 years of age, pregnant women, patients with liver or kidney failure, or patients on disulfiram (ANTABUSE) or metronidazole (FLAGYL).
Do not take AGENERASE Oral Solution if you have had a serious allergic reaction to AGENERASE Oral Solution or any of its ingredients. If you have liver disease, your dosage of AGENERASE Oral Solution may have to be adjusted.
If you are allergic to sulfa drugs, you should inform your doctor.
AGENERASE Oral Solution should not be used in infants and children below 4 years of age.
Children from 4 to 12 years of age can take AGENERASE Oral Solution. Your doctor will tell you if the oral solution or capsule is best for your child. Your child's doctor will decide the right dose based on your child's weight and age.
AGENERASE Oral Solution should not be used by pregnant women. Talk to your doctor if you are pregnant or if you become pregnant while taking AGENERASE Oral Solution.
Mothers with HIV should not breastfeed their infants because HIV in the breast milk can infect the infant.
Talk to your doctor if you are pregnant or if you become pregnant while you are taking AGENERASE Oral Solution.
Also talk to your doctor if you have hemophilia or problems with your liver or kidneys.
AGENERASE Oral Solution should be stored at room temperature and should not be refrigerated.
This medication is prescribed for a particular condition. Do not use it for any other condition or give it to anybody else. Keep AGENERASE Oral Solution and all medicines out of the reach of children.
Ask a healthcare professional any questions you may have about AGENERASE Oral Solution.
AGENERASE is a registered trademark of the Glaxo Wellcome group of companies.
* The brands listed are trademarks of their respective owners and are not trademarks of the Glaxo Wellcome group of companies. The makers of these brands are not affiliated with and do not endorse Glaxo Wellcome or its products.Glaxo Wellcome Inc., Research Triangle Park, NC 27709
Licensed from Vertex Pharmaceuticals Incorporated
Cambridge, MA 02139
AGENERASE is a registered trademark of the Glaxo Wellcome group of companies.
US Patent Nos. 5,585,397; 5,723,490; and 5,646,180
©Copyright 1999, 2000, Glaxo Wellcome Inc. All rights reserved.
May 2000/RL-825