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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 contained in AGENERASE Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the complete prescribing information for AGENERASE Oral Solution for full information. |
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.
Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C. AGENERASE Capsules are available for oral administration in strengths of 50 and 150 mg. Each 50-mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. Each 150-mg capsule contains the inactive ingredients TPGS, polyethylene glycol (PEG 400) 740 mg, and propylene glycol 57 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 150-mg AGENERASE Capsule contains 109 IU vitamin E in the form of d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS). The total amount of vitamin E in the recommended daily adult dose of AGENERASE is 1744 IU.
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 isolates 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, 67 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 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 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 has 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: 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 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.
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.
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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.
Race: The pharmacokinetics of amprenavir do not differ between Blacks and non-Blacks.
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 .
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 139 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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AGENERASE 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.)
Because of the potential toxicity from the large amount of the excipient propylene glycol contained in AGENERASE Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the complete prescribing information for AGENERASE Oral Solution for full information.
AGENERASE is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of this product.
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).
Because of the potential toxicity from the large amount of the excipient propylene glycol contained in AGENERASE Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the complete prescribing information for AGENERASE Oral Solution for full information.
Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in patients treated with AGENERASE (see ADVERSE REACTIONS ). Acute hemolytic anemia has been reported in a patient treated with AGENERASE.
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.
General: AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable on a milligram per milligram basis (see : Pediatric Patients ).
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 (see DOSAGE AND ADMINISTRATION ).
Formulations of AGENERASE provide high daily doses of vitamin E (see Information for Patients , 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.
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 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 Capsules is available for patient information.
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. Please see the complete prescribing information for AGENERASE Oral Solution for full information.
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 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 Capsules and Oral Solution 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: clozapine, 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.
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: Pregnancy Category C. Embryo/fetal development studies were conducted in rats (dosed from 15 days before pairing to day 17 of gestation) and rabbits (dosed from day 8 to day 20 of gestation). In pregnant rabbits, amprenavir administration was associated with abortions and an increased incidence of 3 minor skeletal variations resulting from deficient ossification of the femur, humerus trochlea, and humerus. Systemic exposure at the highest tested dose was approximately one-twentieth of the exposure seen at the recommended human dose. In rat fetuses, thymic elongation and incomplete ossification of bones were attributed to amprenavir. Both findings were seen at systemic exposures that were one half of that associated with the recommended human dose.
Pre- and post-natal developmental studies were performed in rats dosed from day 7 of gestation to day 22 of lactation. Reduced body weights (10% to 20%) were observed in the offspring. The systemic exposure associated with this finding was approximately twice the exposure in humans following administration of the recommended human dose. The subsequent development of these offspring, including fertility and reproductive performance, was not affected by the maternal administration of amprenavir.
There are no adequate and well-controlled studies in pregnant women. AGENERASE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
AGENERASE Oral Solution is contraindicated during pregnancy due to the potential risk of toxicity to the fetus from the high propylene glycol content.
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 recommended 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: 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.
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.
The safety, effectiveness, and pharmacokinetics of amprenavir have not been evaluated in pediatric patients below the age of 4 years (see and DOSAGE AND ADMINISTRATION ).
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 dosing 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 may be taken with or without food; however, a high-fat meal decreases the absorption of amprenavir and should be avoided (see : Effects of Food on Oral Absorption ). Adult and pediatric patients should be advised not to take supplemental vitamin E since the vitamin E content of AGENERASE Capsules exceeds the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
Adults: The recommended oral dose of AGENERASE Capsules for adults is 1200 mg (8 150-mg capsules) twice daily in combination with other antiretroviral agents.
Pediatric Patients: For adolescents (13 to 16 years), the recommended oral dose of AGENERASE Capsules is 1200 mg (8 150-mg capsules) twice daily in combination with other antiretroviral agents. For patients between 4 and 12 years of age or for patients 13 to 16 years of age with weight of <50 kg, the recommended oral dose of AGENERASE Capsules is 20 mg/kg twice daily or 15 mg/kg 3 times daily (to a maximum daily dose of 2400 mg) in combination with other antiretroviral agents.
Before using AGENERASE Oral Solution, the complete prescribing information should be consulted. AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable on a milligram per milligram basis (see ).
Patients with Hepatic Impairment: AGENERASE Capsules should be used with caution in patients with moderate or severe hepatic impairment. Patients with a Child-Pugh score ranging from 5 to 8 should receive a reduced dose of AGENERASE Capsules of 450 mg twice daily, and patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of AGENERASE Capsules of 300 mg twice daily (see CLINICAL PHARACMOLOGY : Hepatic Insufficiency ).
AGENERASE Capsules, 50 mg, are oblong, opaque, off-white to cream-colored soft gelatin capsules printed with "GX CC1" on the side.
Bottles of 480 with child-resistant closures (NDC 0173-0679-00).
AGENERASE Capsules, 150 mg, are oblong, opaque, off-white to cream-colored soft gelatin capsules printed with "GX CC2" on the side.
Bottles of 240 with child-resistant closures (NDC 0173-0672-00).
Store at controlled room temperature of 25°C (77°F) (see USP).
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Please read this information before you start taking AGENERASE (pronounced ah-GEN-er-ase) Capsules, 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 Capsules with some medications can result in serious or life-threatening problems.
You should not switch from AGENERASE Capsules to AGENERASE Oral Solution without talking with your doctor.
AGENERASE Capsules are a medication used to treat HIV infection. HIV is the virus that causes AIDS (acquired immune deficiency syndrome). AGENERASE Capsules are taken by mouth as soft gel capsules. AGENERASE belongs to a class of anti-HIV medicines call protease inhibitors.
AGENERASE Capsules are used only in combination with other anti-HIV medicines. When used in combination therapy, AGENERASE Capsules 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 Capsules do not have these effects in all patients.
Common side effects of AGENERASE Capsules are nausea, vomiting, diarrhea, rash, and a tingling sensation around the mouth. Severe or life-threatening rash has been reported.
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 Capsules 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 Capsules. Talk to your doctor promptly about any side effects you have.
Take AGENERASE Capsules exactly as your doctor prescribes them. The usual dosage for adults and adolescents (at least 13 years of age) is 8 150-mg soft gel capsules twice a day (morning and night), in combination with other anti-HIV medicines.
AGENERASE Capsules 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 Capsules.
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 Capsules 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 Capsules at any one time.
When your supply of AGENERASE Capsules 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 planning to take, including non-prescription drugs.
You should not take any of the following medications with AGENERASE Capsules because serious or life-threatening problems could occur. *
HALCION® (triazolam)
HISMANAL® (astemizole)
Ergot medications (CAFERGOT® and others)
PROPULSID® (cisapride)
VERSED® (midazolam)
VASCOR® (bepridil)
AGENERASE Capsules do 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 Capsules, as well as other anti-HIV medications, have 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.
Do not take AGENERASE Capsules if you have had a serious allergic reaction to AGENERASE or any of its ingredients. If you have liver disease, your dosage of AGENERASE may have to be adjusted.
If you are allergic to sulfa drugs, you should inform your doctor.
Children from 4 to 12 years of age can take AGENERASE Capsules. 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 in infants and children below 4 years of age.
AGENERASE Capsules have not been studied in pregnant women and the risk to the unborn child is not known. Talk to your doctor if you are pregnant or if you become pregnant while taking AGENERASE.
AGENERASE Oral Solution should not be used in pregnant women.
Mothers with HV should not breastfeed their infants because HIV in the breast milk can infect the infant.
Talk of your doctor if you are pregnant or if you become pregnant while you are taking AGENERASE. Also talk to your doctor if you have hemophilia or problems with your liver or kidneys.
AGENERASE Capsules 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 Capsules and all medicines out of the reach of children.
Ask a healthcare professional any questions you may have about AGENERASE.
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 markers of these brands are not affiliated with and do not endorse Glaxo Wellcome or its products.
AGENERASE Capsules are manufactured by
R.P. Scherer, Beinheim, France
for Glaxo Wellcome Inc., Research Triangle Park, NC 27709
Licensed from Vertex Pharmaceuticals Incorporated
Cambridge, MA 02139
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-824