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

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

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

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 may be taken with or without food; however, a high- fat meal decreases the absorption of amprenavir and should be avoided (see CLINICAL PHARMACOLOGY: 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) (see DESCRIPTION).

Adults: The recommended oral dose of AGENERASE Capsules for adults is 1,200 mg (twenty- four 50- mg capsules) twice daily in combination with other antiretroviral agents.

Concomitant Therapy: If AGENERASE and ritonavir are used in combination, the recommended dosage regimens are: AGENERASE 1,200 mg with ritonavir 200 mg once daily or AGENERASE 600 mg with ritonavir 100 mg twice daily.

Pediatric Patients: For adolescents (13 to 16 years), the recommended oral dose of AGENERASE Capsules is 1,200 mg (twenty- four 50- 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 2,400 mg) in combination with other antiretroviral agents. The recommended dose of AGENERASE for use in combination with ritonavir has not been established in pediatric patients.

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 CLINICAL PHARMACOLOGY).

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 PHARMACOLOGY: Hepatic Insufficiency).

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

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

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

AGENERASE Capsules are manufactured by R.P. Scherer Beinheim, France for GlaxoSmithKline, Research Triangle Park, NC 27709. Licensed from: Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139. AGENERASE is a registered trademark of GlaxoSmithKline. May 2005. FDA rev date: 11/4/2005

In clinical studies, adverse events leading to amprenavir discontinuation occurred primarily during the first 12 weeks of therapy, and were mostly due to gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain/discomfort), which were mild to moderate in severity.

Skin rash occurred in 22% of patients treated with amprenavir in studies PROAB3001 and PROAB3006. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rashes had a median onset of 11 days after amprenavir initiation and a median duration of 10 days. Skin rashes led to amprenavir discontinuation in approximately 3% of patients. In some patients with mild or moderate rash, amprenavir dosing was often continued without interruption; if interrupted, reintroduction of amprenavir generally did not result in rash recurrence.

Severe or life-threatening rash (Grade 3 or 4), including cases of Stevens -Johnson syndrome, occurred in approximately 1% of recipients of AGENERASE (see WARNINGS). Amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.

Table 9. Selected Clinical Adverse Events of All Grades Reported in > 5% of Adult Patients

Among amprenavir-treated patients in Phase 3 studies, 2 patients developed de novo diabetes mellitus, 1 patient developed a dorsocervical fat enlargement (buffalo hump), and 9 patients developed fat redistribution.

In studies PROAB3001 and PROAB3006, 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.

Concomitant Therapy with Ritonavir: Tables 10 and 11 present adverse clinical events and laboratory abnormalities observed in subjects who received AGENERASE plus ritonavir. Since the trials were small, open- label, of varying duration, and often included different patient populations, direct comparisons to the frequency of events with AGENERASE alone (see Table 9) cannot be made.

Table 10. Selected Clinical Adverse Events of All Grades Reported in Adult Patients in Open-Label Clinical Trials of AGENERASE in Combination With Ritonavir

Table 11. Grade 3/4 Laboratory Abnormalities Reported in ≥ 2% of Adult Patients in Open-Label Clinical Trials of AGENERASE in Combination With Ritonavir

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).

Table 7. Drugs That Should Not Be Coadministered With AGENERASE

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

ALERT: Find out about medicines that should not be taken with AGENERASE.

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

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

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of AGENERASE with ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and 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).

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 CLINICAL PHARMACOLOGY: Pediatric Patients).

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

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

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

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

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

Fat Redistribution: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Elevations: Treatment with AGENERASE alo ne or in combination with ritonavir 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 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.

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 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 redistributio n 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 Capsules and Oral Solution 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 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).

Carcinogenesis and Mutagenesis: Amprenavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Daily doses of 50, 275 to 300, and 500 to 600 mg/kg/day were administered to mice and doses of 50, 190, and 750 mg/kg/day were administered to rats. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in males of both species at the highest doses tested. Female mice and rats were not affected. These observations were made at systemic exposures equivalent to approximately 2 times (mice) and 4 times (rats) the human exposure (based on AUC_{0-24 hr} measurement) at the recommended dose of 1,200 mg twice daily. Administration of amprenavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. However, 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 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 the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving AGENERASE.

Pediatric Use: Two hundred fifty-one patients aged 4 and above 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 Capsules have not been evaluated in pediatric patients below the age of 4 years (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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.

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.

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.

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

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

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

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

Microbiology

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

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

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

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

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)

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 bioava ilability 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 (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 alpha₁-acid glycoprotein (AAG). The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

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

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

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

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

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

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

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

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

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

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

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

Amprenavir is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Caution should be used whe n 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

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

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): There was no effect of amprena vir on abacavir in subjects receiving both agents based on historical data.

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

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

For information regarding clinical recommendations, see PRECAUTIONS: DRUG INTERACTIONS.

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)

AGENERASE®
(amprenavir) Capsules

ALERT: Find out about medicines that should not be taken with AGENERASE. Read the section: “What important information should I know about taking AGENERASE with other medicines?”

Read this information carefully before you start taking AGENERASE (ah-GEN-er-ase). Read the information each time you get more medicine. There may be new information. This information does not take the place of talks with your healthcare provider when you start this medicine and at checkups.

What is the most important information I should know about AGENERASE?

AGENERASE can cause serious and life-threatening side effects if you take it with certain other medicines. For information about these medicines, see the section “What important information should I know about taking AGENERASE with other medicines?”

What is AGENERASE?

AGENERASE is a medicine you take by mouth to treat HIV infection. HIV is the virus that causes AIDS (acquired immune deficiency syndrome.) AGENERASE belongs to a class of anti-HIV medicines called protease inhibitors.

AGENERASE is used only in combination with other anti-HIV medicines. When used in combination therapy, AGENERASE may help lower the amount of HIV found in your blood, raise CD4 (T) cell counts, and keep your immune system as healthy as possible, so it can help fight infection. However, AGENERASE does not have these effects in all patients.

AGENERASE does not cure HIV infection or AIDS. We do not know if AGENERASE will help you live longer or have fewer of the medical problems (opportunistic infections) that people get with HIV or AIDS. Therefore, be sure to see your healthcare provider regularly. The long-term effects of AGENERASE are not known.

AGENERASE has not been shown to reduce the risk of passing HIV to others through sexual contact or blood. Continue to practice safe sex and do not use or share dirty needles.

Children from 4 to 12 years of age can take AGENERASE. Your healthcare provider will tell you if the oral solution (liquid) or capsule is best for your child. Your child's healthcare provider will decide the right dose based on your child's weight and age.

AGENERASE has not been studied in people who have taken anti-HIV medicine combinations before that included a protease inhibitor.

Who should not take AGENERASE?

Do not take AGENERASE Capsules if

• you are taking certain medicines. Read the section entitled “What important information should I know about taking AGENERASE with other medicines?”
• you have had an allergic reaction to AGENERASE or any of its ingredients.

Children younger than age 4 should not take AGENERASE Capsules or AGENERASE Oral Solution.

Tell your healthcare provider if

• you are pregnant, AGENERASE Capsules may not be right for you.
• you are breastfeeding. Your baby can get HIV from your milk. Also, AGENERASE can pass through your milk and harm the baby.

Tell your healthcare provider about all your medical conditions . AGENERASE may not be right for you, or you may need a dosage change in AGENERASE. Be sure to tell your healthcare provider if you

• have liver or kidney problems.
• have hemophilia.
• are allergic to sulfa medicines. AGENERASE may cause problems for you.

What important information should I know about taking AGENERASE with other medicines? Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and supplements. Some of them may cause dangerous and life-threatening side effects if you take them during treatment with AGENERASE. For other medicines, you may need to change your dose to avoid problems.

• If you are on methadone therapy, talk to your doctor about possible interactions.

Do NOT take the following medicines* with AGENERASE. You could develop serious or life-threatening problems.

• HALCION® (triazolam; used for insomnia)
• CAFERGOT® and other ergot medicines (used for migraine headaches)
• PROPULSID® (cisapride, used for certain stomach problems)
• VERSED® (midazolam; used for sedation)
• ORAP® (pimozide; used for Tourette's disorder)

You will need to be monitored with regular blood tests if you take the following medicines* with AGENERASE.

• CORDARONE® (amiodarone; used for certain abnormal heart rhythms)
• Quinidine (used for certain abnormal heart rhythms)
• COUMADIN® (warfarin; used for blood thinning)
• Lidocaine (used for certain abnormal heart rhythms)
• ELAVIL® (amitriptyline), TOFRANIL® (imipramine) (tricyclic antidepressants)
• SANDIMMUNE® or NEORAL® (cyclosporine), PROGRAF® (tacrolimus), RAPAMUNE® (rapamycin or sirolimus) (immunosuppressants)

You will need to have your dose adjusted if you take the following medicines^* with AGENERASE.

• MYCOBUTIN® (rifabutin; used to prevent Mycobacterium avium complex [MAC])
• NORVIR® (ritonavir; used to treat HIV infection)
• VIAGRA® (sildenafil; used for impotence). You may get increased side effects such as low blood pressure, changes in vision, or erections that last more than 4 hours. If an erection lasts more than 4 hours, get medical help right away.

The following medicines* may cause serious problems if you take them with AGENERASE. Tell your healthcare provider if you are taking any of these medicines.

• RESCRIPTOR® (delavirdine; used for HIV) and certain other anti-HIV medicines
• St. John's wort (hypericum perforatum) or products containing St. John's wort
• VASCOR® (bepridil; used for chronic stable angina)
• RIFADIN® , RIFAMATE® , RIFATER® , or RIMACTANE® (rifampin, used for tuberculosis)
• MEVACOR® (lovastatin), ZOCOR® (simvastatin), and LIPITOR® (atorvastatin) (cholesterol- lowering medicines)
• Phenobarbital (used for seizures)
• TEGRETOL® , CARBATROL® (carbamazepine; used for seizures and trigeminal neuralgia)
• DILANTIN® (phenytoin; used for seizures)
• DECADRON® (dexamethasone, used to reduce inflammation)
• Hormonal contraceptives (e.g., birth control pills) because the effectiveness of one or both drugs may be decreased. Talk to your doctor about choosing a different typ e of contraceptive.
• Vitamin E. AGENERASE contains high daily doses of vitamin E that could interfere with medicines that help you stop bleeding.

This list is not complete. Be sure to tell your healthcare provider about all the medicines you take.

How should I take AGENERASE?

• Take AGENERASE Capsules every day exactly as your healthcare provider has prescribed it, so it will be as effective as possible. Your healthcare provider will decide the right dose for you.
• If you miss a dose by more than 4 hours , wait and take the next dose at the regular time.However, if you miss a dose by fewer than 4 hours, take your missed dose right away. Then take your next dose at the regular time.
• Do not take more or less than your prescribed dose of AGENERASE Capsules at any one time. Do not change your dose or stop taking AGENERASE without talking with your healthcareprovider.
• You can take AGENERASE Capsules with or without food. However, do not take AGENERASE with a high-fat meal. This could reduce the effectiveness of the medicine.
• If you take AGENERASE with the buffered form of VIDEX® (didanosine, ddI), take them at least 1 hour apart.
• If you take AGENERASE Capsules with antacids, take them at least 1 hour apart.
• When your supply of AGENERASE or other anti-HIV medicine starts to run low, arrange to get more from your healthcare provider or pharmacy. The amount of virus in your blood may increase if one or more of the drugs are stopped, even for a short time.
• Stay under the care of a healthcare provider while using AGENERASE.

What should I avoid while taking AGENERASE? Do not

• switch from AGENERASE Capsules to AGENERASE Oral Solution without talking to your healthcare provider. You may get increased side effects if you switch.
• take vitamin E while taking AGENERASE. It contains large amounts of vitamin E.
• take AGENERASE with a high- fat meal. It could reduce the effectiveness of the medicine.

What are the possible side effects of AGENERASE?

AGENERASE can cause a severe or life-threatening rash. Call your healthcare provider right away if you have a rash. Your healthcare provider will advise you whether your symptoms can be managed on therapy or whether AGENERASE should be stopped.

Common side effects of AGENERASE are nausea, vomiting, diarrhea, rash, and a tingling feeling, especially around the mouth, and change in taste. These are usually mild to moderate. Depression and mood problems have also been reported in patients taking AGENERASE.

Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time.

Other side effects include high blood sugar or diabetes, diabetes complications, high cholesterol, or high triglycerides.

This list of side effects is not complete. Your healthcare provider or pharmacist can give you a more complete list of possible side effects. Talk with your healthcare provider about any concerns about the way you are feeling while you are taking AGENERASE.

How should I store AGENERASE Capsules?

AGENERASE Capsules should be stored at room temperature and should no t be refrigerated.

General advice about prescription medicines

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use AGENERASE for a condition for which it was not prescribed. Do not give AGENERASE to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about AGENERASE. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about AGENERASE that is written for health professionals.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

AMPRENAVIR - ORAL

(am-PREN-a-vir)

COMMON BRAND NAME(S): Agenerase

WARNING: Amprenavir is known to interact with many different types of medicines, in some cases causing severe (sometimes fatal) reactions. Consult your doctor or pharmacist about which medications should not be taken with amprenavir. (See also Drug Interactions section.)

USES: This drug, used in combination with at least 2 other medications, helps to control your HIV infection, thereby improving your quality of life. It also lowers your risk of getting HIV complications (e.g., new infections, cancer). Amprenavir belongs to a class of drugs known as protease inhibitors.

Amprenavir is not a cure for HIV, and it does not prevent the spread of HIV to others through sexual contact or blood contamination (e.g., sharing used needles).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to prevent HIV infection after contact with the virus.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking amprenavir and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with or without a meal (low-fat) or up to 2 hours after a meal, usually 2 times daily or as directed by your doctor.

The dosage is based on your weight, liver function, medical condition, other medications, and response to therapy.

It is very important to continue taking this medication (and other HIV medications) exactly as prescribed by your doctor.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it at the same times each day.

Do not take more or less of this drug than prescribed or stop taking it (or other HIV medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects.

This medication contains vitamin E to help preserve the amprenavir. Do not take any other vitamin E supplements unless directed to do so by your doctor because too much vitamin E can cause health problems.

If you are taking antacids (including didanosine dispersible tablets /solution), take amprenavir at least 1 hour before or after the antacid.

The capsule and liquid forms of amprenavir are not equal in strength. Do not switch forms without consulting your doctor or pharmacist.

SIDE EFFECTS: See also Warning section.

Diarrhea, nausea, vomiting, heartburn, stomach pain, gas, loss of appetite, headache, tiredness, strange taste in the mouth, or tingling/numbness of hands/feet/mouth area may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: persistent nausea, stomach/abdominal pain, dark urine, yellowing eyes/skin, decreased sexual interest, mental/mood changes (e.g., depression, anxiety), increasing tiredness, increased urination (especially at night), increased thirst, fruity breath odor.

Tell your doctor immediately if any of these rare but very serious side effects occur: severe tiredness, fainting, pale lips/nails/skin, fast heartbeat, fast breathing.

Changes in body fat may occur while you are taking this medication (e.g., increased fat in the upper back and stomach areas, decreased fat in the arms and legs). The cause and long-term effects of these changes are unknown. Discuss the risks and benefits of therapy with your doctor, as well as the possible role of exercise to reduce this side effect.

If you are taking HIV medications for the first time, you may experience symptoms of an old infection. This may happen as your immune system begins to work better. Contact your doctor immediately if you notice any of the following symptoms: new cough, trouble breathing, fever, new vision problems, new headaches, new skin problems.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking amprenavir, tell your doctor or pharmacist if you are allergic to it; or to sulfa drugs; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems (e.g., hepatitis B, hepatitis C), alcohol use, diabetes, hemophilia, high blood fats (high cholesterol/triglycerides).

If you have diabetes, this product may increase your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar, such as increased thirst and urination. Your anti-diabetic medication or diet may need to be adjusted.

This medication should be used only when clearly needed during pregnancy. However, it is now normal to prescribe HIV medicines for pregnant women with HIV. This has been shown to decrease the risk of giving HIV to the baby. Amprenavir may be part of that treatment. Discuss the risks and benefits with your doctor.

It is not known if this medication passes into breast milk. Because breast milk can transmit HIV, do not breast-feed.

DRUG INTERACTIONS: See also How to Use section.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: amiodarone, bepridil, delavirdine, etravirine, quinidine, tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine), cisapride, pimozide, dihydroergotamine, ergonovine, ergotamine, methylergonovine, St John's wort, midazolam, triazolam, simvastatin, lovastatin, rifampin, ranolazine, artemether/lumefantrine.

Avoid using hormonal birth control (e.g., pills, patch, ring) while taking this medication. Using hormonal birth control while also taking this medication can make both drugs less effective. Consult your doctor or pharmacist for more details and for information about other birth control methods. To reduce the risk of spreading HIV to others, always use effective barrier protection during all sexual activity. (See also Notes section.)

If amprenavir is taken with ritonavir, the following medications should also not be used: flecainide, propafenone.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: garlic capsules, sildenafil, tadalafil, vardenafil, trazodone, ketoconazole, itraconazole, saquinavir, lopinavir/ritonavir, indinavir, nelfinavir, didanosine (dispersible tablets/solution), nevirapine, efavirenz, carbamazepine, phenobarbital, phenytoin, rifabutin, fluticasone, atorvastatin, certain calcium channel blockers (e.g., nifedipine, felodipine, nicardipine), warfarin, ranitidine, dexamethasone, certain drugs that weaken the immune system (cyclosporine, tacrolimus, sirolimus), temsirolimus, alprazolam, diazepam, flurazepam, clonazepam, clorazepate, estazolam, methadone.

If any of these medications are taken with amprenavir, your doctor may change your dose of amprenavir or the other drug(s), or your doctor may monitor you specially. Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: To reduce the risk of spreading HIV to others, always use effective barrier protections (e.g., latex or polyurethane condoms, dental dams) during all sexual activity. Consult your doctor or pharmacist for more details.

Do not share this medication with others.

Laboratory and/or medical tests (e.g., liver tests, viral load, t-cell counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Keep all medical and laboratory appointments.

MISSED DOSE: If you miss a dose, take it as soon as you remember unless it is less than 2 hours before the time for your next dose. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Refrigerate the U.S. product between 36-46 degrees F (2-8 degrees C) away from light and moisture. Amprenavir may also be stored at room temperature below 77 degrees F (25 degrees C), but in this case it should be used within 30 days. Do not store in the bathroom.

Store the Canadian product between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.