Agenerase

%medicine_name% (amprenavir 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).

%medicine_name% (amprenavir 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

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 %medicine_name% (amprenavir capsules) exceeds the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU) (see DESCRIPTION).

Adults: The recommended oral dose of %medicine_name% (amprenavir 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 %medicine_name% (amprenavir 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 %medicine_name% (amprenavir 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.

%medicine_name% (amprenavir capsules) and AGENERASE Oral Solution are not interchangeable on a milligram-per-milligram basis (see CLINICAL PHARMACOLOGY).

Patients with Hepatic Impairment: %medicine_name% (amprenavir 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 %medicine_name% (amprenavir capsules) of 450 mg twice daily, and patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of %medicine_name% of 300 mg twice daily (see CLINICAL PHARMACOLOGY: Hepatic Insufficiency).

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.

WARNINGS

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.

PRECAUTIONS

General: %medicine_name% (amprenavir 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 %medicine_name% (amprenavir capsules) is available for patient information. Patients treated with %medicine_name% (amprenavir 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 %medicine_name% (amprenavir 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.

%medicine_name% (amprenavir 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.

SIDE EFFECTS

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

DRUG INTERACTIONS

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

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

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

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

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.