Because of the potential risk of toxicity from the large amount of the excipient, propylene glycol, AGENERASE Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CONTRAINDICATIONS AND WARNINGS). AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options.
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warnings
WARNINGS ALERT: Find out about medicines that should not be taken with AGENERASE. Because of the potential risk of toxicity from the large amount of the excipient , propylene glycol, AGENERASE Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and PRECAUTIONS). Because of the possible toxicity associated with the large amount of propylene glycol and the lack of information on chronic exposure to large amounts of propylene glycol, AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options. Certain ethnic populations (Asians, Eskimos, Native Americans) and women may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol; no data are available on propylene glycol metabolism in these groups (see CLINICAL PHARMACOLOGY: Special Populations: Gender and Race). If patients require treatment with AGENERASE Oral Solution, they should bemonitored closely for propylene glycol-associated adverse events, including seizures, stupor, tachycardia, hyperosmolality , lactic acidosis, renal toxicity, and hemolysis . Patients should be switched from AGENERASE Oral Solution to AGENERASE Capsules as soon as they are able to take the capsule formulation. Concurrent use of AGENERASE Oral Solution and NORVIR ( ritonavir ) Oral Solution is not recommended because the large amount of propylene glycol in AGENERASE Oral Solution and ethanol in NORVIR Oral Solution may compete for the same metabolic pathway for elimination. Use of alcoholic beverages is not recommended in patients treated with AGENERASE Oral Solution. Serious and/or life-threatening drug interactions could occur between amprenavir and amiodarone , lidocaine (systemic), tricyclic antidepressants, and quinidine . Concentration monitoring of these agents is recommended if these agents are used concomitantly with AGENERASE (see CONTRAINDICATIONS). Rifampin should not be used in combination with amprenavir because it reduces plasma concentrations and AUC of amprenavir by about 90%. A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of AGENERASE with ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and AGENERASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS: Drug Interactions). Concomitant use of AGENERASE and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of protease inhibitors, including AGENERASE, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in suboptimal levels of amprenavir and lead to loss of virologic response and possible resistance to AGENERASE or to the class of protease inhibitors. Concomitant use of AGENERASE with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including AGENERASE, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including amprenavir, are used in combination with these drugs. Particular caution should be used when prescribing sildenafil in patients receiving amprenavir. Coadministration of AGENERASE with sildenafil is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS: Drug Interactions and Information for Patients, and the complete prescribing information for sildenafil). Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in patients treated with AGENERASE (see ADVERSE REACTIONS). Acute hemolytic anemia has been reported in a patient treated with AGENERASE. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.
ADVERSE REACTIONS 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 Adverse Event PROAB3001 Therapy-Naive Patients PROAB3006 NRTI-Experienced Patients AGENERASE * / Lamivudine/ Zidovudine (n = 113) Lamivudine/ Zidovudine (n = 109) AGENERASE * / NRTI (n = 245) Indinavir/ NRTI (n = 241) Digestive Nausea 74% 50% 43% 35% Vomiting 34% 17% 24% 20% Diarrhea or loose stools 39% 35% 60% 41% Taste disorders 10% 6% 2% 8% Skin Rash 27% 6% 20% 15% Nervous Paresthesia, oral/perioral 26% 6% 31% 2% Paresthesia, peripheral 10% 4% 14% 10% Psychiatric Depressive or mood disorders 16% 4% 9% 13% * AGENERASE Capsules. 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 Capsules 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 Capsules in Combination With Ritonavir Capsules Adverse Event AGENERASE 1,200 mg plus Ritonavir 200 mg q.d. * (n = 101) AGENERASE 600 mg plus Ritonavir 100 mg b.i.d. † (n = 239) Nausea 31% 23% Diarrhea/loose stools 30% 28% Headache 16% 12% Abdominal symptoms 14% 14% Vomiting 11% 9% Rash 10% 9% Paresthesias 9% 11% Fatigue 7% 14% Depressive & mood disorders 4% 9% * Data from 2 open-label studies in treatment-naive patients also receiving abacavir/lamivudine. † Data from 3 open-label studies in treatment-naive and treatment-experienced patients receiving combination antiretroviral therapy. Table 11. Grade 3/4 Laboratory Abnormalities Reported in ≥2% of Adult Patients in Open-Label Clinical Trials of AGENERASE Capsules in Combination With Ritonavir Laboratory Abnormality (non-fasting specimens) AGENERASE 1,200 mg plus Ritonavir 200 mg q.d. * (n = 101) AGENERASE 600 mg plus Ritonavir 100 mg b.i.d. † (n = 239) Hypertriglyceridemia (>750 mg/dL) 8% 13% Hyperglycemia (>251 mg/dL) 2% 3% AST (>5 x ULN) 3% 5% ALT (>5 x ULN) 4% 4% Amylase (>2 x ULN) 4% 3% * Data from 2 open-label studies in treatment-naive patients also receiving abacavir/lamivudine. † Data from 3 open-label studies in treatment-naive and treatment-experienced patients receiving combination antiretroviral therapy.