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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 PROAB 3001 Therapy-Naive Patients PROAB 3006 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%

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

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 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.