1 INDICATIONS AND USAGE Fosamprenavir calcium tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.

The following points should be considered when initiating therapy with fosamprenavir calcium tablets plus ritonavir in protease inhibitor-experienced patients: The protease inhibitor-experienced patient trial was not large enough to reach a definitive conclusion that fosamprenavir calcium tablets plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)] .

Once-daily administration of fosamprenavir calcium tablets plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.2, 2.3), Clinical Studies (14.2, 14.3)] .

Dosing of fosamprenavir calcium tablets plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see Clinical Pharmacology (12.3)] .

Fosamprenavir calcium tablets are HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

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6 ADVERSE REACTIONS Severe or life-threatening skin reactions have been reported with the use of fosamprenavir calcium [see Warnings and Precautions (5.2)].

The most common moderate to severe adverse reactions in clinical trials of fosamprenavir calcium were diarrhea, rash, nausea, vomiting, and headache.

Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir calcium and in 5.9% of subjects receiving comparator treatments.

The most common adverse reactions leading to discontinuation of fosamprenavir calcium (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.

In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache.

(6.1) Vomiting and neutropenia were more frequent in pediatrics than in adults.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc.

at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adult Trials The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1-infected subjects to fosamprenavir calcium tablets, including 599 subjects exposed to fosamprenavir calcium for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks.

The population age ranged from 17 to 72 years.

Of these subjects, 26% were female, 51% white, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive.

Sixty-one percent received fosamprenavir calcium 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir calcium 1,400 mg twice daily; and 15% received fosamprenavir calcium 700 mg twice daily plus ritonavir 100 mg twice daily.

Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir calcium are shown in Tables 2 and 3.

Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks.

Table 2.

Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects Adverse Reaction APV30001 a APV30002 a Fosamprenavir Calcium 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir Calcium 1,400 mg and Ritonavir 200 mg Once Daily (n = 322) Nelfinavir 1,250 mg Twice Daily (n = 327) Gastrointestinal Diarrhea 5% 18% 10% 18% Nausea 7% 4% 7% 5% Vomiting 2% 4% 6% 4% Abdominal pain 1% 0% 2% 2% Skin Rash 8% 2% 3% 2% General disorders Fatigue 2% 1% 4% 2% Nervous system Headache 2% 4% 3% 3% a All subjects also received abacavir and lamivudine twice daily.

Table 3.

Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003) Adverse Reaction Fosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily a (n = 106) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily a (n = 103) Gastrointestinal Diarrhea 13% 11% Nausea 3% 9% Vomiting 3% 5% Abdominal pain < 1% 2% Skin Rash 3% 0% Nervous system Headache 4% 2% a All subjects also received 2 reverse transcriptase inhibitors.

Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with fosamprenavir calcium in the pivotal efficacy trials.

Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus.

Rash had a median onset of 11 days after initiation of fosamprenavir calcium and had a median duration of 13 days.

Skin rash led to discontinuation of fosamprenavir calcium in less than 1% of subjects.

In some subjects with mild or moderate rash, dosing with fosamprenavir calcium was often continued without interruption; if interrupted, reintroduction of fosamprenavir calcium generally did not result in rash recurrence.

The percentages of subjects with Grade 3 or 4 laboratory abnormalities in the clinical efficacy trials of fosamprenavir calcium are presented in Tables 4 and 5.

Table 4.

Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002 Laboratory Abnormality APV30001 a APV30002 a Fosamprenavir Calcium 1,400 mg Twice Daily (n = 166) Nelfinavir 1,250 mg Twice Daily (n = 83) Fosamprenavir Calcium 1,400 mg and Ritonavir 200 mg Once Daily (n = 322) Nelfinavir 1,250 mg Twice Daily (n = 327) ALT (> 5 x ULN) 6% 5% 8% 8% AST (> 5 x ULN) 6% 6% 6% 7% Serum lipase (> 2 x ULN) 8% 4% 6% 4% Triglycerides b (> 750 mg/dL) 0% 1% 6% 2% Neutrophil count, absolute (< 750 cells/mm 3 ) 3% 6% 3% 4% a All subjects also received abacavir and lamivudine twice daily.

b Fasting specimens.

ULN = Upper limit of normal.

The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received fosamprenavir calcium in the pivotal trials was less than 1%.

Table 5.

Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003 Laboratory Abnormality Fosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily a (n = 104) Lopinavir 400 mg and Ritonavir 100 mg Twice Daily a (n = 103) Triglycerides b (> 750 mg/dL) 11% c 6% c Serum lipase (> 2 x ULN) 5% 12% ALT (> 5 x ULN) 4% 4% AST (> 5 x ULN) 4% 2% Glucose (> 251 mg/dL) 2% c 2% c a All subjects also received 2 reverse transcriptase inhibitors.

b Fasting specimens.

c n = 100 for fosamprenavir calcium plus ritonavir, n = 98 for lopinavir plus ritonavir.

ULN = Upper limit of normal.

Pediatric Trials Fosamprenavir calcium with and without ritonavir was studied in 237 HIV-1-infected pediatric subjects aged at least 4 weeks to 18 years in 3 open-label trials; APV20002, APV20003, and APV29005 [see Clinical Studies (14.3)] .

Vomiting and neutropenia occurred more frequently in pediatric subjects compared with adults.

Other adverse events occurred with similar frequency in pediatric subjects compared with adults.

The frequency of vomiting among pediatric subjects receiving fosamprenavir calcium twice daily with ritonavir was 20% in subjects aged at least 4 weeks to younger than 2 years and 36% in subjects aged 2 to 18 years compared with 10% in adults.

The frequency of vomiting among pediatric subjects receiving fosamprenavir calcium twice daily without ritonavir was 60% in subjects aged 2 to 5 years compared with 16% in adults.

The median duration of drug-related vomiting episodes in APV29005 was 1 day (range: 1 to 3 days), in APV20003 was 16 days (range: 1 to 38 days), and in APV20002 was 9 days (range: 4 to 13 days).

Vomiting was treatment limiting in 4 pediatric subjects across all 3 trials.

The incidence of Grade 3 or 4 neutropenia (neutrophils less than 750 cells per mm 3 ) seen in pediatric subjects treated with fosamprenavir calcium with and without ritonavir was higher (15%) than the incidence seen in adult subjects (3%).

Grade 3/4 neutropenia occurred in 10% (5 of 51) of subjects aged at least 4 weeks to younger than 2 years and 16% (28 of 170) of subjects aged 2 to 18 years.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fosamprenavir calcium.

Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to fosamprenavir calcium.

Cardiac Disorders Myocardial infarction.

Metabolism and Nutrition Disorders Hypercholesterolemia.

Nervous System Disorders Oral paresthesia.

Skin and Subcutaneous Tissue Disorders Angioedema.

Urogenital Nephrolithiasis.