Aptivus (Page 3 of 10)

5.11 Elevated Lipids

Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6) ]. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate; taking into account any potential drug-drug interactions [see Drug Interactions (7.2) ].

5.12 Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.

5.13 Resistance/Cross Resistance

Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in APTIVUS/ritonavir treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.

6 ADVERSE REACTIONS

The following adverse reactions are described, in greater detail, in other sections:

Due to the need for co-administration of APTIVUS with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

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

6.1 Clinical Trials in Adults

APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks [see Clinical Studies (14) ].

In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated patients and 10.8% for the comparator arm patients.

Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 — 4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below.

Table 2 Adverse Reactions Reported in Randomized, Controlled Clinical Trials (1182.12 and 1182.48) Based on Treatment-Emergent Clinical Adverse Reactions of Moderate to Severe Intensity (Grades 2 — 4) in at least 2% of Treatment-Experienced Subjects in either Treatment Groupa (48-week Analyses)
Percentage of patients (rate per 100 patient-exposure years)
APTIVUS/ritonavir (500/200 mg BID) + OBRc (n=749; 757.4 patient-exposure years) Comparator PI/ritonavirb + OBR (n=737; 503.9 patient-exposure years)
a Excludes laboratory abnormalities that were Adverse Events
b Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID
c Optimized Background Regimen
Blood and Lymphatic Disorders
Anemia 3.3% (3.4) 2.3% (3.4)
Neutropenia 2.0% (2.0) 1.0% (1.4)
Gastrointestinal Disorders
Diarrhea 15.0% (16.5) 13.4% (21.6)
Nausea 8.5% (9.0) 6.4% (9.7)
Vomiting 5.9% (6.0) 4.1% (6.1)
Abdominal pain 4.4% (4.5) 3.4% (5.1)
Abdominal pain upper 1.5% (1.5) 2.3% (3.4)
General Disorders
Pyrexia 7.5% (7.7) 5.4% (8.2)
Fatigue 5.7% (5.9) 5.6% (8.4)
Investigations
Weight decreased 3.1% (3.1) 2.2% (3.2)
ALT increased 2.0% (2.0) 0.5% (0.8)
GGT increased 2.0% (2.0) 0.4% (0.6)
Metabolism and Nutrition Disorders
Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0)
Hyperlipidemia 2.5% (2.6) 0.8% (1.2)
Dehydration 2.1% (2.1) 1.1% (1.6)
Musculoskeletal and Connective Tissue Disorders
Myalgia 2.3% (2.3) 1.8% (2.6)
Nervous System Disorders
Headache 5.2% (5.3) 4.2% (6.3)
Peripheral neuropathy 1.5% (1.5) 2.0% (3.0)
Psychiatric Disorders
Insomnia 1.7% (1.7) 3.7% (5.5)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea 2.1% (2.1) 1.0% (1.4)
Skin and Subcutaneous Tissue Disorders
Rash 3.1% (3.1) 3.8% (5.7)

Less Common Adverse Reactions

Other adverse reactions reported in <2% of adult patients (n=1474) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system:

Blood and Lymphatic System Disorders: thrombocytopenia

Gastrointestinal Disorders: abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis

General Disorders: influenza-like illness, malaise

Hepatobiliary Disorders: hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis

Immune System Disorders: hypersensitivity

Investigations: hepatic enzymes increased, liver function test abnormal, lipase increased

Metabolism and Nutrition Disorders: anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity

Musculoskeletal and Connective Tissue Disorders: muscle cramp

Nervous System Disorders: dizziness, intracranial hemorrhage, somnolence

Psychiatric Disorders: sleep disorder

Renal and Urinary Disorders: renal insufficiency

Skin and Subcutaneous System Disorders: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus

Laboratory Abnormalities

Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below.

Table 3 Treatment-Emergent Laboratory Abnormalities Reported in ≥2% of Adult Patients (48-week Analyses)
Randomized, Controlled Clinical Trials 1182.12 and 1182.48
Percentage of Patients (rate per 100 patient-exposure years)
Limit APTIVUS/ritonavir (500/200 mg BID) + OBR(n=738) Comparator PI/ritonavir + OBR*(n=724)
*Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID
Hematology
WBC count decrease
Grade 3 <2.0 × 103 /µL 5.4% (5.6) 4.8% (7.7)
Grade 4 <1.0 × 103 /µL 0.3% (0.3) 1.1% (1.7)
Chemistry
Amylase
Grade 3 >2.5 × ULN 5.7% (5.9) 6.4% (10.4)
Grade 4 >5 × ULN 0.3% (0.3) 0.7% (1.1)
ALT
Grade 2 >2.5-5 × ULN 14.9% (16.5) 7.5% (12.4)
Grade 3 >5-10 × ULN 5.6% (5.7) 1.7% (2.6)
Grade 4 >10 × ULN 4.1% (4.1) 0.4% (0.7)
AST
Grade 2 >2.5-5 × ULN 9.9% (10.5) 8.0% (13.3)
Grade 3 >5-10 × ULN 4.5% (4.6) 1.4% (2.2)
Grade 4 >10 × ULN 1.6% (1.6) 0.4% (0.6)
ALT and/or AST
Grade 2-4 >2.5 × ULN 26.0% (31.5) 13.7% (23.8)
Cholesterol
Grade 2 >300 – 400 mg/dL 15.6% (17.7) 6.4% (10.5)
Grade 3 >400 – 500 mg/dL 3.3% (3.3) 0.3% (0.4)
Grade 4 >500 mg/dL 0.9% (1.0) 0.1% (0.2)
Triglycerides
Grade 2 400 – 750 mg/dL 35.9% (49.9) 26.8% (51.0)
Grade 3 >750 – 1200 mg/dL 16.9% (19.4) 8.7% (14.6)
Grade 4 >1200 mg/dL 8.0% (8.4) 4.3% (7.0)

In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 32.1% at week 96 with APTIVUS/ritonavir. The risk of developing transaminase elevations is greater during the first year of therapy.

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