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

  • Hepatic Impairment and Toxicity [see WARNINGS AND PRECAUTIONS]
  • Intracranial Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Rash [see WARNINGS AND PRECAUTIONS]

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.

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].

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)
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)
aExcludes laboratory abnormalities that were Adverse Events
bComparator 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
cOptimized Background Regimen

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)

  Limit Randomized, Controlled Clinical Trials 1182.12 and 1182.48
Percentage of Patients (rate per 100 patient-exposure years)
APTIVUS/ritonavir (500/200 mgBID) + OBR
(n=738)
Comparator PI/ritonavir + OBR*
(n=724)
Hematology
  WBC count decrease
    Grade 3  < 2.0 x 103/μL 5.4% (5.6) 4.8% (7.7)
    Grade 4 < 1.0 x 103/μL 0.3% (0.3) 1.1% (1.7)
Chemistry
  Amylase
    Grade 3 > 2.5 x ULN 5.7% (5.9) 6.4% (10.4)
    Grade 4 > 5 x ULN 0.3% (0.3) 0.7% (1.1)
  ALT
    Grade 2 > 2.5-5 x ULN 14.9% (16.5) 7.5% (12.4)
    Grade 3 > 5-10 x ULN 5.6% (5.7) 1.7% (2.6)
    Grade 4 > 10 x ULN 4.1% (4.1) 0.4% (0.7)
  AST
    Grade 2 > 2.5-5 x ULN 9.9% (10.5) 8.0% (13.3)
    Grade 3 > 5-10 x ULN 4.5% (4.6) 1.4% (2.2)
    Grade 4 > 10 x ULN 1.6% (1.6) 0.4% (0.6)
  ALT and/or AST
    Grade 2-4 > 2.5 x 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)
*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

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.

Clinical Trials In Pediatric Patients

APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs.

The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults.

The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%).

Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of > 1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction.