6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. Drug Interactions [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Pancreatitis [see Warnings and Precautions (5.3)] Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.4)] When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions. The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The safety of NORVIR alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 2 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies. The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving NORVIR in Combined Phase II/IV Studies (N = 1,755) Adverse Reactions n % Eye disorders Blurred vision 113 6.4 Gastrointestinal disorders Abdominal Pain (upper and lower)* 464 26.4 Diarrhea including severe with electrolyte imbalance* 1,192 67.9 Dyspepsia 201 11.5 Flatulence 142 8.1 Gastrointestinal hemorrhage* 41 2.3 Gastroesophageal reflux disease (GERD) 19 1.1 Nausea 1,007 57.4 Vomiting* 559 31.9 General disorders and administration site conditions Fatigue including asthenia* 811 46.2 Hepatobiliary disorders Blood bilirubin increased (including jaundice)* 25 1.4 Hepatitis (including increased AST, ALT, GGT)* 153 8.7 Immune system disorders Hypersensitivity including urticatria and face edema* 114 8.2 Metabolism and nutrition disorders Edema and peripheral edema* 110 6.3 Gout* 24 1.4 Hypercholesterolemia* 52 3.0 Hypertriglyceridemia* 158 9.0 Lipodystrophy acquired* 51 2.9 Musculoskeletal and connective tissue disorders Arthralgia and back pain* 326 18.6 Myopathy/creatine phosphokinase increased* 66 3.8 Myalgia 156 8.9 Nervous system disorders Dizziness* 274 15.6 Dysgeusia* 285 16.2 Paresthesia (including oral paresthesia)* 889 50.7 Peripheral neuropathy 178 10.1 Syncope* 58 3.3 Psychiatric disorders Confusion* 52 3.0 Disturbance in attention 44 2.5 Renal and urinary disorders Increased urination* 74 4.2 Respiratory, thoracic and mediastinal disorders Coughing* 380 21.7 Oropharyngeal Pain* 279 15.9 Skin and subcutaneous tissue disorders Acne* 67 3.8 Pruritus* 214 12.2 Rash (includes erythematous and maculopapular)* 475 27.1 Vascular disorders Flushing, feeling hot* 232 13.2 Hypertension* 58 3.3 Hypotension including orthostatic hypotension* 30 1.7 Peripheral coldness* 21 1.2 * Represents a medical concept including several similar MedDRA PTs Laboratory Abnormalities in Adults Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities. - Indicates no events reported. Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving NORVIR Study 245 Naive Patients Study 247 Advanced Patients Study 462 PI-Naive Patients Variable Limit NORVIR plus ZDV NORVIR ZDV NORVIR Placebo NORVIR plus Saquinavir Chemistry High Cholesterol > 240 mg/dL 30.7 44.8 9.3 36.5 8.0 65.2 CPK > 1000 IU/L 9.6 12.1 11.0 9.1 6.3 9.9 GGT > 300 IU/L 1.8 5.2 1.7 19.6 11.3 9.2 SGOT (AST) > 180 IU/L 5.3 9.5 2.5 6.4 7.0 7.8 SGPT (ALT) > 215 IU/L 5.3 7.8 3.4 8.5 4.4 9.2 Triglycerides > 800 mg/dL 9.6 17.2 3.4 33.6 9.4 23.4 Triglycerides > 1500 mg/dL 1.8 2.6 - 12.6 0.4 11.3 Triglycerides Fasting > 1500 mg/dL 1.5 1.3 - 9.9 0.3 - Uric Acid > 12 mg/dL - - - 3.8 0.2 1.4 Hematology Low Hematocrit < 30% 2.6 - 0.8 17.3 22.0 0.7 Hemoglobin < 8.0 g/dL 0.9 - - 3.8 3.9 - Neutrophils ≤ 0.5 x 109/L - - - 6.0 8.3 - RBC < 3.0 x 1012/L 1.8 - 5.9 18.6 24.4 - WBC < 2.5 x 109/L - 0.9 6.8 36.9 59.4 3.5 Adverse Reactions in Pediatric Patients NORVIR has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients. Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in NORVIR clinical trials. Laboratory Abnormalities in Pediatric Patients The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%). 6.2 Postmarketing Experience The following adverse events have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure. Body as a Whole Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration. Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Cardiovascular System First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see Warnings and Precautions (5.5)]. Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded. Endocrine System Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide. Nervous System There have been postmarketing reports of seizure. Also, see Cardiovascular System. Skin and subcutaneous tissue disorders Toxic epidermal necrolysis (TEN) has been reported.