Ritonavir Film Coated Side Effects

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 ( 5.3 )] Pancreatitis [see Warnings and Precautions ( 5.4 )] Allergic Reactions/Hypersensitivity [see Warnings and Precautions ( 5.5 )] When co-administering ritonavir 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 ritonavir 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 Cipla Ltd., India at 1-866-604-3268 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 reactions 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 practice.

Adverse Reactions in Adults The safety of ritonavir 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 ritonavir in combined Phase II/IV studies.

The most frequently reported adverse drug reactions among patients receiving ritonavir 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.

Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving Ritonavir 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 urticaria 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.

Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving Ritonavir Study 245 Naive Patients Study 247 Advanced Patients Study 462 PI-Naive Patients Variable Limit Ritonavir plus ZDV Ritonavir ZDV Ritonavir Placebo Ritonavir plus Saquinavir Chemistry High Cholesterol > 240 mg/dL 30.7 44.8 9.3 36.5 8.0 65.2 CPK > 1,000 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 > 1,500 mg/dL 1.8 2.6 - 12.6 0.4 11.3 Triglycerides Fasting > 1,500 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 10 9 /L - - - 6.0 8.3 - RBC < 3.0 x 10 12 /L 1.8 - 5.9 18.6 24.4 - WBC < 2.5 x 10 9 /L - 0.9 6.8 36.9 59.4 3.5 - Indicates no events reported.

Adverse Reactions in Pediatric Patients Ritonavir has been studied in 265 pediatric patients greater than 1 month to 21 years of age.