FDA label 48bc7b9c-4246-4ed3-887d-1cec5845238e

5 WARNINGS AND PRECAUTIONS Mineralocorticoid excess: Use abiraterone acetate with caution in patients with a history of cardiovascular disease. The safety of abiraterone acetate in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. ( 5.1 ) Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.2 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue abiraterone acetate dosing as recommended. ( 5.3 ) 5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [ see Clinical Pharmacology (12.1) ] . In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with abiraterone acetate [see Adverse Reactions (6) ] . Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use abiraterone acetate with caution in patients with a history of cardiovascular disease. The safety of abiraterone acetate in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) ] . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with abiraterone acetate. 5.2 Adrenocortical Insufficiency Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions (5.1) ]. 5.3 Hepatotoxicity In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2) ] . In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5× ULN) were reported in 4% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking abiraterone acetate. No deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt abiraterone acetate treatment and closely monitor liver function. Re-treatment with abiraterone acetate at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5× ULN and total bilirubin less than or equal to 1.5× ULN [see Dosage and Administration (2.2) ] . Permanently discontinue abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2) ] . The safety of abiraterone acetate re-treatment of patients who develop AST or ALT greater than or equal to 20× ULN and/or bilirubin greater than or equal to 10× ULN is unknown.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions (5.1) ] . Adrenocortical Insufficiency [see Warnings and Precautions (5.2) ] . Hepatotoxicity [see Warnings and Precautions (5.3) ] . The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) 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. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 abiraterone acetate was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5× ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5× ULN. Table 1 shows adverse reactions on the abiraterone acetate arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with abiraterone acetate was 8 months. Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1 Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) System/Organ Class All Grades Adverse events graded according to CTCAE version 3.0. Grade 3–4 All Grades Grade 3–4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 29.5 4.2 23.4 4.1 Muscle discomfort Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 26.2 3.0 23.1 2.3 General disorders Edema Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema. 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures Includes all fractures with the exception of pathological fracture. 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7.2 1.1 4.6 1.0 Chest pain or chest discomfort Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate arm (1.3% vs. 1.1% respectively). 3.8 0.5 2.8 0 Cardiac failure Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. 2.3 1.9 1.0 0.3 Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the abiraterone acetate arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory Abnormality All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5× ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the abiraterone acetate arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with abiraterone acetate was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2 Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) System/Organ Class All Grades Adverse events graded according to CTCAE version 3.0. Grade 3–4 All Grades Grade 3–4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema Includes terms Edema peripheral, Pitting edema, and Generalized edema. 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the abiraterone acetate arm. Table 4: Laboratory Abnormalities in >15% of Patients in the Abiraterone Acetate Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Abnormality Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia Based on non-fasting blood draws 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 Cardiovascular Adverse Reactions In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking abiraterone acetate and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the abiraterone acetate arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the abiraterone acetate arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the abiraterone acetate arms. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. Hepatobiliary Disorders : fulminant hepatitis, including acute hepatic failure and death.

<table width="90%"> <caption>Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1</caption> <col width="40%" align="left" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="2">Abiraterone Acetate with Prednisone (N=791)</th> <th colspan="2">Placebo with Prednisone (N=394)</th> </tr> <tr> <th>System/Organ Class</th> <th>All Grades<footnote ID="foot11">Adverse events graded according to CTCAE version 3.0.</footnote> </th> <th>Grade 3&#x2013;4</th> <th>All Grades</th> <th>Grade 3&#x2013;4</th> </tr> <tr> <th> Adverse reaction</th> <th>%</th> <th>%</th> <th>%</th> <th>%</th> </tr> </thead> <tbody> <tr> <td colspan="5"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </td> </tr> <tr> <td> Joint swelling/discomfort<footnote ID="foot12">Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.</footnote> </td> <td>29.5</td> <td>4.2</td> <td>23.4</td> <td>4.1</td> </tr> <tr> <td> Muscle discomfort<footnote ID="foot13">Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.</footnote> </td> <td>26.2</td> <td>3.0</td> <td>23.1</td> <td>2.3</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">General disorders</content> </td> </tr> <tr> <td> Edema<footnote ID="foot14">Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema.</footnote> </td> <td>26.7</td> <td>1.9</td> <td>18.3</td> <td>0.8</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Vascular disorders</content> </td> </tr> <tr> <td> Hot flush</td> <td>19.0</td> <td>0.3</td> <td>16.8</td> <td>0.3</td> </tr> <tr> <td> Hypertension</td> <td>8.5</td> <td>1.3</td> <td>6.9</td> <td>0.3</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr> <td> Diarrhea</td> <td>17.6</td> <td>0.6</td> <td>13.5</td> <td>1.3</td> </tr> <tr> <td> Dyspepsia</td> <td>6.1</td> <td>0</td> <td>3.3</td> <td>0</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Infections and infestations</content> </td> </tr> <tr> <td> Urinary tract infection</td> <td>11.5</td> <td>2.1</td> <td>7.1</td> <td>0.5</td> </tr> <tr> <td> Upper respiratory tract infection</td> <td>5.4</td> <td>0</td> <td>2.5</td> <td>0</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </td> </tr> <tr> <td> Cough</td> <td>10.6</td> <td>0</td> <td>7.6</td> <td>0</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Renal and urinary disorders</content> </td> </tr> <tr> <td> Urinary frequency</td> <td>7.2</td> <td>0.3</td> <td>5.1</td> <td>0.3</td> </tr> <tr> <td> Nocturia</td> <td>6.2</td> <td>0</td> <td>4.1</td> <td>0</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Injury, poisoning and procedural complications</content> </td> </tr> <tr> <td> Fractures<footnote ID="foot15">Includes all fractures with the exception of pathological fracture.</footnote> </td> <td>5.9</td> <td>1.4</td> <td>2.3</td> <td>0</td> </tr> <tr> <td colspan="5"> <content styleCode="bold">Cardiac disorders</content> </td> </tr> <tr> <td> Arrhythmia<footnote ID="foot16">Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.</footnote> </td> <td>7.2</td> <td>1.1</td> <td>4.6</td> <td>1.0</td> </tr> <tr> <td> Chest pain or chest discomfort<footnote ID="foot17">Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate arm (1.3% vs. 1.1% respectively).</footnote> </td> <td>3.8</td> <td>0.5</td> <td>2.8</td> <td>0</td> </tr> <tr> <td> Cardiac failure<footnote ID="foot18">Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.</footnote> </td> <td>2.3</td> <td>1.9</td> <td>1.0</td> <td>0.3</td> </tr> </tbody> </table>

<table width="90%"> <caption>Table 2: Laboratory Abnormalities of Interest in Study 1</caption> <col width="40%" align="left" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <thead> <tr> <th/> <th styleCode="Botrule" colspan="2">Abiraterone (N=791)</th> <th styleCode="Botrule" colspan="2">Placebo (N=394)</th> </tr> <tr> <th>Laboratory Abnormality</th> <th>All Grades (%)</th> <th>Grade 3&#x2013;4 (%)</th> <th>All Grades (%)</th> <th>Grade 3&#x2013;4 (%)</th> </tr> </thead> <tbody> <tr> <td>Hypertriglyceridemia</td> <td>62.5</td> <td>0.4</td> <td>53.0</td> <td>0</td> </tr> <tr> <td>High AST</td> <td>30.6</td> <td>2.1</td> <td>36.3</td> <td>1.5</td> </tr> <tr> <td>Hypokalemia</td> <td>28.3</td> <td>5.3</td> <td>19.8</td> <td>1.0</td> </tr> <tr> <td>Hypophosphatemia</td> <td>23.8</td> <td>7.2</td> <td>15.7</td> <td>5.8</td> </tr> <tr> <td>High ALT</td> <td>11.1</td> <td>1.4</td> <td>10.4</td> <td>0.8</td> </tr> <tr> <td>High Total Bilirubin</td> <td>6.6</td> <td>0.1</td> <td>4.6</td> <td>0</td> </tr> </tbody> </table>

<table width="90%"> <caption>Table 3: Adverse Reactions in &#x2265;5% of Patients on the Abiraterone Acetate Arm in Study 2</caption> <col width="30%" align="left" valign="top"/> <col width="10%" align="left" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="3" align="center">Abiraterone Acetate with Prednisone (N=542)</th> <th colspan="2" align="center">Placebo with Prednisone (N=540)</th> </tr> <tr> <th colspan="2">System/Organ Class</th> <th>All Grades<footnote ID="foot31">Adverse events graded according to CTCAE version 3.0.</footnote> </th> <th>Grade 3&#x2013;4</th> <th>All Grades</th> <th>Grade 3&#x2013;4</th> </tr> <tr> <th colspan="2"> Adverse reaction</th> <th>%</th> <th>%</th> <th>%</th> <th>%</th> </tr> </thead> <tbody> <tr> <td colspan="6"> <content styleCode="bold">General disorders</content> </td> </tr> <tr> <td colspan="2"> Fatigue</td> <td>39.1</td> <td>2.2</td> <td>34.3</td> <td>1.7</td> </tr> <tr> <td colspan="2"> Edema<footnote ID="foot32">Includes terms Edema peripheral, Pitting edema, and Generalized edema.</footnote> </td> <td>25.1</td> <td>0.4</td> <td>20.7</td> <td>1.1</td> </tr> <tr> <td colspan="2"> Pyrexia</td> <td>8.7</td> <td>0.6</td> <td>5.9</td> <td>0.2</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </td> </tr> <tr> <td colspan="2"> Joint swelling/discomfort<footnote ID="foot33">Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.</footnote> </td> <td>30.3</td> <td>2.0</td> <td>25.2</td> <td>2.0</td> </tr> <tr> <td colspan="2"> Groin pain</td> <td>6.6</td> <td>0.4</td> <td>4.1</td> <td>0.7</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr> <td colspan="2"> Constipation</td> <td>23.1</td> <td>0.4</td> <td>19.1</td> <td>0.6</td> </tr> <tr> <td colspan="2"> Diarrhea</td> <td>21.6</td> <td>0.9</td> <td>17.8</td> <td>0.9</td> </tr> <tr> <td colspan="2"> Dyspepsia</td> <td>11.1</td> <td>0.0</td> <td>5.0</td> <td>0.2</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Vascular disorders</content> </td> </tr> <tr> <td colspan="2"> Hot flush</td> <td>22.3</td> <td>0.2</td> <td>18.1</td> <td>0.0</td> </tr> <tr> <td colspan="2"> Hypertension</td> <td>21.6</td> <td>3.9</td> <td>13.1</td> <td>3.0</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </td> </tr> <tr> <td colspan="2"> Cough</td> <td>17.3</td> <td>0.0</td> <td>13.5</td> <td>0.2</td> </tr> <tr> <td colspan="2"> Dyspnea</td> <td>11.8</td> <td>2.4</td> <td>9.6</td> <td>0.9</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Psychiatric disorders</content> </td> </tr> <tr> <td colspan="2"> Insomnia</td> <td>13.5</td> <td>0.2</td> <td>11.3</td> <td>0.0</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Injury, poisoning and procedural complications</content> </td> </tr> <tr> <td colspan="2"> Contusion</td> <td>13.3</td> <td>0.0</td> <td>9.1</td> <td>0.0</td> </tr> <tr> <td colspan="2"> Falls</td> <td>5.9</td> <td>0.0</td> <td>3.3</td> <td>0.0</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Infections and infestations </content> </td> </tr> <tr> <td colspan="2"> Upper respiratory tract infection</td> <td>12.7</td> <td>0.0</td> <td>8.0</td> <td>0.0</td> </tr> <tr> <td colspan="2"> Nasopharyngitis</td> <td>10.7</td> <td>0.0</td> <td>8.1</td> <td>0.0</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Renal and urinary disorders</content> </td> </tr> <tr> <td colspan="2"> Hematuria</td> <td>10.3</td> <td>1.3</td> <td>5.6</td> <td>0.6</td> </tr> <tr> <td colspan="6"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> </tr> <tr> <td colspan="2"> Rash</td> <td>8.1</td> <td>0.0</td> <td>3.7</td> <td>0.0</td> </tr> </tbody> </table>