FDA label 87294858-2843-498d-ac1b-8b907006de8b

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [ see Warnings and Precautions (5.1) ]. • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [ see Warnings and Precautions (5.1) ]. WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE See full prescribing information for complete boxed warning. Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1) . • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (5.1) . • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1) .

5 WARNINGS AND PRECAUTIONS • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefits (5.1) . Use caution in patients with coexistent cardiovascular disease and stroke (5.1) . • Hypertension: Control hypertension prior to initiating and during treatment with OMONTYS (5.3) . 5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism 1. In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups. 2. Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke [ see Dosage and Administration (2.2) ]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. 3. In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke. 4. In controlled clinical trials, ESAs increased risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures. The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp ® Therapy (TREAT)). Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD NHS (N = 1265) CHOIR (N = 1432) TREAT (N = 4038) Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009 Population Patients with CKD on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa Patients with CKD not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL Hemoglobin Target; Higher vs. Lower (g/dL) 14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0 Median (Q1, Q3) Achieved Hemoglobin level (g/dL) 12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) 13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6) 12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) Primary Endpoint All-cause mortality or non-fatal MI All-cause mortality, MI, hospitalization for CHF, or stroke All-cause mortality, MI, myocardial ischemia, heart failure, and stroke Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 - 1.56) 1.34 (1.03 - 1.74) 1.05 (0.94 - 1.17) Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 - 1.54) 1.48 (0.97 - 2.27) 1.92 (1.38 - 2.68) Patients with Chronic Kidney Disease Not on Dialysis OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis. A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81). 5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated. The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy. 5.3 Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension. Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [ see Patient Counseling Information (17) ]. 5.4 Serious Allergic Reactions Serious allergic reactions, including anaphylactic reactions, hypotension, bronchospasm, angioedema and generalized pruritus, may occur in patients treated with OMONTYS. Immediately and permanently discontinue OMONTYS and administer appropriate therapy if a serious allergic reaction occurs. 5.5 Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy [ see Dosage and Administration (2.2) ]. Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies. 5.6 Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis. 5.7 Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [ see Dosage and Administration (2.1) ]. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable.

<table ID="_RefID0EOWAG"> <caption>Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD</caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">NHS</content> <content styleCode="bold">(N = 1265)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">CHOIR</content> <content styleCode="bold">(N = 1432)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">TREAT</content> <content styleCode="bold">(N = 4038)</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Time Period of Trial</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1993 to 1996</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2003 to 2006</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2004 to 2009</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Population</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Patients with CKD on hemodialysis with coexisting CHF or CAD, hematocrit 30 &#xB1; 3% on epoetin alfa</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Patients with CKD not on dialysis with hemoglobin &lt; 11 g/dL not previously administered epoetin alfa</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Patients with CKD not on dialysis with type II diabetes, hemoglobin &#x2264; 11 g/dL</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hemoglobin Target;</content> <content styleCode="bold">Higher vs. Lower</content> <content styleCode="bold">(g/dL)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14.0 vs. 10.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.5 vs. 11.3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.0 vs. &#x2265; 9.0</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Median (Q1, Q3)</content> <content styleCode="bold">Achieved Hemoglobin</content> <content styleCode="bold">level (g/dL)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Primary Endpoint</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>All-cause mortality or non-fatal MI</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>All-cause mortality, MI, hospitalization for CHF, or stroke</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>All-cause mortality, MI, myocardial ischemia, heart failure, and stroke</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hazard Ratio or</content> <content styleCode="bold">Relative Risk</content> <content styleCode="bold">(95% CI)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.28 (1.06 - 1.56)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.34 (1.03 - 1.74)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.05 (0.94 - 1.17)</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Adverse Outcome</content> <content styleCode="bold">for Higher Target Group</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>All-cause mortality</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>All-cause mortality</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Stroke</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Hazard Ratio or</content> <content styleCode="bold">Relative Risk</content> <content styleCode="bold">(95% CI)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.27 (1.04 - 1.54)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.48 (0.97 - 2.27)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.92 (1.38 - 2.68)</paragraph> </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: 1. Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [ see Warnings and Precautions ( 5.1 ) ]. 2. Hypertension [ see Warnings and Precautions ( 5.3 ) ]. 3. Serious allergic reactions [ see Warnings and Precautions ( 5.4 ) ] The most common adverse events (≥10%) are dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication (6) . To report SUSPECTED ADVERSE REACTIONS, contact Affymax, Inc. at 1-855-466-6689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07 mg/kg and 113 U/week/kg of epoetin. Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS Table 3 Adverse Reactions Occurring in ≥ 10% of Dialysis Patients treated with OMONTYS Adverse Reactions Dialysis Patients Treated with OMONTYS (N = 1066) Dialysis Patients Treated with Epoetin (N = 542) Gastrointestinal Disorders Diarrhea 18.4% 15.9% Nausea 17.4% 19.6% Vomiting 15.3% 13.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% 19.4% Cough 15.9% 16.6% Injury, Poisoning and Procedural Complications Arteriovenous Fistula Site Complication 16.1% 16.6% Procedural Hypotension 10.9% 12.5% Nervous System Disorders Headache 15.4% 15.9% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% 17.2% Pain in Extremity 10.9% 12.7% Back Pain 10.9% 11.3% Arthralgia 10.7% 9.8% Vascular Disorders Hypotension 14.2% 14.6% Hypertension 13.2% 11.4% General Disorders and Administration Site Conditions Pyrexia 12.2% 14.0% Metabolism and Nutrition Disorders Hyperkalemia 11.4% 11.8% Infections and Infestations Upper Respiratory Tract Infection 11.0% 12.4% Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. Allergic and infusion-related reactions have been reported in patients treated with OMONTYS. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious allergic reactions have been reported during postmarketing use of OMONTYS [ see Warnings and Precautions ( 5.4 ) ]. 6.3 Immunogenicity Of the 2357 patients tested during clinical trials, 29 (1.2%) had detectable levels of peginesatide-specific binding antibodies. There was a higher incidence of peginesatide-specific binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%). In approximately half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials.

<table ID="_RefID0E5DBG"> <caption>Table 3 Adverse Reactions Occurring in &#x2265; 10% of Dialysis Patients treated with OMONTYS</caption> <col width="27%"/> <col width="25%"/> <col width="24%"/> <col width="20%"/> <col width="20%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reactions</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Dialysis Patients Treated with OMONTYS</content> <content styleCode="bold"> (N = 1066)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Dialysis Patients Treated with Epoetin</content> <content styleCode="bold"> (N = 542) </content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule " valign="top"> <paragraph>18.4%</paragraph> </td> <td align="center" styleCode="Rrule Lrule " valign="top"> <paragraph>15.9%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>17.4%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>19.6%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15.3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.3%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>18.4%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>19.4%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Cough</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15.9%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16.6%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Injury, Poisoning and Procedural Complications</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Arteriovenous Fistula Site Complication</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>16.1%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>16.6%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Procedural Hypotension</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10.9%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.5%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15.4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15.9%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Muscle Spasms</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>15.3%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>17.2%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Pain in Extremity</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>10.9%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>12.7%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Back Pain</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>10.9%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>11.3%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Arthralgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10.7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9.8%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Vascular Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph> Hypotension</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>14.2%</paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph>14.6%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Hypertension</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11.4%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Pyrexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14.0%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Hyperkalemia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11.4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11.8%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Upper Respiratory Tract Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11.0%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.4%</paragraph> </td> </tr> </tbody> </table>