Actoplus Met

WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS Congestive Heart Failure Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET ® , cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1) ] . After initiation of ACTOPLUS MET, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET [see Warnings and Precautions (5.1) ] . ACTOPLUS MET is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1) ] . Initiation of ACTOPLUS MET in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) , Warnings and Precautions (5.1) ] . Lactic Acidosis Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions (5.2) ] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.2) ] . Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.2) , Drug Interactions (7) , Use in Specific Populations (8.6 , 8.7) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue ACTOPLUS MET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2) ]. WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Congestive Heart Failure Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET, cause or exacerbate congestive heart failure in some patients. ( 5.1 ) After initiation of ACTOPLUS MET, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET. ( 5.1 ) ACTOPLUS MET is not recommended in patients with symptomatic heart failure. ( 5.1 ) Initiation of ACTOPLUS MET in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. ( 4 , 5.1 ) Lactic Acidosis Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/ pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. ( 5.2 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. ( 5.2 ) If lactic acidosis is suspected, discontinue ACTOPLUS MET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Congestive Heart Failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 ) Edema: Dose-related edema may occur. ( 5.3 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with ACTOPLUS MET. ( 5.4 ) Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt ACTOPLUS MET and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ACTOPLUS MET if liver injury is confirmed and no alternate etiology can be found. ( 5.5 ) Urinary Bladder Tumors: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. ( 5.6 ) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.7 ) Macular Edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.8 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Monitor hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.9 ) 5.1 Congestive Heart Failure Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET [see Boxed Warning , Contraindications (4) , Adverse Reactions (6.1) ] . 5.2 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of ACTOPLUS MET. In ACTOPLUS MET-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue ACTOPLUS MET and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ]. Before initiating ACTOPLUS MET, obtain an eGFR. ACTOPLUS MET is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of ACTOPLUS MET is not recommended in patients with eGFR between 30 to 45 mL/min [see Contraindications (4) ] . Obtain an eGFR at least annually in all patients taking ACTOPLUS MET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy . Drug Interactions The concomitant use of ACTOPLUS MET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop ACTOPLUS MET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart ACTOPLUS MET if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. ACTOPLUS MET should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue ACTOPLUS MET. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving ACTOPLUS MET. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of ACTOPLUS MET in patients with clinical or laboratory evidence of hepatic disease. Mitochondrial Diseases Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). ACTOPLUS MET is not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD. If a patient taking ACTOPLUS MET develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue ACTOPLUS MET. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease. 5.3 Edema In controlled clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related [see Adverse Reactions (6.1) ] . In postmarketing experience, reports of new onset or worsening of edema have been received. ACTOPLUS MET should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOPLUS MET should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOPLUS MET should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] . 5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ACTOPLUS MET [see Drug Interactions (7.6 , 7.7) ] . 5.5 Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see Adverse Reactions (6.1) ] . Patients with type 2 diabetes mellitus may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating ACTOPLUS MET therapy. In patients with abnormal liver tests, ACTOPLUS MET should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, ACTOPLUS MET should be interrupted and investigation done to establish the probable cause. ACTOPLUS MET should not be restarted in these patients without another explanation for the liver test abnormalities. 5.6 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two year carcinogenicity study [see Nonclinical Toxicology (13.1) ] . In addition, during the three year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo [Hazard Ratio (HR) = 1.00; (95% Confidence Interval (CI) : 0.59, 1.72)]. Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective10 year observational cohort study conducted in the United States (U.S) found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone [HR = 1.06; (95% CI: 0.89, 1.26)]. A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer [HR = 1.63; (95% CI: 1.22, 2.19)]. Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET should be considered in patients with a prior history of bladder cancer. 5.7 Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOPLUS MET and attention should be given to assessing and maintaining bone health according to current standards of care. 5.8 Macular Edema Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see Adverse Reactions (6.1) ] . 5.9 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on ACTOPLUS MET and manage any abnormalities [see Adverse Reactions (6.1) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] Lactic acidosis [see Boxed Warning , Warnings and Precautions (5.2) ] Edema [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4) ] Hepatic Effects [see Warnings and Precautions (5.5) ] Urinary Bladder Tumors [see Warnings and Precautions (5.6) ] Fractures [see Warnings and Precautions (5.7) ] Macular Edema [see Warnings and Precautions (5.8 ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.9 ] Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327 and the ACTOPLUS MET website at: www.actoplusmet.com 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 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. Pioglitazone Over 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 patients have been treated with pioglitazone for at least two years. In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16 to 26 Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. Table 2: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16 to 24 Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3: 16 to 24 Week Clinical Trials of Pioglitazone Add-on to Metformin Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” 16 Week Placebo-Controlled Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Edema 2.5 6.0 Headache 1.9 6.0 24 Week Non-Controlled Double-Blind Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Common Adverse Events: 24 Week ACTOPLUS MET Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24 week double-blind clinical trial of ACTOPLUS MET dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600). Table 4: Adverse Events (≥5% for ACTOPLUS MET) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24 Week Double-Blind Clinical Trial of ACTOPLUS MET Administered Twice Daily % of Patients ACTOPLUS MET 15/850 mg Twice Daily N=201 Pioglitazone 15 mg Twice Daily N=190 Metformin 850 mg Twice Daily N=209 Diarrhea 9.0 2.6 15.3 Headache 5.5 2.6 4.8 In this 24 week trial, abdominal pain was reported in 2.0% of patients in the ACTOPLUS MET group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group. Common Adverse Events: PROactive Trial A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo Mean duration of patient follow-up was 34.5 months. % of Patients Placebo N=2,633 Pioglitazone N=2,605 Hypoglycemia 18.8 27.3 Edema 15.3 26.7 Cardiac Failure 6.1 8.1 Pain in Extremity 5.7 6.4 Back Pain 5.1 5.5 Chest Pain 5.0 5.1 Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24 week add-on to metformin trials. None of the events were fatal. Table 6: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 7: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Sulfonylurea N=187 Pioglitazone 15 mg + Sulfonylurea N=184 Pioglitazone 30 mg + Sulfonylurea N=189 Pioglitazone 30 mg + Sulfonylurea N=351 Pioglitazone 45 mg + Sulfonylurea N=351 At least one congestive heart failure event 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%) Hospitalized 2 (1.1%) 0 0 0 2 (0.6%) Patients Treated with Pioglitazone or Placebo Added on to Insulin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Insulin N=187 Pioglitazone 15 mg + Insulin N=191 Pioglitazone 30 mg + Insulin N=188 Pioglitazone 30 mg + Insulin N=345 Pioglitazone 45 mg + Insulin N=345 At least one congestive heart failure event 0 2 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 8: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide Number (%) of Subjects Pioglitazone N=262 Glyburide N=256 Death due to cardiovascular causes (adjudicated) 5 (1.9%) 6 (2.3%) Overnight hospitalization for worsening CHF (adjudicated) 26 (9.9%) 12 (4.7%) Emergency room visit for CHF (adjudicated) 4 (1.5%) 3 (1.2%) Patients experiencing CHF progression during study 35 (13.4%) 21 (8.2%) Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 9. Table 9: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial Number (%) of Patients Placebo N=2,633 Pioglitazone N=2,605 At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1.0%) Hospitalized, nonfatal 86 (3.3%) 124 (4.7%) Cardiovascular Safety In the PROactive trial, 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins, and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (HR = 0.90; 95% CI: 0.80, 1.02; p=0.10). Although there was no statistically significant difference between pioglitazone and placebo for the three year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 10. Table 10: PROactive Trial: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint CABG = coronary artery bypass grafting; PCI = percutaneous intervention. Cardiovascular Events Placebo N=2,633 Pioglitazone N=2,605 First Events n (%) Total events n First Events n (%) Total events n Any event 572 (21.7) 900 514 (19.7) 803 All-cause mortality 122 (4.6) 186 110 (4.2) 177 Nonfatal myocardial infarction (MI) 118 (4.5) 157 105 (4.0) 131 Stroke 96 (3.6) 119 76 (2.9) 92 Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65 Cardiac intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195 Major leg amputation 15 (0.6) 28 9 (0.3) 28 Leg revascularization 57 (2.2) 92 71 (2.7) 115 Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Tables 11, 12, and 13 summarize the changes in body weight with pioglitazone and placebo in the 16 to 26 week randomized, double-blind monotherapy and 16 to 24 week combination add-on therapy trials, the PROactive trial, and the 24 week ACTOPLUS MET trial. Table 11: Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials Control Group (Placebo) Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Monotherapy (16 to 26 weeks) -1.4 (-2.7, 0.0) N=256 0.9 (-0.5, 3.4) N=79 1.0 (-0.9, 3.4) N=188 2.6 (0.2, 5.4) N=79 Combination Therapy (16 to 24 weeks) Sulfonylurea -0.5 (-1.8, 0.7) N=187 2.0 (0.2, 3.2) N=183 3.1 (1.1, 5.4) N=528 4.1 (1.8, 7.3) N=333 Metformin -1.4 (-3.2, 0.3) N=160 N/A 0.9 (-1.3, 3.2) N=567 1.8 (-0.9, 5.0) N=407 Insulin 0.2 (-1.4, 1.4) N=182 2.3 (0.5, 4.3) N=190 3.3 (0.9, 6.3) N=522 4.1 (1.4, 6.8) N=338 Table 12: Median Change in Body Weight in Patients Treated with Pioglitazone vs Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial Note: Median exposure for both pioglitazone and placebo was 2.7 years. Placebo Pioglitazone Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Change from baseline to final visit (kg) -0.5 (-3.3, 2.0) N=2,581 +3.6 (0.0, 7.5) N=2,560 Table 13: Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with ACTOPLUS MET in Patients with Inadequate Glycemic Control on Diet and Exercise Note: Trial duration of 24 weeks. ACTOPLUS MET 15/850 mg Twice Daily Pioglitazone 15 mg Twice Daily Metformin 850 mg Twice Daily Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Change from baseline to final visit (kg) 1.00 (-1.0, 3.0) N=198 1.35 (-0.7, 4.1) N=178 -1.00 (-2.6, 0.4) N=203 Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is co-existing congestive heart failure. In the 24 week ACTOPLUS MET trial, edema was reported in 3.0% of patients in the ACTOPLUS MET group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the metformin monotherapy group. A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 14. Table 14: Adverse Events of Edema in Patients Treated with Pioglitazone Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” Number (%) of Patients Placebo Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Monotherapy (16 to 26 weeks) 3 (1.2%) N=259 2 (2.5%) N= 81 13 (4.7%) N= 275 11 (6.5%) N=169 Combined Therapy (16 to 24 weeks) Sulfonylurea 4 (2.1%) N=187 3 (1.6%) N=184 61 (11.3%) N=540 81 (23.1%) N=351 Metformin 4 (2.5%) N=160 N/A 34 (5.9%) N=579 58 (13.9%) N=416 Insulin 13 (7.0%) N=187 24 (12.6%) N=191 109 (20.5%) N=533 90 (26.1%) N=345 Table 15: Adverse Events of Edema in Patients in the PROactive Trial Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” Number (%) of Patients Placebo N=2,633 Pioglitazone N=2,605 419 (15.9%) 712 (27.3%) Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1,051 (0.3%) patients treated with pioglitazone and 9/1,046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury. Hypoglycemia In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. In the 16 week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16 week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo. The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24 week add-on to sulfonylurea trial (15.7% vs 13.4%) and in the 24-week add-on to insulin trial (47.8% vs 43.5%). Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24 week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12). Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two year carcinogenicity study [see Nonclinical Toxicology (13.1) ] . During the three-year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR = 1.00; [95% CI: 0.59 1.72]) [see Warnings and Precautions (5.6) ] . Metformin HCl In a double-blind clinical study of metformin in patients with type 2 diabetes mellitus, a total of 141 patients received metformin therapy (up to 2,550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 16. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Table 16: Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy Reactions that were more common in metformin than placebo-treated patients. Adverse Reaction Metformin Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 Laboratory Abnormalities Pioglitazone Hematologic Effects Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects. Creatine Phosphokinase During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2,150 to 11,400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown. Metformin Vitamin B 12 Concentrations In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pioglitazone and/or metformin. 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. Pioglitazone Cardiac Disorders: Rapid increases in weight, edema, congestive heart failure with and without previously known heart disease or concomitant insulin administration Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders: Fatal and nonfatal hepatic failure Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

<table width="75%"><caption>Table 2: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence &gt;5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo</caption><colgroup><col width="50%"/><col width="25%"/><col width="25%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule" colspan="3" align="center"><paragraph><content styleCode="bold">% of Patients</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Placebo N=259</content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Pioglitazone N=606</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Upper Respiratory Tract Infection</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>8.5</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>13.2</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>6.9</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>9.1</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>4.6</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>6.3</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Myalgia</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>2.7</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.4</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Pharyngitis</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>0.8</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.1</paragraph></td></tr></tbody></table>

<table width="75%"><caption>Table 3: 16 to 24 Week Clinical Trials of Pioglitazone Add-on to Metformin</caption><colgroup><col width="50%"/><col width="25%"/><col width="25%"/></colgroup><tfoot><tr styleCode="First Last"><td colspan="3" align="left">Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of &#x201C;edema.&#x201D;</td></tr></tfoot><tbody><tr><td styleCode="Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" colspan="2" align="center"><paragraph><content styleCode="bold">16 Week Placebo-Controlled Trial Adverse Events Reported in &gt;5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" colspan="2" align="center"><paragraph><content styleCode="bold">% of Patients</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph><content styleCode="bold">Placebo + Metformin N=160</content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph><content styleCode="bold">Pioglitazone 30 mg + Metformin N=168</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Edema</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>2.5</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>6.0</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>1.9</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>6.0</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" rowspan="3"/><td styleCode="Botrule Lrule Rrule" colspan="2" align="center" valign="middle"><paragraph><content styleCode="bold">24 Week Non-Controlled Double-Blind Trial Adverse Events Reported in &gt;5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="center"><paragraph><content styleCode="bold"> % of Patients </content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Pioglitazone 30 mg + Metformin N=411</content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph><content styleCode="bold">Pioglitazone 45 mg + Metformin N=416</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Upper Respiratory Tract Infection</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>12.4</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>13.5</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Edema</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.8</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>13.9</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.4</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.8</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Weight Increased</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>2.9</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>6.7</paragraph></td></tr></tbody></table>

<table width="75%"><caption>Table 4: Adverse Events (&#x2265;5% for ACTOPLUS MET) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24 Week Double-Blind Clinical Trial of ACTOPLUS MET Administered Twice Daily</caption><colgroup><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="center"><paragraph><content styleCode="bold">% of Patients</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">ACTOPLUS MET</content> <content styleCode="bold">15/850 mg</content> <content styleCode="bold">Twice Daily N=201</content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Pioglitazone</content> <content styleCode="bold">15 mg</content> <content styleCode="bold">Twice Daily N=190</content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Metformin</content> <content styleCode="bold">850 mg</content> <content styleCode="bold">Twice Daily N=209</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>9.0</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>2.6</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>15.3</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>5.5</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>2.6</paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="middle"><paragraph>4.8</paragraph></td></tr></tbody></table>