nintedanib

5 WARNINGS AND PRECAUTIONS Hepatic impairment: Nintedanib is not recommended for use in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage is 100 mg twice daily approximately 12 hours apart taken with food. Consider treatment interruption, or discontinuation for management of adverse reactions in these patients. ( 2.3 , 2.4 , 5.1 , 8.6 , 12.3 ) Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with nintedanib, including cases of drug-induced liver injury. In the postmarketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. Monitor ALT, AST, and bilirubin prior to initiation of treatment, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Temporary dosage reductions or discontinuations may be required. ( 2.1 , 2.4 , 5.2 ) Gastrointestinal disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue nintedanib if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. ( 5.3 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use highly effective contraception. Advise women taking oral hormonal contraceptives experiencing vomiting, diarrhea, or other conditions where the drug absorption may be reduced to use alternative highly effective contraception. ( 5.4 , 8.1 , 8.3 ) Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. ( 5.5 ) Bleeding events have been reported. Use nintedanib in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. ( 5.6 ) Gastrointestinal perforation has been reported. Use nintedanib with caution when treating patients with recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs. Discontinue nintedanib in patients who develop gastrointestinal perforation. Only use nintedanib in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. ( 5.7 ) Nephrotic range proteinuria has been reported. Consider treatment interruption in patients who develop new or worsening proteinuria. ( 5.8 ) 5.1 Hepatic Impairment Treatment with nintedanib is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of nintedanib [see Dosage and Administration ( 2.3 )] . 5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury Cases of drug-induced liver injury (DILI) have been observed with nintedanib treatment. In the clinical trials and postmarketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. In IPF studies (Study 1, Study 2, and Study 3), the majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), the majority (95%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (94%) of patients with bilirubin elevations had elevations less than 2 times ULN [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Patients with a low body weight (less than 65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes [see Clinical Pharmacology ( 12.3 )] . Conduct liver function tests (ALT, AST, and bilirubin) prior to initiation of treatment with nintedanib, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. 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. Dosage modifications or interruption may be necessary for liver enzyme elevations [see Dosage and Administration ( 2.1 , 2.4 )] . 5.3 Gastrointestinal Disorders Diarrhea In clinical trials, diarrhea was the most frequent gastrointestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In IPF studies (Study 1, Study 2, and Study 3), diarrhea was reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )]. Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib compared to 0 placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 5% of the patients compared to less than 1% of placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), diarrhea was reported in 67% versus 24% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )]. Diarrhea led to permanent dose reduction in 16% of patients treated with nintedanib compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 6% of the patients compared to less than 1% of placebo-treated patients. Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider dose reduction or treatment interruption if diarrhea continues [see Dosage and Administration ( 2.4 )]. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with nintedanib. Nausea and Vomiting In IPF studies (Study 1, Study 2, and Study 3), nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with nintedanib and placebo, respectively. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea was reported in 29% versus 9% and vomiting was reported in 18% versus 5% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )] . In most patients, these events were of mild to moderate intensity. In IPF studies (Study 1, Study 2, and Study 3), nausea led to discontinuation of nintedanib in 2% of patients and vomiting led to discontinuation of nintedanib in 1% of the patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of nintedanib in less than 1% of patients and vomiting led to discontinuation of nintedanib in 1% of the patients. For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required [see Dosage and Administration ( 2.4 )] . Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with nintedanib. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, nintedanib can cause fetal harm when administered to a pregnant woman. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits when administered during organogenesis at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose (MRHD) in adults. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with nintedanib and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of nintedanib. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced. Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception. Verify pregnancy status prior to treatment with nintedanib and during treatment as appropriate [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 , 12.3 )]. 5.5 Arterial Thromboembolic Events Arterial thromboembolic events have been reported in patients taking nintedanib. In IPF studies (Study 1, Study 2, and Study 3), arterial thromboembolic events were reported in 2.5% of patients treated with nintedanib and less than 1% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of nintedanib-treated patients compared to less than 1% of placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), arterial thromboembolic events were reported in less than 1% of patients in both treatment arms. Myocardial infarction was observed in less than 1% of patients in both treatment arms. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia. 5.6 Risk of Bleeding Based on the mechanism of action (VEGFR inhibition), nintedanib may increase the risk of bleeding. In IPF studies (Study 1, Study 2, and Study 3), bleeding events were reported in 10% of patients treated with nintedanib and in 7% of patients treated with placebo. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), bleeding events were reported in 11% of patients treated with nintedanib and in 13% of patients treated with placebo. In clinical trials, epistaxis was the most frequent bleeding event reported. In the postmarketing period non-serious and serious bleeding events, some of which were fatal, have been observed. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk. 5.7 Gastrointestinal Perforation Based on the mechanism of action, nintedanib may increase the risk of gastrointestinal perforation. In IPF studies (Study 1, Study 2, and Study 3), gastrointestinal perforation was reported in less than 1% of patients treated with nintedanib, compared to 0 cases in the placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), gastrointestinal perforation was not reported in any patients in any treatment arm. In the postmarketing period, cases of gastrointestinal perforations have been reported, some of which were fatal. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs. Discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Only use nintedanib in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. 5.8 Nephrotic Range Proteinuria Cases of proteinuria within the nephrotic range have been reported in the postmarketing period. Histological findings, when available, were consistent with glomerular microangiopathy with or without renal thrombi. Improvement in proteinuria has been observed after nintedanib was discontinued; however, in some cases, residual proteinuria persisted. Consider treatment interruption in patients who develop new or worsening proteinuria.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Elevated Liver Enzymes and Drug-Induced Liver Injury [see Warnings and Precautions ( 5.2 )] Gastrointestinal Disorders [see Warnings and Precautions ( 5.3 )] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.4 )] Arterial Thromboembolic Events [see Warnings and Precautions ( 5.5 )] Risk of Bleeding [see Warnings and Precautions ( 5.6 )] Gastrointestinal Perforation [see Warnings and Precautions ( 5.7 )] Nephrotic Range Proteinuria [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361 3993 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. The safety of nintedanib was evaluated in over 1000 IPF patients, 332 patients with chronic fibrosing ILDs with a progressive phenotype. Over 200 IPF patients were exposed to nintedanib for more than 2 years in clinical trials. Idiopathic Pulmonary Fibrosis Nintedanib was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Study 2 and Study 3) trials, 723 patients with IPF received nintedanib 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with nintedanib and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%). The most frequent serious adverse reactions reported in patients treated with nintedanib, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with nintedanib, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib-treated patients and 1.8% of placebo-treated patients. Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib was diarrhea (11%). Adverse reactions leading to discontinuation were reported in 21% of nintedanib-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%). The most common adverse reactions with an incidence of greater than or equal to 5% and more frequent in the nintedanib than placebo treatment group are listed in Table 1. Table 1 Adverse Reactions Occurring in ≥5% of Nintedanib-treated Patients with Idiopathic Pulmonary Fibrosis and More Commonly Than Placebo in Study 1, Study 2, and Study 3 Adverse Reaction Nintedanib, 150 mg n=723 Placebo n=508 Gastrointestinal disorders Diarrhea 62% 18% Nausea 24% 7% Abdominal pain a 15% 6% Vomiting 12% 3% Hepatobiliary disorders Liver enzyme elevation b 14% 3% Metabolism and nutrition disorders Decreased appetite 11% 5% Nervous system disorders Headache 8% 5% Investigations Weight decreased 10% 3% Vascular disorders Hypertension c 5% 4% a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain and abdominal tenderness. b Includes gamma-glutamyltransferase increased, hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal, liver function test abnormal, transaminase increased, blood alkaline phosphatase-increased, alanine aminotransferase abnormal, aspartate aminotransferase abnormal, and gamma-glutamyltransferase abnormal. c Includes hypertension, blood pressure increased, hypertensive crisis, and hypertensive cardiomyopathy. In addition, hypothyroidism was reported in patients treated with nintedanib, more than placebo (1.1% vs. 0.6%). Alopecia was also reported in more patients treated with nintedanib than placebo (0.8% vs. 0.4%). Combination with Pirfenidone Concomitant treatment with nintedanib and pirfenidone was investigated in an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to Week 12. Gastrointestinal adverse events were in line with the established safety profile of each component and were experienced in 37 (70%) patients treated with pirfenidone added to nintedanib versus 27 (53%) patients treated with nintedanib alone. Diarrhea, nausea, vomiting, and abdominal pain (includes upper abdominal pain, abdominal discomfort, and abdominal pain) were the most frequent adverse events reported in 20 (38%) versus 16 (31%), in 22 (42%) versus 6 (12%), in 15 (28%) versus 6 (12%), and in 15 (28%) versus 7 (14%) patients treated with pirfenidone added to nintedanib versus nintedanib alone, respectively. More subjects reported AST or ALT elevations (greater than or equal to 3 times the upper limit of normal) when using pirfenidone in combination with nintedanib (n=3 (6%)) compared to nintedanib alone (n=0) [see Warnings and Precautions ( 5.2 , 5.3 )] . Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib was studied in a phase 3, double-blind, placebo-controlled trial (Study 5) in which 663 patients with chronic fibrosing ILDs with a progressive phenotype were randomized to receive nintedanib 150 mg twice daily (n=332) or placebo (n=331) for at least 52 weeks. At 52 weeks, the median duration of exposure was 12 months for patients in both treatment arms. Subjects ranged in age from 27 to 87 years (median age of 67 years). The majority of patients were Caucasian (74%) or Asian (25%). Most patients were male (54%). The most frequent serious adverse event reported in patients treated with nintedanib, more than placebo, was pneumonia (4% vs. 3%). Adverse events leading to death were reported in 3% of patients treated with nintedanib and in 5% of patients treated with placebo. No pattern was identified in the adverse events leading to death. Adverse reactions leading to permanent dose reductions were reported in 33% of nintedanib -treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib was diarrhea (16%). Adverse reactions leading to discontinuation were reported in 20% of nintedanib-treated patients and 10% of placebo-treated patients. The most frequent adverse reaction that led to discontinuation in nintedanib-treated patients was diarrhea (6%). The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with nintedanib was consistent with that observed in IPF patients. In addition, the following adverse events were reported in nintedanib more than placebo in chronic progressive fibrosing ILD: nasopharyngitis (13% vs. 12%), upper respiratory tract infection (7% vs 6%), urinary tract infection (6% vs. 4%), fatigue (10% vs. 6%), and back pain (6% vs. 5%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of nintedanib. 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. Blood and Lymphatic System Disorders : Thrombocytopenia Gastrointestinal Disorders : Pancreatitis Hepatobiliary Disorders : Drug-induced liver injury Nervous System Disorders : Posterior reversible encephalopathy syndrome Renal and Urinary Disorders : Proteinuria Skin and Subcutaneous Tissue Disorders : Pruritus, rash Vascular Disorders : Non-serious and serious bleeding events, some of which were fatal To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%" cellpadding="0pt"><col width="62%"/><col width="27%"/><col width="11%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nintedanib, 150 mg</content></paragraph><paragraph><content styleCode="bold">n=723</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">n=508</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Gastrointestinal disorders</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Diarrhea</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>62%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Nausea</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Abdominal pain ^a</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Vomiting</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Hepatobiliary disorders</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Liver enzyme elevation ^b</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Metabolism and nutrition disorders</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Decreased appetite</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Nervous system disorders</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Headache</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Investigations</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item>Weight decreased</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><content styleCode="bold">Vascular disorders</content></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item>Hypertension ^c</item></list></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5%</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>