Fluvastatin Sodium

5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs. Discontinue fluvastatin sodium extended-release tablets if markedly elevated creatine kinase (CK) levels occur, or myopathy is diagnosed or suspected. Temporarily discontinue fluvastatin sodium extended-release tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing fluvastatin sodium extended-release tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue fluvastatin sodium extended-release tablets if IMNM is suspected. ( 5.2 ) Hepatic Dysfunction : Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue fluvastatin sodium extended-release tablets ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis Fluvastatin sodium extended-release tablets may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including fluvastatin sodium extended-release tablets. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was <0.1% in fluvastatin clinical trials [see Adverse Reactions ( 6.1 )] . Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies) [see Drug Interactions ( 7.1 )] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of fluvastatin sodium extended-release tablets with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with fluvastatin sodium extended-release tablets, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions ( 7.1 )] . Discontinue fluvastatin sodium extended-release tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if fluvastatin sodium extended-release tablets are discontinued. Temporarily discontinue fluvastatin sodium extended-release tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting fluvastatin sodium extended-release tablets. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum CK, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue fluvastatin sodium extended-release tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of fluvastatin sodium extended-release tablets [see Adverse Reactions ( 6.1 )] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials. Marked persistent increases of hepatic transaminases have also occurred with fluvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin sodium extended-release tablets. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before fluvastatin sodium extended-release tablets initiation and thereafter, when clinically indicated. Fluvastatin sodium extended-release tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue fluvastatin sodium extended-release tablets. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including fluvastatin sodium extended-release tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )] Most frequent adverse reactions occurring in ≥ 2.5% of subjects treated with fluvastatin sodium extended-release tablets and more than placebo are: influenza-like symptoms, sinusitis, dyspepsia, urinary tract infection, bronchitis, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 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. In the fluvastatin capsule, clinical trials there were 2326 patients treated with fluvastatin (age range, 18 to 75 years, 44% women, 94% White, 4% Black or African American, 2% other ethnicities) with a median treatment duration of 24 weeks. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%), and diarrhea (0.2%). In the fluvastatin sodium extended-release tablet clinical trials there were 912 patients treated with fluvastatin sodium extended-release tablets (age range, 21 to 87 years, 52% women, 91% White, 4% Black or African American, 5% other ethnicities) with a median treatment duration of 24 weeks. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%) and chest pain (0.3%). Adverse reactions occurring in the fluvastatin capsules and fluvastatin sodium extended-release tablets controlled trials with a frequency ≥2% included the following: Table 1. Adverse Reactions Reported in ≥2% in Patients Treated with Fluvastatin Capsules/Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages Adverse reaction Placebo a N = 960 (%) Fluvastatin capsules a N = 2326 (%) Fluvastatin Sodium Extended-Release Tablets b N = 912 (%) Influenza-like symptoms 5.7 5.1 7.1 Headache 7.8 8.9 4.7 Myalgia 4.5 5.0 3.8 Abdominal pain 3.8 4.9 3.7 Dyspepsia 3.2 7.9 3.5 Sinusitis 1.9 2.6 3.5 Diarrhea 4.2 4.9 3.3 Arthropathy NA NA 3.2 Urinary tract infection 1.1 1.6 2.7 Nausea 2.0 3.2 2.5 Bronchitis 1.0 1.8 2.6 Fatigue 2.3 2.7 1.6 Flatulence 2.5 2.6 1.4 Arthritis 2.0 2.1 1.3 Allergy 2.2 2.3 1.0 Insomnia 1.4 2.7 0.8 a. Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo. b. Controlled trials with fluvastatin sodium extended-release tablets, 80 mg as compared to fluvastatin capsules. In the Fluvastatin Capsules Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with coronary heart disease who had undergone a percutaneous coronary intervention. This was a multicenter, randomized, double-blind, placebo-controlled trial, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules 40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years [see Clinical Studies ( 14.3 )] . Table 2. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/fluvastatin sodium extended-release tablets and at an Incidence Greater Than Placebo in the LIPS Trial. Table 2. Adverse Reactions Reported in ≥2% in Patients Treated with Fluvastatin Capsules/Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial Adverse reaction Placebo N = 818 (%) Fluvastatin Capsules 40 mg twice daily N = 822 (%) Abdominal pain upper 4.5 6.3 Hypertension 4.2 5.8 Fatigue 3.8 4.7 Dyspepsia 4.0 4.5 Edema peripheral 2.9 4.4 Pain in extremity 2.7 4.1 Dizziness 3.5 3.9 Constipation 2.1 3.3 Nasopharyngitis 2.1 2.8 Dyspnea exertional 2.4 2.8 Gastric disorder 2.1 2.7 Nausea 2.3 2.7 Atrial fibrillation 2.0 2.4 Syncope 2.2 2.4 Bronchitis 2.0 2.3 Intermittent claudication 2.1 2.3 Myalgia 1.6 2.2 Arthralgia 1.8 2.1 Elevations in Liver Enzyme Tests Approximately 1.1% of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the ULN. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic. In a pooled analysis of all placebo-controlled studies in which fluvastatin capsules were used, persistent transaminase elevations (> 3 times the ULN on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) fluvastatin capsules, respectively. Ninety-one percent of the cases of persistent ALT/AST increased abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8. In the pooled analysis of 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8%, and 4.9% of patients treated with fluvastatin sodium extended-release tablets 80 mg, fluvastatin capsules 40 mg and fluvastatin capsules 40 mg twice daily, respectively. In 13 of 16 patients treated with fluvastatin sodium extended-release tablets the abnormality occurred within 12 weeks of initiation of treatment with fluvastatin sodium extended-release tablets 80 mg. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluvastatin. 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. Musculoskeletal: Muscle cramps, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of IMNM associated with statin use [see Warnings and Precautions ( 5.2 )] . Neurological: Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric: Anxiety, depression, psychic disturbances Respiratory: Interstitial lung disease Hypersensitivity reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Gastrointestinal: Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and non-fatal hepatic failure. Skin: Rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, lichen planus, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails). Reproductive: Gynecomastia, loss of libido, erectile dysfunction. Eye: Progression of cataracts (lens opacities), ophthalmoplegia. Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities.

<table cellspacing="0" cellpadding="0" border="1"><col width="539.5pt"/><col/><col/><col/><tbody><tr><td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Table 1. Adverse Reactions Reported in &#x2265;2% in Patients Treated with Fluvastatin Capsules/Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo^a</content></paragraph><paragraph><content styleCode="bold">N = 960</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Fluvastatin capsules^a</content></paragraph><paragraph><content styleCode="bold">N = 2326</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Fluvastatin Sodium Extended-Release Tablets</content><content styleCode="bold">^b</content></paragraph><paragraph><content styleCode="bold">N = 912</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Influenza-like symptoms</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Myalgia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthropathy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NA</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NA</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Bronchitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Flatulence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Allergy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>a. Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo.</paragraph><paragraph>b. Controlled trials with fluvastatin sodium extended-release tablets, 80 mg as compared to fluvastatin capsules.</paragraph></td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="1"><col width="539.5pt"/><col/><col/><tbody><tr><td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"> Table 2. Adverse Reactions Reported in &#x2265;2% in Patients Treated with Fluvastatin Capsules/Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adverse reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo</paragraph><paragraph>N = 818 (%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fluvastatin Capsules 40 mg twice daily</paragraph><paragraph>N = 822 (%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain upper</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypertension</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Edema peripheral</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pain in extremity</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspnea exertional</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastric disorder</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Atrial fibrillation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Syncope</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Bronchitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Intermittent claudication</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Myalgia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthralgia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.1</paragraph></td></tr></tbody></table>