FDA label d6f8af0e-660f-191c-e053-2995a90a45fc

5 WARNINGS AND PRECAUTIONS Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.1 ) Bradycardia, hypotension, worsening heart failure/fluid retention may occur. Reduce the dose as needed. ( 5.2 , 5.3 , 5.4 ) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. ( 4 ) However, if deemed necessary, use with caution and at lowest effective dose. ( 5.5 ) Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. ( 5.6 ) 5.1 Cessation of Therapy Patients with coronary artery disease, who are being treated with Carvedilol Tablets, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of Carvedilol Tablet is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol Tablet should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol Tablet be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Carvedilol Tablet abruptly even in patients treated only for hypertension or heart failure. 5.2 Bradycardia In clinical trials, Carvedilol Tablet caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced. 5.3 Hypotension In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving Carvedilol Tablets compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving Carvedilol Tablets, compared with 0.4% of placebo subjects. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving Carvedilol Tablets compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving Carvedilol Tablets, compared with 0.8% of placebo subjects. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients. In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol Tablet compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol Tablet, compared to 0.2% of placebo patients. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [ see Dosage and Administration ( 2.2 , 2.3 ) ]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. 5.4 Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of Carvedilol Tablet. If such symptoms occur, diuretics should be increased and the Carvedilol Tablet dose should not be advanced until clinical stability resumes [ see Dosage and Administration ( 2 ) ]. Occasionally it is necessary to lower the Carvedilol Tablet dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol. 5.5 Non-Allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol Tablet may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol Tablet is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized. In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol Tablet be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration. 5.6 Glycemic Control in Type 2 Diabetes In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a study designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies ( 14.4 ) ]. 5.7 Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. 5.8 Deterioration of Renal Function Rarely, use of Carvedilol Tablet in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when Carvedilol Tablet was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of Carvedilol Tablet and the drug discontinued or dosage reduced if worsening of renal function occurs. 5.9 Major Surgery Chronically administered beta blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.10 Thyrotoxicosis β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. 5.11 Pheochromocytoma In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Carvedilol Tablet has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of Carvedilol Tablet to patients suspected of having pheochromocytoma. 5.12 Prinzmetal's Variant Angina Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with Carvedilol Tablet in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol Tablet to patients suspected of having Prinzmetal's variant angina. 5.13 Risk of Anaphylactic Reaction While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. 5.14 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with α -1 blockers (Carvedilol Tablet is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

6 ADVERSE REACTIONS Most common adverse events ( 6.1 ): Left ventricular dysfunction following myocardial infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥ 5%): Dizziness To report SUSPECTED ADVERSE REACTIONS, contact Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Carvedilol Tablet has been evaluated for safety in patients with heart failure (mild, moderate and severe), in patients with left ventricular dysfunction following myocardial infarction and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Heart Failure Carvedilol Tablets has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received Carvedilol Tablets for at least 6 months and 30% received Carvedilol Tablets for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with Carvedilol Tablets for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared Carvedilol Tablets in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared Carvedilol Tablets in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial). Table 1 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of >3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure subjects. The adverse event profile of Carvedilol Tablets observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials. Table 1. Adverse Events (%) Occurring More Frequently with Carvedilol Tablet than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Body System/ Adverse Event Mild-to-Moderate HF Severe HF Carvedilol Tablets Placebo Carvedilol Tablets Placebo (n = 765) (n = 437) (n = 1,156) (n = 1,133) Body as a Whole Asthenia 7 7 11 9 Fatigue 24 22 - - Digoxin level increased 5 4 2 1 Edema generalized 5 3 6 5 Edema dependent 4 2 - - Cardiovascular Bradycardia 9 1 10 3 Hypotension 9 3 14 8 Syncope 3 3 8 5 Angina pectoris 2 3 6 4 Central Nervous System Dizziness 32 19 24 17 Headache 8 7 5 3 Gastrointestinal Diarrhea 12 6 5 3 Nausea 9 5 4 3 Vomiting 6 4 1 2 Metabolic Hyperglycemia 12 8 5 3 Weight increase 10 7 12 11 BUN increased 6 5 - - NPN increased 6 5 - - Hypercholesterolemia 4 3 1 1 Edema peripheral 2 1 7 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased 8 9 5 4 Rales 4 4 4 2 Vision Vision abnormal 5 2 - - Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with Carvedilol Tablets in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial. Incidence >1% to ≤ 3% Body as a Whole : Allergy, malaise, hypovolemia, fever, leg edema. Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension. Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia. Gastrointestinal: Melena, periodontitis. Liver and Biliary System: SGPT increased, SGOT increased. Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased. Musculoskeletal: Muscle cramps. Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocyt penia. Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol Tablet has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received Carvedilol Tablet and 980 who received placebo. Approximately 75% of the subjects received Carvedilol Tablet for at least 6 months and 53% received Carvedilol Tablet for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with Carvedilol Tablet and placebo, respectively. The most common adverse events reported with Carvedilol Tablets in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in >3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with Carvedilol Tablet: Flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of patients. In this database, the only cause of discontinuation greater than 1%, and occurring more often on Carvedilol Tablet was hypotension (1.5% on Carvedilol Tablet, 0.2% on placebo). Hypertension: Carvedilol Tablet has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received Carvedilol Tablet for at least 6 months. Most adverse events reported during therapy with Carvedilol Tablet were of mild to moderate severity. In U.S. controlled clinical trials directly comparing Carvedilol Tablet in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of subjects receiving Carvedilol Tablet discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the Carvedilol Tablet group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-controlled trials increased with increasing dose of Carvedilol Tablet. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg. Table 1 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality, and that were more frequent in drug-treated subjects than placebo-treated patients. Table 2. Adverse Events (%) Occurring in U.S. Placebo-Controlled Hypertension Trials (Incidence greater than or equal to 1%, Regardless of Causality)* Body system/ Adverse Event Carvedilol Tablet (n = 1,142) Placebo (n = 462) Cardiovascular Bradycardia 2 - Postural hypotension 2 - Peripheral edema 1 - Central Nervous System Dizziness 6 5 Insomnia 2 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 - Metabolic Hypertriglyceridemia 1 - *Shown are events with rate greater than 1% rounded to nearest integer. Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in patients who received placebo. The following adverse events not described above were reported as possibly or probably related to Carvedilol Tablet in worldwide open or controlled trials with Carvedilol Tablet in patients with hypertension or heart failure. Incidence greater than 0.1% to less than or equal to 1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2)]. Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see Contraindications (4)]. Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating increased. Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia. Hematologic: Anemia, leukopenia. The following events were reported in less than or equal to 0.1% of patients and are potentially important: Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. 6.2 Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with Carvedilol Tablet. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with Carvedilol Tablet and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with Carvedilol Tablet. In a long-term, placebo-controlled trial in severe heart failure, patients treated with Carvedilol Tablet had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by Carvedilol Tablet led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol Tablet has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Carvedilol Tablet. 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 : Aplastic anemia. Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria). Renal and Urinary Disorders: Urinary incontinence. Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

<table border="1"><tbody><tr><td valign="top"><paragraph><content styleCode="bold">Table 1. Adverse Events (%) Occurring More Frequently with Carvedilol Tablet than with</content></paragraph><paragraph><content styleCode="bold">Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial</content></paragraph><paragraph><content styleCode="bold">(Incidence &gt;3% in Subjects Treated with Carvedilol, Regardless of Causality)</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Body System/</content></paragraph><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Mild-to-Moderate HF</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Severe HF</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Carvedilol Tablets</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Carvedilol Tablets</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">(n = 765)</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">(n = 437)</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">(n = 1,156)</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">(n = 1,133)</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td></tr><tr><td valign="top"><paragraph>Asthenia</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>11</paragraph></td><td valign="top"><paragraph>9</paragraph></td></tr><tr><td valign="top"><paragraph>Fatigue</paragraph></td><td valign="top"><paragraph>24</paragraph></td><td valign="top"><paragraph>22</paragraph></td><td valign="top"><paragraph>-</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph>Digoxin level increased</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph>Edema generalized</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td></tr><tr><td valign="top"><paragraph>Edema dependent</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>-</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td></tr><tr><td valign="top"><paragraph>Bradycardia</paragraph></td><td valign="top"><paragraph>9</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>10</paragraph></td><td valign="top"><paragraph>3</paragraph></td></tr><tr><td valign="top"><paragraph>Hypotension</paragraph></td><td valign="top"><paragraph>9</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>14</paragraph></td><td valign="top"><paragraph>8</paragraph></td></tr><tr><td valign="top"><paragraph>Syncope</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>8</paragraph></td><td valign="top"><paragraph>5</paragraph></td></tr><tr><td valign="top"><paragraph>Angina pectoris</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>4</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Central Nervous System</content></paragraph></td></tr><tr><td valign="top"><paragraph>Dizziness</paragraph></td><td valign="top"><paragraph>32</paragraph></td><td valign="top"><paragraph>19</paragraph></td><td valign="top"><paragraph>24</paragraph></td><td valign="top"><paragraph>17</paragraph></td></tr><tr><td valign="top"><paragraph>Headache</paragraph></td><td valign="top"><paragraph>8</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>3</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea</paragraph></td><td valign="top"><paragraph>12</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>3</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td valign="top"><paragraph>9</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>3</paragraph></td></tr><tr><td valign="top"><paragraph>Vomiting</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>2</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Metabolic</content></paragraph></td></tr><tr><td valign="top"><paragraph>Hyperglycemia</paragraph></td><td valign="top"><paragraph>12</paragraph></td><td valign="top"><paragraph>8</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>3</paragraph></td></tr><tr><td valign="top"><paragraph>Weight increase</paragraph></td><td valign="top"><paragraph>10</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>12</paragraph></td><td valign="top"><paragraph>11</paragraph></td></tr><tr><td valign="top"><paragraph>BUN increased</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>-</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph>NPN increased</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>-</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph>Hypercholesterolemia</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>3</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph>Edema peripheral</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>6</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td></tr><tr><td valign="top"><paragraph>Arthralgia</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td></tr><tr><td valign="top"><paragraph>Cough increased</paragraph></td><td valign="top"><paragraph>8</paragraph></td><td valign="top"><paragraph>9</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>4</paragraph></td></tr><tr><td valign="top"><paragraph>Rales</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>4</paragraph></td><td valign="top"><paragraph>2</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Vision</content></paragraph></td></tr><tr><td valign="top"><paragraph>Vision abnormal</paragraph></td><td valign="top"><paragraph>5</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>-</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr></tbody></table>

<table border="1"><tbody><tr><td valign="top"><paragraph><content styleCode="bold">Table 2. Adverse Events (%) Occurring in U.S. Placebo-Controlled</content></paragraph><paragraph><content styleCode="bold">Hypertension Trials (Incidence greater than or equal to 1%, Regardless of Causality)*</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Body system/ Adverse Event</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Carvedilol Tablet (n = 1,142)</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Placebo (n = 462)</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td></tr><tr><td valign="top"><paragraph>Bradycardia</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph>Postural hypotension</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph>Peripheral edema</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Central Nervous System</content></paragraph></td></tr><tr><td valign="top"><paragraph>Dizziness</paragraph></td><td valign="top"><paragraph>6</paragraph></td><td valign="top"><paragraph>5</paragraph></td></tr><tr><td valign="top"><paragraph>Insomnia</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea</paragraph></td><td valign="top"><paragraph>2</paragraph></td><td valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Hematologic</content></paragraph></td></tr><tr><td valign="top"><paragraph>Thrombocytopenia</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Metabolic</content></paragraph></td></tr><tr><td valign="top"><paragraph>Hypertriglyceridemia</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>-</paragraph></td></tr></tbody></table>