FDA label 887b9788-8ac1-4e6e-9b2e-8c0e79dcd023

5 WARNINGS AND PRECAUTIONS In clinical trials of COREG CR in patients with hypertension (338 subjects) and in patients with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediate-release carvedilol. Therefore, the information included within this section is based on data from controlled clinical trials with COREG CR as well as immediate-release carvedilol. 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 COREG CR, 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 COREG CR is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREG CR should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG CR 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 COREG CR abruptly even in patients treated only for hypertension or heart failure. 5.2 Bradycardia In clinical trials with immediate-release carvedilol, bradycardia was reported in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. Bradycardia was reported in 0.5% of patients receiving COREG CR in a study of heart failure patients and myocardial infarction patients with left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of COREG CR in hypertension. However, if pulse rate drops below 55 beats/minute, the dosage of COREG CR should be reduced. 5.3 Hypotension In clinical trials of primarily mild-to-moderate heart failure with immediate-release carvedilol, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilol compared to 3.6% and 2.5% of placebo patients, 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 carvedilol patients, compared to 0.4% of placebo patients. 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 patients receiving carvedilol compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol patients, compared to 0.8% of placebo patients. In a trial comparing heart failure patients switched to COREG CR or maintained on immediate-release carvedilol, there was a 2-fold increase in the combined incidence of hypotension, syncope or dizziness in elderly patients (> 65 years) switched from the highest dose of carvedilol (25 mg twice daily) to COREG CR 80 mg once daily [see Dosage and Administration (2), Use in Specific Populations (8.5)] . In the clinical trial of COREG CR in hypertensive patients, syncope was reported in 0.3% of patients receiving COREG CR compared to 0% of patients receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients receiving immediate-release carvedilol, 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 with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of patients receiving carvedilol 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, 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 (2.1, 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. If such symptoms occur, diuretics should be increased and the dose of COREG CR should not be advanced until clinical stability resumes [see Dosage and Administration (2)] . Occasionally it is necessary to lower the dose of COREG CR or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, COREG CR. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with immediate-release carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients 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 Nonallergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. COREG CR may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG CR 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 COREG CR 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 dosing with COREG CR 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 immediate-release 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 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 <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of COREG CR and the drug discontinued or dosage reduced if worsening of renal function occurs. 5.9 Anesthesia and Major Surgery If treatment with COREG CR is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10) for information on treatment of bradycardia and hypertension] . 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 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 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 in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of COREG CR 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.

6 ADVERSE REACTIONS The safety profile of COREG CR was similar to that observed for immediate-release carvedilol. Most common adverse events seen with immediate-release carvedilol. (6.1): Heart failure and 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 GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Carvedilol 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 reflecting the use of either COREG CR or immediate-release carvedilol 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). COREG CR has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) clinical study (n = 187) which included 157 patients with stable mild, moderate, or severe chronic heart failure and 30 patients with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with COREG CR in this small, short-term study was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for COREG CR and immediate-release carvedilol. Heart Failure The following information describes the safety experience in heart failure with immediate-release carvedilol. Carvedilol has been evaluated for safety in heart failure in more than 4,500 patients 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 for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with carvedilol for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol 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 patients. 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 2 shows adverse events reported in patients 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 patients than placebo-treated patients with an incidence of >3% in patients treated with carvedilol regardless of causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure patients. The adverse event profile of carvedilol observed in the long-term COMET study was generally similar to that observed in the US Heart Failure Trials. Table 2. Adverse Events (%) Occurring More Frequently With Immediate-Release Carvedilol Than With Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Patients Treated With Carvedilol, Regardless of Causality) Mild-to-Moderate HF Severe HF Carvedilol Placebo Carvedilol 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 studies, but the rates were equal or greater in patients who received placebo. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol in either the US placebo-controlled trials in patients with mild-to-moderate heart failure, or in patients 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, thrombocytopenia. Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction Following Myocardial Infarction The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol. Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received carvedilol and 980 who received placebo. Approximately 75% of the patients received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively. The most common adverse events reported with carvedilol 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 patients and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: 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 >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension COREG CR was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with COREG CR was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between COREG CR and placebo. Table 3. Adverse Events (%) Occurring More Frequently With COREG CR Than With Placebo in Patients With Hypertension (Incidence ≥1% in Patients Treated With Carvedilol, Regardless of Causality) COREG CR (n = 253) Placebo (n = 84) Nasopharyngitis 4 0 Dizziness 2 1 Nausea 2 0 Edema peripheral 2 1 Nasal congestion 1 0 Paresthesia 1 0 Sinus congestion 1 0 Diarrhea 1 0 Insomnia 1 0 The following information describes the safety experience in hypertension with immediate-release carvedilol. Carvedilol has been evaluated for safety in hypertension in more than 2,193 patients in US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of carvedilol patients discontinued for adverse events versus 5.2% of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials was found to increase with increasing dose of carvedilol. 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 as single or divided doses. Table 4 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients. Table 4. Adverse Events (% Occurrence) in US Placebo-Controlled Hypertension Trials With Immediate-Release Carvedilol (Incidence ≥1% in Patients Treated With Carvedilol, Regardless of Causality) * Carvedilol (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 >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 in worldwide open or controlled trials with carvedilol in patients with hypertension or heart failure. Incidence >0.1% 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 ≤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. 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 and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, patients treated with carvedilol had lower values for hepatic transaminases than patients treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol therapy 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; fasting serum glucose was not evaluated in the heart failure clinical trials. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG ® or COREG CR. 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. Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received only when carvedilol was administered concomitantly with other medications associated with such reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and urticaria) have been received for COREG and COREG CR, including cases occurring after the initiation of COREG CR in patients previously treated with COREG. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.

<table border="single" width="475.000" ID="id_6517ecf0-4006-4fab-b9ce-ecbf541f1369"> <caption ID="id_2a4ca67e-985d-4e08-80a8-7bcdc291558a">Table 2. Adverse Events (%) Occurring More Frequently With Immediate-Release Carvedilol Than With Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence &gt;3% in Patients Treated With Carvedilol, Regardless of Causality)</caption> <col width="29.3%"/> <col width="17.9%"/> <col width="17.1%"/> <col width="17.9%"/> <col width="17.9%"/> <tbody> <tr ID="id_bf5c15a5-8e7f-4592-bbd2-c9f9280ff1e6"> <td align="left" valign="top" styleCode="Botrule Toprule Rrule Lrule"/> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">Mild-to-Moderate HF</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">Severe HF</td> </tr> <tr ID="id_8bf65418-3b50-4874-a05d-8799ef450a13"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule">Carvedilol</td> <td align="center" valign="top" styleCode="Botrule Rrule">Placebo</td> <td align="center" valign="top" styleCode="Botrule Rrule">Carvedilol</td> <td align="center" valign="top" styleCode="Botrule Rrule">Placebo</td> </tr> <tr ID="id_a1782ec7-6e75-43ec-a450-ea0cf025e85a"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule">(n = 765)</td> <td align="center" valign="top" styleCode="Botrule Rrule">(n = 437)</td> <td align="center" valign="top" styleCode="Botrule Rrule">(n = 1,156)</td> <td align="center" valign="top" styleCode="Botrule Rrule">(n = 1,133)</td> </tr> <tr ID="id_d25032d2-0e25-4056-b346-7cf17d4c91ce"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Body as a Whole</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_11d7a130-9dd4-4a94-808e-3ccc97fcbe61"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Asthenia</td> <td align="center" valign="top" styleCode="Botrule Rrule">7</td> <td align="center" valign="top" styleCode="Botrule Rrule">7</td> <td align="center" valign="top" styleCode="Botrule Rrule">11</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> </tr> <tr ID="id_5354dd72-496e-4d2d-a9eb-dd779837efc3"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Fatigue</td> <td align="center" valign="top" styleCode="Botrule Rrule">24</td> <td align="center" valign="top" styleCode="Botrule Rrule">22</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_9f1389a0-9e63-4eb0-a484-d38657f3c515"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Digoxin level increased</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_6f322979-09bd-4d56-8f1b-e93e2755e1cb"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Edema generalized</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> </tr> <tr ID="id_4f53ee69-e811-4e46-83d7-ae270676238c"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Edema dependent</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_9aa605eb-a0b8-4073-a1eb-2570c3b4c2dd"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Cardiovascular</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_71461b80-786a-4163-a94d-52fee03709a0"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Bradycardia</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">10</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_9c23bdbb-f195-402d-9bc6-b3b239001153"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Hypotension</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">14</td> <td align="center" valign="top" styleCode="Botrule Rrule">8</td> </tr> <tr ID="id_25ce548c-b599-4099-afc9-a5326d5aa031"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Syncope</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">8</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> </tr> <tr ID="id_35202a80-d13b-4419-80a0-117b3957c2e8"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Angina pectoris</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> </tr> <tr ID="id_04696135-c3eb-4def-b45c-0eed0d06684b"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Central Nervous System</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_91b04f20-44ce-4e3d-98bf-82252ec6e9f9"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Dizziness</td> <td align="center" valign="top" styleCode="Botrule Rrule">32</td> <td align="center" valign="top" styleCode="Botrule Rrule">19</td> <td align="center" valign="top" styleCode="Botrule Rrule">24</td> <td align="center" valign="top" styleCode="Botrule Rrule">17</td> </tr> <tr ID="id_826ed765-3b2a-4cb8-9dcf-94c57b58a192"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Headache</td> <td align="center" valign="top" styleCode="Botrule Rrule">8</td> <td align="center" valign="top" styleCode="Botrule Rrule">7</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_a2d36ff2-ef34-4054-9b86-c4b96f3d14ae"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Gastrointestinal</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_8d29210a-af4a-4b67-b42d-5d35e52cadd9"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Diarrhea</td> <td align="center" valign="top" styleCode="Botrule Rrule">12</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_a25dac21-e566-4b2e-bd41-86da384c61df"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Nausea</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_58ff08dc-f201-4d7f-8430-8a433b7c613f"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Vomiting</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> </tr> <tr ID="id_540fcac7-ee34-478f-9818-64f7248b0ec3"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Metabolic</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_d028a159-1b01-49ba-9ab7-47cbb6e3d43d"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Hyperglycemia</td> <td align="center" valign="top" styleCode="Botrule Rrule">12</td> <td align="center" valign="top" styleCode="Botrule Rrule">8</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_f65f359e-0d17-42d0-9889-b24e68b3736e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Weight increase</td> <td align="center" valign="top" styleCode="Botrule Rrule">10</td> <td align="center" valign="top" styleCode="Botrule Rrule">7</td> <td align="center" valign="top" styleCode="Botrule Rrule">12</td> <td align="center" valign="top" styleCode="Botrule Rrule">11</td> </tr> <tr ID="id_3a274d69-1390-4421-a755-9fed33f274ff"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> BUN increased</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_18674a21-a77d-42da-b9f6-4c8c363ecda2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> NPN increased</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_a046c021-955b-49d4-bec1-7ac0a8e43a8e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Hypercholesterolemia</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_3f1d310a-2b9d-4aaf-8106-fcc8c3df9d65"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Edema peripheral</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">7</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> </tr> <tr ID="id_ffef1311-5f66-459f-8450-8bc17cb5cb4b"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Musculoskeletal</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_5ecf0232-4cc8-4c82-94b2-4babf9d1f66b"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Arthralgia</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_f66d02ad-f220-4059-b8d0-d68dcf9ce6f3"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Respiratory</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_f3f181c4-5195-47fa-b75a-f335278a6b85"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Cough increased</td> <td align="center" valign="top" styleCode="Botrule Rrule">8</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> </tr> <tr ID="id_eab5010a-6aca-4466-bbe1-681034d4c431"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Rales</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> </tr> <tr ID="id_de938817-d838-4880-8801-229830f6e737"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Vision</td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_997c0061-b891-4aeb-96b0-010c0f77ee21"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Vision abnormal</td> <td align="center" valign="top" styleCode="Rrule">5</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">&#x2014;</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> </tbody> </table>

<table border="single" width="438.000" ID="id_0c06f8ed-2c2b-45c3-8ba9-4ddbe6cb8a91"> <caption ID="id_ca8631df-f22f-4e0b-b8bd-cf519b6dc8e9">Table 3. Adverse Events (%) Occurring More Frequently With COREG CR Than With Placebo in Patients With Hypertension (Incidence &#x2265;1% in Patients Treated With Carvedilol, Regardless of Causality)</caption> <col width="40.2%"/> <col width="29.9%"/> <col width="29.9%"/> <tbody> <tr ID="id_6edcf8ca-c53d-4ded-9d28-1c50676e6e87"> <td align="left" valign="top" styleCode="Botrule Toprule Rrule Lrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"> <paragraph>COREG CR</paragraph>(n = 253)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> <paragraph>Placebo</paragraph>(n = 84)</td> </tr> <tr ID="id_5d699baf-53dc-446d-afa7-7a575b5c9bdc"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Nasopharyngitis</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_d3b9afbf-b31a-4dbd-bde5-4996567c3de0"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Dizziness</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_f0c362d9-73c5-4807-9fcf-70e5a16bb87d"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Nausea</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_d98251b9-f1ea-4886-8353-cd4de17b21ed"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Edema peripheral</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_a08356d9-df70-4e54-a552-306ea67d62a2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Nasal congestion</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_a932ecd4-7544-45bf-90a2-4d5335cd1cf1"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Paresthesia</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_79984de2-1b98-4f2e-88a0-129fc16130fb"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Sinus congestion</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_13a4eea7-512f-4b96-a37e-165105bb67f2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Diarrhea</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> <tr ID="id_7c63d820-a122-4266-94f7-153f2cb59309"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Insomnia</td> <td align="center" valign="top" styleCode="Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">0</td> </tr> </tbody> </table>

<table border="single" width="438.000" ID="id_8494f6cd-4885-46d8-b7bb-32bd65179fbc"> <caption ID="id_3b4b7aeb-8789-4f5e-bbec-89371bf37fdf">Table 4. Adverse Events (% Occurrence) in US Placebo-Controlled Hypertension Trials With Immediate-Release Carvedilol (Incidence &#x2265;1% in Patients Treated With Carvedilol, Regardless of Causality)^* </caption> <col width="40.2%"/> <col width="29.9%"/> <col width="29.9%"/> <tbody> <tr ID="id_0afec9e4-afbd-4464-93a3-01abb3afbdf9"> <td align="left" valign="top" styleCode="Botrule Toprule Rrule Lrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"> <paragraph>Carvedilol</paragraph>(n = 1,142)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> <paragraph>Placebo</paragraph>(n = 462)</td> </tr> <tr ID="id_f28cae27-a113-4fe5-9423-411e22f1ac3e"> <td align="left" valign="top" styleCode="Lrule Rrule">Cardiovascular</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_2d55d616-2ef2-4f22-800f-634fc69f2da2"> <td align="left" valign="top" styleCode="Lrule Rrule"> Bradycardia</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">&#x2014;</td> </tr> <tr ID="id_99af23b4-93ed-400c-962e-59d3657848e1"> <td align="left" valign="top" styleCode="Lrule Rrule"> Postural hypotension</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">&#x2014;</td> </tr> <tr ID="id_4c154044-3b15-4dcf-b391-7ad01fdfa8df"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Peripheral edema</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_af57c323-49c2-431e-abea-83fed07d0d2d"> <td align="left" valign="top" styleCode="Lrule Rrule">Central Nervous System</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_ac1f35e1-836c-4cfc-aa09-53aa91ca8e1c"> <td align="left" valign="top" styleCode="Lrule Rrule"> Dizziness</td> <td align="center" valign="top" styleCode="Rrule">6</td> <td align="center" valign="top" styleCode="Rrule">5</td> </tr> <tr ID="id_62374bfe-a61e-417b-b667-927ae68e5fec"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Insomnia</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_46f1ed94-a941-49bf-bff3-ea1f7994834a"> <td align="left" valign="top" styleCode="Lrule Rrule">Gastrointestinal</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_ac08cd8e-4003-486e-a5d7-40350883d11d"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Diarrhea</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> </tr> <tr ID="id_15c60368-a49c-4bfd-b608-6dc6eb5ce4c1"> <td align="left" valign="top" styleCode="Lrule Rrule">Hematologic</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_75a6d6bd-2315-4b83-b823-98a7c6e36437"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Thrombocytopenia</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> <tr ID="id_f6a90cc4-b6e9-4d8b-aa7c-e760217a7577"> <td align="left" valign="top" styleCode="Lrule Rrule">Metabolic</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_608e28df-7b06-414d-878c-ea342e851769"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Hypertriglyceridemia</td> <td align="center" valign="top" styleCode="Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">&#x2014;</td> </tr> </tbody> </table>