FDA label 802a50e4-5f27-474c-9680-863ecf00920b

WARNINGS Cardiac Failure Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously. In Patients Without a History of Cardiac Failure Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of bisoprolol should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs. Abrupt Cessation of Therapy Exacerbation of angina pectoris, and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician’s advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with bisoprolol over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol therapy should be reinstituted, at least temporarily. Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta 1 -selectivity, however, bisoprolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta 1 -selectivity is not absolute, the lowest possible dose of bisoprolol should be used, with therapy starting at 2.5 mg. A beta 2 agonist (bronchodilator) should be made available. Anesthesia and Major Surgery If bisoprolol treatment 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 for information on treatment of bradycardia and hypotension. Diabetes and Hypoglycemia Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta 1 -selectivity, this is less likely with bisoprolol. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol should be used with caution. Thyrotoxicosis Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

ADVERSE REACTIONS Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies. In Study A, doses of 5, 10 and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10 and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5 to 20 mg of bisoprolol fumarate; 132 received placebo. Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy. The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo controlled clinical trials (2.5 to 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5 to 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue and sinusitis appear to be dose related. Body System/Adverse Experience All Adverse Experiences (% a 2 ) Bisoprolol Fumarate Placebo 5 to 20 mg 2.5 to 40 mg (n = 132) (n = 273) (n = 404) % % % Skin increased sweating 1.5 0.7 1.0 Musculoskeletal arthralgia 2.3 2.2 2.7 Central Nervous System dizziness 3.8 2.9 3.5 headache 11.4 8.8 10.9 hypoaesthesia 0.8 1.1 1.5 Autonomic Nervous System dry mouth 1.5 0.7 1.3 Heart Rate/Rhythm bradycardia 0 0.4 0.5 Psychiatric vivid dreams 0 0 0 insomnia 2.3 1.5 2.5 depression 0.8 0 0.2 Gastrointestinal diarrhea 1.5 2.6 3.5 nausea 1.5 1.5 2.2 vomiting 0 1.1 1.5 Respiratory bronchospasm 0 0 0 cough 4.5 2.6 2.5 dyspnea 0.8 1.1 1.5 pharyngitis 2.3 2.2 2.2 rhinitis 3.0 2.9 4.0 sinusitis 1.5 2.2 2.2 URI 3.8 4.8 5.0 Body as a Whole asthenia 0 0.4 1.5 chest pain 0.8 1.1 1.5 fatigue 1.5 6.6 8.2 edema (peripheral) 3.8 3.7 3.0 The following is a comprehensive list of adverse experiences reported with bisoprolol in worldwide studies, or in postmarketing experience (in italics): Central Nervous System: Dizziness, unsteadiness , vertigo, syncope , headache, paresthesia, hypoaesthesia, hyperesthesia, somnolence, sleep disturbances , anxiety/restlessness, decreased concentration/memory. Autonomic Nervous System: Dry mouth. Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion. Psychiatric: Vivid dreams, insomnia, depression. Gastrointestinal: Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer. Musculoskeletal: Muscle/joint pain, arthralgia , back/neck pain, muscle cramps, twitching/tremor. Skin: Rash, acne, eczema, psoriasis , skin irritation, pruritus, flushing, sweating, alopecia, dermatitis , angioedema, exfoliative dermatitis , cutaneous vasculitis. Special Senses: Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing , earache, taste abnormalities. Metabolic: Gout. Respiratory: Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI. Genitourinary: Decreased libido/impotence, Peyronie’s disease , cystitis, renal colic, polyuria. Hematologic: Purpura. General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema. In addition a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of bisoprolol. Central Nervous System: Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium. Allergic: Fever, combined with aching and sore throat, laryngospasm, respiratory distress. Hematologic: Agranulocytosis, thrombocytopenia, thrombocytopenic purpura. Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis. Miscellaneous: The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol during investigational use or extensive foreign marketing experience. LABORATORY ABNORMALITIES: In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding. Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol treatment for 4 to 12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal. In the long-term, uncontrolled experience with bisoprolol treatment for 6 to 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol. Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol. As with other beta-blockers, ANA conversions have also been reported on bisoprolol. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy. 2 a percentage of patients with event

<table ID="i324e9676-2625-4e3d-8191-afc0ec09feb5"> <col align="left" width="1"/> <col align="left" width="1"/> <col align="left" width="1"/> <col align="left" width="1"/> <tbody> <tr> <td> <content styleCode="underline">Body System/Adverse Experience</content> </td> <td> <content styleCode="underline">All Adverse Experiences (%</content> <content styleCode="underline"> ^a </content> <linkHtml href="#footnote-2">2</linkHtml> <content styleCode="underline">)</content>Bisoprolol Fumarate</td> </tr> <tr> <td> </td> <td> <content styleCode="underline">Placebo</content> </td> <td> <content styleCode="underline">5 to 20 mg</content> </td> <td> <content styleCode="underline">2.5 to 40 mg</content> </td> </tr> <tr> <td> </td> <td>(n = 132)</td> <td>(n = 273)</td> <td>(n = 404)</td> </tr> <tr> <td> </td> <td> <content styleCode="underline">%</content> </td> <td> <content styleCode="underline">%</content> </td> <td> <content styleCode="underline">%</content> </td> </tr> <tr> <td>Skin</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>increased sweating</td> <td>1.5</td> <td>0.7</td> <td>1.0</td> </tr> <tr> <td>Musculoskeletal</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>arthralgia</td> <td>2.3</td> <td>2.2</td> <td>2.7</td> </tr> <tr> <td>Central Nervous System</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>dizziness</td> <td>3.8</td> <td>2.9</td> <td>3.5</td> </tr> <tr> <td>headache</td> <td>11.4</td> <td>8.8</td> <td>10.9</td> </tr> <tr> <td>hypoaesthesia</td> <td>0.8</td> <td>1.1</td> <td>1.5</td> </tr> <tr> <td>Autonomic Nervous System</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>dry mouth</td> <td>1.5</td> <td>0.7</td> <td>1.3</td> </tr> <tr> <td>Heart Rate/Rhythm</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>bradycardia</td> <td>0</td> <td>0.4</td> <td>0.5</td> </tr> <tr> <td>Psychiatric</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>vivid dreams</td> <td>0</td> <td>0</td> <td>0</td> </tr> <tr> <td>insomnia</td> <td>2.3</td> <td>1.5</td> <td>2.5</td> </tr> <tr> <td>depression</td> <td>0.8</td> <td>0</td> <td>0.2</td> </tr> <tr> <td>Gastrointestinal</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>diarrhea</td> <td>1.5</td> <td>2.6</td> <td>3.5</td> </tr> <tr> <td>nausea</td> <td>1.5</td> <td>1.5</td> <td>2.2</td> </tr> <tr> <td>vomiting</td> <td>0</td> <td>1.1</td> <td>1.5</td> </tr> <tr> <td>Respiratory</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>bronchospasm</td> <td>0</td> <td>0</td> <td>0</td> </tr> <tr> <td>cough</td> <td>4.5</td> <td>2.6</td> <td>2.5</td> </tr> <tr> <td>dyspnea</td> <td>0.8</td> <td>1.1</td> <td>1.5</td> </tr> <tr> <td>pharyngitis</td> <td>2.3</td> <td>2.2</td> <td>2.2</td> </tr> <tr> <td>rhinitis</td> <td>3.0</td> <td>2.9</td> <td>4.0</td> </tr> <tr> <td>sinusitis</td> <td>1.5</td> <td>2.2</td> <td>2.2</td> </tr> <tr> <td>URI</td> <td>3.8</td> <td>4.8</td> <td>5.0</td> </tr> <tr> <td>Body as a Whole</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>asthenia</td> <td>0</td> <td>0.4</td> <td>1.5</td> </tr> <tr> <td>chest pain</td> <td>0.8</td> <td>1.1</td> <td>1.5</td> </tr> <tr> <td>fatigue</td> <td>1.5</td> <td>6.6</td> <td>8.2</td> </tr> <tr> <td>edema (peripheral)</td> <td>3.8</td> <td>3.7</td> <td>3.0</td> </tr> </tbody> </table>