Zebeta (Oral)

ZEBETA^® (bisoprolol fumarate) is supplied as 5 mg and 10 mg tablets.

The 5 mg tablet is pink, heart-shaped, biconvex, film-coated, vertically scored in half on both sides, with an engraved stylized b/stylized b on one side and 6/0 on the reverse side, supplied as follows:

30     Unit-of-use     NDC 51285-060-01

The 10 mg tablet is white, heart-shaped, biconvex, film-coated, with an engraved stylized b on one side and 61 on the reverse side, supplied as follows:

30     Unit-of-use     NDC 51285-061-01

Store at 20 to 25 C (68 to 77 F).

Protect from moisture.

Dispense in tight containers.

Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454. Revised: May 2016

ZEBETA is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.

The dose of ZEBETA must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose (see Bronchospastic Disease in WARNINGS). If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily.

Patients With Renal Or Hepatic Impairment

In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

Geriatric Patients

It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction (see above and Geriatric Use in PRECAUTIONS).

Pediatric Patients

There is no pediatric experience with ZEBETA.

ZEBETA is contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.

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 ZEBETA 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 ZEBETA over approximately one week with the patient under careful observation. If withdrawal symptoms occur, ZEBETA 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 beta₁-selectivity, however, ZEBETA may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta₁-selectivity is not absolute, the lowest possible dose of ZEBETA should be used, with therapy starting at 2.5 mg. A beta₂ agonist (bronchodilator) should be made available.

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.

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 beta₁-selectivity, this is less likely with ZEBETA. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol fumarate 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.

PRECAUTIONS

Impaired Renal Or Hepatic Function

Use caution in adjusting the dose of ZEBETA in patients with renal or hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Risk Of Anaphylactic Reaction

While taking beta-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 reactions.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively.

Pregnancy Category C

In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.

There are no adequate and well-controlled studies in pregnant women. ZEBETA (bisoprolol fumarate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Small amounts of bisoprolol fumarate (< 2% of the dose) have been detected in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when bisoprolol fumarate is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

ZEBETA has been used in elderly patients with hypertension. Response rates and mean decreases in systolic and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies. Although no dose response study was conducted in elderly patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol fumarate.

Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.

SIDE EFFECTS

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 5-20 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- 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5- 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.

The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics):

Central Nervous System

Dizziness, unsteadiness, vertigo, syncope, headache, paresthesia, hypoesthesia, 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 ZEBETA:

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 ZEBETA (bisoprolol fumarate) 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 fumarate treatment for 4-12 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 fumarate treatment for 6-18 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 fumarate.

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 fumarate.

As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. 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.

DRUG INTERACTIONS

ZEBETA should not be combined with other beta-blocking agents. Patients receiving catecholaminedepleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-adrenergic blocking action of ZEBETA may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that ZEBETA be discontinued for several days before the withdrawal of clonidine.

ZEBETA should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Concurrent use of rifampin increases the metabolic clearance of ZEBETA, resulting in a shortened elimination half-life of ZEBETA. However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of ZEBETA on prothrombin time in patients on stable doses of warfarin.

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 5-20 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- 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5- 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.

The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics):

Central Nervous System

Dizziness, unsteadiness, vertigo, syncope, headache, paresthesia, hypoesthesia, 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 ZEBETA:

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 ZEBETA (bisoprolol fumarate) 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 fumarate treatment for 4-12 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 fumarate treatment for 6-18 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 fumarate.

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 fumarate.

As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. 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.

The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.

In general, if overdose occurs, ZEBETA therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:

Bradycardia

Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension

IV fluids and vasopressors should be administered. Intravenous glucagon may be useful.

Heart Block (Second Or Third Degree)

Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Congestive Heart Failure

Initiate conventional therapy (ie, digitalis, diuretics, inotropic agents, vasodilating agents).

Bronchospasm

Administer bronchodilator therapy such as isoproterenol and/or aminophylline.

Hypoglycemia

Administer IV glucose.