bisoprolol fumarate and hydrochlorothiazide 6.25 mg; 10 mg Tablet, 1,000-count — NDC 29300-189-10 (Billing 29300-0189-10)

WARNINGS Cardiac 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 these agents. In such situations, they must be used cautiously.

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 fumarate and hydrochlorothiazide should be considered. In some cases bisoprolol fumarate and hydrochlorothiazide therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation of Therapy Exacerbations 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 fumarate and hydrochlorothiazide over approximately 1 week with the patient under careful observation.

If withdrawal symptoms occur, beta-blocking agent 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 PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative beta 1 -selectivity of bisoprolol fumarate, bisoprolol fumarate and hydrochlorothiazide 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 fumarate and hydrochlorothiazide should be used.

A beta 2 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 Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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. Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting).

Beta-blockers may further increase the risk of severe hypoglycemia when used concurrently with sulfonylureas. Diabetic patients should be advised to carefully monitor blood glucose levels (see PRECAUTIONS - Drug Interactions). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. 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.

Renal Disease Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia. In subjects with creatinine clearance less than 40 mL/min, the plasma half-life of bisoprolol fumarate is increased up to threefold, as compared to healthy subjects.

If progressive renal impairment becomes apparent, bisoprolol fumarate and hydrochlorothiazide should be discontinued. (See Pharmacokinetics and Metabolism ). Hepatic Disease Bisoprolol fumarate and hydrochlorothiazide sho… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Bisoprolol fumarate and hydrochlorothiazide Bisoprolol fumarate/HCTZ 6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild and transient. In more than 65,000 patients treated worldwide with bisoprolol fumarate, occurrences of bronchospasm have been rare.

Discontinuation rates for AEs were similar for bisoprolol fumarate/HCTZ 6.25 mg and placebo-treated patients. In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/ HCTZ 6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/HCTZ 6.25 mg was administered for 4 weeks.

In Study 2, bisoprolol fumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/ HCTZ 6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/ HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table: % of Patients with Adverse Experiences a Body System/ Adverse Experience All Adverse Experiences Drug Related Adverse Experiences Placebo b B2.5-40/H 6.25 b Placebo b B2.5-10/H 6.25 b (n=144) (n=252) (n=144) (n=221) % % % % Cardiovascular bradycardia 0.7 1.1 0.7 0.9 arrhythmia 1.4 0.4 0.0 0.0 peripheral ischemia 0.9 0.7 0.9 0.4 chest pain 0.7 1.8 0.7

0.9Respiratory bronchospasm 0.0 0.0 0.0 0.0 cough 1.0 2.2 0.7 1.5 rhinitis 2.0 0.7 0.7

0.9URI 2.3 2.1 0.0

0.0Body as a Whole asthenia 0.0 0.0 0.0 0.0 fatigue 2.7 4.6 1.7 3.0 peripheral edema 0.7 1.1 0.7

0.9Central Nervous System dizziness 1.8 5.1 1.8 3.2 headache 4.7 4.5 2.7

0.4Musculoskeletal muscle cramps 0.7 1.2 0.7 1.1 myalgia 1.4 2.4 0.0

0.0Psychiatric insomnia 2.4 1.1 2.0 1.2 somnolence 0.7 1.1 0.7 0.9 loss of libido 1.2 0.4 1.2 0.4 impotence 0.7 1.1 0.7

1.1Gastrointestinal diarrhea 1.4 4.3 1.2 1.1 nausea 0.9 1.1 0.9 0.9 dyspepsia 0.7 1.2 0.7 0.9 a Averages adjusted to combine across studies. b Combined across studies. Other adverse experiences that have been reported with the individual components are listed below. Bisoprolol Fumarate In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those listed above, have been reported.

While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to alert the physician to a possible relationship. Central Nervous System Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory. Cardiovascular Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.

Gastrointestinal Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth. Musculoskeletal Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor. Skin Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vasculitis.

Special Senses Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities. Metabolic Gout. Respiratory Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection).

Genitourinary Decreased libido/impotence, Peyronie’s disease (very rarely), cystitis, renal colic, polyuria. 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… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Electrolyte and Fluid Balance Status Although the probability of developing hypokalemia is reduced with bisoprolol fumarate and hydrochlorothiazide because of the very low dose of HCTZ employed, periodic determination of serum electrolytes should be performed, and patients should be observed for signs of fluid or electrolyte disturbances, i.e., hyponatremia, hypochloremic alkalosis, hypokalemia and hypomagnesemia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia.

Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium-rich foods. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than salt administration, except in rare instances when the hyponatremia is life threatening.

In actual salt depletion, appropriate replacement is the therapy of choice. Parathyroid Disease Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy. Hyperuricemia Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.

Bisoprolol fumarate, alone or in combination with HCTZ, has been associated with increases in uric acid. However, in U.S. clinical trials, the incidence of treatment-related increases in uric acid was higher during therapy with HCTZ 25 mg (25%) than with B/H 6.25 mg (10%). Because of the very low dose of HCTZ employed, hyperuricemia may be less likely with bisoprolol fumarate and hydrochlorothiazide.

Drug Interactions Bisoprolol fumarate and hydrochlorothiazide may potentiate the action of other antihypertensive agents used concomitantly. Bisoprolol fumarate and hydrochlorothiazide should not be combined with other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added beta-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity.

In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that bisoprolol fumarate and hydrochlorothiazide be discontinued for several days before the withdrawal of clonidine. Bisoprolol fumarate and hydrochlorothiazide should be used with caution 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. The concomitant use of beta-blockers with sulfonylureas may increase the risk of severe hypoglycemia (see WARNINGS - Hypoglycemia).

Bisoprolol Fumarate Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, shortening its elimination half-life. However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevan… [Excerpted — this section continues on DailyMed.]