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 should be considered. In some cases bisoprolol fumarate 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 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 beta₁-selectivity of bisoprolol fumarate, bisoprolol fumarate 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 bisoprolol fumarate should be used. A beta₂ agonist (bronchodilator) should be made available.

Anesthesia and Major Surgery: If bisoprolol fumarate treatment is to be continued perioperatively, particular care should be taken when anesthetic agents that 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 beta₁-selectivity, this is less likely with bisoprolol fumarate. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. Because of the very low of HCTZ employed, this may be less likely with bisoprolol fumarate.

Thyrotoxicosis: Beta-adrenergic blockade may mask 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 should be discontinued. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.)

Hepatic Disease: Bisoprolol fumarate should be used with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid and electrolyte balance, which may precipitate hepatic coma. Also, elimination of bisoprolol fumarate is significantly slower in patients with cirrhosis than in healthy subjects (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism).

General

Electrolyte and Fluid Balance Status: Although the probability of developing hypokalemia is reduced with bisoprolol fumarate 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, and 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.

Laboratory Test Interactions

Based on reports involving thiazides, bisoprolol fumarate may decrease serum levels of protein-bound iodine without signs of thyroid disturbance.

Because it includes a thiazide, bisoprolol fumarate should be discontinued before carrying out tests for parathyroid function (see Parathyroid Disease - above).

Information for the Patient

Patients, especially those with coronary artery disease, should be warned against discontinuing use of bisoprolol fumarate without a physician's supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop other signs or symptoms of congestive heart failure or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be used with caution.

Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness. Patients should be advised that photosensitivity reactions have been reported with thiazides.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Bisoprolol Fumarate; HCTZ: Long-term studies have not been conducted with the bisoprolol fumarate/hydrochlorothiazide combination.

Bisoprolol Fumarate: 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 50 kg individuals; on a body-surface-area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD.

Hydrochlorothiazide: Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP), treated mice and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body-weight basis, these doses are 2400 times (in mice) and 400 times (in rats)the MRHD of hydrochlorothiazide (12.5 mg/day) in Ziac. On a body-surface-area basis, these doses are 226 times (in mice) and 82 times (in rats) the MRHD. These studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Mutagenesis

Bisoprolol Fumarate; HCTZ: The mutagenic potential of the bisoprolol fumarate/hydrochlorothiazide combination was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosomal aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Bisoprolol Fumarate: 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.

Hydrochlorothiazide: Hydrochlorothiazide was not genotoxic inin vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 mcg/ml. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Impairment of Fertility

Bisoprolol Fumarate; HCTZ: Reproduction studies in rats did not wshow any impairment of fertility with the bisoprolol fumarate/hydrochlorothiazide combination doses containing up to 30 mg/kg/day of bisoprolol in combination with 75 mg/kg/day of hydrochlorothiazide. On a body-weight basis, these doses are 75 and 300 times, respectively, the MRHD of bisoprolol fumarate and hydrochlorothiazide. On a body-surface-area basis, these study doses are 15 and 62 times, respectively, MRHD.

Bisoprolol Fumarate: Reproduction studies in rats did not wshow any impairment at dose 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.

Hydrochlorothiazide: Hydrochlorothiazide had no adverse effects on the fertility of mice and rats, of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding multiples of maximum recommended human doses are 400 (mice) and 16 (rats) on the basis of body-weight and 38 (mice)and 3.3 (rats) on the basis of body-surface-area.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Bisoprolol Fumarate; HCTZ: In rats, the bisoprolol fumarate/hydrochlorothiazide (B/H) combination was not teratogenic at doses up to 51.4 mg/kg/day of bisoprolol fumarate in combination with 128.6 mg/kg/day of hydrochlorothiazide. Bisoprolol fumarate and hydrochlorothiazide doses used in the rat study are, as multiples of the MRHD in the combination, 129 and 514 times greater, respectively, on a body-weight basis, and 26 and 106 times greater, respectively, on the basis of body-surface area. The drug combination was maternotoxic (decreased body weight and food consumption) at B5.7/H14.3 (mg/kg/day) and higher, and fetotoxic (increased late resorptions) at B17.1/H42.9 (mg/kg/day) and higher. Maternotoxicity was present at 14/57 times the MHRD of B/H, respectively, on a body-weight basis, and 3/12 times the MRHD of B/H doses, respectively, on the basis of body-surface area. Fetotoxicity was present at 43/172 times the MHRD of B/H, respectively, on a body-weight basis, and 9/35 times the MRHD of B/H doses, respectively, on the basis of body-surface-area. In rabbits, the B/H combination was not teratogenic at doses of B/10/H25 (mg/kg/day). Bisoprolol fumarate and hydrochlorothiazide used in the rabbit study were not teratogenic at 25/100 times the B/H MRHD, respectively, on a body-weight basis, and 10/40 times the B/H MRHD, respectively, on the basis of body surface area. The drug combination was maternotoxic (decreased body weight) at B1/H2.5 (mg/kg/day) and higher,and fetotoxic (increased resorptions) at B10/H25 (mg/kg/day). The multiples of the MRHD for the B/H combination which were maternotoxic are, respectively, 2.5/10 (on the basis of body-weight) and 1/4 (on the basis of body-surface-area), and for fetotoxicity are, respectively 25/100 (on the basis of body-weight) and 10/40 (on the basis of body surface area).

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

Bisoprolol Fumarate: In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day, which are 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.

Hydrochlorothiazide: Hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively. At these doses, which are multiples of the MRHD equal to 12,000 for mice and 4000 for rats, based on body-weight, and equal to 1129 for mice and 824 for rats, based on body-surface-area, there was no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects: Thiazides cross the placental barrier and appear in the cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Nursing Mothers

Bisoprolol fumarate alone or in combination with HCTZ has not been studied in nursing mothers. Thiazides are excreted in human breast milk. Small amounts of bisoprolol fumarate (<2% of the dose) have been detected in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Geriatric Use

In clinical trials, at least 270 patients treated with bisoprolol fumarate plus HCTZ were 60 years of age or older. HCTZ added significantly to the antihypertensive effect of bisoprolol in elderly hypertensive patients. No overall differences in effectiveness or safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use

Safety and effectiveness of bisoprolol fumarate in children have not been established.

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