bisoprolol fumarate and hydrochlorothiazide

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Overview

What is bisoprolol fumarate and hydrochlorothiazide?

Bisoprolol fumarate and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension. It combines two antihypertensive agents in a once–daily dosage: a synthetic beta-selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a benzothiadiazine diuretic (hydrochlorothiazide).

Bisoprolol fumarate is chemically described as (±)-1-[4-[[-2-(1-methylethoxy)ethoxy]methyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol()-2-butenedioate(2:1)(salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its molecular formula is (CHNO)•CHO and it has a molecular weight of 766.97. Its structural formula is:

Bisoprolol fumarate is a white crystalline powder, approximately equally hydrophilic and lipophilic, and readily soluble in water, methanol, ethanol, and chloroform.

Hydrochlorothiazide (HCTZ) is 6-Chloro-3,4-dihydro--1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white, or practically white, practically odorless crystalline powder. It is slightly soluble in water, sparingly soluble in dilute sodium hydroxide solution, freely soluble in n-butylamine and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. Its molecular formula is CHClNOS and it has a molecular weight of 297.73. Its structural formula is:

Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 2.5 mg/6.25 mg for oral administration contains:

Bisoprolol fumarate USP….. 2.5 mg

Hydrochlorothiazide USP…. 6.25 mg

Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 5 mg/6.25 mg for oral administration contains:

Bisoprolol fumarate USP….. 5 mg

Hydrochlorothiazide USP…. 6.25 mg

Each Bisoprolol Fumarate and Hydrochlorothiazide tablet USP 10 mg/6.25 mg for oral administration contains:

Bisoprolol fumarate USP….. 10 mg

Hydrochlorothiazide USP…. 6.25 mg

Inactive ingredients include pregelatinized starch, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, colloidal silicon dioxide, copovidone and titanium dioxide. The 5 mg/6.25 mg tablet also contains red and yellow iron oxide. The 2.5 mg/6.25 mg tablet also contains yellow iron oxide.

What does bisoprolol fumarate and hydrochlorothiazide look like?

What are the available doses of bisoprolol fumarate and hydrochlorothiazide?

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What should I talk to my health care provider before I take bisoprolol fumarate and hydrochlorothiazide?

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How should I use bisoprolol fumarate and hydrochlorothiazide?

Bisoprolol fumarate and hydrochlorothiazide tablets are indicated in the management of hypertension.

Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 mg to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg, the antihypertensive effects increased with increasing doses of either component.

The adverse effects (see ) of bisoprolol are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea, asthenia, and fatigue) and dose-independent phenomena (e.g., occasional rash); those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., possibly pancreatitis); the dose-dependent phenomena for each being much more common than the dose-independent phenomena. The latter consist of those few that are truly idiosyncratic in nature or those that occur with such low frequency that a dose relationship may be difficult to discern. Therapy with a combination of bisoprolol and hydrochlorothiazide will be associated with both sets of dose-independent adverse effects, and to minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. On the other hand, regimens that combine low doses of bisoprolol and hydrochlorothiazide should produce minimal dose-dependent adverse effects, e.g., bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, i.e., decreases in serum potassium (see ).

What interacts with bisoprolol fumarate and hydrochlorothiazide?

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients in cardiogenic shock, overt cardiac failure (see ), second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

What are the warnings of bisoprolol fumarate and hydrochlorothiazide?

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

ID33

PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative beta-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-selectivity is not absolute, the lowest possible dose of bisoprolol fumarate and hydrochlorothiazide should be used. A beta agonist (bronchodilator) should be made available.

Major Sugery

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 beta-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 dose of HCTZ employed, this may be less likely with bisoprolol fumarate and hydrochlorothiazide.

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 ).

Hepatic Disease

Bisoprolol fumarate and hydrochlorothiazide 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 ).

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

What are the precautions of bisoprolol fumarate and hydrochlorothiazide?

General

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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.

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.

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 relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of bisoprolol fumarate on prothrombin times in patients on stable doses of warfarin.

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.

Hydrochlorothiazide

When given concurrently the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs – additive effect or potentiation.

Cholestyramine and colestipol resins - Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption in the gastrointestinal tract by up to 85 percent and 43 percent, respectively.

Corticosteroids, ACTH - Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.

Lithium-generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with bisoprolol fumarate and hydrochlorothiazide.

Nonsteroidal anti-inflammatory drugs - In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics. Therefore, when bisoprolol fumarate and hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Photosensitivity reactions and possible exacerbation or activation of systemic lupus erythematosus have been reported in patients receiving thiazides. The antihypertensive effects of thiazides may be enhanced in the post-sympathectomy patient.

Laboratory Test Interactions

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

Because it includes a thiazide, bisoprolol fumarate and hydrochlorothiazide should be discontinued before carrying out tests for parathyroid function (see ).

Information For Patients

Patients, especially those with coronary artery disease, should be warned against discontinuing use of bisoprolol fumarate and hydrochlorothiazide 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, Impairment of Fertility

Carcinogenesis

Bisoprolol fumarate and hydrochlorothiazide

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 bisoprolol fumarate and hydrochlorothiazide. 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 and hydrochlorothiazide

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 and 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 and assays.

Hydrochlorothiazide

Hydrochlorothiazide was not genotoxic in assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the sex-linked recessive lethal trait gene. Positive test results were obtained in the CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to1300 µg /mL. Positive test results were also obtained in the non-disjunction assay, using an unspecified concentration of hydrochlorothiazide.

Impairment of Fertility

Bisoprolol fumarate and hydrochlorothiazide

Reproduction studies in rats did not show any impairment of fertility with the bisoprolol fumarate/hydrochlorothiazide combination doses containing up to 30 mg/kg/day of bisoprolol fumarate 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 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.

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

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Teratogenic Effects – Pregnancy Category C

Bisoprolol fumarate and hydrochlorothiazide

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 B 5.7/H 14.3 (mg/kg/day) and higher, and fetotoxic (increased late resorptions) at B 17.1/H 42.9 (mg/kg/day) and higher. Maternotoxicity was present at 14/57 times the MRHD 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 MRHD 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/H 25 (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 B 1/H 2.5 (mg/kg/day) and higher, and fetotoxic (increased resorptions) at B 10/H 25 (mg/kg/day). The multiples of the MRHD for the B/H combination that 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 were, 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 with bisoprolol fumarate and hydrochlorothiazide in pregnant women. Bisoprolol fumarate and hydrochlorothiazide 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 were 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 that 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.

Pediatric Use

Safety and effectiveness of bisoprolol fumarate and hydrochlorothiazide in pediatric patients have not been established.

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.

What are the side effects of bisoprolol fumarate and hydrochlorothiazide?

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:

Other adverse experiences that have been reported with the individual components are listed below.

Array	a) Averages adjusted to combine across studies.	b) Combined across studies.



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	0.9
Respiratory
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	0.9
URI	2.3	2.1	0.0	0.0
Body 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	0.9
Central Nervous System
dizziness	1.8	5.1	1.8	3.2
headache	4.7	4.5	2.7	0.4
Musculoskeletal
muscle cramps	0.7	1.2	0.7	1.1
myalgia	1.4	2.4	0.0	0.0
Psychiatric
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	1.1
Gastrointestinal
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

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 effects:

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, and respiratory distress.

Hematologic

Agranulocytosis, thrombocytopenia.

Gastrointestinal

Mesenteric arterial thrombosis and ischemic colitis.

Miscellaneous

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive foreign marketing experience.

Hydrochlorothiazide

The following adverse experiences, in addition to those listed in the above table, have been reported with hydrochlorothiazide (generally with doses of 25 mg or greater).

General

Weakness.

Central Nervous System

Vertigo, paresthesia, restlessness.

Cardiovascular

Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).

Gastrointestinal

Anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis, dry mouth.

Musculoskeletal

Muscle spasm.

Hypersensitive Reactions

Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Special Senses

Transient blurred vision, xanthopsia.

Metabolic

Gout.

Genitourinary

Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis.

Skin

Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

Laboratory Abnormalities

Bisoprolol fumarate and hydrochlorothiazide

Because of the low dose of hydrochlorothiazide in bisoprolol fumarate and hydrochlorothiazide, adverse metabolic effects with bisoprolol fumarate/HCTZ 6.25 mg are less frequent and of smaller magnitude than with HCTZ 25 mg. Laboratory data on serum potassium from the U.S. placebo-controlled trials are shown in the following table:

Treatment with both beta-blockers and thiazide diuretics is associated with increases in uric acid. However, the magnitude of the change in patients treated with bisoprolol fumarate/HCTZ 6.25 mg was smaller than in patients treated with HCTZ 25 mg. Mean increases in serum triglycerides were observed in patients treated with bisoprolol fumarate and hydrochlorothiazide 6.25 mg. Total cholesterol was generally unaffected, but small decreases in HDL cholesterol were noted.

Other laboratory abnormalities that have been reported with the individual components are listed below.

Array	a) Combined across studies.	b)Patients with normal serum potassium at baseline.	c) Mean change from baseline at Week 4.	d) Percentage of patients with abnormality at Week 4.
	Placebo


Mean Change (mEq/L)	+0.04	+0.11	-0.08	0.00	-0.30%
Hypokalemia	0.0%	0.0%	0.7%	0.0%	5.5%

Bisoprolol Fumarate

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. There have been occasional reports of eosinophilia. 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.

Hydrochlorothiazide

Hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances (see ), hyperlipidemia, hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with HCTZ therapy.

What should I look out for while using bisoprolol fumarate and hydrochlorothiazide?

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients in cardiogenic shock, overt cardiac failure (see ), second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

What might happen if I take too much bisoprolol fumarate and hydrochlorothiazide?

There are limited data on overdose with bisoprolol fumarate and hydrochlorothiazide. However, several cases of overdose with bisoprolol fumarate have been reported (maximum: 2000 mg). Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.

The most frequently observed signs expected with overdosage of a beta-blocker are bradycardia and hypotension. Lethargy is also common, and with severe overdoses, delirium, coma, convulsions, and respiratory arrest have been reported to occur. Congestive heart failure, bronchospasm, and hypoglycemia may occur, particularly in patients with underlying conditions. With thiazide diuretics, acute intoxication is rare. The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and symptoms include cardiovascular (tachycardia, hypotension, shock), neuromuscular (weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness), gastrointestinal (nausea, vomiting, thirst), renal (polyuria, oliguria, or anuria [due to hemoconcentration]), and laboratory findings (hypokalemia, hyponatremia, hypochloremia, alkalosis, increased BUN [especially in patients with renal insufficiency]).

If overdosage of bisoprolol fumarate and hydrochlorothiazide is suspected, therapy with bisoprolol fumarate and hydrochlorothiazide should be discontinued and the patient observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprolol fumarate is not dialyzable; similarly, there is no indication that hydrochlorothiazide is dialyzable. Suggested general measures include induction of emesis and/or gastric lavage, administration of activated charcoal, respiratory support, correction of fluid and electrolyte imbalance, and treatment of convulsions. Based on the expected pharmacologic actions and recommendations for other beta-blockers and hydrochlorothiazide, the following measures should be considered when clinically warranted:

How should I store and handle bisoprolol fumarate and hydrochlorothiazide?

Unopened vials of gemcitabine for injection, USP are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature] [].Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.Bisoprolol Fumarate and Hydrochlorothiazide Tablets USP are supplied as2.5 mg/6.25 mgLight yellow coloured, biconvex, round, film coated tablets debossed with UL on one side and | on other side.Bottles of 30: NDC 29300-187-13Bottles of 100: NDC 29300-187-01Bottles of 500: NDC 29300-187-05Bottles of 1000: NDC 29300-187-105 mg/6.25 mgSalmon pink coloured, biconvex, round, film coated tablets debossed with UL on one side and | | on other side.Bottles of 30: NDC 29300-188-13Bottles of 100: NDC 29300-188-01Bottles of 500: NDC 29300-188-05Bottles of 1000: NDC 29300-188-1010 mg/6.25 mgWhite coloured, biconvex, round, film coated tablets debossed with UL on one side and | | | on other side.Bottles of 30: NDC 29300-189-13Bottles of 100: NDC 29300-189-01Bottles of 500: NDC 29300-189-05Bottles of 1000: NDC 29300-189-10Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in a tight container.Please address medical inquiries to Unichem's toll free # 1-866-562-4616.

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Bisoprolol fumarate and hydrochlorothiazide

In healthy volunteers, both bisoprolol fumarate and hydrochlorothiazide are well absorbed following oral administration of bisoprolol fumarate and hydrochlorothiazide. No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether bisoprolol fumarate and hydrochlorothiazide is taken with or without food. Mean peak bisoprolol fumarate plasma concentrations of about 9 ng/mL, 19 ng/mL and 36 ng/mL occur approximately 3 hours after the administration of the 2.5 mg/6.25 mg, 5 mg/6.25 mg and 10 mg/6.25 mg combination tablets, respectively. Mean peak plasma hydrochlorothiazide concentrations of 30 ng/mL occur approximately 2.5 hours following the administration of the combination. Dose proportional increases in plasma bisoprolol concentrations are observed between the 2.5 and 5, as well as between the 5 and 10 mg doses. The elimination Tof bisoprolol ranges from 7 to 15 hours, and that of hydrochlorothiazide ranges from 4 to 10 hours. The percent of dose excreted unchanged in urine is about 55% for bisoprolol and about 60% for hydrochlorothiazide.

Bisoprolol Fumarate

The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. The first pass metabolism of bisoprolol fumarate is about 20%.

The pharmacokinetic profile of bisoprolol fumarate has been examined following single doses and at steady state. Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of dosing with 2.5 to 20 mg, and mean peak values range from 9 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with bisoprolol fumarate results in less than two-fold intersubject variation in peak plasma concentrations. Plasma concentrations are proportional to the administered dose in the range of 2.5 to 20 mg. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part because of decreased renal function. Steady state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the half-life and once-daily dosing. Bisoprolol is eliminated equally by renal and nonrenal pathways with about 50% of the dose appearing unchanged in the urine and the remainder in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. The pharmacokinetic characteristics of the two enantiomers are similar. Bisoprolol is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).

In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.

In patients with liver cirrhosis, the rate of elimination of bisoprolol is more variable and significantly slower than that in healthy subjects, with a plasma half-life ranging from 8 to 22 hours.

In elderly subjects, mean plasma concentrations at steady state are increased, in part attributed to lower creatinine clearance. However, no significant differences in the degree of bisoprolol accumulation is found between young and elderly populations.

Hydrochlorothiazide

Hydrochlorothiazide is well absorbed (65%-75%) following oral administration. Absorption of hydrochlorothiazide is reduced in patients with congestive heart failure.

Peak plasma concentrations are observed within 1-5 hours of dosing, and range from 70 to 490 ng/mL following oral doses of 12.5 to 100 mg. Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide are 1.6-1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6-15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 to 100 mg, 55%-77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. Plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged in patients with renal disease.

Non-Clinical Toxicology

Bisoprolol fumarate and hydrochlorothiazide tablets are contraindicated in patients in cardiogenic shock, overt cardiac failure (see ), second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.

Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued.

Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and C of 43% and 39%, respectively.

Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see and )

Digoxin - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram and lithium are coadministered.

Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or C of pimozide. The mechanism of this pharmacodynamic interaction is not known.

Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.

Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the C and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

CYP2C19 Inhibitors – Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see , and ).

Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the betaadrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine and Other Tricyclic Antidepressants (TCAs) - studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram.

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.

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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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