Bisoprolol Fumarate Hydrochlorothiazide

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Overview

What is Bisoprolol Fumarate Hydrochlorothiazide?

Bisoprolol fumarate and hydrochlorothiazide is 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)•CHOand 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 USP (HCTZ) is 6-Chloro-3,4-dihydro-2-1,2,4-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 sodiumum 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 CHCINOS and it has a molecular weight of 297.73. Its structural formula is:

Each tablet, for oral administration contains 2.5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, 5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, or 10 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide. In addition, each tablet contains the following inactive ingredients: colloidal silicone dioxide, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The film-coating contains the following ingredients: hypromellose, lactose monohydrate (2.5 mg/6.25 mg and 5 mg/6.25 mg only), polyethylene glycol (10 mg/6.25 mg only), polydextrose (10 mg/6.25 mg only), purified stearic acid (5 mg/6.25 mg only), synthetic red iron oxide (5 mg/6.25 mg only), synthetic yellow iron oxide (2.5 mg/6.25 mg and 5 mg/6.25 mg only), titanium dioxide, and triacetin.

What does Bisoprolol Fumarate Hydrochlorothiazide look like?

What are the available doses of Bisoprolol Fumarate Hydrochlorothiazide?

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What should I talk to my health care provider before I take Bisoprolol Fumarate Hydrochlorothiazide?

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How should I use Bisoprolol Fumarate Hydrochlorothiazide?

Bisoprolol and hydrochlorothiazide is indicated in the management of hypertension.

Bisoprolol fumarate 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 mg to 50 mg. In clinical trials of bisoprolol fumarate/hydrochlorothiazide combination therapy using bisoprolol fumarate doses of 2.5 mg 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 fumarate are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea, asthenia and fatigue) and dose-independent phenomena (eg, occasional rash); those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, 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 fumarate 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 fumarate and hydrochlorothiazide should produce minimal dose dependent adverse effects, eg, bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, ie, decreases in serum potassium (see ).

What interacts with Bisoprolol Fumarate Hydrochlorothiazide?

Bisoprolol and hydrochlorothiazide is 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 Hydrochlorothiazide?

Codeine is habit-forming and potentially abusable. Consequently, the extended use of this product is not recommended.

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive heart 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 and hydrochlorothiazide should be considered. In some cases bisoprolol 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 and hydrochlorothiazide over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking 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

Anesthesia and Major Surgery

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

Hepatic Disease

Bisoprolol 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 is significantly slower in patients with cirrhosis than in healthy subjects. (See ).

What are the precautions of Bisoprolol Fumarate Hydrochlorothiazide?

General

Although the probability of developing hypokalemia is reduced with bisoprolol 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, ie, 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.

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 or acute gout may be precipitated in certain patients receiving thiazide diuretics. Bisoprolol, 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 and hydrochlorothiazide.

Drug interactions

Bisoprolol and hydrochlorothiazide may potentiate the action of other antihypertensive agents used concomitantly. Bisoprolol 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 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 and hydrochlorothiazide be discontinued for several days before the withdrawal of clonidine.

Bisoprolol 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.

Concurrent use of rifampin increases the metabolic clearance of bisoprolol, 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, digoxin and cimetidine. There was no effect of bisoprolol on prothrombin times in patients on stable doses of warfarin.

Risk of Anaphylactic Reaction:

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 reduces its absorption in the gastrointestinal tract by up to 85 and 43 percent, respectively.

Cortocosteroids, ACTH - Intensified electrolyte depletion, particularly hypokalemia.

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

Skeletal muscle relaxants, nondepolarizing (eg, 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 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 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 and hydrochlorothiazide may decrease serum levels of protein-bound iodine without signs of thyroid disturbance.

Because it includes a thiazide, bisoprolol 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 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 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

Pregnancy

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 alone or in combination with HCTZ has not been studied in nursing mothers. Thiazides are excreted in human breast milk. Small amounts of bisoprolol (<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 and hydrochlorothiazide in pediatric patients have not been established.

Geriatric Use

In clinical trials, at least 270 patients treated with bisoprolol 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 Hydrochlorothiazide?

Bisoprolol and hydrochlorothiazide:

Bisoprolol/H6.25 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, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for B/H6.25 mg and placebo-treated patients.

In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/H6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/H6.25 mg was administered for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10 or 40/H6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with B2.5-10/H6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/H6.25 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.

% of Patients with Adverse Experiences*
*Averages adjusted to combine across studies.
†
	Body System/		Drug Related
	Adverse Experience	All Adverse Experiences	Adverse Experiences
	Placebo	B2.5-40/ H6.25	Placebo	B2.5-10/ H6.25
	(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	0.9
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
mylagia	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

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.

Laboratory Abnormalities

Because of the low dose of hydrochlorothiazide in bisoprolol and hydrochlorothiazide, adverse metabolic effects with B/H6.25 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 B/H 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 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.

**Serum Potassium Data from U.S. Placebo Controlled Studies**
* Patients with normal serum potassium at baseline.
a
b
†
		B2.5/H6.25 mg		B5/H6.25 mg		B10/H6.25 mg
	(n=130*)	(n=28*)	(n=149*)	(n=28*)	(n=142*)
	Potassium
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%

In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.

Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT of between 1-2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.

In the long-term, uncontrolled experience with bisoprolol treatment for 6-18 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 occurrence was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol.

Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. There have been occasional reports of eosinophilia. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol.

As with other beta-blockers, ANA conversions have also been reported on bisoprolol. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.

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

What should I look out for while using Bisoprolol Fumarate Hydrochlorothiazide?

Bisoprolol and hydrochlorothiazide is 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.

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive heart 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 and hydrochlorothiazide should be considered. In some cases bisoprolol 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 and hydrochlorothiazide over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking 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

-selectively of bisoprolol fumarate, bisoprolol 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 and hydrochlorothiazide should be used. A beta

agonist (bronchodilator) should be made available.

Anesthesia and Major Surgery

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

Hepatic Disease

Bisoprolol 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 is significantly slower in patients with cirrhosis than in healthy subjects. (See ).

What might happen if I take too much Bisoprolol Fumarate Hydrochlorothiazide?

There are limited data on overdose with bisoprolol and hydrochlorothiazide. However, several cases of overdose with bisoprolol 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 and hydrochlorothiazide is suspected, therapy with bisoprolol and hydrochlorothiazide should be discontinued and the patient observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprolol 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 betablockers and hydrochlorothiazide, the following measures should be considered when clinically warranted.

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

Hypotension, Shock: The patient’s legs should be elevated. IV fluids should be administered and lost electrolytes (potassium, sodium) replaced. Intravenous glucagon may be useful. Vasopressors should be considered.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Congestive Heart Failure: Initiate conventional therapy (ie, digitalis, diuretics, vasodilating agents, inotropic agents).

Bronchospasm: Administer a bronchodilator such as isoproterenol and/or aminophylline.

Hypoglycemia: Administer IV glucose.

Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until normalized.

How should I store and handle Bisoprolol Fumarate Hydrochlorothiazide?

Store unreconstituted vials at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F) (See USP Controlled Room Temperature).Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:Bisoprolol Fumarate and Hydrochlorothiazide Tablets (film-coated) are supplied as follows:2.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Yellow, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed and , in bottles of 100 and 500.10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed and , in bottles of 30 and 100.Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a well-closed container as defined in USP/NF.Manufactured forManufactured by:

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Bisoprolol and HCTZ have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive; HCTZ 6.25 mg significantly increases the antihypertensive effect of bisoprolol. The incidence of hypokalemia with the bisoprolol fumarate and HCTZ 6.25 mg combination (B/H) is significantly lower than with HCTZ 25 mg. In clinical trials of bisoprolol and hydrochlorothiazide, mean changes in serum potassium for patients treated with bisoprolol fumarate and hydrochlorothiazide 2.5/6.25 mg, or 5/6.25 mg or 10/6.25 mg or placebo were less than ± 0.1 mEq/L. Mean changes in serum potassium for patients treated with any dose of bisoprolol in combination with HCTZ 25 mg ranged from -0.1 to -0.3 mEq/L.

Bisoprolol is a beta-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses (≥20 mg) bisoprolol also inhibits beta-adrenoreceptors located in bronchial and vascular musculature. To retain relative selectivity, it is important to use the lowest effective dose.

Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanisms of electrolyte reabsorption and increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

Non-Clinical Toxicology

Bisoprolol and hydrochlorothiazide is 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.

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive heart 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 and hydrochlorothiazide should be considered. In some cases bisoprolol 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 and hydrochlorothiazide over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking 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

-selectively of bisoprolol fumarate, bisoprolol 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 and hydrochlorothiazide should be used. A beta

agonist (bronchodilator) should be made available.

Anesthesia and Major Surgery

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

Hepatic Disease

Bisoprolol 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 is significantly slower in patients with cirrhosis than in healthy subjects. (See ).

Bisoprolol and hydrochlorothiazide may potentiate the action of other antihypertensive agents used concomitantly. Bisoprolol 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 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 and hydrochlorothiazide be discontinued for several days before the withdrawal of clonidine.

Bisoprolol 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.

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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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