Bisoprolol Fumarate and Hydrochlorothiazide Tablets
Revised: July 2003
Rx only

Bisoprolol fumarate and hydrochlorothiazide is indicated for the treatment of hypertension. It combines two antihypertensive agents in a once-daily dosage: a synthetic beta₁-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(E)-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 (C₁₈H₃₁NO₄)₂•C₄H₄O₄ 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 USP (HCTZ) is 6-Chloro-3,4-dihydro-2H-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 C₇H₈CIN₃O₄S₂ 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.

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 beta₁-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 beta₂-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.

In controlled clinical trials, bisoprolol fumarate/hydrochlorothiazide 6.25 mg has been shown to reduce systolic and diastolic blood pressure throughout a 24-hour period when administered once daily. The effects on systolic and diastolic blood pressure reduction of the combination of bisoprolol and hydrochlorothiazide were additive. Further, treatment effects were consistent across age groups (< 60, ≥ 60 years), racial groups (black, nonblack), and gender (male, female).

In two randomized, double-blind, placebo-controlled trials conducted in the U.S., reductions in systolic and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies mean systolic/diastolic blood pressure and heart rate at baseline were approximately 151/101 mm Hg and 77 bpm.

Blood pressure responses were seen within 1 week of treatment but the maximum effect was apparent after 2 to 3 weeks of treatment. Overall, significantly greater blood pressure reductions were observed on bisoprolol and hydrochlorothiazide than on placebo. Further, blood pressure reductions were significantly greater for each of the bisoprolol plus hydrochlorothiazide combinations than for either of the components used alone regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.

Bisoprolol and hydrochlorothiazide is indicated in the management of hypertension.

Bisoprolol and hydrochlorothiazide is contraindicated in patients in cardiogenic shock, overt cardiac failure (see WARNINGS), 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 beta₁-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 beta₁-selectivity is not absolute, the lowest possible dose of bisoprolol and hydrochlorothiazide should be used. A beta₂ 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 OVERDOSAGE for information on treatment of bradycardia and hypotension.

Diabetes and Hypoglycemia

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of the beta₁-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
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 is increased up to threefold, as compared to healthy subjects. If progressive renal impairment becomes apparent, bisoprolol and hydrochlorothiazide should be discontinued. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

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 CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

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.

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 PRECAUTIONS - Parathyroid Disease).

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.

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.

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

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.

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 uled below.

In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those uled above, have been reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are uled 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.

The following adverse experiences, in addition to those uled 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.

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.

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 WARNINGS) 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 CLINICAL PHARMACOLOGY).

A patient whose blood pressure is not adequately controlled with 2.5 mg to 20 mg bisoprolol fumarate daily may instead be given bisoprolol fumarate and hydrochlorothiazide. Patients whose blood pressures are adequately controlled with 50 mg of hydrochlorthiazide daily, but who experience significant potassium loss with this regimen, may achieve similar blood pressure control without electrolyte disturbance if they are switched to bisoprolol fumarate and hydrochlorothiazide.

Antihypertensive therapy may be initiated with the lowest dose of bisoprolol fumarate, one 2.5/6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with bisoprolol fumarate and hydrochlorothiazide tablets up to the maximum recommended dose 20/12.5 mg (two 10/6.25 mg tablets) once daily, as appropriate.

The combination may be substituted for the titrated individual components.

If withdrawal of bisoprolol fumarate and hydrochlorothiazide therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed.

Patients with Renal or Hepatic Impairment: As noted in the WARNINGS section, caution must be used in dosing/titrating patients with hepatic impairment or renal dysfunction. Since there is no indication that hydrochlorothiazide is dialyzable, and limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

Geriatric Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction (see above and WARNINGS section).

Pediatric Patients: There is no pediatric experience with bisoprolol fumarate and hydrochlorothiazide.

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 WATSON and 841, in bottles of 100 and 500.

5 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: Pink, round, biconvex, film-coated tablets debossed WATSON and 842, in bottles of 100 and 500.

10 mg Bisoprolol fumarate/6.25 mg hydrochlorothiazide tablets: White, round, biconvex, film-coated tablets debossed WATSON and 843, 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 for:
Watson Laboratories, Inc.
Corona, CA 92880 USA

Manufactured by:
Patheon Pharmaceuticals Inc.
Cincinnati, OH 45215 USA
Revised: July 2003