Bisoprolol and Hydrochlorothiazide (Ziac)
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Bisoprolol and Hydrochlorothiazide (Ziac)

ZIAC®
(bisoprolol fumarate and hydrochlorothiazide) Tablets

DRUG DESCRIPTION

ZIAC® (bisoprolol fumarate and hydrochlorothiazide) is indicated for the treatment of hypertension. It combines two antihypertensive agents in a once-daily dosage: a synthetic betar selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a benzothiadiazine diuretic (hydrochlorothiazide).

Bisoprolol fumarate is chemically described as (±)-l-[4-[[2-(l- methylethoxy)ethoxy]methyl]phenoxy]-3-[(l-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 empirical formula is (C18H31NO4)2•C4H4O4 and it has a molecular weight of 766.97. Its structural formula is:

Bisoprolol fumarate Structural Formula Illustration

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-2H-l,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 empirical formula is C7H8ClN3O4S2 and it has a molecular weight of 297.73. Its structural formula is:

Hydrochlorothiazide Structural Formula Illustration

Each ZIAC®-2.5 mg/6.25 mg tablet for oral administration contains:

Bisoprolol fumarate................................2.5 mg
Hydrochlorothiazide...............................6.25 mg

Each ZIAC®-5 mg/6.25 mg tablet for oral administration contains:

Bisoprolol fumarate................................5 mg
Hydrochlorothiazide...............................6.25 mg

Each ZIAC®-10 mg/6.25 mg tablet for oral administration contains:

Bisoprolol fumarate................................10 mg
Hydrochlorothiazide...............................6.25 mg

Inactive ingredients include Corn Starch, Dibasic Calcium Phosphate, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80, and Titanium Dioxide. The 10 mg/6.25 mg tablet also contains Colloidal Silicon Dioxide. The 5 mg/6.25 mg tablet also contains Colloidal Silicon Dioxide, and Red and Yellow Iron Oxide. The 2.5 mg/6.25 mg tablet also contains Crospovidone, Pregelatinized Starch, and Yellow Iron Oxide.

What are the possible side effects of hydrochlorothiazide and bisoprolol (Ziac)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using this medication and call your doctor at once if you have any of these serious side effects:

  • eye pain, vision problems;
  • swelling, rapid weight gain, feeling short of breath, even with mild exertion;
  • fast, slow, or uneven heartbeat;
  • easy bruising or bleeding;
  • sudden numbness or weakness, especially on one side of the body;
  • sudden severe...

Read All Potential Side Effects and See Pictures of Ziac »

What are the precautions when taking bisoprolol and hydrochlorothiazide (Ziac)?

Before taking this medication, tell your doctor or pharmacist if you are allergic to bisoprolol or hydrochlorothiazide; or to other beta blockers (e.g., metoprolol, atenolol); or to other thiazide diuretics (e.g., chlorothiazide); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain types of heart rhythm problems (e.g., sinus bradycardia, second- or third-degree atrioventricular block), certain serious heart conditions (cardiogenic shock, severe heart failure), inability to urinate...

Read All Potential Precautions of Ziac »

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

ZIAC (bisoprolol fumarate and hydrochlorothiazide) is indicated in the management of hypertension.

DOSAGE AND ADMINISTRATION

Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 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 to 25 mg, the antihypertensive effects increased with increasing doses of either component.

The adverse effects (see WARNINGS) of bisoprolol 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 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, eg, bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, ie, decreases in serum potassium (see CLINICAL PHARMACOLOGY).

Therapy Guided by Clinical Effect

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

Initial Therapy

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

Replacement Therapy

The combination may be substituted for the titrated individual components.

Cessation of Therapy

If withdrawal of ZIAC 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 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 ZIAC.

HOW SUPPLIED

ZIAC®-2.5 mg/6.25 mg Tablets (bisoprolol fumarate 2.5 mg and hydrochlorothiazide 6.25 mg): Yellow, round, film-coated, unscored tablets. Debossed with stylized b within an engraved heart shape on one side and 47 on the other side, supplied as follows:

Bottle of 100 Tablets NDC 5 1285-047-02

ZIAC®-5 mg/6.25 mg Tablets (bisoprolol fumarate 5 mg and hydrochlorothiazide 6.25 mg): Pink, round, film-coated, unscored tablets. Debossed with stylized b within an engraved heart shape on one side and 50 on the other side, supplied as follows:

Bottle of 100 Tablets NDC 5 1285-050-02

ZIAC®-10 mg/6.25 mg Tablets (bisoprolol fumarate 10 mg and hydrochlorothiazide 6.25 mg): White, round, film-coated, unscored tablets. Debossed with stylized b within an engraved heart shape on one side and 40 on the other side, supplied as follows:

Bottle of 30 Tablets with child resistant closure NDC 5 1285-040-01

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight container.

Duramed Pharmaceuticals, Inc., Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970. Revised March 2011

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

ZIAC

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 rumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/HCTZ 6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table:

% of Patients with Adverse Experiencesa

Body System/Adverse Experience All Adverse Experiences Drug Related
Adverse Experiences
Placebob B2.5-40/H6.25b Placebob B2.5-10/H6.25b
(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
  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
a) Averages adjusted to combine across studies, b) Combined across studies.

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

Bisoprolol Fumarate

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

Central Nervous System

Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory.

Cardiovascular

Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.

Gastrointestinal

Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth.

Musculoskeletal

Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.

Skin

Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vasculitis.

Special Senses

Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.

Metabolic

Gout.

Respiratory

Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection).

Genitourinary

Decreased libido/impotence, Peyronie's disease (very rarely), cystitis, renal colic, polyuria.

General

Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.

In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse 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

ZIAC

Because of the low dose of hydrochlorothiazide in ZIAC (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:

Serum Potassium Data from U.S. Placebo Controlled Studies

  Placeboa B2.5/H6.25 mg B5/H6.25 mg B10/H6.25 mg HCTZ 25mga
  (N=130b) (N=28b) (N=149b) (N=28b) (N=142b)
Potassium
Mean Changec (mEq/L) +0.04 +0.11 -0.08 0.00 -0.30%
Hypokalemiad 0.0% 0.0% 0.7% 0.0% 5.5%
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.

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 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.

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 PRECAUTIONS), hyperlipidemia, hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with HCTZ therapy.

Read the Ziac (bisoprolol and hydrochlorothiazide) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

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

ZIAC 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 ZLAC.

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 ZLAC 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, ZIAC (bisoprolol fumarate and hydrochlorothiazide) may decrease serum levels of protein-bound iodine without signs of thyroid disturbance.

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

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure, it may be necessary to utilize these agents. In such situations, they must be used cautiously.

Patients Without a History of Cardiac Failure

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of ZIAC should be considered. In some cases ZIAC 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 ZIAC (bisoprolol fumarate and hydrochlorothiazide) over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative betai-selectivity of bisoprolol fumarate, ZIAC may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since betai-selectivity is not absolute, the lowest possible dose of ZIAC should be used. A beta2 agonist (bronchodilator) should be made available.

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Diabetes and Hyopglycemia

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 betai-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 ZIAC.

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, ZIAC should be discontinued (See Pharmacokinetics and Metabolism).

Hepatic Disease

ZIAC 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 Pharmacokinetics and Metabolism).

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.

PRECAUTIONS

General

Electrolyte and Fluid Balance Status

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

Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium-rich foods.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than salt administration, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Parathyroid Disease

Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

Hyperuricemia

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

ZIAC

Long-term studies have not been conducted with the bisoprolol fumarate/hydrochlorothiazide combination.

Bisoprolol Fumarate

Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, or 0.4 mg/kg/day, based on 50 kg individuals; on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD.

Hydrochlorothiazide

Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP), treated mice and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body weight basis, these doses are 2400 times (in mice) and 400 times (in rats) the MRHD of hydrochlorothiazide (12.5 mg/day) in ZIAC (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

ZIAC

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

Bisoprolol Fumarate

The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Hydrochlorothiazide

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

Impairment of Fertility

ZIAC

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

Teratogenic Effects-Pregnancy Category C

ZIAC

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

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There are limited data on overdose with ZLAC. 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 ZIAC (bisoprolol fumarate and hydrochlorothiazide) is suspected, therapy with ZIAC 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:

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.

CONTRAINDICATIONS

ZIAC 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.

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Bisoprolol fumarate 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 fumarate. 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 ZIAC, mean changes in serum potassium for patients treated with ZIAC 2.5/6.25 mg, 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 fumarate is a betai-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses ( ≥ 20 mg) bisoprolol fumarate 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.

Pharmacokinctics and Metabolism

ZIAC

In healthy volunteers, both bisoprolol fumarate and hydrochlorothiazide are well absorbed following oral administration of ZIAC. No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether ZIAC is taken with or without food. Mean peak bisoprolol fumarate plasma concentrations of about 9.0 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 T1/2 of 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 9.0 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with bisoprolol fumarate results in less than twofold 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 70-490 ng/mL following oral doses of 12.5-100 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 12.5-100 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.

Pharmacodynamics

Bisoprolol Fumarate

Findings in clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blockers. The most prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater.

In controlled clinical trials, bisoprolol fumarate given as a single daily dose has been shown to be an effective antihypertensive agent when used alone or concomitantly with thiazide diuretics (see Clinical Studies).

The mechanism of bisoprolol fumarate's antihypertensive effect has not been completely established. Factors that may be involved include:

  1. Decreased cardiac output,
  2. Inhibition of renin release by the kidneys,
  3. Diminution of tonic sympathetic outflow from vasomotor centers in the brain.

Beta1-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta2-adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.

Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.

Hydrochlorothiazide

Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased.

Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours.

Clinical Studies

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 fumarate 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.

Sitting Systolic/Diastolic Pressure (BP) and Heart Rate (HR)

  Mean Decrease (Δ) After 3-4 Weeks  
  Study 1 Study 2
  Placebo B5/H6.25 mg Placebo H6.25 mg B2.5/H6.25 mg B10/H6.25 mg
n= 75 150 56 23 28 25
Total ABP (mmHg) -2.9/-3.9 -15.8/-12.6 -3.0/-3.7 -6.6/-5.8 -14.1/-10.5 -15.3/-14.3
Drug Effecta -/- -12.9/-8.7 -/- -3.6/-2.1 -11.1/-6.8 -12.3/-10.6
Total ΔHR (bpm) -0.3 -6.9 -1.6 -0.8 -3.7 -9.8
Drug Effecta - -6.6 - +0.8 -2.1 -8.2
a) Observed mean change from baseline minus placebo.

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 ZIAC than on placebo. Further, blood pressure reductions were significantly greater for each of the bisoprolol fumarate 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.

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patients, especially those with coronary artery disease, should be warned against discontinuing use of ZIAC 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.

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Patients, especially those with coronary artery disease, should be warned against discontinuing use of ZIAC 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.

Last reviewed on RxList: 8/16/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Ziac Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

BISOPROLOL/HYDROCHLOROTHIAZIDE - ORAL

(BIS-oh-PROE-lol/HYE-droe-KLOR-oh-THYE-a-zide)

COMMON BRAND NAME(S): Ziac

WARNING: If you have chest pain (angina) or heart disease (e.g., coronary artery disease, ischemic heart disease, high blood pressure), do not stop using this drug without first consulting your doctor. Your condition may become worse when the drug is suddenly stopped. If your doctor decides you should no longer use this drug, you must gradually decrease your dose according to your doctor's instructions.

When gradually stopping this medication, it is recommended that you temporarily limit physical activity to decrease strain on the heart. Seek immediate medical attention if you develop: worsening chest pain, tightness or pressure in the chest, chest pain spreading to the jaw/neck/arm, sweating, trouble breathing, or fast/irregular heartbeat.

USES: This combination medication is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.

This product contains two medications. Bisoprolol is a beta blocker that works by blocking the effect of certain natural chemicals (e.g., epinephrine) on the heart and blood vessels. This slows your heartbeat, lowers blood pressure, and reduces strain on the heart. Hydrochlorothiazide is a "water pill" (diuretic) that works by increasing the amount of urine that you make. This causes your body to get rid of extra salt and water, which probably helps to relax the blood vessels so that blood can flow more easily. These two drugs are used together when one medication is not controlling your blood pressure. Using these two drugs together can also reduce the amount of each drug you must take, thereby decreasing the chances of side effects.

HOW TO USE: See also Warning section.

Take this medication by mouth with or without food, usually once daily as directed by your doctor.

The dosage is based on your medical condition and response to therapy.

It is best to avoid taking this medication within 4 hours of your bedtime to avoid having to get up to urinate. Consult your doctor or pharmacist if you have questions about your dosing schedule.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. It may take up to 3 weeks before you get the full benefit of this drug.

Inform your doctor if your condition worsens (e.g., your routine blood pressure readings increase).

Disclaimer

Ziac Consumer (continued)

SIDE EFFECTS: See also Precautions section.

Dizziness, lightheadedness, tiredness, and drowsiness may occur as your body adjusts to the medication. Nausea, stomach upset, diarrhea, cough, constipation and trouble sleeping may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

To lower your risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

This product may reduce blood flow to your hands and feet, causing them to feel cold. Smoking may worsen this effect. Dress warmly and avoid tobacco use.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

The hydrochlorothiazide in this product may cause too much body water and salts to be lost (dehydration). Tell your doctor immediately if you have any of these unlikely but serious symptoms of dehydration: very dry mouth, extreme thirst, muscle cramps/weakness, fast heartbeat, severe dizziness, unusual decrease in the amount of urine, fainting, seizures.

Tell your doctor immediately if any of these unlikely but serious side effects occur: very slow/irregular heartbeat, swelling of the ankles/feet, sudden/unexplained weight gain, loss of feeling/tingling in the fingers/toes, hair loss, decrease in vision, eye pain, mental/mood changes, decreased sexual ability/interest, muscle/joint pain, persistent nausea/vomiting, yellowing eyes/skin, severe stomach/abdominal pain, dark urine, nervousness, shaking, confusion, easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), change in the amount of urine (not including the normal increase in urine when you first start this drug).

Seek immediate medical attention if this rare but very serious side effect occurs: trouble breathing.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Ziac (bisoprolol and hydrochlorothiazide) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to bisoprolol or hydrochlorothiazide; or to other beta blockers (e.g., metoprolol, atenolol); or to other thiazide diuretics (e.g., chlorothiazide); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain types of heart rhythm problems (e.g., sinus bradycardia, second- or third-degree atrioventricular block), certain serious heart conditions (cardiogenic shock, severe heart failure), inability to urinate (anuria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, heart failure (treated, stable type), lung disease (e.g., asthma, bronchitis, chronic obstructive pulmonary disease-COPD), overactive thyroid (hyperthyroidism), diabetes, gout, untreated salt imbalance (e.g., high calcium, low potassium/magnesium), loss of too much body water (dehydration), blood circulation problems (e.g., peripheral vascular disease), certain muscle diseases (e.g., myasthenia gravis), lupus, high cholesterol/triglyceride levels, recent nerve surgery (e.g., sympathectomy).

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Drink plenty of fluids while taking this medication to help prevent dizziness. Too much sweating, diarrhea, or vomiting may cause you to feel lightheaded. Avoid heavy exercise and hot weather. Report prolonged diarrhea or vomiting to your doctor.

If you have diabetes, this product may mask the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of a low blood sugar level, such as dizziness/sweating, are unaffected by this drug. This product also may make it harder to control your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar such as increased thirst, hunger, and urination. Your anti-diabetic medication or diet may need to be adjusted.

This medication may reduce the potassium levels in your blood. Ask your doctor about adding potassium to your diet. A potassium supplement may be prescribed by your doctor.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This drug passes into breast milk and could have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.

Disclaimer

Ziac Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: arbutamine, cisapride, dofetilide.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha blockers (e.g., prazosin, terazosin), barbiturates (e.g., phenobarbital), diazoxide, digoxin, drugs that affect heart rhythm (e.g., procainamide, disopyramide), drugs that may decrease your potassium level (e.g., amphotericin B, corticotropin, corticosteroids including prednisone), drugs whose removal from the body is affected by the acid level of urine (e.g., amphetamine, methenamine, quinidine), epinephrine, fenoldopam, lithium, narcotic drugs for pain (e.g., morphine, codeine), other drugs for high blood pressure (e.g., clonidine, reserpine, calcium channel blockers such as diltiazem, verapamil, nifedipine), probenecid, rifamycins (e.g., rifampin), St John's wort.

Cholestyramine and colestipol may decrease the absorption of this medication. If you are taking either of these drugs, separate them from this medication by at least 4 hours.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, nonsteroidal anti-inflammatory drugs-NSAIDs for pain/fever reduction) because they may contain ingredients that could increase your blood pressure (e.g., pseudoephedrine, phenylephrine) or reduce the effect of this medication (e.g., ibuprofen, naproxen). Ask your pharmacist about the safe use of those products.

This product can affect the results of certain lab tests (e.g., parathyroid, protein-bound iodide, tyramine and phentolamine tests). Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center. Symptoms of overdose may include: very slow heartbeat, severe dizziness, fainting, severe weakness, trouble breathing.

NOTES: Do not share this medication with others.

Talk with your doctor about making changes to your lifestyle that may increase the effectiveness of this medication (e.g., stress reduction programs, exercise, and dietary changes).

Laboratory and/or medical tests (e.g., electrolyte levels, liver function tests, complete blood counts) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure checked regularly while taking this medication. Learn how to monitor your own blood pressure at home, and share the results with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised May 2012. Copyright(c) 2012 First Databank, Inc.

Ziac Patient Information Including Side Effects

Brand Names: Ziac

Generic Name: hydrochlorothiazide and bisoprolol (Pronunciation: HYE droe klor oh THYE a zide and bi SOE proe lol)

What is hydrochlorothiazide and bisoprolol (Ziac)?

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Bisoprolol is a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through arteries and veins).

The combination of hydrochlorothiazide and bisoprolol is used to treat high blood pressure (hypertension).

Hydrochlorothiazide and bisoprolol may also be used for purposes not listed in this medication guide.

Bisoprolol-HCT 10 mg-6.25 mg-PUR

oblong, white, imprinted with 652, R

Bisoprolol-HCT 10 mg-6.25 mg-WAT

round, white, imprinted with 843, WATSON

Bisoprolol-HCT 2.5 mg-6.25 mg-WAT

round, yellow, imprinted with 841, WATSON

Bisoprolol-HCT 5 mg-6.25 mg-WAT

round, pink, imprinted with 842, WATSON

Bisoprolol-HCTZ 10 mg-6.25 mg-EON

round, white, imprinted with E 707

Bisoprolol-HCTZ 10-6.25 mg-MYL

round, white, imprinted with 505, M

Bisoprolol-HCTZ 2.5 mg-6.25 mg-EON

round, peach, imprinted with E 701

Bisoprolol-HCTZ 2.5-6.25 mg-MYL

round, orange, imprinted with 501, M

Bisoprolol-HCTZ 5 mg-6.25 mg-EON

round, red, imprinted with E 704

Bisoprolol-HCTZ 5-6.25 mg-MYL

round, blue, imprinted with 503, M

Ziac 10 mg

round, white, imprinted with LL, B 14

Ziac 10 mg-BAR

round, white, imprinted with b, 40

Ziac 2.5 mg

round, yellow, imprinted with LL, B 12

Ziac 2.5 mg-BAR

round, yellow, imprinted with b, 47

Ziac 5 mg

round, pink, imprinted with LL, B 13

Ziac 5 mg-BAR

round, pink, imprinted with b, 50

What are the possible side effects of hydrochlorothiazide and bisoprolol (Ziac)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using this medication and call your doctor at once if you have any of these serious side effects:

  • eye pain, vision problems;
  • swelling, rapid weight gain, feeling short of breath, even with mild exertion;
  • fast, slow, or uneven heartbeat;
  • easy bruising or bleeding;
  • sudden numbness or weakness, especially on one side of the body;
  • sudden severe headache, confusion, problems with speech or balance;
  • chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;
  • pain, swelling, warmth, or redness in one or both legs;
  • numbness or tingly feeling in your hands or feet;
  • feeling weak, drowsy, restless, or light-headed;
  • dry mouth, extreme thirst, confusion, increased urination, leg discomfort, muscle weakness or limp feeling, nausea and vomiting;
  • urinating less than usual or not at all;
  • fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; or
  • upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • diarrhea, constipation, upset stomach;
  • dizziness, spinning sensation;
  • cough, runny nose;
  • ringing in your ears; or
  • blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Ziac (bisoprolol and hydrochlorothiazide) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about hydrochlorothiazide and bisoprolol (Ziac)?

You should not use this medication if you have severe or uncontrolled heart failure, a heart condition called "sick sinus syndrome" or "AV block," slow heartbeats, an allergy to sulfa drugs, or if you are unable to urinate.

Before using this medication, tell your doctor if you have congestive heart failure, circulation problems, kidney or liver disease, cirrhosis, glaucoma, asthma, bronchospastic lung disease, a thyroid disorder, lupus, gout, diabetes, or a penicillin allergy.

If you are diabetic, check your blood sugar carefully. Using bisoprolol can make it harder for you to tell when you have low blood sugar. Your insulin or diabetic medication needs may change while you are taking hydrochlorothiazide and bisoprolol. Talk with your doctor before changing any doses.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and bisoprolol.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Keep using this medication even if you feel fine. High blood pressure often has no symptoms.

There are many other medicines that can interact with hydrochlorothiazide and bisoprolol. Tell your doctor about all the prescription and over-the-counter medications you use.

Side Effects Centers

Ziac Patient Information including How Should I Take

What should I discuss with my doctor before taking hydrochlorothiazide and bisoprolol (Ziac)?

You should not use this medication if you are allergic to hydrochlorothiazide or bisoprolol, or if you have:

  • severe or uncontrolled heart failure;
  • a heart condition called "sick sinus syndrome" or "AV block" (2nd or 3rd degree);
  • slow heartbeats;
  • if you are unable to urinate;
  • if you are allergic to sulfa drugs; or
  • if you are allergic to any beta-blocker medication, such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), timolol (Blocadren), and others.

To make sure you can safely take hydrochlorothiazide and bisoprolol, tell your doctor if you have any of these other conditions:

  • congestive heart failure;
  • blood circulation problems;
  • kidney disease;
  • liver disease (or cirrhosis);
  • glaucoma;
  • asthma, or bronchospastic lung disease;
  • a thyroid disorder;
  • lupus;
  • gout;
  • diabetes; or
  • a penicillin allergy.

FDA pregnancy category C. It is not known whether hydrochlorothiazide and bisoprolol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Hydrochlorothiazide can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using hydrochlorothiazide and bisoprolol.

How should I take hydrochlorothiazide and bisoprolol (Ziac)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take the medicine with a meal or right after you eat.

Your doctor may occasionally change your dose to make sure you get the best results.

Do not stop using hydrochlorothiazide and bisoprolol suddenly, or you could have a serious or life-threatening heart problem. Talk to your doctor about how to avoid withdrawal symptoms when stopping the medication.

Your blood pressure will need to be checked often. Your blood and urine may both be tested if you have been vomiting or are dehydrated. Visit your doctor regularly.

If you are diabetic, check your blood sugar carefully. Using bisoprolol can make it harder for you to tell when you have low blood sugar. Your insulin or diabetic medication needs may change while you are taking hydrochlorothiazide and bisoprolol. Talk with your doctor before changing any doses.

Hydrochlorothiazide and bisoprolol can affect the results of certain thyroid tests. Tell any doctor who treats you that you are using this medication.

If you need surgery, tell the surgeon ahead of time that you are using hydrochlorothiazide and bisoprolol. You may need to stop using the medicine for a short time.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store in a tightly closed container at room temperature, away from heat, moisture, and light.

Side Effects Centers

Ziac Patient Information including If I Miss a Dose

What happens if I miss a dose (Ziac)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Ziac)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include fast or slow heart rate, confusion, weakness, shallow breathing, swelling, increased urination, and feeling like you might pass out.

What should I avoid while taking hydrochlorothiazide and bisoprolol (Ziac)?

Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and bisoprolol.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect hydrochlorothiazide and bisoprolol (Ziac)?

Tell your doctor if you regularly use any other medicines that make you light-headed (especially narcotic pain medication or barbiturates). They can add to the side effects of hydrochlorothiazide and bisoprolol.

Many drugs can interact with hydrochlorothiazide and bisoprolol. Below is just a partial list. Tell your doctor if you are using:

  • insulin or oral diabetes medication;
  • colestipol (Colestid) or cholestyramine (Prevalite, Questran);
  • steroids (prednisone and others);
  • lithium (Lithobid);
  • rifampin (Rifadin, Rifamate, Rimactane);
  • NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others;
  • other heart or blood pressure medications such as clonidine (Catapres) or reserpine; or
  • a calcium channel blocker such as amlodipine (Norvasc, Caduet, Exforge, Lotrel, Tekamlo, Tribenzor, Twynsta, Amturnide), diltiazem (Cartia, Cardizem), nifedipine (Nifedical, Procardia), or verapamil (Calan, Covera, Isoptin, Verelan).

This list is not complete and other drugs may interact with hydrochlorothiazide and bisoprolol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about hydrochlorothiazide and bisoprolol.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 6.01. Revision date: 5/10/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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