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Questions & Answers
Side Effects & Adverse Reactions
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.
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.
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.
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative beta1-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 beta1-selectivity is not absolute, the lowest possible dose of ZIAC should be used. A beta2 agonist (bronchodilator) should be made available.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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.
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less likely with bisoprolol fumarate. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. Because of the very low dose of HCTZ employed, this may be less likely with ZIAC.
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.
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).
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).
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.
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
ZIAC (bisoprolol fumarate and hydrochlorothiazide) is indicated in the management of hypertension.
History
There is currently no drug history available for this drug.
Other Information
ZIAC (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 empirical 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 (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 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:
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/6.25mg 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.
Sources
Ziac Manufacturers
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Teva Women’s Health, Inc.
![Ziac (Bisoprolol Fumarate And Hydrochlorothiazide) Tablet, Film Coated [Teva Women’s Health, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Ziac | Teva Women's Health, Inc.
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 EffectA 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 TherapyAntihypertensive 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 TherapyThe combination may be substituted for the titrated individual components.
Cessation of TherapyIf 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.
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