Ziac 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 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 (C18 H31 NO4 )2 ?C4 H4 O4 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-2 H -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 C7 H8 ClN3 O4 S2 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.

Ziac Indications And Usage

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

Ziac 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.

Ziac Side Effects

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 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.

Anesthesia and Major Surgery

If ZIAC treatment is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. See OVERDOSAGE for information on treatment of bradycardia and hypotension.

Diabetes and 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 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.

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.)

Ziac 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.

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 ZIAC.

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 ZIAC 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).

Ziac Information For Patients

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.

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.

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.

Ziac Overdosage

There are limited data on overdose with ZIAC. 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.