Bisoprolol Fumarate 10 MG / Hydrochlorothiazide 6.25 MG Oral Tablet
Generic Name: BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE
Brand Name: Ziac
- Substance Name(s):
- BISOPROLOL FUMARATE
- HYDROCHLOROTHIAZIDE
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 beta 1 -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 beta 1 -selectivity is not absolute, the lowest possible dose of ZIAC should be used.
A beta 2 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Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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 Hypoglycemia Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.
Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels.
Because of its beta 1 -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.
DRUG INTERACTIONS
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.
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.
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 beta 1 -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 (C 18 H 31 NO 4 ) 2 •C 4 H 4 O 4 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 C 7 H 8 ClN 3 O 4 S 2 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.
Bisoprolol Fumarate Structural Formula Hydrochlorothiazide Structural Formula
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 ΔBP (mm Hg) -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 Effect Observed mean change from baseline minus placebo.
-/- -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 Effect – -6.6 – +0.8 -2.1 -8.2 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.
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 51285-047-02 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 51285-050-02 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 51285-040-01 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight container.
Distributed by: TEVA PHARMACEUTICALS USA, INC.
Parsippany, NJ 07054 ZIAC-002 Rev.
08/2020
GERIATRIC USE
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.
INDICATIONS AND USAGE
ZIAC (bisoprolol fumarate and hydrochlorothiazide) is indicated in the management of hypertension.
PEDIATRIC USE
Pediatric Use Safety and effectiveness of ZIAC in pediatric patients have not been established.
PREGNANCY
Pregnancy Teratogenic Effects 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.
NUSRING MOTHERS
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.
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.
Non-melanoma Skin Cancer Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.
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.