| Composition |
Each BisoprololFumarate and Hydrochlorothiazide Tablet, 2.5 mg/6.25 mg for oral administration contains:
Bisoprololfumarate USP....................................................................................................2.5 mg
Hydrochlorothiazide USP ................................................................................................6.25 mg
Each BisoprololFumarate and Hydrochlorothiazide Tablet, 5 mg/6.25 mg for oral administration contains:
Bisoprololfumarate USP........................................................................................................5 mg
Hydrochlorothiazide USP..................................................................................................6.25 mg
Each BisoprololFumarate and Hydrochlorothiazide Tablet, 10 mg/6.25 mg for oral administration contains:
Bisoprololfumarate USP.....................................................................................................10 mg
Hydrochlorothiazide USP.................................................................................................6.25 mg |
| Pharmacodynamics properties |
Bisoprololfumarate is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant
membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses
(>20 mg) bisoprololfumarate USP 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. |
| Therapeutic indications |
| Bisoprololfumarate and hydrochlorothiazide tablets are indicated in the management of hypertension. |
| Side effect |
Central Nervous System: Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance, restlessness.
Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities.
Gastrointestinal: Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea.
Skin: Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating. |
| Contraindication |
| Bisoprololfumarate and hydrochlorothiazide is contraindicated in patients in cardiogenic shock, second or third degree AV block, marked sinus bradycardia, anuria, andhypersensitivity to either component of this product or to other sulfonamide-derived drugs. |
| Warnings and precautions |
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 bisoprololfumarate and hydrochlorothiazide should be considered. In some cases bisoprololfumarate and hydrochlorothiazide therapy canbe continued while heart failure is treated with other drug.
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 betablockers.
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 bisoprololfumarate, may be used with caution in patients with bronchospastic disease who do not respond to,or who cannot tolerate other antihypertensive treatment.
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 beta1-selectivity, this is less likely with bisoprololfumarate.
Thyrotoxicosis
Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawalof beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitatethyroid 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 bisoprololfumarate is increased up to threefold, as compared to healthy subjects. If progressive renalimpairment becomes apparent, bisoprololfumarate and hydrochlorothiazide should be discontinued.
Hepatic Disease
Bisoprololfumarate and hydrochlorothiazide should be used with caution in patients with impaired hepatic function. Thiazides may alter fluid and electrolyte balance, which may precipitatehepatic coma. Also, elimination of bisoprololfumarate is significantly slower in patients with cirrhosis than inhealthy subjects.
Precautions
Electrolyte and Fluid Balance Status
Although the probability of developing hypokalemia is reduced with bisoprololfumarate and
hydrochlorothiazide because of the very low dose of hydrochlorothiazide employed
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. |
| Pregnancy and lactation |
Pregnancy Category C
There are no adequate and well-controlled studies with bisoprololfumarate and hydrochlorothiazide in pregnant women. Bisoprolol fumarate and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Nursing Mothers
Bisoprolol fumarate alone or in combination with hydrochlorothiazide has not been studied in nursing mothers.
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. |
| Drug interactions |
Bisoprolol fumarate and hydrochlorothiazide may potentiate the action of other antihypertensive agents used concomitantly.
Bisoprolol fumarate and hydrochlorothiazide should be used with caution when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (verapamil and diltiazem) 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. |
| DOSAGE & ADMINISTRATION |
| Initial Therapy:Antihypertensive therapy may be initiated with the lowest dose of bisoprolol fumarate and hydrochlorothiazide, one 2.5 mg/6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with bisoprolol fumarate and hydrochlorothiazide up to the maximum recommended dose 20 mg/12.5 mg (two 10 mg/6.25 mg tablets) once daily, as appropriate. |
| Overdose |
There are limited data on overdose with bisoprolol fumarate and hydrochlorothiazide. 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.
If overdosage of bisoprolol fumarate and hydrochlorothiazide is suspected, therapy with bisoprolol and hydrochlorothiazide should be discontinued and the patient observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprololfumarate is not dialyzable; similarly,there is no indication that hydrochlorothiazide USP is dialyzable. Suggested general measures include induction of emesis and/or gastric lavage, administration of activated charcoal, respiratory support, correctionof fluid and electrolyte imbalance, and treatment of convulsions.
Based on the expected pharmacologicactions and recommendations for other beta-blockers and hydrochlorothiazide USP, the following measuresshould 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. |
