Bisoprolol Fumarate and Hydrochlorothiazide (Page 5 of 5)

OVERDOSAGE

There are limited data on overdose with bisoprolol fumarate and hydrochlorothiazide tablets. 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 bisoprolol fumarate and hydrochlorothiazide tablets is suspected, therapy with bisoprolol fumarate and hydrochlorothiazide tablets 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.

DOSAGE & 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 phenomenafor 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 bisoprolol fumarate and hydrochlorothiazide tablets. 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 bisoprolol fumarate and hydrochlorothiazide tablets.

Initial Therapy

Antihypertensive therapy may be initiated with the lowest dose of bisoprolol fumarate and hydrochlorothiazide tablets, one 2.5/6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with bisoprolol fumarate and hydrochlorothiazide 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 bisoprolol fumarate and hydrochlorothiazide tablets 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 bisoprolol fumarate and hydrochlorothiazide tablets.

HOW SUPPLIED

Bisoprolol Fumarate and Hydrochlorothiazide — 2.5 mg/6.25 mg Tablets, USP (bisoprolol fumarate 2.5 mg and hydrochlorothiazide 6.25 mg): Yellow, round, uncoated, unscored tablets debossed “N” and “412” on one side and plain on the other side, supplied as follows:

Bottle of 100 Tablets NDC 10135-0740-01

Bottle of 500 Tablets NDC 10135-0740-05

Bisoprolol Fumarate and Hydrochlorothiazide — 5 mg/6.25 mg Tablets, USP (bisoprolol fumarate 5 mg and hydrochlorothiazide 6.25 mg): Pink, round, uncoated, unscored tablets debossed “N” and “413” on one side and plain on the other side, supplied as follows:

Bottle of 100 Tablets NDC 10135-0741-01

Bottle of 500 Tablets NDC 10135-0741-05

Bisoprolol Fumarate and Hydrochlorothiazide — 10 mg/6.25 mg Tablets, USP (bisoprolol fumarate 10 mg and hydrochlorothiazide 6.25 mg): Blue, round, uncoated, unscored tablets debossed “N” and “414” on one side and plain on the other side, supplied as follows:

Bottle of 30 Tablets NDC 10135-0742-30

Bottle of 500 Tablets NDC 10135-0742-05

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

Manufactured for/ Distributed by:

Marlex Pharmaceuticals, Inc.

New Castle, DE 19720

Rev. 05/22 NP

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Bisoprolol Fumarate and Hydrochlorothiazide Tablets, USP 2.5 mg/6.25 mg — 100’s count

Bisoprolol Fumarate and Hydrochlorothiazide Tablets, USP 5 mg/6.25 mg — 100’s count

Bisoprolol Fumarate and Hydrochlorothiazide Tablets, USP 5 mg/6.25 mg — 500’s count

Bisoprolol Fumarate and Hydrochlorothiazide Tablets, USP 10 mg/6.25 mg — 30’s count

Bisoprolol Fumarate and Hydrochlorothiazide Tablets, USP 10 mg/6.25 mg — 500’s count

BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE bisoprolol fumarate and hydrochlorothiazide tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10135-740(NDC:70954-412) Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BISOPROLOL FUMARATE (BISOPROLOL) BISOPROLOL FUMARATE 2.5 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 6.25 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS STARCH, CORN SILICON DIOXIDE MAGNESIUM STEARATE FERRIC OXIDE YELLOW

Product Characteristics Color yellow Score no score Shape ROUND Size 6mm Flavor Imprint Code N412 Contains

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:10135-740-01 100 TABLET in 1 BOTTLE None 2 NDC:10135-740-05 500 TABLET in 1 BOTTLE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA215562 05/01/2022

BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE bisoprolol fumarate and hydrochlorothiazide tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10135-741(NDC:70954-413) Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BISOPROLOL FUMARATE (BISOPROLOL) BISOPROLOL FUMARATE 5 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 6.25 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS STARCH, CORN SILICON DIOXIDE MAGNESIUM STEARATE FERROSOFERRIC OXIDE FERRIC OXIDE RED

Product Characteristics Color pink Score no score Shape ROUND Size 7mm Flavor Imprint Code N413 Contains

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:10135-741-01 100 TABLET in 1 BOTTLE None 2 NDC:10135-741-05 500 TABLET in 1 BOTTLE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA215562 05/01/2022

BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE bisoprolol fumarate and hydrochlorothiazide tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10135-742(NDC:70954-414) Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BISOPROLOL FUMARATE (BISOPROLOL) BISOPROLOL FUMARATE 10 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 6.25 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE FD&C BLUE NO. 1 ALUMINUM LAKE CELLULOSE, MICROCRYSTALLINE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS STARCH, CORN SILICON DIOXIDE

Product Characteristics Color blue Score no score Shape ROUND Size 7mm Flavor Imprint Code N414 Contains

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:10135-742-30 30 TABLET in 1 BOTTLE None 2 NDC:10135-742-05 500 TABLET in 1 BOTTLE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA215562 05/01/2022

Labeler — Marlex Pharmaceuticals, Inc. (782540215)

Revised: 02/2023 Marlex Pharmaceuticals, Inc.