Bisoprolol Fumarate and Hydrochlorothiazide

INDICATIONS AND USAGE Bisoprolol fumarate and hydrochlorothiazide tablets are indicated in the management of hypertension.

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 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 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.

CONTRAINDICATIONS Bisoprolol fumarate and hydrochlorothiazide tablets are 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.

ADVERSE REACTIONS Bisoprolol Fumarate and Hydrochlorothiazide Tablets Bisoprolol fumarate/HCTZ 6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild and transient. In more than 65,000 patients treated worldwide with bisoprolol fumarate, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for bisoprolol fumarate/HCTZ 6.25 mg and placebo-treated patients. In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)/HCTZ 6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, bisoprolol fumarate 5/HCTZ 6.25 mg was administered for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10, or 40/HCTZ 6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with bisoprolol fumarate 2.5-10/HCTZ 6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/HCTZ 6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table: % of Patients with Adverse Experiences a Body System/ AdverseExperience All AdverseExperiences Drug Related Adverse Experiences Placebo b B2.5-40/H6.25 b Placebo b B2.5-10/H6.25 b (n=144) (n=252) (n=144) (n=221) % % % % Cardiovascular bradycardia 0.7 1.1 0.7 0.9 arrhythmia 1.4 0.4 0.0 0.0 peripheral ischemia 0.9 0.7 0.9 0.4 chest pain 0.7 1.8 0.7 0.9 Respiratory bronchospasm 0.0 0.0 0.0 0.0 cough 1.0 2.2 0.7 1.5 rhinitis 2.0 0.7 0.7 0.9 URI 2.3 2.1 0.0 0.0 Body as a Whole asthenia 0.0 0.0 0.0 0.0 fatigue 2.7 4.6 1.7 3.0 peripheral edema 0.7 1.1 0.7 0.9 Central Nervous System dizziness 1.8 5.1 1.8 3.2 headache 4.7 4.5 2.7 0.4 Musculoskeletal muscle cramps 0.7 1.2 0.7 1.1 myalgia 1.4 2.4 0.0 0.0 Psychiatric insomnia 2.4 1.1 2.0 1.2 somnolence 0.7 1.1 0.7 0.9 loss of libido 1.2 0.4 1.2 0.4 impotence 0.7 1.1 0.7 1.1 Gastrointestinal diarrhea 1.4 4.3 1.2 1.1 nausea 0.9 1.1 0.9 0.9 dyspepsia 0.7 1.2 0.7 0.9 a Averages adjusted to combine acrossstudies. b Combined acrossstudies. Other adverse experiences that have been reported with the individual components are listed below. Bisoprolol Fumarate In clinical trials worldwide, or in postmarketing experience, a variety of other AEs, in addition to those listed above, have been reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to alert the physician to a possible relationship. Central Nervous System Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory. Cardiovascular Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea onexertion. Gastrointestinal Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth. Musculoskeletal Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor. Skin Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vasculitis. Special Senses Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities. Metabolic Gout. Respiratory Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection). Genitourinary Decreased libido/impotence, Peyronie’s disease (very rarely), cystitis, renal colic, polyuria. General Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema. In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse e …

DESCRIPTION Bisoprolol fumarate and hydrochlorothiazide tablets, USP are 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 bisoprolol fumarate and hydrochlorothiazide - 2.5 mg/6.25 mg tablet, USP for oral administration contains: Bisoprolol fumarate..................................................2.5 mg Hydrochlorothiazide...............................................6.25 mg Each bisoprolol fumarate and hydrochlorothiazide - 5 mg/6.25 mg tablet, USP for oral administration contains: Bisoprolol fumarate................................................... 5 mg Hydrochlorothiazide............................................... 6.25 mg Each bisoprolol fumarate and hydrochlorothiazide - 10 mg/6.25 mg tablet, USP for oral administration contains: Bisoprolol fumarate...................................................10 mg Hydrochlorothiazide............................................... 6.25 mg Inactive ingredients include pregelatinized starch, anhydrous dicalcium phosphate, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide. The 10 mg/6.25mg tablet also contains FD&C blue #1 aluminum lake. The 5 mg/6.25 mg tablet also contains iron oxide red & ferrosoferric oxide. The 2.5 mg/6.25 mg tablet also contains ferric oxide. FDA approved dissolution test specifications differ from USP. Bisoprolol-Fumarate thiazide-structure

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.

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 30 Tablets NDC 70954-412-10 Bottle of 100 Tablets NDC 70954-412-30 Bottle of 500 Tablets NDC 70954-412-40 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 30 Tablets NDC 70954-413-10 Bottle of 100 Tablets NDC 70954-413-30 Bottle of 500 Tablets NDC 70954-413-40 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 70954-414-10 Bottle of 100 Tablets NDC 70954-414-30 Bottle of 500 Tablets NDC 70954-414-40 Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container. Manufactured by: Novitium Pharma LLC 70 Lake Drive, East Windsor New Jersey 08520 Issued: 07/2026 LB4310-03