Bisoprolol

INDICATIONS AND USAGE Bisoprolol fumarate tablets are indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.

DOSAGE AND ADMINISTRATION The dose of bisoprolol fumarate tablets must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose (see Bronchospastic Disease in WARNINGS ). If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily. Patients with Renal or Hepatic Impairment In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis. Geriatric Patients It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction (see above and Geriatric Use in PRECAUTIONS ). Pediatric Patients There is no pediatric experience with bisoprolol fumarate tablets.

CONTRAINDICATIONS Bisoprolol fumarate tablets are contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.

ADVERSE REACTIONS Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies. In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5 to 20 mg of bisoprolol fumarate; 132 received placebo. Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy. The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5 to 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5 to 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related. Body System/Adverse Experience All Adverse Experiences (% a ) Bisoprolol Fumarate Placebo (n=132) % 5-20 mg (n=273) % 2.5-40 mg (n=404) % Skin increased sweating 1.5 0.7 1.0 Musculoskeletal arthralgia 2.3 2.2 2.7 Central Nervous System dizziness headache hypoaesthesia 3.8 11.4 0.8 2.9 8.8 1.1 3.5 10.9 1.5 Autonomic Nervous System dry mouth 1.5 0.7 1.3 Heart Rate/Rhythm bradycardia 0 0.4 0.5 Psychiatric vivid dreams insomnia depression 0 2.3 0.8 0 1.5 0 0 2.5 0.2 Gastrointestinal diarrhea nausea vomiting 1.5 1.5 0 2.6 1.5 1.1 3.5 2.2 1.5 Respiratory bronchospasm cough dyspnea pharyngitis rhinitis sinusitis URI 0 4.5 0.8 2.3 3.0 1.5 3.8 0 2.6 1.1 2.2 2.9 2.2 4.8 0 2.5 1.5 2.2 4.0 2.2 5.0 Body as a Whole asthenia chest pain fatigue edema (peripheral) 0 0.8 1.5 3.8 0.4 1.1 6.6 3.7 1.5 1.5 8.2 3.0 a percentage of patients with event The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics): Central Nervous System Dizziness, unsteadiness , vertigo, syncope , headache, paresthesia, hypoesthesia, hyperesthesia, somnolence, sleep disturbances , anxiety/restlessness, decreased concentration/memory. Autonomic Nervous System Dry mouth. Cardiovascular Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion. Psychiatric Vivid dreams, insomnia, depression. Gastrointestinal Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer. Musculoskeletal Muscle/joint pain, arthralgia , back/neck pain, muscle cramps, twitching/tremor. Skin Rash, acne, eczema, psoriasis , skin irritation, pruritus, flushing, sweating, alopecia, dermatitis, angioedema, exfoliative dermatitis , cutaneous vasculitis. Special Senses Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing , earache, taste abnormalities. Metabolic Gout. Respiratory Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI. Genitourinary Decreased libido/impotence, Peyronie’s disease , cystitis, renal colic, polyuria. Hematologic Purpura. 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 effects of bisoprolol fumarate: Central Nervous System Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium. Allergic Fever, combined with aching and sore throat, laryngospasm, respiratory distress. Hematol …

Drug Interactions Bisoprolol fumarate 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 tablets may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that bisoprolol fumarate tablets be discontinued for several days before the withdrawal of clonidine. Bisoprolol fumarate should be used with care 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. Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life of bisoprolol fumarate. 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 time 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.

DESCRIPTION Bisoprolol fumarate, USP is a synthetic, beta1-selective (cardio-selective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-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 molecular formula is (C 18 H 31 NO 4 ) 2 •C 4 H 4 O 4 and its structure is: Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol and chloroform. Bisoprolol fumarate is available as 5 mg or 10 mg for oral administration. Inactive ingredients include carnauba wax, colloidal silicon dioxide, corn starch, crospovidone, dibasic calcium phosphate, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide, triacetin. The 5 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake. Meets USP Dissolution Test 2. The structure formula for Bisoprolol fumarate, USP is a synthetic, beta1-selective (cardio-selective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-1-[4-[[2-(1-Methyle

OVERDOSAGE The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered. In general, if overdose occurs, bisoprolol fumarate therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general 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 IV fluids and vasopressors should be administered. Intravenous glucagon may be useful. 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 (i.e., digitalis, diuretics, inotropic agents, vasodilating agents). Bronchospasm Administer bronchodilator therapy such as isoproterenol and/or aminophylline. Hypoglycemia Administer IV glucose.

HOW SUPPLIED Bisoprolol fumarate tablets, USP are supplied as 5 mg and 10 mg tablets. The 5 mg tablets are pink, round-shaped, film-coated tablets, with deep score-line on one side and convex with ' ǀ ' debossed on other side. They are supplied as follows: Bottles of 30 Unit-of-use with child-resistant closure: NDC 42571-470-30 Bottles of 100 with child-resistant closure: NDC 42571-470-01 Bottles of 500: NDC 42571-470-05 The 10 mg tablets are white to off-white, round, biconvex film-coated tablets debossed with ' ǀ ǀ ' on one side and plain on other side. They are supplied as follows: Bottles of 30 Unit-of-use with child-resistant closure: NDC 42571-471-30 Bottles of 100 with child-resistant closure: NDC 42571-471-01 Bottles of 500: NDC 42571-471-05 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant containers. Manufactured by: Micro Labs Limited Goa-403 722, INDIA Manufactured for: Micro Labs USA, Inc. Somerset, NJ 08873 Rev. 09/2023