Labetalol Hydrochloride

INDICATIONS AND USAGE Labetalol Hydrochloride Injection is indicated for control of blood pressure in severe hypertension.

DOSAGE AND ADMINISTRATION Labetalol hydrochloride injection is intended for intravenous use in hospitalized patients. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing. Patients should always be kept in a supine position during the period of intravenous drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient's ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities. Either of two methods of administration of labetalol hydrochloride injection may be used: a) repeated intravenous injections, b) slow continuous infusion. Repeated Intravenous Injection Initially, labetalol hydrochloride injection should be given in a dose of 20 mg labetalol HCl (which corresponds to 0.25 mg/kg for an 80 kg patient) by slow intravenous injection over a 2-minute period. Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 mg or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300 mg labetalol HCl has been injected. The maximum effect usually occurs within 5 minutes of each injection. Slow Continuous Infusion Labetalol hydrochloride injection is prepared for continuous intravenous infusion by diluting the contents with commonly used intravenous fluids (see below). Examples of methods of preparing the infusion solution are: The contents of either two 20 mL vials (40 mL), or one 40 mL vial, are added to 160 mL of a commonly used intravenous fluid such that the resultant 200 mL of solution contains 200 mg of labetalol hydrochloride, 1 mg per mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min. Alternatively, the contents of either two 20 mL vials (40 mL), or one 40 mL vial, of labetalol hydrochloride injection are added to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol hydrochloride, approximately 2 mg per 3 mL. The diluted solution should be administered at a rate of 3 mL/min to deliver approximately 2 mg/min. The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump. Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol hydrochloride started. The effective intravenous dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients. Blood Pressure Monitoring The blood pressure should be monitored during and after completion of the infusion or intravenous injections. Rapid or excessive falls in either systolic or diastolic blood pressure during intravenous treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as indicator of effectiveness in addition to the response of the diastolic pressure. Initiation of Dosing with Labetalol Hydrochloride Tablets Subsequent oral dosing with labetalol hydrochloride tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with labetalol hydrochloride tablets may proceed as follows: * If needed, the total daily dos …

CONTRAINDICATIONS Labetalol hydrochloride injection is contraindicated in bronchial asthma, overt cardiac failure, greater than first degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension, and in patients with a history of hypersensitivity to any component of the product (see WARNINGS ). Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.

ADVERSE REACTIONS Labetalol hydrochloride injection is usually well tolerated. Most adverse effects have been mild and transient and in controlled trials involving 92 patients did not require labetalol withdrawal. Symptomatic postural hypotension (incidence 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol hydrochloride injection. Moderate hypotension occurred in 1 of 100 patients while supine. Increased sweating was noted in 4 of 100 patients, and flushing occurred in 1 of 100 patients. The following also were reported with labetalol hydrochloride injection with the incidence per 100 patients as noted: Cardiovascular System: Ventricular arrhythmia in 1. Central and Peripheral Nervous Systems: Dizziness in 9; tingling of the scalp/skin 7; hypoesthesia (numbness) and vertigo, 1 each. Gastrointestinal System: Nausea in 13; vomiting 4; dyspepsia and taste distortion, 1 each. Metabolic Disorders: Transient increases in blood urea nitrogen and serum creatinine levels occurred in 8 of 100 patients; these were associated with drops in blood pressure, generally in patients with prior renal insufficiency. Psychiatric Disorders: Somnolence/yawning in 3. Respiratory System: Wheezing in 1. Skin: Pruritus in 1. The incidence of adverse reactions depends upon the dose of labetalol. The largest experience is with oral labetalol. Certain of the side effects increased with increasing oral dose as shown in the table below which depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related. Labetalol Daily Dose (mg) 200 300 400 600 800 900 1200 1600 2400 Number of Patients 522 181 606 608 503 117 411 242 175 Dizziness (%) 2 3 3 3 5 1 9 13 16 Fatigue 2 1 4 4 5 3 7 6 10 Nausea <1 0 1 2 4 0 7 11 19 Vomiting 0 0 <1 <1 <1 0 1 2 3 Dyspepsia 1 0 2 1 1 0 2 2 4 Paresthesias 2 0 2 2 1 1 2 5 5 Nasal Stuffiness 1 1 2 2 2 2 4 5 6 Ejaculation Failure 0 2 1 2 3 0 4 3 5 Impotence 1 1 1 1 2 4 3 4 3 Edema 1 0 1 1 1 0 1 2 2 In addition, a number of other less common adverse events have been reported: Cardiovascular: Hypotension, and rarely, syncope, bradycardia, heart block. Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests. Hypersensitivity: Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol during investigational use and extensive foreign marketing experience. Clinical Laboratory Tests Among patients dosed with labetalol hydrochloride tablets, there have been reversible increases of serum transaminases in 4% of patients tested, and more rarely, reversible increases in blood urea. To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions Since labetalol injection may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and treat promptly any undesired effect from concomitant administration. In one survey, 2.3% of patients taking labetalol orally in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol alone. The contribution of each of the treatments to this adverse reaction is unknown but the possibility of a drug interaction cannot be excluded. Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal antiasthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol administered orally. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol, special care should be used in establishing the dose required for blood pressure control in such patients. Synergism has been shown between halothane anesthesia and intravenously administered labetalol. During controlled hypotensive anesthesia using labetalol in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol. Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type. When drug products that are alkaline, such as furosemide, have been administered in combination with labetalol, a white precipitate has been noted. Therefore, these drugs should not be administered in the same infusion line. Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reactions 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 Labetalol hydrochloride is an adrenergic receptor blocking agent that has both selective alpha 1 - and nonselective beta-adrenergic receptor blocking actions in a single substance. Labetalol hydrochloride is a racemate, chemically designated as 5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino]ethyl]salicylamide monohydrochloride and has the following structural formula: Labetalol hydrochloride has the molecular formula C 19 H 24 N 2 O 3 • HCl and a molecular weight of 364.87 g/mol. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic labetalol. Labetalol hydrochloride, USP is a white to off-white powder, sparingly soluble in water and in ethanol (96%), practically insoluble in methylene chloride. Labetalol hydrochloride injection, USP is a clear, colorless to light yellow aqueous sterile isotonic solution for intravenous injection. It has a pH range of 3.0 to 4.5. Each mL contains 5 mg labetalol hydrochloride, USP; 45 mg anhydrous dextrose; 0.1 mg edetate disodium; 0.8 mg methylparaben and 0.1 mg propylparaben as preservatives; citric acid monohydrate and sodium hydroxide, as necessary, to bring the solution into the pH range. 1

OVERDOSAGE Overdosage with labetalol hydrochloride injection causes excessive hypotension that is posture sensitive, and sometimes, excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. If overdosage with labetalol follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. The following additional measures should be employed if necessary: Excessive bradycardia -administer atropine or epinephrine. Cardiac failure -administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. Hypotension -administer vasopressors, e.g., norepinephrine. There is pharmacological evidence that norepinephrine may be the drug of choice. Bronchospasm -administer epinephrine and/or an aerosolized beta 2 -agonist. Seizures -administer diazepam. In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg/hr that can be reduced as the patient improves). Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (<1%). The oral LD 50 value of labetalol in the mouse is approximately 600 mg/kg and in the rat is greater than 2 g/kg. The intravenous LD 50 in these species is 50 to 60 mg/kg.

HOW SUPPLIED Labetalol hydrochloride injection USP, 5 mg/mL is available as clear, colorless to light yellow solution filled in 5 mL clear glass syringe, free from cracks and damage with luer lock OVS tip cap assembled with grey plunger stopper and natural plunger rod. It is supplied in below presentations: Concentration Each Unit of Sale 20 mg/4 mL (5 mg/mL) NDC 70121-2428-1 4 mL Single-Dose syringe in 1 Carton NDC 70121-2428-3 Unit of 24 Instructions for Use of the Syringe Systems 1. Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and carefully tilt cap back and forth (DO NOT TWIST CAP) until the cap disconnects for removal (see Figure 1). 2. Pull the cap (A) off in a straight upward direction. DO NOT TOUCH THE STERILE SYRINGE TIP (Luer-Lok) (B) (see Figure 2). 3. Hold plunger and push barrel forward to relieve any resistance that may be present (see Figure 3). 4. Pull the barrel down until air is expelled from the syringe (see Figure 4). 5. Connect the syringe to an appropriate injection connection. 6. Depress plunger rod to deliver the required dose. Discard unused portion. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. Protect syringe from light. Note: To prevent needle-stick injuries, needles and blunt cannulas should not be recapped, purposely bent, or broken by hand. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382213, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 08-2025-00 2 3 03 04