LABETALOL HCL

Labetalol Hydrochloride Injection, USP is an adrenergic receptor blocking agent that has both selective alpha1-adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance. Labetalol hydrochloride (HCl) is a racemate chemically designated as 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-salicylamide monohydrochloride and it has the following structural formula: Labetalol HCl has the molecular formula C19H24N2O3•HCl and a molecular weight of 364.87. 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 HCl is a white or off-white crystalline powder, soluble in water. Labetalol HCl Injection, USP is a clear, colorless to light yellow, aqueous, sterile, isotonic solution for intravenous injection. It has a pH range of 3 to 4. Each milliliter contains 5 mg of labetalol HCl, 45 mg of anhydrous dextrose, 0.1 mg of edetate disodium; 0.8 mg of methylparaben and 0.1 mg of propylparaben as preservatives; and citric acid monohydrate and sodium hydroxide, as necessary, to bring the solution into the pH range. STRUCTURE

INDICATIONS & USAGE Labetalol HCl Injection, USP is indicated for control of blood pressure in severe hypertension.

DOSAGE & ADMINISTRATION Labetalol HCl 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 HCl injection may be used: a) repeated intravenous injection, or b) slow continuous infusion. Repeated Intravenous Injection Initially, labetalol HCl injection should be given in a 20 mg dose (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 or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300 mg of labetalol HCl injection has been injected. The maximum effect usually occurs within 5 minutes of each injection. Slow Continuous Infusion Labetalol HCl injection is prepared for continuous intravenous infusion by diluting the vial contents with commonly used intravenous fluids (see below). Examples of two 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 HCl, 1 mg/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 HCl injection are added to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol HCl, approximately 2 mg/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 HCl started (see below). 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 injection. 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 an indicator of effectiveness in addition to the response of the diastolic pressure. Initiation of Dosing with Labetalol HCl Tablets Subsequent oral dosing with labetalol HCl 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 HCl tablets may proceed as follows: While in the hospital, the dosage of labetalol HCl tablets may be increased at 1 day intervals to achieve the desired blood pressure reduction. For subsequent outpatient titration or maintenance dosing see Labetalol HCl Tablet Product Information DOSAGE AND ADMINISTRATION for additional recommendations. Compatibility with Commonly Used Intravenous Fluids Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. Labetalol HCl injection was tested for compatibility with commonly used intravenous fluids at final concentrations of 1.25 mg to 3.75 mg of labetalol HCl per milliliter of the mixture. Labetalol HCl injection was found to be compatible with and stable (for 24 hours refrigerated or at room temperature) in mixtures with the following solutions: Ringer’s Injection Lactated Ringer’s Injection 5% Dextrose and Ringer’s Injection 5% Lactated Ringer’s and 5% Dextrose Injection 5% Dextrose Injection 0.9% Sodium Chloride Injection 5% Dextrose and 0.2% Sodium Chloride Injection 2.5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose and 0.33% Sodium Chloride Injection. Labetalol HCl injection was NOT compatible with 5% sodium bicarbonate injection. Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together. DOSAGE

Labetalol HCl 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.

Labetalol HCl 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 HCl. 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 HCl 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 in 7, hypoesthesia (numbness) and vertigo in 1 each. Gastrointestinal System: Nausea in 13, vomiting in 4, dyspepsia and taste distortion in 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 HCl. The largest experience is with oral labetalol HCl (see Labetalol HCl Tablet Product Information for details). Certain of the side effects increased with increasing oral dose, as shown in the following table that depicts the entire US therapeutic trials data base for adverse reactions that are clearly or possibly dose related. 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 HCl during investigational use and extensive foreign marketing experience. Clinical Laboratory Tests Among patients dosed with labetalol tablets, there have been reversible increases of serum transaminases in 4% of patients tested and, more rarely, reversible increases in blood urea. ADVERSE