LABETALOL HYDROCHLORIDE

Labetalol Hydrochloride Injection, USP is an adrenergic receptor blocking agent that has both selective alpha 1 -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: Structural Formula Labetalol HCl has the molecular formula C 19 H 24 N 2 O 3 •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. Structural Formula

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

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: Inpatient Titration Instructions Regimen Daily Dose If needed, the total daily dose may be given in three divided doses. 200 mg b.i.d. 400 mg 400 mg b.i.d. 800 mg 800 mg b.i.d. 1,600 mg 1,200 mg b.i.d. 2,400 mg 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.

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. Labetalol HCl 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 Paresthesia 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 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.

Since labetalol HCl 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 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 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 reaction.