Labetalol

LABETALOL- labetalol hydrochloride injection, solution
Sagent Pharmaceuticals

SAGENT™
Rx only

DESCRIPTION

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 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride, and it has the following structure:

chemical structure

Labetalol HCl has the molecular formula C19 H24 N2 O3 •HCl and a molecular weight of 364.9. 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 powder, soluble in water.

Labetalol hydrochloride injection is a clear, colorless to light yellow, aqueous, sterile, isotonic solution for intravenous (IV) injection. It has a pH range of 3.0 to 4.5. 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 anhydrous citric acid and sodium hydroxide, as necessary, to bring the solution into the pH range.

CLINICAL PHARMACOLOGY

Labetalol HCl combines both selective, competitive, alpha1 -adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and IV administration, respectively. Beta2 -agonist activity has been demonstrated in animals with minimal beta1 -agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane stabilizing effect has been demonstrated.

Pharmacodynamics

The capacity of labetalol HCl to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice-cold water (“cold-pressor test”). Labetalol HCl’s beta1 -receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta2 -receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol HCl contribute to a decrease in blood pressure in hypertensive patients. Labetalol HCl consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol HCl dosing.

Single oral doses of labetalol HCl administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV labetalol HCl slightly prolonged A-V nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on A-V nodal refractoriness were inconsistent.

Labetalol HCl produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.

Doses of labetalol HCl that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function.

Due to the alpha1 -receptor blocking activity of labetalol HCl, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension can occur. During dosing with IV labetalol HCl, the contribution of the postural component should be considered when positioning the patients for treatment, and the patient should not be allowed to move to an erect position unmonitored until their ability to do so is established.

In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol HCl administered to patients in the supine position decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15-minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol HCl caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of IV treatment with labetalol HCl, the blood pressure rose gradually and progressively, approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients.

Similar results were obtained in the treatment of patients with severe hypertension who required urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 or 80 mg at 10-minute intervals to achieve the desired effect, or up to a cumulative dose of 300 mg.

Labetalol HCl administered as a continuous IV infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours (mean of 2 hours and 39 minutes), lowered the blood pressure by an average of 60/35 mmHg.

Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.

Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen A-V block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2 -adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and it may also interfere with exogenous bronchodilators in such patients.

Pharmacokinetics and Metabolism

Following IV infusion of labetalol, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min/kg. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased “first-pass” metabolism.

The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. The metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing.

Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol HCl from the general circulation (<1%).

INDICATIONS AND USAGE

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

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.

WARNINGS

Hepatic Injury

Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology. Similar hepatic events have been reported with a related compound, dilevalol HCl, including two deaths. Dilevalol HCl is one of the four isomers of labetalol HCl. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Laboratory testing should be done at the very first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms). If the patient has laboratory evidence of liver injury or jaundice, labetalol should be stopped and not restarted.

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