Labetalol Information
Labetalol ()
Labetalol () Description
Labetalol () hydrochloride injection, USP is an adrenergic receptor blocking agent that has both selective alpha-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:
Labetalol () HCl has the molecular formula CHNO•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.
Labetalol () Clinical Pharmacology
Labetalol () HCl combines both selective, competitive, alpha-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. Beta-agonist activity has been demonstrated in animals with minimal beta-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.
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 beta-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. Beta-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 alpha-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. Beta-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.
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 (
Labetalol () Indications And Usage
Labetalol () hydrochloride injection is indicated for control of blood pressure in severe hypertension.
Labetalol () 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 ).
Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
Labetalol () Warnings
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, Labetalol () HCl can be used with caution in patients with a history of heart failure who are well compensated.
Congestive heart failure has been observed in patients receiving Labetalol () HCl. Labetalol () HCl does not abolish the inotropic action of digitalis on heart muscle.
Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of Labetalol () 's alpha adrenergic activity has not been evaluated in this setting.
Several deaths have occurred when Labetalol () hydrochloride injection was used during surgery (including when used in cases to control bleeding).
A synergism between Labetalol () HCl and halothane anesthesia has been shown (see ).
Labetalol () Precautions
The following information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. During and immediately following (for up to 3 hours) Labetalol () hydrochloride injection, the patient should remain supine. Subsequently, the patient should be advised on how to proceed gradually to become ambulatory and should be observed at the time of first ambulation.
When the patient is started on Labetalol () hydrochloride tablets following adequate control of blood pressure with Labetalol () hydrochloride injection, appropriate directions for titration of dosage should be provided (see ).
As with all drugs with beta-blocking activity, certain advice to patients being treated with Labetalol () HCl is warranted. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with Labetalol () HCl, dosing with Labetalol () hydrochloride tablets should not be interrupted or discontinued without a physician's advice. Patients being treated with Labetalol () hydrochloride tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction (see ). Also, transient scalp tingling may occur, usually when treatment with Labetalol () hydrochloride tablets is initiated (see ).
Since Labetalol () hydrochloride 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 () HCl orally in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with Labetalol () HCl 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 () HCl administered orally. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of Labetalol () HCl, 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 () HCl. During controlled hypotensive anesthesia using Labetalol () HCl 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 () HCl.
Labetalol () HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If Labetalol () HCl 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.
The presence of Labetalol () metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with Labetalol () HCl, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., 385:241,1987) should be employed in determining levels of catecholamines.
Labetalol () HCl has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi-Lab A (thin-layer chromatographic assay) and Emit-d.a.u. (radioenzymatic assay). When patients being treated with Labetalol () have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.
Labetalol () 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 () HCl 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:
Ventricular arrhythmia in 1.
Dizziness in 9, tingling of the scalp/skin in 7, hypoesthesia (numbness) and vertigo in 1 each.
Nausea in 13, vomiting in 4, dyspepsia and taste distortion in 1 each.
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.
Somnolence/yawning in 3.
Wheezing in 1.
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 U.S. 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:
Hypotension, and rarely, syncope, bradycardia, heart block.
Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.
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.
Labetalol () Overdosage
Overdosage with Labetalol () HCl 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 () HCl 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: —administer atropine or epinephrine. —administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. —administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. —administer epinephrine and/or an aerosolized beta-agonist. —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 (
The oral LD value of Labetalol () HCl in the mouse is approximately 600 mg/kg and in the rat is greater than 2 g/kg. The IV LD in these species is 50 to 60 mg/kg.
Labetalol () Dosage And Administration
Labetalol () hydrochloride injection is intended for IV use in hospitalized patients. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing.
Either of two methods of administration of Labetalol () hydrochloride injection may be used: a) repeated IV injection, or b) slow continuous infusion.
Labetalol () How Supplied
Labetalol () Hydrochloride Injection, USP is supplied as follows:
Labetalol () Package Label – Principal Display Panel – Vial Label
Rx only
20 mL Multi-Dose Vial
Labetalol () Package Label – Principal Display Panel – Vial Label
Rx only
40 mL Multi-Dose Vial
