Trandate Information
Trandate (Labetalol hcl) Description
Trandate (Labetalol hcl) Tablets are adrenergic receptor blocking agents that have 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 empirical 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 crystalline powder, soluble in water.
Trandate (Labetalol hcl) Tablets contain 100, 200, or 300 mg of labetalol HCl and are taken orally. The tablets also contain the inactive ingredients corn starch, FD&C Yellow No. 6 (100- and 300-mg tablets only), hydroxypropyl methylcellulose, lactose, magnesium stearate, pregelatinized corn starch, sodium benzoate (200-mg tablet only), talc (100-mg tablet only), and titanium dioxide.
Trandate (Labetalol hcl) 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 intravenous (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.
Pharmacodynamics:
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 (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed (see ). Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.
The peak effects of single oral doses of labetalol HCl occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.
The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of labetalol HCl and the logarithm of the plasma concentration.
About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.
The antianginal efficacy of labetalol HCl has not been studied. In 37 patients with hypertension and coronary artery disease, labetalol HCl did not increase the incidence or severity of angina attacks.
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.
Pharmacokinetics and Metabolism:
The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. 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. These 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 (
Elderly Patients:
Trandate (Labetalol hcl) Indications And Usage
Trandate (Labetalol hcl) Tablets are indicated in the management of hypertension. Trandate (Labetalol hcl) Tablets may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.
Trandate (Labetalol hcl) Contraindications
Trandate (Labetalol hcl) Tablets are 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.
Trandate (Labetalol hcl) Warnings
Hepatic Injury:
Cardiac Failure:
In Patients Without a History of Cardiac Failure
Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema): Patients with bronchospastic disease should, in general, not receive beta-blockers.
Pheochromocytoma:
Diabetes Mellitus and Hypoglycemia:
Major Surgery:
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.
A synergism between labetalol HCl and halothane anesthesia has been shown (see ).
Trandate (Labetalol hcl) Precautions
Information for Patients:
WARNINGS
ADVERSE REACTIONS
Laboratory Tests:
Drug Interactions:
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. 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.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Pregnancy:
Teratogenic Effects: Pregnancy Category C:
Nonteratogenic Effects:
Labor and Delivery:
Nursing Mothers:
Pediatric Use:
Elderly Patients:
Trandate (Labetalol hcl) Adverse Reactions
Most adverse effects are mild and transient and occur early in the course of treatment. In controlled clinical trials of 3 to 4 months' duration, discontinuation of Trandate (Labetalol hcl) Tablets due to one or more adverse effects was required in 7% of all patients. In these same trials, other agents with solely beta-blocking activity used in the control groups led to discontinuation in 8% to 10% of patients, and a centrally acting alpha-agonist led to discontinuation in 30% of patients.
The incidence rates of adverse reactions listed in the following table were derived from multicenter, controlled clinical trials comparing labetalol HCl, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol HCl and placebo is similar, causal relationship is uncertain. The rates are based on adverse reactions considered probably drug related by the investigator. If all reports are considered, the rates are somewhat higher (e.g., dizziness, 20%; nausea, 14%; fatigue, 11%), but the overall conclusions are unchanged.
The adverse effects were reported spontaneously and are representative of the incidence of adverse effects that may be observed in a properly selected hypertensive patient population, i.e., a group excluding patients with bronchospastic disease, overt congestive heart failure, or other contraindications to beta-blocker therapy.
Clinical trials also included studies utilizing daily doses up to 2,400 mg in more severely hypertensive patients. Certain of the side effects increased with increasing 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:
Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6,800 patients was conducted for further safety and efficacy evaluation of this product. Results of this survey indicate that the type, severity, and incidence of adverse effects were comparable to those cited above.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.
Trandate (Labetalol hcl) 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 per hour that can be reduced as the patient improves).
Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol HCl from the general circulation (
The oral LD value of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD in these species is 50 to 60 mg/kg.
Trandate (Labetalol hcl) Dosage And Administration
DOSAGE MUST BE INDIVIDUALIZED. The recommended dosage is 100 mg daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days. The usual dosage of labetalol HCl is between 200 and 400 mg daily.
Since the full antihypertensive effect of labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary.
Patients with severe hypertension may require from 1,200 to 2,400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.
When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl dosage adjustment. As with most antihypertensive drugs, optimal dosages of Trandate (Labetalol hcl) Tablets are usually lower in patients also receiving a diuretic.
When transferring patients from other antihypertensive drugs, Trandate (Labetalol hcl) Tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased.
Trandate (Labetalol hcl) How Supplied
Trandate (Labetalol hcl) Tablets, 100 mg, light orange, round, scored, film-coated tablets engraved on one side with "Trandate (Labetalol hcl) 100," bottles of 100 (NDC 65483-391-10) and 500 (NDC 65483-391-50) and unit dose packs of 100 tablets (NDC 65483-391-11).
Trandate (Labetalol hcl) Tablets, 200 mg, white, round, scored, film-coated tablets engraved on one side with "Trandate (Labetalol hcl) 200," bottles of 100 (NDC 65483-392-10) and 500 (NDC 65483-392-50) and unit dose packs of 100 tablets (NDC 65483-392-22).
Trandate (Labetalol hcl) Tablets, 300 mg, mid-orange, round, scored, film-coated tablets engraved on one side with "Trandate (Labetalol hcl) 300," bottles of 100 (NDC 65483-393-10) and 500 (NDC 65483-393-50) and unit dose packs of 100 tablets (NDC 65483-393-33).
Prometheus Laboratories Inc.Manufactured in Canada by WellSpring Pharmaceutical Canada Corp.Oakville, ON L6H 1M5for Prometheus Laboratories Inc.San Diego, CA 92121
Trandate (Labetalol hcl) is a registered trademark of Prometheus Laboratories, Inc.
TOXI-LAB is a registered trademark of Varian, Inc.
EMIT and EMIT-d.a.u. are registered trademarks of Siemens Healthcare Diagnostics, Inc.
© 2010 Prometheus Laboratories Inc.All rights reservedNovember 2010
TR002C
Trandate (Labetalol hcl) Principle Display Panel - Mg Ct Bottle Label
NDC 65483-391-10
Prometheus Laboratories
Trandate (Labetalol hcl)
(labetalol hydrochloride)
100 mg
Each tablet
contains labetalol
hydrochloride
100 mg
Rx only
100 Tablets
Trandate (Labetalol hcl) Principle Display Panel - Mg Ct Bottle Label
NDC 65483-392-10
Prometheus Laboratories
Trandate (Labetalol hcl)
(labetalol hydrochloride)
200 mg
Each tablet
contains labetalol
hydrochloride
200 mg
Rx only
100 Tablets
Trandate (Labetalol hcl) Principle Display Panel - Mg Ct Bottle Label
NDC 65483-393-10
Prometheus Laboratories
Trandate (Labetalol hcl)
(labetalol hydrochloride)
300 mg
Each tablet
contains labetalol
hydrochloride
300 mg
Rx only
100 Tablets
