Labetalol Hydrochloride

Description

DESCRIPTION Labetalol hydrochloride tablets USP are 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 USP 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 hydrochloride USP has the molecular formula C 19 H 24 N 2 O 3

What Is Labetalol Hydrochloride Used For?

INDICATIONS AND USAGE Labetalol hydrochloride tablets USP are indicated in the management of hypertension. Labetalol hydrochloride tablets USP may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.

Dosage and Administration

DOSAGE AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. The recommended initial dosage is 100 mg twice 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 maintenance dosage of labetalol hydrochloride tablets is between 200 mg and 400 mg twice daily. Since the full antihypertensive effect of labetalol hydrochloride tablets 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 1200 mg to 2400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered b.i.d.(twice daily), the same total daily dose administered t.i.d. (three times daily) may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg b.i.d. (twice daily). When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol hydrochloride tablet dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets are usually lower in patients also receiving a diuretic. When transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased. Elderly Patients As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 mg and 200 mg b.i.d.

Side Effects (Adverse Reactions)

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 labetalol hydrochloride 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 hydrochloride, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol hydrochloride 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. Labetalol Hydrochloride Placebo Propranolol Metoprolol (N=227) (N=98) (N=84) (N=49) % % % % Body as a whole Fatigue 5 0 12 12 Asthenia 1 1 1 0 Headache 2 1 1 2 Gastrointestinal Nausea 6 1 1 2 Vomiting < 1 0 0 0 Dyspepsia 3 1 1 0 Abdominal pain 0 0 1 2 Diarrhea < 1 0 2 0 Taste distortion 1 0 0 0 Central and Peripheral Nervous Systems Dizziness 11 3 4 4 Paresthesia < 1 0 0 0 Drowsiness < 1 2 2 2 Autonomic Nervous System Nasal stuffiness 3 0 0 0 Ejaculation failure 2 0 0 0 Impotence 1 0 1 3 Increased sweating < 1 0 0 0 Cardiovascular Edema 1 0 0 0 Postural hypotension 1 0 0 0 Bradycardia 0 0 5 12 Respiratory Dyspnea 2 0 1 2 Skin Rash 1 0 0 0 Special Senses Vision abnormality 1 0 0 0 Vertigo 2 1 0 0 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 2400 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 U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related. Labetalol Hydrochloride 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 Paresthesias 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: Body as a Whole Fever. Cardiovascular Hypotension, and rarely, syncope, bradycardia, heart block. Central and Peripheral Nervous Systems Paresthesia, most frequently described as scalp tingling. In most cases, it was mild and transient and usually occurred at the beginning of treatment. Collagen Disorders Systemic lupus erythematosus, positive antinuclear factor. Eyes Dry eyes. Immunological System Antimitochondrial antibodies. Liver and Biliary System Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests. Musculoskeletal System Muscle cramps, toxic myopathy. Respiratory System Bronchospasm. Skin and Appendages Rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriaform, and facial erythema; Peyronie's disease, reversible alopecia. Urinary System Difficulty in micturition, including acute urinary bladder retention. Hypersensitivity Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus,...

Drug Interactions

Drug Interactions In one survey, 2.3% of patients taking labetalol hydrochloride in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol hydrochloride 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 anti-asthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol hydrochloride. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol hydrochloride, 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 hydrochloride. During controlled hypotensive anesthesia using labetalol hydrochloride 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 hydrochloride. Labetalol hydrochloride blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride 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. 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.

Contraindications

CONTRAINDICATIONS Labetalol hydrochloride 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.

Pregnancy and Breastfeeding

Pregnancy Teratogenic Effects Pregnancy Category C Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol hydrochloride for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Nursing Mothers Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol hydrochloride is administered to a nursing woman.

Overdosage

OVERDOSAGE Overdosage with labetalol hydrochloride 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 hydrochloride 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: Excessive bradycardia Administer atropine or epinephrine. Cardiac failure Administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. Hypotension Administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. Bronchospasm administer epinephrine and/or an aerosolized beta 2 -agonist. Seizures 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 mg 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 hydrochloride from the general circulation (< 1%). The oral LD 50 value of labetalol hydrochloride in the mouse is approximately 600 mg/kg and in the rat is > 2 g/kg. The intravenous LD 50 in these species is 50 mg/kg to 60 mg/kg.

How Supplied

HOW SUPPLIED Labetalol Hydrochloride Tablets, USP, for oral administration, are available as 100 mg White to off-white, round film coated tablets debossed with "252" on one side &"U" on either side of score line on other side and supplied as: NDC 29300-252-01 bottles of 100 NDC 29300-252-05 bottles of 500 200 mg White to off-white, round film coated tablets debossed with "253" on one side &"U" on either side of score line on other side and supplied as: NDC 29300-253-01 bottles of 100 NDC 29300-253-05 bottles of 500 300 mg White to off-white, round film coated tablets debossed with "254" on one side &"U" on other side and supplied as: NDC 29300-254-01 bottles of 100 NDC 29300-254-05 bottles of 500 Labetalol Hydrochloride Tablets, USP should be stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] . Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure as required. To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Manufactured by UNICHEM LABORATORIES LTD. Pilerne Ind. Estate, Pilerne, Bardez, Goa 403 511, India. Manufactured for: East Brunswick, NJ 08816 02-R-02/2026 13016828 Image