INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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 (seeWARNINGS).

Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.

ADVERSE REACTIONS

Most adverse effects are mild, transient and occur early in the course of treatment. In controlled clinical trials of 3 to 4 months’ duration, discontinuation of 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 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.

	Labetalol HCl (N=227) %	Placebo (N=98) %	Propranolol (N=84) %	Metoprolol (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 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
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, 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, angioedema, dyspnea) and anaphylactoid reactions.

Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6800 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.

Potential Adverse Effects

In addition, other adverse effects not listed above have been reported with other beta-adrenergic blocking agents.

**Central Nervous System:**Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on psychometrics.

Cardiovascular:Intensification of A-V block (seeCONTRAINDICATIONS).

**Allergic:**Fever combined with aching and sore throat, laryngospasm, respiratory distress.

**Hematologic:**Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.

**Gastrointestinal:**Mesenteric artery thrombosis, ischemic colitis.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.

Clinical Laboratory Tests

There have been reversible increases of serum transaminases in 4% of patients treated with labetalol HCl and tested and, more rarely, reversible increases in blood urea.

WARNINGS

**Hepatic Injury:**Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with therapy 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 research 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. Appropriate laboratory testing should also be done at the very first symptom/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.

**Cardiac Failure:**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.

**In Patients Without A History Of Cardiac Failure:**In patients with latent cardiac insufficiency, continued depression of the myocardium with beta- blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, therapy with labetalol HCl tablets should be withdrawn (gradually, if possible).

**Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal:**Angina pectoris has not been reported upon labetalol HCl discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered labetalol HCl tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol HCl tablets should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with labetalol HCl tablets abruptly in patients being treated for hypertension.

**Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema) Patients with bronchospastic disease should, in general, not receive beta-blockers. **Labetalol HCl tablets may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if labetalol HCl tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous beta-agonists is minimized.

**Pheochromocytoma:**Labetalol HCl has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.

**Diabetes Mellitus and Hypoglycemia:**Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g, tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta- blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.

**Major Surgery:**The necessity or desirability of withdrawing beta-blocking therapy before major surgery is controversial. Protracted severe hypotension and difficulty in restarting or maintaining a heartbeat have been reported with beta-blockers. The effect of labetalol HCl’s alpha-adrenergic activity has not been evaluated in this setting.

A synergism between labetalol HCl and halothane anesthesia has been shown (see PRECAUTIONS: Drug Interactions).

PRECAUTIONS

General

**Impaired Hepatic Function:**Labetalol HCl tablets should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.

Jaundice or Hepatic Dysfunction:(SeeWARNINGS).

Information for Patients

As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol HCl is warranted. This 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. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol HCl, dosing with labetalol HCl tablets should not be interrupted or discontinued without a physician’s advice. Patients being treated with labetalol HCl tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction (seeWARNINGS). Also, transient scalp tingling may occur, usually when treatment with labetalol HCl tablets is initiated (seeADVERSE REACTIONS).

Laboratory Tests

As with any new drug given over prolonged periods, laboratory parameters should be observed over regular intervals. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.

Drug Interactions

In one survey, 2.3% of patients taking labetalol HCl 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. 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 channel antagonists of the verapamil type.

**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.

Drug/Laboratory Test Interactions

The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid 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., J Chromatogr 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral dosing studies with labetalol HCl for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol HCl, using dominant lethal assays in rats and mice, and exposing microorganisms according to modified Ames tests, showed no evidence of mutagenesis.

Pregnancy:

Teratogenic Effects:

Pregnancy Category C:

Teratogenic studies have been 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 approximately the MRHD. A teratology study performed with labetalol in rabbits at IV 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 HCl 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.

Labor and Delivery

Labetalol HCl given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

**Elderly Patients:**As in the general population, some elderly patients (60 years of age and older) have experienced orthostatic hypotension, dizziness, or lightheadedness during treatment with labetalol. Because elderly patients are generally more likely than younger patients to experience orthostatic symptoms, they should be cautioned about the possibility of such side effects during treatment with labetalol.