INDICATIONS AND USAGE Labetalol HCl Injection, USP is indicated for control of blood pressure in severe hypertension.

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.

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 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 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 should be observed closely.

If cardiac failure continues despite adequate digitalization and diuretic, labetalol therapy should be withdrawn (gradually, if possible).

Ischemic Heart Disease Angina pectoris has not been reported upon labetalol discontinuation.

However, following abrupt cessation of therapy with some beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported.

Therefore, such patients should be cautioned against interruption of therapy without the physician’s advice.

Even in the absence of overt angina pectoris, when discontinuation of labetalol is planned, the patient should be carefully observed and should be advised to limit physical activity.

If angina markedly worsens or acute coronary insufficiency develops, labetalol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken.

Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema) Since labetalol HCl at the usual intravenous therapeutic doses has not been studied in patients with nonallergic bronchospastic disease, it should not be used in such patients.

Pheochromocytoma Intravenous labetalol has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma; higher than usual doses may be required.

However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol 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 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 HCl injection was used during surgery (including when used in cases to control bleeding).

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

Rapid Decreases of Blood Pressure Caution must be observed when reducing severely elevated blood pressure.

A number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days.

The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient’s status.

ADVERSE REACTIONS Labetalol HCl injection is usually well tolerated.

Most adverse effects have been mild and transient and, in controlled trials involving 92 patients, did not require labetalol 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 HCl.

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 HCl with the incidence per 100 patients as noted: Cardiovascular System: Ventricular arrhythmia in 1.

Central and Peripheral Nervous Systems: Dizziness in 9, tingling of the scalp/skin in 7, hypoesthesia (numbness) and vertigo in 1 each.

Gastrointestinal System: Nausea in 13, vomiting in 4, dyspepsia and taste distortion in 1 each.

Metabolic Disorders: 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.

Psychiatric Disorders: Somnolence/yawning in 3.

Respiratory System: Wheezing in 1.

Skin: 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 US 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 Paresthesia 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: Cardiovascular: Hypotension, and rarely, syncope, bradycardia, heart block.

Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.

Hypersensitivity: 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.

Clinical Laboratory Tests Among patients dosed with labetalol tablets, there have been reversible increases of serum transaminases in 4% of patients tested and, more rarely, reversible increases in blood urea.