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labetalol Hydrochloride Injection, USP - CARPUJECT Warnings and Precautions

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. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Laboratory testing should also 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 jaundice or laboratory evidence of liver injury, 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. 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 lead, in some cases, 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 If cardiac failure continues, despite adequate digitalization and diuretic, labetalol therapy should be withdrawn (gradually if possible).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 injection 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 the 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 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.


PRECAUTIONS

General

Labetalol injection should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.

Hypotension

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 injection. Therefore, the patient's ability to tolerate an upright position should be established before permitting any ambulation.

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Following Coronary Artery Bypass Surgery

In one uncontrolled study, patients with low cardiac indices and elevated systemic vascular resistance following intravenous labetalol experienced significant declines in cardiac output with little change in systemic vascular resistance. One of these patients developed hypotension following labetalol treatment. Therefore, use of labetalol should be avoided in such patients.

High-Dose Labetalol

Administration of up to 3 g/d as an infusion for up to 2 to 3 days has been anecdotally reported; several patients experienced hypotension or bradycardia.

Jaundice or Hepatic Dysfunction

(see WARNINGS).

Information for Patients

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 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 DOSAGE AND ADMINISTRATION).

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

Laboratory Tests

Routine laboratory tests are ordinarily not required before or after intravenous labetalol. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.

Drug Interactions

Since labetalol 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 orally in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol 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 administered orally. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol, 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. During controlled hypotensive anesthesia using labetalol 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.

Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol 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.

Risk of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reactions 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 (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol, 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 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 for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol, using dominant lethal assays in rats and mice, and exposing microorganisms according to modified Ames tests, showed no evidence of mutagenesis.

Pregnancy

Teratogenic Effects

Teratogenic studies have been performed with labetalol in rats and rabbits at oral doses up to approximately 6 and 4 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 for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of 2 to 4 times the MRHD caused a decrease in neonatal survival.

Labor and Delivery

Labetalol 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 injection is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

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