Labetalol Hydrochloride 300 mg Tablet, Film Coated, 100-count

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 research compound, dilevalol hydrochloride, including two deaths. Dilevalol hydrochloride is one of the four isomers of labetalol hydrochloride. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate.

Appropriate laboratory testing should be done at the 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 hydrochloride 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 hydrochloride.

Labetalol hydrochloride 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cardiac failure continues, despite adequate digitalization and diuretic, therapy with labetalol hydrochloride should be withdrawn (gradually, if possible). Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal Angina pectoris has not been reported upon labetalol hydrochloride 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 hydrochloride, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 week to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride administration 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 hydrochloride abruptly in patients being treated for hypertension. Non allergic Bronchospasm (e.g. Chronic Bronchitis and Emphysema) Patients with Bronchospastic disease should, in general, not receive beta-blockers .

Labetalol hydrochloride may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if labetalol hydrochloride is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous beta-agonists is minimized. Pheochromocytoma Labetalol hydrochloride has been shown to be effective in lowering blood pressure and relieving symptoms in patients w…

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 (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 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 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 1,200 1,600 2,400 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, pr…

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.

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 hydrochloride, 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 hydrochloride 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 hydrochloride for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol hydrochloride 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 were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respect…