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WARNINGS Hepatic Injury Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with therapy with labetalol. The hep tic 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 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 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 observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, therapy with labetalol should be withdrawn (gradually if possible). Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal Angina pectoris has not been reported upon labetalol 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 However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy.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, 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, labetalol 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 abruptly even in patients treated only for hypertension. Nonallergic bronchospasm (e.g., chronic bronchitis and emphysema) patients with bronchospastic disease should, in general, not receive beta-blockers . Labetalol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if labetalol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous beta-agonists is minimized. Pheochromocytoma Labetalol 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 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 prior to 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's alpha-adrenergic activity has not been evaluated in this setting. A synergism between labetalol and halothane anesthesia has been shown (see PRECAUTIONS-Drug Interactions ).
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, beta-blocker control agents 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, placebo, metoprolol and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol 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 (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 greater then 1 0 0 0 dyspepsia 3 1 1 0 abdominal pain 0 0 1 2 diarrhea greater then 1 0 2 0 taste distortion 1 0 0 0 Central and Peripheral Nervous Systems dizziness 11 3 4 4 paresthesias greater then 1 0 0 0 drowsiness greater then 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 greater then 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 table below which depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly drug related. Labetalol HCl Daily Dose (mg) 200 300 400 600 800 Number of Patients 522 181 606 608 503 Dizziness (%) 2 3 3 3 5 Fatigue 2 1 4 4 5 Nausea greater then 1 0 1 2 4 Vomiting 0 0 greater then 1 greater then 1 greater then 1 Dyspepsia 1 0 2 1 1 Paresthesias 2 0 2 2 1 Nasal Stuffiness 1 1 2 2 2 Ejaculation Failure 0 2 1 2 3 Impotence 1 1 1 1 2 Edema 1 0 1 1 1 Daily Dose (mg) 900 1200 1600 2400 Number of Patients 117 411 242 175 Dizziness (%) 1 9 13 16 Fatigue 3 7 6 10 Nausea 0 7 11 19 Vomiting 0 1 2 3 Dyspepsia 0 2 2 4 Paresthesias 1 2 5 5 Nasal Stuffiness 2 4 5 6 Ejaculation Failure 0 4 3 5 Impotence 4 3 4 3 Edema 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 Paresthesias, 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 (ANF). 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; 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 6,800 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 neuropsychometrics. Cardiovascular Intensification of AV block (see CONTRAINDICATIONS ). 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. Clinical Laboratory Tests There have been reversible increases of serum transaminases in 4% of patients treated with labetalol and tested, and more rarely, reversible increases in blood urea.