tarted. 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cardiac failure continues, despite adequate digitalization and diuretic, therapy with labetalol hydrochloride should be withdrawn (gradually, if possible).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 however, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy.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 to 2 weeks and the patient should be carefully monitored. if angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride 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. nonallergic 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 with pheochromocytoma. however, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol hydrochloride 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 hydrochloride’s alpha-adrenergic activity has not been evaluated in this setting. a synergism between labetalol hydrochloride and halothane anesthesia has been shown ( see precautions , drug interactions ).

uld side effects (principally nausea or dizziness) occur with these doses administered b.i.d. (twice daily), the same total daily dose administered t.i.d. (three times daily) may improve tolerability and facilitate further titration. titration increments should not exceed 200 mg b.i.d. (twice daily). when a diuretic is added, an additive antihypertensive effect can be expected. in some cases this may necessitate a labetalol hydrochloride tablets, usp dosage adjustment. as with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets, usp are usually lower in patients also receiving a diuretic. when transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets, usp should be introduced as recommended and the dosage of the existing therapy progressively decreased. elderly patients as in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. (twice daily) as required for control of blood pressure. since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. the majority of elderly patients will require between 100 mg and 200 mg b.i.d. (twice daily).

d, the rates are somewhat higher (e.g., dizziness, 20%; nausea, 14%; fatigue, 11%), but the overall conclusions are unchanged. 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. 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, 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 psychometrics. cardiovascular intensification of a-v 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 hydrochloride. clinical laboratory tests there have been reversible increases of serum transaminases in 4% of patients treated with labetalol hydrochloride and tested and, more rarely, reversible increases in blood urea. table1 table2

by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. beta 2 -receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. both the alpha- and beta-blocking actions of orally administered labetalol hydrochloride contribute to a decrease in blood pressure in hypertensive patients. labetalol hydrochloride consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. the pulmonary circulation during exercise was not affected by labetalol hydrochloride dosing. single oral doses of labetalol hydrochloride administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or qrs duration. the atrioventricular (a-v) conduction time was modestly prolonged in two of seven patients. in another study, intravenous (iv) labetalol hydrochloride slightly prolonged a-v nodal conduction time and atrial effective refractory period with only small changes in heart rate. the effects on a-v nodal refractoriness were inconsistent. labetalol hydrochloride produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha-blocking and beta-blocking effects. hemodynamic effects are variable with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. elevated plasma renins are reduced. doses of labetalol hydrochloride that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function. due to the alpha 1 -receptor blocking activity of labetalol hydrochloride, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed ( see dosage and administration ). symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose. the peak effects of single oral doses of labetalol hydrochloride occur within 2 to 4 hours. the duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. the maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours. the antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of labetalol hydrochloride and the logarithm of the plasma concentration. about 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours. the antianginal efficacy of labetalol hydrochloride has not been studied. in 37 patients with hypertension and coronary artery disease, labetalol hydrochloride did not increase the incidence or severity of angina attacks. exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors. although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. for example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. beta-adrenergic blockade may worsen a-v block by preventing the necessary facilitating effects of sympathetic activity on conduction. beta 2 -adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and it may also interfere with exogenous bronchodilators in such patients. pharmacokinetics and metabolism labetalol hydrochloride is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. the relative bioavailability of labetalol hydrochloride compared to an oral solution is 100%. the absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an intravenous infusion is 25%; this is due to extensive “first-pass” metabolism. despite “first-pass” metabolism, there is a linear relationship between oral doses of 100 mg to 3000 mg and peak plasma levels. the absolute bioavailability of labetalol is increased when administered with food. the plasma half-life of labetalol following oral administration is about 6 to 8 hours. steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. in patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased “first-pass” metabolism. the metabolism of labetalol is mainly through conjugation to glucuronide metabolites. these metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing. labetalol has been shown to cross the placental barrier in humans. only negligible amounts of the drug crossed the blood-brain barrier in animal studies. labetalol is approximately 50% protein bound. neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (less than 1%). elderly patients some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. therefore, although elderly patients may initiate therapy at the currently recommended dosage of 100 mg b.i.d. (twice daily), elderly patients will generally require lower maintenance dosages than nonelderly patients.

ix, llc. at 1-844-466-6469 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. distributed by: innogenix, llc. amityville, ny 11701 rev. 09/2020