AHFS Class:

• beta-Adrenergic Blocking Agents 24:20

Generic Name(s):

• Labetalol Hydrochloride

Labetalol hydrochloride is an α- and β-adrenergic blocking agent.1,2,3,4,5,6,7,8,9,19,21,22,23,32

Labetalol is used for the management of hypertension.2,4,253,1200 The drug is used for hypertension associated with angina160,161,162,163,164 or pheochromocytoma1,2,3,4,51,85,181,182,183,184 and during pregnancy.7,63,64,65,66,68,70,95,185,245,298,540,1200 IV labetalol is used for hypertension associated with myocardial infarction (MI)165,166,167 and to control blood pressure in patients with severe hypertension or in hypertensive crises.1,3,7,8,14,15,16,51,52,53,73,79,93,94,152,197,198,209,210,235,236,240,502,542,1200

In addition, IV labetalol has been used to produce controlled hypotension during anesthesia†7,183,190,191,192,193,194,195 and to control blood pressure in eclampsia† or preeclampsia†.502,540,1200 The drug also has been used in the management of sympathetic overactivity syndrome with severe tetanus†196,200,201,202 and in angina† .7,17,18,127

The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.327,701,702,703,704,705,706,707,708,709,710,711,712 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.701,703,704,705,706,707,708,709,710,711,712 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent. 703,704,705,706,709,711,712

Hypertension

Labetalol hydrochloride is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.2,4,253,1200

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke.337,501,503,504,515,1200 However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501,502,503,504,523,524,527,700,1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501,502,503,504,515,1200,1201

A 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a target blood pressure goal (i.e., blood pressure to achieve with drug therapy and/or nonpharmacologic intervention) of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg generally is recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 These blood pressure goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210 Previous hypertension guidelines, such as those from an expert panel of the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients501,504,536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200 The blood pressure thresholds used to define hypertension, the optimum blood pressure threshold at which to initiate antihypertensive drug therapy, and the ideal target blood pressure values remain controversial.501,503,504,505,506,507,508,515,523,526,530,1200,1201,1207,1209,1222,1223,1229

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers.327,334,335,501,504,1200 Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic.500 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Atenolol 24:24 and in Metoprolol 24:24.)

For additional information on the role of β-blockers in the management of hypertension, see Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension, in Adults, in the Thiazides General Statement 40:28.20.

Hypertension Associated with Angina or Myocardial Infarction

Oral labetalol has been used effectively for the management of hypertension in patients with coexisting angina pectoris,160,161,162,163,164 and IV labetalol has been used effectively for the management of hypertension associated with acute myocardial infarction.165,166,167 In patients with hypertension and ischemic heart disease, oral labetalol therapy reduced blood pressure and heart rate and was associated with elimination or reduction of anginal pain, improvement in exercise tolerance, and decreased consumption of nitroglycerin.161,162,163,164 In the management of hypertension associated with acute myocardial infarction, IV infusions of labetalol decreased blood pressure and heart rate and generally decreased cardiac index and pulmonary artery wedge pressure, without producing adverse hemodynamic effects.165,166,167

Hypertension during Pregnancy

Labetalol has been used for the management of hypertension in pregnant women.7,63,64,65,66,68,70,95,185,245,298,540 The drug has been effective in controlling blood pressure in pregnant women with moderate to severe hypertension,64,68,185,285 in those with severe pregnancy-induced hypertension,64,68,95,185,244,285,298 and in those with hypertension and superimposed pregnancy-induced hypertension.64,68,185,285 In addition, in hypertensive pregnant women with proteinuria, labetalol therapy has resulted in substantially less proteinuria.64,65,68,185

The goal of antihypertensive treatment in pregnant women with hypertension is to minimize the acute complications of maternal hypertension while avoiding therapy that would compromise fetal well-being.298 Antihypertensive therapy is recommended in pregnant women with chronic hypertension who have persistent, severely elevated blood pressure (e.g., systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 105 mm Hg or higher); it is less clear whether antihypertensive therapy should be initiated in women with mild to moderate chronic hypertension.298,540 If initiation of antihypertensive therapy is considered necessary in a pregnant woman, use of labetalol, nifedipine, or methyldopa is recommended by the American College of Obstetricians and Gynecologists (ACOG) and other experts.298,502,540 In women who are already receiving antihypertensive therapy prior to pregnancy, ACOG states that data are insufficient to make recommendations regarding the continuance or discontinuance of such therapy; treatment decisions should be individualized in these situations.298 Some other experts state that women with hypertension who become pregnant or who are planning to become pregnant should have their antihypertensive therapy transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy.1200 Antihypertensive therapy can reduce the risk of severe hypertension but has not been shown to prevent the development of preeclampsia.540 Use of labetalol in association with careful prenatal management during pregnancy does not appear to adversely affect the fetus.7,63,64,65,66,68,70,95,185,245 (See Cautions: Pregnancy, Fertility, and Lactation.)

Labetalol also has been used parenterally in the hospital setting for urgent lowering of blood pressure in severely hypertensive pregnant women, including those with preeclampsia† or eclampsia†.298,502,540,1200 Recommendations for the management of such patients are based principally on experience in women with preeclampsia or gestational hypertension in the third trimester.298 Delivery is the preferred method of management for women with severe preeclampsia; however, use of antihypertensive drugs is recommended in such women who have severely elevated blood pressures (sustained systolic blood pressure of at least 160 mm Hg or diastolic blood pressure of at least 110 mm Hg) to prevent potentially life-threatening cardiovascular, renal, and cerebrovascular complications.298,540,1200 Results of several randomized clinical trials evaluating antihypertensive therapy in women with severe hypertension during pregnancy suggest that IV labetalol, IV hydralazine, or oral nifedipine are appropriate antihypertensives for urgently lowering blood pressure in such patients; choice of therapy should be based on clinician experience and preference as well as patient-specific factors (e.g., concomitant medical conditions or therapies) and drug-related factors (e.g., route of administration, adverse effects, contraindications, local availability, cost).298,338,540 Although hydralazine historically has been considered the agent of choice for management of hypertensive emergencies associated with pregnancy, some clinicians now prefer IV labetalol for its more rapid onset and shorter duration of action and its more predictable hypotensive effect.502,542

Hypertension Associated with Pheochromocytoma

Because of labetalol's α- and β-adrenergic blocking activity, the drug has been used alone to control hypertension and symptoms resulting from excessive β-receptor stimulation in patients with pheochromocytoma.51,85,181,182,183,184 Labetalol generally appears to be effective in these patients;1,2,3,4,51,85,181,182,183,184 some evidence suggests that the drug may be more effective in patients whose tumors predominantly secrete epinephrine rather than norepinephrine and in patients with sustained rather than paroxysmal hypertension.85 Since there have been reports that oral labetalol may induce a paradoxical hypertensive crisis in some patients with pheochromocytoma186,187 (possibly because the drug's predominant β-adrenergic blockade leaves α-adrenergic stimulation relatively unopposed),7,187,203 the manufacturers recommend that the drug be used with caution in patients with this tumor.1,2,3,4 Although labetalol has some α-adrenergic blocking activity, some clinicians caution that the drug, like other β-adrenergic blocking agents, should not be used in patients with pheochromocytoma unless they have received pretreatment with an α-adrenergic blocking agent (e.g., IV phentolamine).7 If labetalol is used in patients with known or suspected pheochromocytoma, appropriate methods for determining urinary catecholamines should be employed.1,2,3,4 (See Laboratory Test Interferences: Urinary Catecholamines.)

Severe Hypertension and Hypertensive Crises

IV labetalol hydrochloride is used to control blood pressure in patients with severe hypertension or in hypertensive crises for the immediate reduction in blood pressure in patients in whom such reduction is considered an emergency (hypertensive emergencies).1,3,7,8,14,15,16,51,52,53,73,79,93,94,152,197,198,209,210,235,240,502,542,1200 Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage.1200 Such emergency situations include hypertensive encephalopathy, acute MI, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, unstable angina pectoris, acute ischemic stroke, and acute renal failure1200 , and labetalol generally is suitable for most hypertensive emergencies (e.g., acute aortic dissection, acute coronary syndromes) except when acute cardiac failure is present.239,1200 Patients with hypertensive emergencies require hospitalization and are treated with an appropriate parenteral agent.542,1200 Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.1200 The risks of overly aggressive therapy in any hypertensive crisis must always be considered.542,1200 Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.542,1200

Labetalol usually produces a prompt, but gradual reduction of blood pressure without substantial changes in heart rate or cardiac output.7,51,52,53,73,79,93,94,197,209,210,236,240 IV labetalol appears to adequately reduce blood pressure in about 80-90% of patients with severe hypertension or hypertensive emergencies,51,52,53,73,79,93,94,210 irrespective of etiology,51,52,53,79,93,94,210 and may be useful even when other drugs have failed.53,79 The exact effects of previous antihypertensive therapy on the efficacy of IV labetalol have not been fully determined.7,15,16,53,79,94,152 IV labetalol generally appears to be effective regardless of whether patients have received other hypotensive drugs, including β-blockers;53,79,94,152,236 however, in some studies, the drug was reported to be ineffective, usually in patients who received a single IV injection and who were receiving other hypotensive drugs, including β-blockers.7,15,16,235 The possibility of a diminished response to IV labetalol should be considered in patients receiving α- or β-blockers.7

The comparative efficacy and safety of IV labetalol and other currently available parenteral hypotensive agents in the management of severe hypertension and hypertensive emergencies have not been fully evaluated,7,14,15,16,54,199 but IV labetalol is considered one of several parenteral drugs of choice for the management of these forms of hypertension.53,73,502,542,1200 IV labetalol appears to be as effective as IV diazoxide (parenteral formulation no longer commercially available in the US),14,15,16,199 but may be less likely to induce excessive hypotension and adverse neurologic or cardiovascular sequelae.7,15,16 Because of its usual lack of substantial changes in heart rate or cardiac output, IV labetalol may be particularly useful in severely hypertensive patients with ischemic heart disease.7,53,73,79 In addition, IV labetalol has an advantage over most other parenteral hypotensive agents in that oral therapy with the drug may be continued after parenteral therapy when long-term control of blood pressure is necessary.7,73,79,240 IV labetalol also has been used effectively to control blood pressure and the rate of left ventricular pressure rise (dp/dt) in a few patients with acute dissection of the aorta;249,250,251 the drug produced a gradual reduction in blood pressure without a concomitant increase in heart rate.249,250

Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage.1200 Hypertensive urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen and treatment of anxiety if needed.1200 Experts state that there is no need for rapid reduction of blood pressure in the emergency department in such patients and hospitalization also is unnecessary.1200

IV labetalol has been used effectively in a small number of patients for the management of hypertensive crises following discontinuance of clonidine†,51,181,246 and oral labetalol has been used effectively in a small number of patients to prevent such crises during withdrawal from clonidine therapy†.188 However, since severe rebound hypertension reportedly has occurred in at least one patient during gradual withdrawal of clonidine and concurrent oral administration of labetalol,189 some clinicians caution that labetalol not be used in such patients unless they have received pretreatment with an α-blocker (e.g., IV phentolamine).7

Controlled Hypotension during Anesthesia

IV labetalol hydrochloride has been used effectively to produce controlled hypotension during anesthesia† in order to reduce bleeding resulting from surgical procedures.7,183,190,191,192,193,194,195 When labetalol and halothane are used concomitantly, a synergistic hypotensive effect results, which may be used to therapeutic advantage.183,190,191,192,193,194,195 (See Drug Interactions: Halothane.) Labetalol has also been effective in the management of uncontrolled hypertension before anesthesia and during surgery†, and for the management and/or prevention of acute hypertensive responses during laryngoscopy†.183

Chronic Stable Angina

Labetalol has been used in a limited number of patients for the long-term management of chronic stable angina pectoris†.7,17,18,127 Use of the drug has been associated with a reduction in the frequency and severity of anginal attacks, a decrease in nitrate dosage, and an increase in exercise tolerance.7,17,18,127β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication.1101 For additional information on the role of β-blockers in the management of chronic stable angina, see Uses: Chronic Stable Angina, in Metoprolol 24:24.

Tetanus

Labetalol has been used with good results for the management of the sympathetic overactivity syndrome associated with severe tetanus†.196,200,201,202 The drug generally has been effective in stabilizing the cardiovascular disturbances, including hypertension, tachycardia, and increased systemic arteriolar resistance, that occur in patients with severe tetanus.196,200,201,202

Administration

Labetalol hydrochloride is usually administered orally,2,4,7,8,19,23,47,49 but may be administered by slow, direct IV injection or by slow, continuous IV infusion.1,3,7,19,23,51,52,53,73,79,93,94,210

Oral Administration

Labetalol hydrochloride is usually administered orally in 2 divided doses daily; however, if adverse effects (e.g., nausea, dizziness) occur and are intolerable (particularly with dosages of 1.2 g daily or higher), administration of the drug in 3 divided doses daily may improve patient tolerance and/or facilitate dosage titration.2,4

Labetalol also has been administered as an extemporaneously compounded oral suspension using the commercially available tablets.13

Standardize 4 Safety

Standardized concentrations for an oral compounded liquid formulation of labetalol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 342Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 342 For additional information on S4S (including updates that may be available), see [Web].

IV Administration

To control blood pressure in patients with severe hypertension or hypertensive emergencies, repeated doses of labetalol hydrochloride may be given by slow, direct IV injection over a 2-minute period at intervals of 10 minutes,1,3,53,73,79,94,298,1200 or a diluted solution of the drug may be administered by slow, continuous IV infusion.1,3,51,73,210,1200 For IV infusion, labetalol hydrochloride solutions are prepared by diluting the injection to an appropriate concentration in a compatible IV infusion solution.1,3 (See Chemistry and Stability: Stability.) For example, 200 mg of the drug may be added to 160 mL of 5% dextrose injection to provide a solution containing 1 mg/mL. To facilitate a desired rate of infusion, diluted solutions of the drug can be administered via a controlled-infusion device.1,3 Labetalol hydrochloride injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1,3 Prefilled syringes of the drug should be destroyed and discarded if damaged in any manner; if the cannula is bent, no attempt should be made to straighten it.3

Patients receiving IV labetalol must be kept in a supine position during administration of the drug; a substantial fall in blood pressure on standing should be expected in these patients .1,3 Since symptomatic orthostatic hypotension is likely to occur if these patients are tilted upward or allowed to assume an upright position within 3 hours after administration of the drug, they should remain in a supine position during this time period.1,3 The patient's ability to tolerate an upright position must be established before any ambulation is permitted.1,3 (See Cautions: Precautions and Contraindications.) Blood pressure must be closely monitored during and after completion of IV administration of labetalol.1,3 Rapid or excessive reductions in systolic or diastolic blood pressure during IV therapy with the drug should be avoided.1,3 In patients with excessive systolic hypertension, the decrease in systolic pressure, as well as the decrease in diastolic pressure, should be used to assess response to the drug.1,3 When labetalol is administered by direct IV injection, blood pressure should be monitored before and at 5-minute intervals after each injection;1,3,53,79,94 the maximum hypotensive effect usually occurs within 5-15 minutes after each injection.1,3,53,54,55,298 When the drug is administered by continuous IV infusion, the rate of infusion may be adjusted according to the supine blood pressure response.1,3 After the desired supine blood pressure is attained or the maximum recommended cumulative dose has been given, IV administration of labetalol should be discontinued.1,3 Following discontinuance of IV labetalol, blood pressure is usually monitored at 5-minute intervals for 30 minutes, then at 30-minute intervals for 2 hours, then hourly for about 6 hours, and as necessary thereafter.79,94 Oral therapy with the drug may be initiated when it has been established that the supine diastolic blood pressure has begun to increase1,3 (usually determined by an increase of 10 mm Hg).53,79,94

Standardize 4 Safety

Standardized concentrations for IV labetalol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 339,340Multidisciplinary expert panels were convened to determine recommended standard concentrations. 339,340Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 339,340 For additional information on S4S (including updates that may be available), see [Web].339,340

Dosage

Hypertension

Dosage of oral labetalol hydrochloride should be adjusted according to standing blood pressure.2,4 Some adverse effects (e.g., nausea, dizziness) of the drug may be minimized or avoided and patient tolerance improved if dosage is adjusted more gradually (e.g., every 2-4 weeks)203 over a period of 4-12 weeks.9,75,76,203 The maximum, steady-state blood pressure response with twice-daily dosing occurs within 1-3 days and, with continued dosing, blood pressure can be measured approximately 12 hours after a dose to determine if further dosage titration is necessary.2,4 Since the maximum hypotensive effect of the drug is usually evident within 1-4 hours,2,4,6,7,34,48,56 lack of an excessive hypotensive response to the initial dose or a dose increment can usually be established in an ambulatory clinical setting.2,4

If long-term labetalol therapy is to be discontinued, dosage of the drug should be reduced gradually over a period of 1-2 weeks.2,4 (See Cautions: Precautions and Contraindications.)

Usual Dosage

For the management of hypertension in adults, the recommended initial oral dosage of labetalol hydrochloride is 100 mg twice daily, given alone or in combination with a diuretic.2,4,293 Dosage may be adjusted in increments of 100 mg twice daily every 2 or 3 days until the optimum blood pressure response is achieved.2,4

The usual oral maintenance dosage of labetalol hydrochloride recommended by the manufacturers for adults is 200-400 mg twice daily.2,4 Some experts recommend a lower usual dosage range of 100-400 mg twice daily;1200 the rationale for this reduced dosage is that it usually is preferable to add another antihypertensive agent to the regimen than to continue increasing labetalol hydrochloride dosage since the patient may not tolerate such continued increases.332 Because some geriatric individuals eliminate labetalol more slowly than younger adults, a lower maintenance dosage than that recommended for the general population may be adequate to control blood pressure in these older patients.4 Some manufacturers suggest that a maintenance dosage of 100-200 mg twice daily may be adequate for most geriatric patients.4 The manufacturers state that some adults with severe hypertension may require labetalol hydrochloride dosages of up to 2.4 g daily given in 2 divided doses, administered alone or in combination with a diuretic; in these patients, dosage titration increments should not exceed 200 mg twice daily.2,4

When diuretic therapy is initiated in a patient already receiving labetalol hydrochloride, adjustment of labetalol dosage may be necessary.2,4 Optimum maintenance dosage of oral labetalol hydrochloride is usually lower in patients also receiving a diuretic.2,4

When patients are transferred from therapy with other antihypertensive agents, oral therapy with labetalol hydrochloride should be initiated in the usual initial dosage and dosage of the existing regimen gradually decreased.2,4

If labetalol hydrochloride is used for the management of hypertension in children†, some experts have recommended an initial oral dosage of 1-3 mg/kg daily given in 2 divided doses.333 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 10-12 mg/kg (up to 1.2 g) daily given in 2 divided doses.333 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with labetalol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Severe Hypertension and Hypertensive Crises

Dosage of labetalol hydrochloride must be adjusted according to the severity of hypertension and the patient's blood pressure response and tolerance.600 IV dosage of labetalol hydrochloride should be adjusted according to supine blood pressure.600 When IV labetalol hydrochloride is used in the management of a hypertensive emergency in adults without a compelling indication, the initial goal of such therapy is to reduce systolic blood pressure by no more than 25% within the first hour, followed by further blood pressure reduction if stable to 160/110 or 160/100 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.542,1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours.1200 Adults who have hypertensive crisis with a compelling indication (e.g., aortic dissection, severe preeclampsia or eclampsia, pheochromocytoma crisis) should have their systolic blood pressure reduced to less than 140 mm Hg during the first hour, and, in patients with aortic dissection, to less than 120 mm Hg within the first 20 minutes.1200

To control blood pressure in adults with severe hypertension or hypertensive emergencies, the manufacturer recommends that IV labetalol hydrochloride be given in an initial dose of 20 mg by slow (over 2 minutes), direct IV injection.600 Alternatively, some experts recommend an initial IV labetalol dosage of 0.3-1 mg/kg (maximum 20 mg) administered by slow, direct IV injection every 10 minutes.1200 Higher initial doses (e.g., 1-2 mg/kg) have been administered by direct IV injection,51,55,235 but the 20-mg dose is recommended to minimize adverse effects (e.g., nausea, excessive hypotension) and the risks associated with too rapid reduction in blood pressure.23,53,79 Additional labetalol doses of 40 or 80 mg600 may be given at 10-minute intervals until the desired supine blood pressure is achieved or a total cumulative dose of 300 mg has been administered;7,19,53,73,79,94,274,298,600 IV labetalol should then be discontinued and oral therapy with the drug (administered as tablets) may be initiated when the supine diastolic blood pressure begins to increase.600

As an alternative to direct IV injections, the manufacturer states that labetalol hydrochloride may be given by continuous IV infusion at an initial rate of 2 mg/minute, with the rate of infusion adjusted according to the blood pressure response.600 Some experts recommend an initial IV infusion rate of 0.4-1 mg/kg per hour and increasing the rate as needed up to 3 mg/kg per hour.1200 The usual effective cumulative dose administered by IV infusion is 50-200 mg, although up to 300 mg may be required in some patients.600 A total cumulative dose of 300 mg has been recommended by some experts.1200 Because of the elimination half-life of labetalol, steady-state plasma concentrations of the drug are not attained during the usual infusion period.600 The infusion should be continued until an adequate response is obtained (or the maximum recommended cumulative dose has been given) and then discontinued, and oral therapy with the drug initiated when the supine diastolic blood pressure begins to increase.600 Some clinicians have used a progressive, incremental IV infusion regimen† (i.e., infusing 20, 40, 80, and 160 mg/hour for 1 hour at each dose level, or until the desired blood pressure is achieved) and believe this method may result in a more gradual reduction of blood pressure and minimize adverse effects compared with repeated IV injections of the drug;21,51,197 however, controlled comparisons of the various methods of IV administration are not available. Some clinicians have also used oral regimens† for urgent reduction of blood pressure in severely hypertensive patients.56,92

For rapid reduction of blood pressure in children and adolescents with acute severe hypertension† and life-threatening symptoms, some experts recommend administration of labetalol hydrochloride as a direct IV injection of 0.2-1 mg/kg per dose, up to 40 mg per dose.1150 As an alternative to direct IV injections, labetalol hydrochloride may be given by continuous IV infusion at a rate of 0.25-3 mg/kg per hour.1150 These experts suggest that blood pressure should be reduced by no more than 25% of the planned reduction over the first 8 hours.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

When oral labetalol therapy is initiated following IV therapy with the drug, the recommended initial oral dose in adults is 200 mg, followed in 6-12 hours by an additional oral dose of 200 or 400 mg, depending on the blood pressure response.600 Thereafter, while the patient is hospitalized, oral dosage may be increased in usual increments at 1-day intervals (dosage range: 400-2400 mg daily administered in 2 or 3 divided doses), if necessary, to achieve the desired blood pressure control; for subsequent outpatient dosage titration or maintenance dosing, the usual oral dosage recommendations should be followed.600

Severe Hypertension During Pregnancy

To control acute severe hypertension in pregnant women, including preeclampsia†, some experts recommend an initial IV labetalol hydrochloride dose of 10-20 mg administered by direct IV injection, followed by 20-80 mg every 20-30 minutes as needed up to a maximum cumulative dose of 300 mg.298 Alternatively, the drug may be administered by continuous IV infusion at a rate of 1-2 mg/minute.298 Antihypertensive therapy is recommended for women with preeclampsia who have persistent systolic blood pressures of 160 mm Hg or higher or diastolic blood pressures of 110 mm Hg or higher.298,540

Controlled Hypotension during Anesthesia

To produce controlled hypotension during halothane anesthesia† in adults, IV labetalol hydrochloride has been given in an initial dose of 20 mg (range: 10-25 mg) following induction of anesthesia; if necessary, additional doses of 5-10 mg (range: 2.5-15 mg) were given.183,191,192,193 When IV labetalol hydrochloride and halothane anesthesia are used concomitantly, the degree and duration of the synergistic hypotensive response can be controlled by adjusting the inspired halothane concentration.183,190,191,192,193,194,195 (See Drug Interactions: Halothane.) To produce controlled hypotension during anesthesia with other anesthetic agents† in adults, IV labetalol hydrochloride has been given in an initial dose of 30 mg, with additional doses of 5-10 mg given if necessary.192,193

Dosage in Renal and Hepatic Impairment

Modification of labetalol hydrochloride dosage does not appear to be necessary in patients with mild to moderate renal impairment.60,146,147,239 In patients with severe renal impairment (i.e., creatinine clearance less than 10 mL/minute) undergoing dialysis, adequate blood pressure control may be possible with once-daily dosing of the drug.241

Although specific data are currently not available, dosage reduction may be necessary in patients with impaired hepatic function since metabolism of the drug may be decreased in these patients.7,39

Labetalol hydrochloride shares the toxic potentials of β-adrenergic and postsynaptic α₁-adrenergic blocking agents.7,8,9 Most adverse reactions to labetalol are mild, transient, and occur early in the course of treatment.1,2,3,4,7,8,9,53,74,75,76,77,78,79,81,82,85,87,90,94,96,108 Adverse effects of labetalol can generally be divided into 3 groups (in decreasing order of frequency): nonspecific effects, effects related to the α-adrenergic blocking activity of the drug, and effects related to its β-adrenergic blocking activity.7,81,108 During controlled clinical studies in patients receiving oral labetalol for 3-4 months, adverse reactions requiring discontinuance of the drug occurred in about 7% of patients; in these same comparative studies, adverse reactions requiring discontinuance of therapy occurred in 8-10% of patients receiving pure β-adrenergic blocking agents (i.e., metoprolol, propranolol) and in 30% of patients receiving a centrally acting adrenergic inhibitor (i.e., methyldopa).2,4 Evidence from clinical studies in patients receiving oral labetalol hydrochloride dosages of 200 mg to 2.4 g daily suggests that some adverse effects, including dizziness, fatigue, nausea, vomiting, dyspepsia, paresthesia, nasal congestion, failure to ejaculate, impotence, and edema, are dose related.1,2,3,4 The incidence and/or severity of some labetalol-induced adverse reactions may occasionally be obviated by slow, upward titration of dosage over 4-12 weeks.9,75,76

Cardiovascular Effects

The most frequent adverse cardiovascular effect of labetalol is symptomatic orthostatic hypotension,1,2,3,4,7,8,9,19,23,46,51,54,55,79,81,83,88,91,94,96,100,108,122,129,132,158,159 which occurs in about 1-5%2,4,7,108,122,129,247,248 or 60%1,3,51,54,55,132 of patients following oral or IV administration of the drug, respectively. Orthostatic hypotension has been associated with loss of consciousness occasionally following IV administration51,54,55,132 and rarely following oral administration.2,4 Symptomatic orthostatic hypotension is likely to occur if supine patients are tilted upward or allowed to assume the upright position within 3 hours following IV administration of labetalol.1,3 (See Cautions: Precautions and Contraindications.) Moderate hypotension occurs in about 1% of patients in the supine position who are receiving the drug IV.1,3 Following oral administration, orthostatic hypotension appears to occur more frequently during initiation of therapy, in patients receiving concomitant administration of a diuretic, and in those receiving higher dosages of the drug.7,23,78,108,122,129

Development or exacerbation of heart failure has occurred in some patients receiving labetalol,1,2,3,4,19,81,90,174 although the drug appears to be less likely to precipitate heart failure than pure β-adrenergic blocking agents.9,81,85,110 At the first sign or symptom of impending cardiac failure during labetalol therapy, patients should receive adequate treatment (e.g., cardiac glycoside, diuretic) and should be observed closely;1,2,3,4 if cardiac failure continues, labetalol should be discontinued, gradually if possible.1,2,3,4

Ventricular arrhythmia1,3,79,94 (including ventricular premature contractions),79,94 edema or fluid retention,1,2,3,4,19,75,76,81,85,90 bradycardia,1,2,3,4,9,19,85,247 hypotension,1,2,3,4,247 syncope,1,2,3,4,247 chest pain,76 atrioventricular (AV) conduction delay,19 and AV block1,2,3,4,247 have occurred during therapy with labetalol.

Nervous System Effects

Adverse nervous system effects occur with variable frequency with labetalol and most of these effects appear to be dose related.1,2,3,4,7,8 At the usual labetalol hydrochloride dosage of 200-400 mg twice daily, most adverse nervous system effects occur in 5% or less of patients.1,2,3,4,247,248 Adverse nervous system effects of the drug include drowsiness or tiredness,7,8,75,78,79,80,81,82,85,88,159 dizziness1,2,3,4,8,23,74,75,76,79,80,81,82,88,90,158,159 or lightheadedness23,51,53,85 (often posture related),7,23 headache,2,4,7,8,19,23,53,75,76,79,81,82,85,90,159 fatigue,1,2,3,4,23,75,76,78,87,159 lethargy,23,90,159 and nightmares or vivid dreams.19,75,81,85,87,90,159 Paresthesia, usually mild, transient tingling of the scalp or skin,1,2,3,4,7,8,19,23,33,51,53,63,74,76,79,80,81,82,83,88,90,93,94,109,158,159,168,169,247,248 may also occur following oral or IV administration of the drug, usually at the beginning of therapy.1,2,3,4,7 Hypoesthesia or numbness1,3,79,85 and circumoral paresthesia170 have also occurred. Mental depression,8,19,81,87,90 paroniria,247,248 vertigo,1,2,3,4 somnolence,1,3 yawning,1,3 tremor,19,81 asthenia,2,4,76,78 and insomnia90 have also been reported. Some adverse nervous system effects such as fatigue, mental depression, and sleep disorders may occur less frequently with labetalol than with pure β-adrenergic blocking agents.9,81,85,110 Adverse nervous system effects of labetalol may be obviated by a reduction in dosage or alteration of dosage schedule.2,4

GI Effects

The most frequent adverse GI effects associated with labetalol therapy are nausea,1,2,3,4,7,8,19,23,51,53,74,75,76,78,79,80,81,82,83,87,90,93,94,158,159,247,248 dyspepsia,1,2,3,4,7,8,23,74,75,76,79,82,83,93,94,158,159,247,248 and vomiting.1,2,3,4,7,8,23,51,53,76,79,81,82,83,90,93,158,159 Alteration or distortion in taste,1,3,76,79 abdominal pain,7,76,81,90 constipation,7,23,80,81,85,158,159,247,248 diarrhea,2,4,7,76,81,90,159 and flatulence76,247,248 have also been reported.

Hepatic Effects

Elevated liver function test results,1,2,3,4,248,255,275,276 including reversible increases in serum aminotransferase concentrations;1,2,3,4,19,74,75,78,247,248,255,275,276 jaundice1,2,3,4,19,247,248,255,275,276 (including cholestatic jaundice);1,2,3,4,247 and hepatitis1,2,3,4,248 have been reported in patients receiving labetalol. Severe hepatocellular injury, which has recurred during rechallenge,255,275,276 has occurred rarely during labetalol therapy;1,2,3,4,247,248,255,275,276 hepatocellular injury may be accompanied by clinical symptoms of hepatotoxicity, including pruritus, dark urine, persistent anorexia, jaundice, flu-like syndrome, and/or right upper quadrant tenderness.1,2,3,4,247,248,254,255,275,276 Hepatocellular injury is usually reversible; however, hepatic necrosis and death have been reported.1,2,3,4,247,248,254,255,275,276 Hepatic injury may occur after short- or long-term labetalol therapy.1,2,3,4,247,248 Similar severe adverse hepatic effects, including at least 2 fatalities, have been reported with dilevalol hydrochloride; dilevalol is one of the 4 stereoisomers that make up the racemic mixture labetalol.1,3,4 (See Chemistry and Stability: Chemistry.)

Respiratory Effects

Adverse respiratory effects of labetalol, including dyspnea,2,4,8,76,78,81,159 wheezing,1,3,79,87,90,94 bronchospasm,2,4,19,23,81,159,247,248 and nasal congestion,1,2,3,4,7,19,75,76,79,81,87,90,247,248 occur occasionally. Rhinorrhea94 and rhinitis247,248 also have been reported.

Genitourinary Effects

Ejaculatory failure,1,2,3,4,19,75,76,78,90,247,248 impotence,1,2,3,4,7,8,19,74,75,76,78,81,85,90,172,247,248 difficult or painful micturition,2,4,19,75,81,90,164 and acute urinary retention2,4,7,19,81,247,248 have occurred occasionally in patients receiving labetalol alone or in fixed combination with hydrochlorothiazide. Peyronie's disease2,4,7,8,19,171 and priapism7,172 have been reported rarely. Urinary frequency,247,248 nocturia,247,248 and polyuria247,248 have been reported when the drug was used in fixed combination with hydrochlorothiazide.247,248

Dermatologic and Sensitivity Reactions

Rashes, including maculopapular, lichenoid, urticarial, and psoriasiform lesions, have developed in some patients during labetalol therapy (alone or in fixed combination with hydrochlorothiazide).2,4,7,8,81,87,90,159,247,248 Pruritus,1,3,19,81 bullous lichen planus,2,4,88 facial erythema,2,4 and reversible alopecia2,4 have also occurred. Hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions have been reported rarely in patients receiving labetalol.1,3,4,247

Endocrine Effects

Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-adrenergic blocking agents in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy.313,314 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-adrenergic blocking agents or no drug therapy, respectively.313 The association between the risk of developing type 2 diabetes mellitus and use of β-adrenergic blocking agents reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.313,314 It is not known if the risk of developing diabetes is affected by β-receptor selectivity.313 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance.314 Therefore, until results of such studies are available, the proven benefits of β-adrenergic blocking agents in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.313

Hypoglycemia,312 which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-adrenergic blocking agents. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.312

β-Adrenergic blocking agents may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.1,312 Although it has been suggested that nonselective β-adrenergic blocking agents are more likely to induce hypoglycemia than selective β-blockers agents, such an adverse effect also has been reported with selective β-blocking agents (e.g., atenolol).312 In addition, selective β-adrenergic blocking agents are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-adrenergic blocking agents because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.312

Other Adverse Effects

Lupus erythematosus-like illness,2,4,7,8,19,175 positive antinuclear antibody (ANA) titer,2,4,7,19,81,176 mild hyperglycemia,53,74 leukopenia,19 and development of positive antimitochondrial antibodies2,4,7,8,177 have occurred in patients receiving labetalol. Transient increases in BUN1,2,3,4,91 and serum creatinine concentrations1,3,91 associated with decreases in blood pressure have also occurred, usually in patients with renal insufficiency.1,3 Flushing or a feeling of warmth,1,3,53,79,81 fever,1,2,4,243,248 rigors,247,248 increased sweating,1,3,76,79 dry mouth76,78,81,85,87 or eyes,2,4,90 blurred vision,74,81,159 visual disturbances,2,4,75,159,247,248 pallor,51 shivering,51,93 decreased libido,19,76,81,87 muscle cramps,2,4,81 toxic myopathy,2,4,173 claudication,81 Raynaud's phenomenon,81 burning sensation of the groin,51,93 and pain at the injection site have been reported.51,53,79,93 In addition, leg cramps,247,248 pain,247,248 gout,247,248 increased appetite,247,248 hypokalemia,247,248 and increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations247,248 have been reported when the drug was used in fixed combination with hydrochlorothiazide.247,248

The possibility that other adverse effects associated with other β-adrenergic blocking agents may occur during labetalol therapy should be considered.1,2,3,4 These include, but may not be limited to, hematologic reactions (e.g., agranulocytosis, nonthrombocytopenic or thrombocytopenic purpura); allergic reactions characterized by fever, sore throat, laryngospasm, and respiratory distress; GI reactions including mesenteric thrombosis or ischemic colitis; and CNS reactions including reversible mental depression progressing to catatonia, short-term memory loss, decreased performance on neuropsychometric tests, and oculomucocutaneous syndrome.2,4

Precautions and Contraindications

Labetalol shares the toxic potentials of β-adrenergic and postsynaptic α₁-adrenergic blocking agents,1,2,3,4,7,8,9 and the usual precautions of these agents should be observed.1,2,3,4,7

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function.1,2,3 Labetalol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when labetalol therapy is administered.1,2,3,4,7 In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure.1,2,3,4 Although β-adrenergic blocking agents should be avoided in patients with overt heart failure, labetalol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).1,2,3,4 Patients receiving labetalol therapy should be instructed to consult their clinician at the first sign or symptom of impending cardiac failure1,2,3,4 and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, labetalol should be discontinued, gradually if possible.1,2,3,4

Further experience is necessary, but labetalol may be less likely than pure β-adrenergic blocking agents to produce adverse cardiovascular withdrawal reactions (e.g., angina, rebound hypertension) following abrupt withdrawal.9,74,75,76,77,78,164 Although angina pectoris has not been reported to date following discontinuance of labetalol therapy, exacerbation of angina pectoris and precipitation of myocardial infarction have occurred following abrupt cessation of therapy with some β-adrenergic blocking agents in patients with coronary artery disease.1,2,3,4 Therefore, patients receiving labetalol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician.1,2,3,4 When discontinuance of long-term labetalol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of 1-2 weeks.2,4 When labetalol therapy is discontinued, patients should be carefully monitored1,2,3,4 and advised to temporarily limit their physical activity.1,3 If exacerbation of angina occurs or acute coronary insufficiency develops after labetalol therapy is interrupted or discontinued, treatment with the drug should be reinstituted promptly, at least temporarily, and appropriate measures for the management of unstable angina pectoris should be initiated.1,2,3,4 Because coronary artery disease is common and may be unrecognized, the manufacturers caution that it may be prudent not to discontinue labetalol therapy abruptly, even in patients being treated only for hypertension.2,4

Since β-adrenergic blocking agents may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease;2,4 however, oral labetalol may be used with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) who do not respond to or cannot tolerate other hypotensive agents.2,4 (See Pharmacology: Respiratory Effects.) If oral labetalol is administered to such patients, the smallest effective dose should be used so that inhibition of endogenous or exogenous β-adrenergic agonist activity is minimized.2,4 Because IV labetalol at the usual therapeutic doses has not been studied in patients with nonallergic bronchospasm, the manufacturers state that it should not be used in these patients.1,3

Although labetalol has been used effectively in the management of hypertension and relief of symptoms associated with pheochromocytoma,51,85,181,182,183,184 the drug should be used with caution in patients with this tumor since paradoxical hypertensive responses have been reported in a few patients.1,2,3,4,186,187 (See Hypertension Associated with Pheochromocytoma under Uses: Hypertension.)

It is recommended that labetalol be used with caution in patients with diabetes mellitus receiving hypoglycemic agents, especially those with labile disease1,2,3,4 or those prone to hypoglycemia203 since the drug may mask the signs and symptoms associated with acute hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating).1,2,3,4β-Adrenergic blocking agents also may impair glucose tolerance; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation.211,212 (See Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-adrenergic blocking agents.310 (See Uses: Heart Failure, in Metoprolol 24:24.) If labetalol is used in diabetic patients receiving hypoglycemic agents, it may be necessary to adjust the dosage of the hypoglycemic agent.1,2,3,4

The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial.1,2,3,4 Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-adrenergic blocking agents.1,2,3,4 The effect of labetalol's α-adrenergic activity in patients undergoing major surgery has not been evaluated.1,2,3,4 However, several deaths have been reported in patients in whom labetalol hydrochloride injection was used during surgery, including those receiving the drug to control bleeding.1,3 In addition, a synergistic hypotensive response occurs in patients receiving IV labetalol and halothane anesthesia concomitantly.1,2,3,4,183,190,191,192,193,194,195 (See Drug Interactions: Halothane.) If labetalol therapy is continued in a patient undergoing major surgery, the anesthesiologist should be informed that the patient is receiving the drug.1,2,3,4

Caution must be employed when reducing severely elevated blood pressure.1,3 The manufacturers state that IV labetalol is intended for use in hospitalized patients.1,3 When IV labetalol is used in patients with severely elevated blood pressure, the desired blood pressure reduction should be achieved over as long a period of time as is compatible with the patient's clinical status.1,3 Serious adverse effects, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the ECG, have been reported with other hypotensive agents when severely elevated blood pressure was reduced over periods ranging from several hours to as long as 1 or 2 days.311 Rapid or excessive reductions in systolic or diastolic blood pressure should be avoided;1,3 while these effects are unlikely with the recommended dosage schedules of IV labetalol,51,53,79,94 they can occasionally occur.51,79,197 Transient hypotension occurring with IV labetalol is usually readily managed by placing the patient in Trendelenburg's position, administering IV fluids, and/or temporarily discontinuing administration of the drug.51,79,94,197 Patients should remain supine during and for up to 3 hours after IV administration of the drug, since symptomatic orthostatic hypotension is likely to occur if they are tilted upward or allowed to assume an upright position during this period.1,3 The patient's ability to tolerate an upright position should be established before any ambulation (e.g., use of toilet facilities) is permitted; the patient should be advised on how to proceed gradually to become ambulatory and should be observed at the time of initial ambulation.1,3

Labetalol should be used with caution in patients with impaired hepatic function, since metabolism of the drug may be decreased in such patients.1,2,3,4,7,39,247,248 Since labetalol has been rarely associated with the development of jaundice, hepatitis, severe hepatocellular injury, and elevated liver function test results, the manufacturers recommend that the drug be discontinued immediately if jaundice or laboratory evidence of hepatic injury occurs.1,2,3,4,247,248 Jaundice and hepatic dysfunction usually are reversible following discontinuance of the drug.1,2,3,4,247,248 Liver function tests should be performed at the first signs or symptoms of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, flu-like syndrome).1,2,3,4,247,248

Routine laboratory tests are usually not required before or after IV administration of labetalol,1,3 but the manufacturers recommend that laboratory parameters be monitored at regular intervals in patients receiving long-term oral therapy with the drug.2,4 In patients with concomitant illnesses (e.g., impaired renal function), appropriate tests should be performed to monitor these conditions.1,2,3,4

Patients should be advised that transient scalp tingling may occur, usually during initiation of labetalol therapy.1,2,3,4

Patients with a history of atopy or severe anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenge with such allergens while receiving a β-adrenergic blocking agent.1 These patients may be less responsive than other patients to usual dosages of epinephrine or may develop a paradoxical response to epinephrine when that drug is used to treat anaphylactic reactions.1,3,4

Labetalol is contraindicated in patients with a history of obstructive airway disease (e.g., bronchial asthma), overt cardiac failure, heart block of severity greater than first degree, cardiogenic shock, severe bradycardia,1,2,3,4,311 and/or other conditions associated with severe and prolonged hypotension.1,3,4,247 The drug also is contraindicated in patients with a history of hypersensitivity to any component of the formulation.1,3,4,247

Because of similarity in spelling between labetalol hydrochloride and Lamictal^® (the trade name for lamotrigine, an anticonvulsant agent), several dispensing errors have been reported to the manufacturer of Lamictal^® (GlaxoSmithKline).319,320 These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated.319,320 Therefore, the manufacturer of Lamictal^® cautions that extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal^® and labetalol.319,320 The manufacturer also recommends that when appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist.319 The manufacturer also recommends that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another in product storage areas, patient counseling).320

Pediatric Precautions

Although safety and efficacy remain to be fully established in children,1,2,3,4,247,248 some experts have recommended pediatric dosages for hypertension based on clinical experience.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

Orthostatic hypotension, dizziness, or lightheadedness, similar to that reported in younger adults, have been reported in geriatric patients (i.e., those 60 years of age or older) receiving labetalol.4 Geriatric individuals are generally more likely than younger adults to experience orthostatic symptoms and these individuals should be cautioned about the possibility of these adverse effects during therapy with the drug.4 Because elimination of labetalol may be decreased in some geriatric patients, usual maintenance dosage of the drug is slightly lower in geriatric individuals than in younger adults.4 (See Dosage and Administration: Dosage.)

Mutagenicity and Carcinogenicity

It is not known if labetalol is mutagenic or carcinogenic in humans.203 No evidence of labetalol-induced mutagenesis was seen with the modified Ames test or in studies in mice and rats using dominant lethal assays.1,2,3,4

No evidence of carcinogenesis was seen in mice receiving oral labetalol hydrochloride dosages up to 200 mg/kg daily for 18 months or in rats receiving oral dosages up to 225 mg/kg daily for up to 113 weeks in females and up to 116 weeks in males.1,2,3,4,5

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral labetalol hydrochloride dosages up to about 6 and 4 times the maximum recommended human dosage, respectively, have not revealed reproducible evidence of fetal malformation; however, oral dosages approximating the maximum recommended human dosage were associated with an increased incidence of fetal resorption in both species.1,2,3,4,5 There was no evidence of drug-related fetotoxicity in rabbits receiving IV dosages of the drug up to 1.7 times the maximum recommended human dosage.1,2,3,4,247,248 In rats, oral administration of labetalol hydrochloride at dosages 2-4 times the maximum recommended human dosage during the period of late gestation through weaning was associated with decreased neonatal survival.1,2,3,4,5 Reproduction studies in rats or rabbits using combined oral labetalol hydrochloride and hydrochlorothiazide dosages up to about 15 and 80 times the maximum recommended human dosage, respectively, have not revealed evidence of teratogenicity, although combined oral dosages 3.5 and 20 times the maximum recommended human dosage, respectively, were maternotoxic with resultant fetotoxicity in rabbits.247,248 The combination appeared to be more toxic than either drug alone in rabbits.247,248

Labetalol has been used orally for the management of hypertension in pregnant women64,65,66,68,70,95,185,298,540 and IV to control blood pressure in severely hypertensive pregnant women requiring urgent blood pressure reduction.7,63,65,95,185,244,298,540,542 (See Hypertension during Pregnancy under Uses: Hypertension.) Labetalol has been effective for the management of hypertension associated with pregnancy,3,63,64,65,66,68,70,95,185,244,245,298 and is one of several preferred agents for such use.298,502,540 Infants of mothers who received labetalol for the management of hypertension during pregnancy have not appeared to be adversely affected by the drug;1,2,3,4,64,65,95,185,245 however, transient hypotension1,2,3,4,245,247,248 (including slight decreases in systolic blood pressure during the first 24 hours after delivery),245 bradycardia,1,2,3,4,247 respiratory depression,1,3,4,247 and hypoglycemia1,2,3,4,247,248 have been reported rarely in neonates. Maternal labetalol therapy reportedly has been associated with a beneficial effect on development of fetal pulmonary maturity.64,65,68,185 Use of labetalol in pregnant women with hypertension does not appear to affect the usual course of labor and delivery,1,2,3,4,64,65,95,185,244,298 and the drug has been used IV to treat severe hypertension during labor.298 Following a single IV dose of the drug in pregnant women with preeclampsia, maternal blood pressure was reduced but placental and fetal blood flow were not affected.244 The manufacturers state that there are no adequate and controlled studies to date using labetalol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,3,4,247,248

Fertility

The effects of labetalol on fertility in humans have not been fully determined. Ejaculatory failure1,2,3,4,19,75,76,78,90,247,248 and impotence1,2,3,4,7,8,19,74,75,76,78,81,85,90,172,247,248 in males and decreased libido19,76,81,87,247,248 have been reported in patients receiving labetalol.

Lactation

Since small amounts (about 0.004% of the maternal dose)1,2,3,4 of labetalol are distributed into milk,1,2,3,4,6,7,64,68,69 the drug should be used with caution in nursing women.1,2,3,4

Since IV labetalol hydrochloride may be administered to patients receiving other drugs, including other hypotensive agents, careful monitoring of these patients is necessary to detect and promptly treat any adverse effect resulting from concomitant administration.1,3

Diuretics and Cardiovascular Drugs

When labetalol is administered with diuretics or other hypotensive drugs, the hypotensive effect may be increased.2,4,7,8,9,15,19,72,76,77,78,80,81,82,83,85,87,90,91,96,97,99,231,234 This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary to avoid excessive hypotension when these drugs are used concomitantly.2,4,7,8,9,15,19,72,76,77,78,80,81,82,83,85,87,90,91,96,97,99,231,234 When β-adrenergic blocking agents are administered with calcium-channel blocking agents, therapeutic256,257,258,259,260,261,262,263,264,265,267,268,269,270,271,272,273 as well as adverse effects257,261,264,266,267,268,271,272,273 may be additive. Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy.290,291 The manufacturers of labetalol and some clinicians state that labetalol and a calcium-channel blocking agent (e.g., verapamil, diltiazem) should be used concomitantly with caution.1,3,4,247,258,259,260,261,264,266,268,271,272,273,290,291

Halothane

Concomitant administration of IV labetalol and halothane anesthesia results in a synergistic hypotensive effect, the degree and duration of which may be controlled by adjusting the halothane concentration;183,190,191,192,193,194,195 however, excessive hypotension can result in a large reduction in cardiac output and an increase in central venous pressure.1,2,3,4,183,190,191,192,193,194,195 To minimize the risk of excessive hypotension during controlled hypotensive anesthesia with IV labetalol and halothane, inspired halothane concentrations of 3% or higher should not be used.1,2,3,4 If labetalol therapy is continued in a patient undergoing major surgery, the anesthesiologist should be informed that the patient is receiving the drug.1,2,3,4

Cimetidine

Concomitant administration of oral cimetidine has been shown to substantially increase the absolute bioavailability of oral labetalol, possibly via enhanced absorption or decreased first-pass hepatic metabolism of labetalol.1,2,3,4,180,229 If labetalol and cimetidine are administered concomitantly, dosage of labetalol required for optimal control of blood pressure should be carefully adjusted.1,2,3,4,229

Glutethimide

Concomitant administration of oral glutethimide (no longer commercially available in the US) has been shown to substantially decrease the absolute bioavailability of oral labetalol, possibly by increasing first-pass hepatic metabolism (glucuronidation) of labetalol.229 If labetalol and glutethimide are administered concomitantly, dosage of labetalol required for optimal control of blood pressure should be carefully adjusted.229

Other Drugs

Labetalol, like other drugs with β-adrenergic blocking activity, can antagonize the bronchodilation produced by β-adrenergic agonists in patients with bronchospasm, and greater than usual dosages of β-adrenergic agonist bronchodilators may be required in patients receiving labetalol.1,2,3,4

Labetalol antagonizes the reflex tachycardia produced by nitroglycerin without preventing the hypotensive effect of the nitrate.1,2,3,4 If labetalol is used concurrently with nitroglycerin, an additive hypotensive effect may occur.1,2,3,4

An increased incidence of tremor has been reported in patients receiving labetalol and tricyclic antidepressants concomitantly compared with those receiving labetalol alone.1,2,3,4 Although the contribution of each drug to this adverse reaction is not known, the possibility of a drug interaction cannot be excluded.1,2,3,4

Laboratory Test Interferences

Urinary Catecholamines

The presence of labetalol metabolites in urine may result in false-positive elevations of urinary free216 and total217 catecholamines, metanephrine, normetanephrine, and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, VMA) measured by fluorometric or photometric methods.1,2,3,4,216,217,218,248 When screening labetalol-treated patients suspected of having pheochromocytoma or when evaluating labetalol-treated patients with the tumor, specific assay methods such as high-performance liquid chromatography (HPLC) with solid phase extraction1,2,3,4,218,248,252 should be used to determine concentrations of catecholamines or their metabolites.1,2,3,4,216,217,218,248

Acute Toxicity

Pathogenesis

The acute lethal dose of labetalol in humans is not known.203,204 The oral LD₅₀ of labetalol hydrochloride is approximately 0.6,1,2,3,4 greater than 2,1,2,3,4 and greater than 1 g/kg5 in mice, rats, and dogs, respectively; the IV LD₅₀ in these species is about 50-60 mg/kg.1,2,3,4,5

Manifestations

In general, overdosage of labetalol may be expected to produce effects that are extensions of pharmacologic effects, particularly those involving the cardiovascular system;203,204 hypotension (which is posture dependent and may be severe), bradycardia (which may be severe), cardiac failure, and bronchospasm may occur.1,2,3,4 Common, dose-related adverse effects (e.g., nausea, vomiting, headache) might also occur.223 In one adult who was reported to have intentionally ingested labetalol hydrochloride 7.2 g, acebutolol hydrochloride 9.6 g, and trimipramine 625 mg, loss of consciousness, bradycardia, and profound hypotension resulted.237

Treatment

Treatment of labetalol overdosage generally involves symptomatic and supportive care.1,2,3,4,12,237,238 Following acute ingestion of the drug, the stomach should be emptied immediately by inducing emesis or by gastric lavage.1,2,3,4,238 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.179,238 Administration of activated charcoal after emesis or gastric lavage may be useful in preventing absorption of labetalol,203,238 although specific data are not available. Patients should be placed in a supine position and their legs elevated if necessary to improve blood supply to the brain.1,2,3,4 For symptomatic bradycardia, atropine or epinephrine242 may be given.242 A vasopressor (e.g., norepinephrine, dopamine) may be given for severe hypotension.1,2,3,4,12,238,242 For heart failure, a cardiac glycoside and diuretic may be used;1,2,3,4,242 dopamine or dobutamine may also be useful.242 Glucagon may also be useful for the management of myocardial depression and hypotension.203,213,214,215,238,242 A β₂-adrenergic agonist and/or a theophylline derivative may be used for bronchospasm.1,2,3,4,12,238 For seizures, diazepam may be used.242 Labetalol is not appreciably removed (less than 1% of a dose) by hemodialysis or peritoneal dialysis.203,204,223,241,242

Pharmacology

Labetalol is a nonselective β-adrenergic blocking agent and a selective α₁-adrenergic blocking agent.1,2,3,4,5,6,7,8,9,22,23,32,44,101,107,108 The pharmacology of labetalol is complex and in some ways resembles that of other β-adrenergic blocking agents and that of postsynaptic α₁-adrenergic blocking agents such as prazosin; however, the overall pharmacologic profile of labetalol differs from that of these other drugs.1,2,3,4,7,8,9,21,22,23,24,28,29,30,32,44,101,107,108 The β-adrenergic blocking activity of labetalol is approximately 3 or 7 times greater than the α-adrenergic blocking activity following oral1,2,3,4,5,50 or IV1,2,3,4,5,178 administration, respectively; it has not been clearly established whether the ratio changes with dosage of the drug7,107 or following long-term administration.25,203

The principal physiologic action of labetalol is to competitively block adrenergic stimulation of β-receptors within the myocardium (β₁-receptors) and within bronchial and vascular smooth muscle (β₂-receptors) and α₁-receptors within vascular smooth muscle.1,2,3,4,7,8,9,21,22,23,24,28,29,30,32,44 In addition to inhibiting access of endogenous or exogenous catecholamines to β-adrenergic receptors, labetalol has been shown to exhibit some intrinsic β₂-agonist activity in animals;1,2,3,4,7,30,62,221,222 however, the drug exerts little, if any, intrinsic β₁-agonist activity.1,2,3,4,7,8,9,30,62,107 Labetalol does not exhibit intrinsic α-adrenergic agonist activity.7,28,30 There is some evidence from animal studies suggesting that the drug may have a vasodilating effect, possibly resulting from a direct or β₂-agonist action.7,30,61,225 In animals, at doses greater than those required for α- or β-adrenergic blockade, labetalol also has a membrane-stabilizing effect on the heart1,2,3,4,7,8,9,23,28,30 which is similar to that of quinidine;7,8,9,23,28,30 however, this effect is unlikely to be clinically important since it occurs only at doses higher than those required for α- or β-adrenergic blockade.23,24,28,107

Cardiovascular Effects

The hemodynamic effects of labetalol are variable following oral or IV administration.1,2,3,4,7,8,9 Labetalol, unlike pure β-adrenergic blocking agents, produces a dose-dependent (at usual doses) decrease in systemic arterial blood pressure and systemic vascular resistance without a substantial reduction in resting heart rate, cardiac output, or stroke volume, apparently because of its combined α- and β-adrenergic blocking activity.1,2,3,4,7,112,113,114 Labetalol effectively reduces blood pressure in the standing or supine position, but because of the drug's α₁-adrenergic blocking activity, the effect on blood pressure is position dependent; labetalol-induced decreases in blood pressure are greater in the standing than in the supine position, and orthostatic hypotension can occur.1,2,3,4,7,8,9,112,113,114,115,116,117,118,119,120,121,122,123,124 (See Cautions: Cardiovascular Effects.) The blunting of exercise-induced increases in blood pressure by oral or IV labetalol is generally greater than that produced by pure β-adrenergic blocking agents (e.g., propranolol), but the blunting of exercise-induced tachycardia produced by labetalol is generally less than that produced by pure β-adrenergic blocking agents.7,8,32,113,114,128

Following oral administration of labetalol hydrochloride dosages of 200 mg to 2.4 g daily for 1 week to 20 months in clinical studies in patients with hypertension, blood pressure and heart rate were reduced at rest or during exercise and in the supine or standing position.47,112,113,114,121,122,123 During oral labetalol therapy, cardiac output is generally decreased or unchanged and stroke volume is generally increased or unchanged; however, unlike most pure β-adrenergic blocking agents, oral labetalol usually decreases systemic vascular resistance.47,112,113,114,121,122,123 Following IV administration of single labetalol doses in patients with hypertension, the drug decreases blood pressure and systemic vascular resistance in the supine position without substantially reducing cardiac output or stroke volume.7,113,114,115,116,117,118,119,120 Although substantial changes in heart rate usually do not occur in the supine position following IV administration,113,114,115,116,117,118,119,120 heart rate and cardiac output generally are reduced in an upright or tilted upright position or during exercise.7,8,113,114,118,120 In one study in patients with severe hypertension, an initial 0.25-mg/kg IV dose of the drug decreased supine blood pressure by an average of 11/7 mm Hg;1,3,240 additional 0.5-mg/kg IV doses administered at 15-minute intervals up to a total cumulative dose of 1.75 mg/kg caused further dose-related decreases in blood pressure in these patients.1,3,240 Similar results in patients with severe hypertension have also been produced with an initial 20-mg IV dose followed by IV doses of 40 or 80 mg at 10-minute intervals until blood pressure was adequately controlled or a total cumulative dose of 300 mg was administered.1,3,53,79,94 Following continuous IV infusion of a mean labetalol hydrochloride dose of 136 mg (range: 27-300 mg) over 2-3 hours in patients with severe hypertension, blood pressure was reportedly decreased by an average of 60/35 mm Hg.1,3 IV administration of a single labetalol dose does not appear to produce a clinically important reduction in cerebral blood flow following rapid reduction of blood pressure in severely hypertensive patients,14 and long-term oral administration of the drug also does not appear to affect cerebral blood flow.124

Following IV administration of labetalol in normotensive patients with coronary artery disease, blood pressure,125,126,127 heart rate,126,127 systemic vascular resistance,125,126,127 and coronary vascular resistance126 are generally decreased; cardiac index,125,126,127 left ventricular end-diastolic pressure (LVEDP),127 and pulmonary artery wedge pressure125,126 are generally unchanged; and coronary sinus blood flow may be increased.126 In patients with hypertension associated with acute myocardial infarction, IV labetalol decreases blood pressure and heart rate and generally decreases cardiac index and pulmonary artery wedge pressure.165,166,167 In normotensive patients with acute myocardial infarction, IV labetalol may decrease blood pressure, heart rate, and cardiac index without affecting systemic vascular resistance.226

The electrophysiologic effects of labetalol are variable and appear to be mediated via the drug's myocardial β₁-adrenergic blocking activity.1,2,3,4,7,111,219,220 Labetalol may decrease conduction velocity through the atrioventricular (AV) node and increase the atrial effective refractory period (ERP), but the drug appears to have inconsistent effects on sinoatrial (SA) conduction time and the AV nodal refractory period;1,2,3,4,7,111 the decrease in AV nodal conduction velocity produced by labetalol is less than that produced by pure β-adrenergic blocking agents.7 In healthy individuals and in patients with cardiac disease (e.g., coronary artery disease), labetalol generally has little effect on sinus rate, intraventricular conduction, the His-Purkinje system, or duration of the QRS complex.1,2,3,4,7,111 In one study in hypertensive patients, oral labetalol therapy was associated with a substantial reduction in ventricular premature contractions,219 and in another study in hypertensive patients, IV labetalol rapidly restored sinus rhythm in some patients with supraventricular or ventricular arrhythmias.220 Further studies are needed to adequately evaluate the drug's antiarrhythmic activity.7,219,220

Renal Effects

Unlike therapy with some pure β-adrenergic blocking agents (e.g., propranolol), labetalol therapy does not appear to be associated with a reduction in glomerular filtration rate or renal plasma flow following short- or long-term administration in patients with hypertension and normal renal function.115,141,142,143,144,145,146 Labetalol's apparent lack of effect on renal hemodynamics may be related to the drug's α-adrenergic blocking action on renal vasculature or its minimal effect on cardiac output.7,115,141,142,143,144,145,146 Use of the drug in patients with hypertension and chronic renal failure has generally not been associated with any deterioration in renal function.142,145,147,148 Although not consistently found,141 increases in plasma volume have been reported in some patients with hypertension receiving oral labetalol alone,104,148 and edema and/or fluid retention have been reported in some patients during therapy with the drug.1,2,3,4,19,75,76,81,85,90

In several studies in patients with hypertension and elevated plasma renin activity (PRA), long-term oral administration of labetalol hydrochloride (150 mg to 2.4 g daily) has been reported to suppress PRA at rest and during exercise, and in the supine and standing positions; in most of the studies, the net suppressive effect on renin was generally proportional to basal PRA.102,103,104,105,106 In other studies, labetalol has been reported to have an inconsistent overall effect on resting PRA, but there was considerable interindividual variation in PRA in these studies.112,129,130,131 Following acute IV administration, labetalol has been reported to produce substantial reductions in plasma angiotensin II concentration, particularly in patients with high basal values.54,55,132 Although labetalol has been reported to have little, if any, effect on plasma aldosterone concentration following long-term oral administration in several studies,7,104,131 there is some evidence that the drug may decrease plasma aldosterone concentration following oral103 or IV54 administration. Labetalol has also been reported to decrease urinary aldosterone excretion following oral administration in patients with hypertension.105

Endocrine and Metabolic Effects

The exact mechanism is unknown and the effect has not been clinically important, but labetalol may increase plasma glucose concentration.133,134,135 Serum cholesterol and triglyceride concentrations have generally been unchanged or very slightly decreased during labetalol therapy;75,136,137,138,139 although data currently are limited, long-term administration of the drug does not appear to be associated with any clinically important adverse effects on plasma lipid concentrations.7,138,139 Labetalol does not appear to substantially alter serum concentrations of insulin, C-peptide, free fatty acids, growth hormone, or prolactin; however, following IV administration in one preliminary study, labetalol caused a substantial increase in serum prolactin concentration which was more marked in females than in males.133 Although subsequent studies have not demonstrated an effect on serum prolactin concentration following oral administration of the drug, IV administration appears to be associated with hyperprolactinemia, apparently resulting from a drug-induced CNS effect; the clinical importance of this finding is not known.140

Respiratory Effects

Through its β₂-adrenergic blocking action in the respiratory tract, labetalol may increase airway resistance, especially in patients with asthma or chronic obstructive pulmonary disease;1,2,3,4,7,150,157,158,159 however, since α-adrenergic receptors in the respiratory tract may be involved in the pathogenesis of bronchoconstriction, it is possible that the α-adrenergic blocking action of labetalol may attenuate some of the potential adverse respiratory effects resulting from the drug's β-adrenergic blocking action.7 In addition, labetalol's apparent β₂-adrenergic agonist activity may contribute to attenuation of the drug's potential adverse respiratory effects.203 Although an increase in airway resistance as measured by forced expiratory volume in 1 second (FEV₁) or by resting and post-exercise peak expiratory flow rates was not observed in many studies in healthy individuals or patients with asthma or chronic obstructive pulmonary disease (COPD) who received labetalol,149,150,151,152,153,154,155,156,227 evidence of increased airway resistance has occurred in some studies in healthy individuals or in patients with or without COPD who received the drug.157,158,159,228 Labetalol's effect on airway resistance generally appears to be less than that of nonselective β-adrenergic blocking agents (e.g., propranolol),149,150,151,154,158,227 but generally comparable to that of β₁-selective agents (e.g., atenolol).149,228 Labetalol has been used without evidence of a substantial increase in airway resistance in a limited number of hypertensive patients with bronchial asthma in whom propranolol had increased airway resistance.227

Pharmacokinetics

Absorption

Labetalol hydrochloride is rapidly and approximately 90-100% absorbed from the GI tract following oral administration,2,4,5,6,7,8,10,34,58,59 but the drug undergoes extensive first-pass metabolism in the liver and/or GI mucosa.2,4,5,6,7,8,10,23,33,34,35,37,41,58 Only about 25% of an oral dose reaches systemic circulation unchanged in fasted adults.2,4,5,6,7,34,37 Although absolute bioavailability in one study reportedly ranged from 11-86% (mean: 33%) following oral administration of a single 100-mg dose in fasted adults,33 the considerable interindividual variability in this study may have resulted from use of a relatively insensitive spectrofluorometric assay.7 Food delays GI absorption of labetalol hydrochloride36 but increases absolute bioavailability of the drug,2,4,5,7,10,36,37 possibly by decreasing first-pass metabolism and/or hepatic blood flow.10,36,37 Following oral administration of a single 200-mg dose in healthy adults in one study, absolute bioavailability of the drug averaged 26 and 36% in the fasted and nonfasted state, respectively.37 First-pass metabolism may also be reduced and bioavailability substantially increased in geriatric patients7,10,38 and in patients with hepatic dysfunction.1,2,3,4,5,10,39 However, in one study in patients with hepatosplenic schistosomiasis, mean absolute bioavailability of the drug was reportedly decreased when compared with healthy individuals.40 Oral cimetidine increases, and glutethimide decreases,229 the bioavailability of labetalol.1,2,3,4,180,229 (See Drug Interactions.) Concomitant oral administration of labetalol hydrochloride and hydrochlorothiazide does not affect the bioavailability of either drug.247,248

Following multiple-dose oral administration of labetalol hydrochloride, peak plasma concentrations are generally achieved within 40 minutes to 2 hours.5,7,10,42,43,59 Peak plasma concentrations reportedly increase proportionately with oral dosage at dosages ranging from 100 mg to 3 g daily.2,3,5,42 In one study in hypertensive patients, peak plasma labetalol concentration following oral administration of 200 mg 3 times daily or 300 mg twice daily averaged 323 or 430 ng/mL, respectively, and the steady-state plasma drug concentration averaged 149 or 145 ng/mL, respectively; based on pharmacokinetic and pharmacodynamic (i.e., blood pressure response) evaluation, these dosage regimens were considered equivalent.5,43 Following IV injection over 1 minute of a 1.5-mg/kg dose of labetalol hydrochloride in one study, a mean peak plasma concentration of about 5.7 mcg/mL occurred 2 minutes after injection and plasma concentration had declined to an average of 575 ng/mL at 10.5 minutes after injection.50

The relationship between plasma labetalol concentration and pharmacologic effects of the drug has not been clearly established.7,10,203 Relationships between pharmacologic effects (e.g., blood pressure response, response of exercise-induced tachycardia) and dose, logarithm of plasma labetalol concentration, and/or area under the plasma concentration-time curve (AUC) have been reported in some studies,5,7,10,35,43,46,47,48,50 but such relationships were not found in other studies.7,10,33,42,49 In general, there appears to be a correlation between plasma labetalol concentration and blood pressure reduction, particularly in the upright position, but there is wide interindividual variation.10,35,43,46

Following oral administration of labetalol hydrochloride, the hypotensive effect of the drug is generally apparent within 20 minutes to 2 hours,6,10,34,43,48,56,57 maximal within 1-4 hours,2,4,5,6,7,34,43,48,56 and persists in a dose-dependent manner for about 8-12 or 12-24 hours after a single 200- or 300-mg dose, respectively.2,4,5,6,43,57 The maximum, steady-state blood pressure response with twice-daily dosing occurs within 1-3 days.2,4 Following slow, direct IV injection of the drug, the hypotensive effect is apparent within 2-5 minutes,5,6,7,33,47,51,52,53,54,55,240 is usually maximal within 5-15 minutes,1,3,53,54,55,240 and generally persists for about 2-4 hours,6,53,55 although a longer duration of effect (i.e., up to 24 hours) has been reported in some patients.6,33,53,55,240

Distribution

Following IV administration, labetalol is rapidly and widely distributed into the extravascular space.5,7,10,33,34,35 The drug has an apparent volume of distribution of 3.2-15.7 L/kg.7,33,34,35,38,241 In one study in healthy adults, the volume of distribution in the central compartment (V_c) and at steady state (V_ss) averaged 1.1 and 9.4 L/kg, respectively.35 The apparent volume of distribution is reportedly decreased in patients with impaired hepatic function39 but is similar to that of healthy individuals in patients with impaired renal function60,241 or in pregnant women.63 In animals, the drug distributes in highest concentrations into the lungs, liver, and kidneys;5,7,10,58 only minimal amounts cross the blood-brain barrier.1,2,3,4,5,7,10,58

In vitro, labetalol is approximately 50% bound to plasma proteins at plasma labetalol concentrations of 0.1-50 mcg/mL.1,2,3,4,5,7,10,58

Labetalol crosses the placenta.1,2,3,4,5,6,58,64,65,66,67,70 In one study in several pregnant women receiving the drug orally (200 mg 3 times daily) for about 7 days, the median ratio of fetal cord to maternal plasma concentration at parturition was 0.5.66 Small amounts of unchanged labetalol have been shown to distribute into the fetal uveal tract following administration of radiolabeled drug in pregnant animals; the drug bound reversibly to melanin in the uveal tract but was not oculotoxic.5,58,67 Small amounts of labetalol and its metabolites are distributed into milk,1,2,3,4,5,6,7,64,68,69 principally as unbound labetalol.5

Elimination

Plasma concentrations of labetalol appear to decline in a biphasic5,7,10,33,35,43,58,59 or possibly triphasic10,33,241 manner. In healthy adults and adults with hypertension, the half-life in the distribution phase (t_½α) has been reported to average 6-44 minutes5,35,43,59 and the half-life in the terminal elimination phase (t_½β) has been reported to average 2.5-8 hours.1,2,3,4,5,7,10,33,35,37,38,39,41,43,58,60,63 The variability in reported mean half-lives for the drug may have resulted in part from use of a relatively insensitive spectrofluorometric assay in some studies.7 The manufacturers state that the drug has a plasma elimination half-life of 5.5 or 6-8 hours following IV or oral administration, respectively.1,2,3,4 The elimination half-life of the drug appears to be unchanged in individuals with renal1,2,3,4,5,10,60,71,239 or hepatic impairment,1,2,3,4,39 but may be increased in patients with severe renal impairment (i.e., creatinine clearance less than 10 mL/minute) undergoing dialysis.241 Results of some studies indicate that elimination of labetalol may be reduced in geriatric individuals;4 elimination half-life of the drug reportedly may be slightly increased (but within the reported range) in some geriatric individuals.7,10,38 Total body clearance of labetalol from plasma has been reported to average 19-33 mL/minute per kg in individuals with normal renal and hepatic function.1,3,35,60,63 Plasma clearance appears to be unaffected by renal impairment10,17,60,241 but may be decreased in patients with hepatic impairment.40

Labetalol is extensively metabolized in the liver and possibly in the GI mucosa following oral administration, principally by conjugation with glucuronic acid.1,2,3,4,5,7,10,58 The major metabolite is the O -alkylglucuronide,5 with smaller amounts of the O -phenylglucuronide and N -glucuronide being formed.5,10,58 Following oral administration, labetalol undergoes extensive first-pass metabolism in the liver and/or GI mucosa.2,4,5,6,7,8,10,23,33,34,35,37,41,58 (See Pharmacokinetics: Absorption.)

Labetalol and its metabolites are excreted in feces via biliary elimination and in urine.1,2,3,4,5,7,10,58 About 55-60% of a dose is excreted in urine, mainly as glucuronide conjugates, within 24 hours,1,2,3,4,5,7,10,58 and about 30% is excreted in feces within 4 days.58 Less than 5% of a dose is excreted unchanged in urine.7,10,58 Labetalol is not appreciably removed (less than 1% of a dose) by hemodialysis203,204,241,242 or peritoneal dialysis.203,223,241,242

Chemistry and Stability

Chemistry

Labetalol hydrochloride is an α- and β-adrenergic blocking agent.1,2,3,4,5,6,7,8,9,19,21,22,23,32 The drug is commercially available as a racemic mixture of its 4 stereoisomers.1,2,3,4,5,6,10,26,44 The RR -isomer, dilevalol, makes up 25% of the racemic mixture.1,3,4 Dilevalol has about 2-4 times the β-adrenergic blocking activity of the racemic mixture but has only minimal α₁-adrenergic blocking activity;26,44,61,62 dilevalol also appears to possess some β₂-agonist activity.61,221,222,223 Most of the α₁-adrenergic blocking activity of labetalol hydrochloride is attributable to the SR -isomer.26,44

Labetalol hydrochloride occurs as a white or off-white crystalline powder1,2,3,4,5,6 and is sparingly soluble in water (approximately 20 mg/mL) and freely soluble to soluble in alcohol (at least 100 mg/mL).204,223 Labetalol is less lipophilic than propranolol but more lipophilic than most other currently available β-adrenergic blocking agents.224 The drug has a pK_a of 9.3.223 Labetalol hydrochloride injection is a sterile, isotonic solution of the drug in water for injection.1,3,5 The injection occurs as a clear, colorless to light yellow solution and has a pH of 3-4.1,3,5 The injection also contains parabens as preservatives, dextrose, and edetate sodium; citric acid and sodium hydroxide may be added during manufacture of the injection to adjust pH.1,3,5

Stability

Labetalol hydrochloride tablets should be stored in well-closed containers20 at 2-30°C;2,4,5,6 tablets in unit-dose packages should be protected from excessive moisture.2,4,5,6 Labetalol hydrochloride injection should be stored at 2-30°C and protected from light and freezing.1,3,5,6 Labetalol hydrochloride tablets and injection have an expiration date of 3 and 2 years, respectively, after the date of manufacture.5

Labetalol hydrochloride is most stable in solutions having a pH of 2-4.5,6 The drug is physically and chemically compatible with the following IV solutions: 5% dextrose; 0.9% sodium chloride; 2.5% dextrose and 0.45% sodium chloride; 5% dextrose and 0.2, 0.33, or 0.9% sodium chloride; 5% dextrose and lactated Ringer's or Ringer's; lactated Ringer's; or Ringer's.1,4,5,31 Following dilution of labetalol hydrochloride injection with one of these IV solutions, solutions containing 1.25-3.75 mg/mL are stable for at least 24 hours when refrigerated or stored at room temperature.1,3,5,6,31 In one study, these solutions were stable for at least 72 hours at 4 or 25°C.31 Appreciable changes in pH or osmolarity of these IV solutions did not occur following admixture of labetalol hydrochloride injection.31 The drug is physically and/or chemically incompatible with 5% sodium bicarbonate injection;1,3,5,6,31 labetalol hydrochloride solutions containing 1.25-3.75 mg/mL in 5% sodium bicarbonate have a pH of 7.6-8 and form a white precipitate, probably the free base,45 within 6 hours after admixture.5,6,31 A white precipitate also has been observed following concomitant infusion of other alkaline drugs (e.g., furosemide) and labetalol hydrochloride injection; therefore, labetalol hydrochloride injection should not be given in the same infusion line with other alkaline solutions.1,3

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Schering Corporation. Normodyne^® (labetalol hydrochloride) injection prescribing information (dated 1997 Feb). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economical Company Inc; 1998(Suppl A):A280-2.

2. Schering Corporation. Normodyne^® tablets prescribing information. Kenilworth, NJ; 1990 Apr.

3. Glaxo Wellcome. Hanburys. Trandate^® (labetalol hydrochloride) injection prescribing information. Research Triangle Park, NC; 1998 Apr.

4. Glaxo Wellcome. Trandate^® (labetalol hydrochloride) tablets prescribing information. Research Triangle Park, NC; 1998 Jun.

5. Schering Corporation. Normodyne^® (labetalol HCl) product monograph. Kenilworth, NJ; 1984.

6. Glaxo Inc. Product information form for American Hospital Formulary Service on Trandate^®. Research Triangle Park, NC; 1984 Aug 24.

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