Labetalol

Class: beta-Adrenergic Blocking Agents
VA Class: CV100
Chemical Name: 2-Hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride
Molecular Formula: C₁₉H₂₄N₂O₃•HCl
CAS Number: 32780-64-6

Medically reviewed by Drugs.com. Last updated on Feb 25, 2019.

Uses
Dosage
Cautions
Interactions
Pharmacokinetics
Patient advice
Preparations

Introduction

Selective α₁- and nonselective β-adrenergic blocking agent (β-blocker).¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁹ ²¹ ²² ²³ ³²

Uses for Labetalol

Hypertension

Management of hypertension, alone or in combination with other classes of antihypertensive agents.² ⁴ ²⁵³ ¹²⁰⁰

β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in 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 (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics).³³⁷ ⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ⁵²³ ⁵²⁴ ⁵²⁷ ⁷⁰⁰ ¹²⁰⁰ A 2017 ACC/AHA multidisciplinary hypertension guideline states that β-blockers used for ischemic heart disease that are also effective in lowering BP include bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol.¹²⁰⁰

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ¹²⁰⁰ ¹²⁰¹

The 2017 ACC/AHA hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200
Category	SBP (mm Hg)		DBP (mm Hg)
Normal	<120	and	<80
Elevated	120–129	and	<80
Hypertension, Stage 1	130–139	or	80–89
Hypertension, Stage 2	≥140	or	≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.⁵⁰¹ ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁷ ⁵⁰⁸ ⁵¹⁵ ⁵²³ ⁵²⁶ ⁵³⁰ ¹²⁰⁰ ¹²⁰¹ ¹²⁰⁷ ¹²⁰⁹ ¹²²² ¹²²³ ¹²²⁹

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.¹²⁰⁰ ¹²⁰² ¹²¹⁰

Other hypertension guidelines generally have based target BP goals on age and comorbidities.⁵⁰¹ ⁵⁰⁴ ⁵³⁶ Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients⁵⁰¹ ⁵⁰⁴ compared with those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.¹²²² ¹²²³ ¹²²⁴ ¹²²⁹

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.¹²⁰⁰ ¹²²⁰

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.¹²⁰⁰ ¹²⁰⁷ ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰ Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.⁵⁰² ¹²⁰⁰

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers.³²⁷ ³³⁴ ³³⁵ ⁵⁰¹ ⁵⁰⁴ ¹²⁰⁰ However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.⁵⁰⁰

Recommended by ACOG and other experts as an appropriate drug of choice in pregnant women who require antihypertensive therapy.²⁹⁸ ⁵⁰² ⁵⁴⁰

Severe Hypertension and Hypertensive Crisis

Used parenterally for immediate BP reduction in severe hypertension or hypertensive emergency;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 generally suitable for most hypertensive emergencies except when acute cardiac failure is present.²³⁹ ¹²⁰⁰

One of several recommended parenteral agents for use in the hospital setting to urgently lower BP in severely hypertensive pregnant women, including those with preeclampsia† or eclampsia†.²⁹⁸ ³³⁸ ⁵⁴⁰ ¹²⁰⁰

Has been used for rapid reduction of BP in children and adolescents† with acute severe hypertension† and life-threatening symptoms.¹¹⁵⁰

Pheochromocytoma

Has been used alone in patients with pheochromocytoma to control hypertension and symptoms resulting from excessive β-receptor stimulation.⁵¹ ⁸⁵ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴ However, some clinicians caution against use unless pretreatment with α-adrenergic blocking agents (e.g., IV phentolamine) has occurred.⁷ May be more effective when tumors predominantly secrete epinephrine rather than norepinephrine, and with sustained rather than paroxysmal hypertension.⁸⁵ (See Pheochromocytoma under Cautions.)

Controlled Hypotension during Anesthesia

Treatment to produce controlled hypotension during anesthesia† to reduce bleeding resulting from surgical procedures.⁷ ¹⁸³ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵

Chronic Stable Angina

Long-term management of chronic stable angina pectoris†.⁷ ¹⁷ ¹⁸ ¹²⁷

β-Blockers are recommended as first-line anti-ischemic drugs 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 use.¹¹⁰¹

Tetanus

Management of sympathetic overactivity syndrome associated with severe tetanus†.¹⁹⁶ ²⁰⁰ ²⁰¹ ²⁰²

Labetalol Dosage and Administration

General

If long-term therapy is discontinued, gradually reduce dosage over a period of 1–2 weeks.² ⁴ ²⁹³ (See Abrupt Withdrawal of Therapy under Cautions.)

BP Monitoring and Treatment Goals

Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰
If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.¹²¹⁶
If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic).¹²⁰⁰ ¹²¹⁶ Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.¹²⁰⁰ ¹²¹⁶

Severe Hypertension and Hypertensive Crisis

Adjust dosage according to the severity of hypertension and the patient’s supine BP response and tolerance.⁶⁰⁰
Initial goal of IV therapy in adults without a compelling indication is to reduce SBP by ≤25% within 1 hour, followed by further BP reduction if stable to 160/100 or 160/110 mm Hg within the next 2–6 hours; avoid excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.⁵⁴² ¹²⁰⁰ If this BP is well tolerated and the patient is clinically stable, may implement further gradual reductions toward normal BP in the next 24–48 hours.¹²⁰⁰
Adults with severe preeclampsia or eclampsia or pheochromocytoma crisis: Reduce SBP to <140 mm Hg during the first hour.¹²⁰⁰
Adults with aortic dissection: Reduce SBP to <120 mm Hg within the first 20 minutes.¹²⁰⁰
Children and adolescents: Some experts suggest reducing BP by ≤25% of the planned reduction over the first 8 hours.¹¹⁵⁰

Administration

Administer orally,² ⁴ ⁷ ⁸ ¹⁹ ²³ ⁴⁷ ⁴⁹ by direct IV injection, or by continuous IV infusion.¹ ³ ⁷ ¹⁹ ²³ ⁵¹ ⁵² ⁵³ ⁷³ ⁷⁹ ⁹³ ⁹⁴ ²¹⁰

Oral Administration

Usually administered in 2 divided doses daily.² ⁴ If adverse effects (e.g., nausea, dizziness) occur and are intolerable (particularly with dosages ≥1.2 g daily), administration in 3 divided doses daily may improve patient tolerance and/or facilitate dosage titration.² ⁴

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow, direct IV injection or by slow, continuous IV infusion.¹ ³ ⁷ ¹⁹ ²³ ⁵¹ ⁵² ⁵³ ⁷³ ⁷⁹ ⁹³ ⁹⁴ ²¹⁰

Labetalol injection is intended for use in hospitalized patients.¹

Patients must be kept in a supine position during and for 3 hours after IV administration since symptomatic orthostatic hypotension is likely to occur if patients are tilted upward or allowed to assume an upright position.¹ ³ (See Hypotension under Cautions.)

Dilution

For IV infusion, dilute labetalol injection to an appropriate concentration in a compatible IV infusion solution (e.g., add 200 mg of the drug to 160 mL of 5% dextrose injection to provide a solution containing 1 mg/mL).¹ ³

Rate of Administration

Administer repeat doses by slow, direct IV injection over a 2-minute period at intervals of 10 minutes.¹ ³ ⁵³ ⁷³ ⁷⁹ ⁹⁴ ²⁹⁸ ¹²⁰⁰

Administer diluted solutions by slow, continuous IV infusion¹ ³ ⁵¹ ⁷³ ²¹⁰ with a controlled-infusion device to facilitate a desired rate of infusion.¹ ³

Dosage

Available as labetalol hydrochloride; dosage expressed in terms of the salt.

Pediatric Patients

Hypertension†

Oral

Some experts have recommended an initial dosage of 1–3 mg/kg daily given in 2 divided doses.³³³ Increase dosage as necessary up to a maximum of 10–12 mg/kg or 1.2 g daily given in 2 divided doses.³³³

Severe Hypertension†

Rapid Reduction of BP†

IV Injection

Children and adolescents: 0.2–1 mg/kg up to maximum of 40 mg per dose by direct IV injection.¹¹⁵⁰

IV Infusion

Alternatively, 0.25–3 mg/kg per hour by continuous IV infusion.¹¹⁵⁰

Adults

Hypertension

Oral

Initially, 100 mg twice daily, either alone or in combination with a diuretic.² ⁴ ²⁹³

Adjust dosage in increments of 100 mg twice daily every 2 or 3 days until optimum BP response is achieved.² ⁴

For maintenance, manufacturers recommend a usual dosage of 200–400 mg twice daily.² ⁴ Manufacturers state that some adults with severe hypertension may require up to 1.2–2.4 g daily in 2 or 3 divided doses.² ⁴ ^a

Some experts recommend a usual range of 100–400 mg twice daily.¹²⁰⁰ Rationale for lower dosage range is that it may be preferable to add another drug rather than continue to increase dosage.³³²

Adjustment of labetalol dosage may be necessary when diuretic is initiated in a patient already receiving labetalol; optimum maintenance dosage is usually lower.² ⁴

When transferring from other antihypertensive agents, start with usual initial labetalol dosage and gradually decrease dosage of the existing regimen.² ⁴

Severe Hypertension and Hypertensive Crisis

IV Injection

Manufacturer recommends initial dose of 20 mg by slow (over 2 minutes), direct IV injection.⁶⁰⁰ Alternatively, some experts recommend initial dosage of 0.3–1 mg/kg (maximum 20 mg) by slow, direct IV injection every 10 minutes.¹²⁰⁰

Higher initial doses (e.g., 1–2 mg/kg) have been administered,⁵¹ ⁵⁵ ²³⁵ but the 20-mg dose is recommended to minimize adverse effects and the risks associated with too rapid reduction in BP.²³ ⁵³ ⁷⁹

May give additional doses of 40 or 80 mg⁶⁰⁰ at 10-minute intervals until the desired supine BP is achieved or up to a total cumulative dose of 300 mg.⁷ ¹⁹ ⁵³ ⁷³ ⁷⁹ ⁹⁴ ²⁷⁴ ²⁹⁸ ⁶⁰⁰

IV Infusion

As an alternative to direct IV injection, manufacturer recommends initial rate of 2 mg/minute by continuous IV infusion; adjust rate according to the BP response.⁶⁰⁰

Some experts recommend initial IV infusion rate of 0.4–1 mg/kg per hour; increase rate as needed up to 3 mg/kg per hour.¹²⁰⁰

The usual effective, cumulative dose is 50–200 mg; up to 300 mg may be required.⁶⁰⁰ ¹²⁰⁰

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 BP is achieved) has been used, and may result in more gradual BP reduction, minimizing adverse effects compared with repeated IV injections of the drug.²¹ ⁵¹ ¹⁹⁷ Controlled comparisons of various IV administration methods are not available.

Oral (following IV dosage)

Discontinue IV therapy and initiate oral labetalol therapy (with tablets) when the supine DBP begins to increase.⁶⁰⁰

Initially 200 mg, followed in 6–12 hours by an additional dose of 200 or 400 mg, depending on the BP response.⁶⁰⁰

If necessary, oral dosage may be increased in usual increments at 1-day intervals while the patient is hospitalized (dosage range: 400–2400 mg daily administered in 2 or 3 divided doses).⁶⁰⁰

Follow the usual oral dosage recommendations for subsequent outpatient dosage titration or maintenance dosing.⁶⁰⁰

Severe Hypertension During Pregnancy (e.g., Preeclampsia†)

IV Injection

Initially, 10–20 mg by direct IV injection, followed by 20–80 mg every 20–30 minutes as needed for a maximum cumulative dose of 300 mg.²⁹⁸

IV Infusion

As an alternative to direct IV injection, some experts recommend continuous IV infusion of 1–2 mg/minute.²⁹⁸

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Maximum 10–12 mg/kg or 1.2 g daily.³³³

Severe Hypertension†

IV Injection

Children and adolescents: Maximum 40 mg per dose.¹¹⁵⁰

Adults

Hypertension

Oral

Maximum titration increment of 200 mg twice daily.^a

Severe Hypertension and Hypertensive Crisis

IV

Maximum cumulative dose of 300 mg.¹ ³ ⁷ ¹⁹ ⁵³ ⁷³ ⁷⁹ ⁹⁴ ²⁷⁴ ²⁹⁸

Severe Hypertension During Pregnancy (e.g., Preeclampsia†)

IV

Maximum cumulative dose of 300 mg.²⁹⁸

Special Populations

Hepatic Impairment

Dosage reduction may be necessary, but specific data are currently not available.⁷ ³⁹

Renal Impairment

No dosage adjustment required in patients with mild to moderate renal impairment.⁶⁰ ¹⁴⁶ ¹⁴⁷ ²³⁹ In patients with severe renal impairment (i.e., Cl_cr <10 mL/minute) undergoing dialysis, once-daily dosing may be adequate.²⁴¹

Geriatric Patients

Oral

Adjustment in initial dosage not required.^a Maintenance dosage requirements are lower in most geriatric patients; 100–200 mg twice daily usually required.⁴ ^a ⁴

Cautions for Labetalol

Contraindications

Obstructive airway disease (e.g., bronchial asthma).¹ ² ³ ⁴ ³¹¹
Overt cardiac failure.¹ ² ³ ⁴ ³¹¹
Heart block greater than first degree.¹ ² ³ ⁴ ³¹¹
Cardiogenic shock.¹ ² ³ ⁴ ³¹¹
Severe bradycardia.¹ ² ³ ⁴ ³¹¹
Other conditions associated with severe and prolonged hypotension.¹ ³ ⁴ ²⁴⁷
Known hypersensitivity to labetalol or any ingredient in the formulation.¹ ³ ⁴ ²⁴⁷

Warnings/Precautions

Warnings

Hepatic Effects

Rarely, jaundice, hepatitis, severe hepatocellular injury, and elevated liver function test results have occurred; usually reversible following discontinuance,¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸ however, hepatic necrosis and death have been reported.¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸ ²⁵⁴ ²⁵⁵ ²⁷⁵ ²⁷⁶

Discontinue immediately if jaundice or laboratory evidence of hepatic injury occurs.¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸

Perform liver function tests 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

Cardiac Failure

Possible precipitation of heart failure.¹ ² ³ ⁴ ⁷ Use contraindicated in patients with overt heart failure;¹ ² ³ ⁴ may use cautiously in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).¹ ² ³ ⁴ Use with caution in patients with inadequate cardiac function.¹ ² ³ ⁴ ⁷

Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs and symptoms of impending cardiac failure occur; if cardiac failure continues, discontinue therapy, gradually if possible.¹ ² ³ ⁴

Abrupt Withdrawal of Therapy

Abrupt withdrawal may exacerbate angina symptoms or precipitate MI in patients with CAD.¹ ² ³ ⁴ Avoid abrupt discontinuance.² ⁴ Gradually decrease dosage over a period of 1–2 weeks, particularly in patients with ischemic heart disease and monitor patients carefully.¹ ² ³ ⁴ If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily, and initiate appropriate measures for the management of unstable angina pectoris.¹ ² ³ ⁴

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 angina pectoris has not been reported to date following discontinuance of labetalol.¹ ² ³ ⁴

Bronchospastic Disease

Possible inhibition of bronchodilation produced by endogenous catecholamines; use generally not recommended in patients with bronchospastic disease.² ⁴

May use oral labetalol 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 use smallest effective dose to minimize inhibition of endogenous or exogenous β-adrenergic agonist activity.² ⁴

Do not use IV labetalol in patients with nonallergic bronchospasm at the usual therapeutic doses; has not been studied adequately.¹ ³

Pheochromocytoma

Use with caution in patients with pheochromocytoma;¹ ² ³ ⁴ ¹⁸⁶ ¹⁸⁷ oral labetalol may induce paradoxical hypertensive crisis.⁷ ¹⁸⁶ ¹⁸⁷ ²⁰³ Use not recommended unless pretreatment with α-adrenergic blocking agents (e.g., IV phentolamine) has occurred.⁷

Employ appropriate methods for determining urinary catecholamines if used in known or suspected pheochromocytoma.¹ ² ³ ⁴ (See Specific Drugs and Laboratory Tests under Interactions.)

Diabetes and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia, BP changes),¹ ² ³ ⁴ impaired glucose tolerance, delayed rate of recovery of blood glucose concentration following drug-induced hypoglycemia, altered hemodynamic response to hypoglycemia (possibly resulting in exaggerated hypertensive response), and impaired peripheral circulation.²¹¹ ²¹²

Use with caution in patients with diabetes mellitus;¹ ² ³ ⁴ dosage adjustment of the hypoglycemic agent may be necessary.¹ ² ³ ⁴

Major Surgery

Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients receiving β-adrenergic blocking agents;¹ ² ³ ⁴ however, withdrawal of β-adrenergic blocking agent prior to major surgery is controversial.¹ ² ³ ⁴

Effect of labetalol’s α-adrenergic activity in patients undergoing major surgery has not been evaluated,¹ ² ³ ⁴ but several deaths have been reported with the use of the injection during surgery, including when used to control bleeding.¹ ³

Synergistic hypotensive response occurs with concomitant use of IV labetalol and halothane anesthesia.¹ ² ³ ⁴ ¹⁸³ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵ (See Specific Drugs and Laboratory Tests under Interactions.)

Severely Elevated BP

Use caution when reducing severely elevated BP.¹ ³

Use IV labetalol in hospitalized patients,¹ ³ and achieve the desired reduction over longest period of time compatible with the patient’s clinical status.¹ ³

Avoid rapid or excessive reductions in SBP or DBP.¹ ³

Serious adverse effects (e.g., cerebral infarction, optic nerve infarction, angina, and ischemic changes in the ECG)⁵¹ ⁷⁹ ¹⁹⁷ have been reported when severely elevated BP was reduced over several hours to up to 1 or 2 days with other hypotensive agents.³¹¹

General Precautions

Hypotension

Orthostatic hypotension associated with loss of consciousness reported 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.¹ ³

If hypotension occurs, place the patient in Trendelenburg’s position, administer IV fluids, and/or temporarily discontinue administration of the drug.⁵¹ ⁷⁹ ⁹⁴ ¹⁹⁷

Patients should remain supine during and for up to 3 hours after IV administration.¹ ³ Establish patient’s ability to tolerate an upright position before any ambulation (e.g., use of toilet facilities) is permitted; advise patient on how to proceed gradually to become ambulatory and observe at the time of initial ambulation.¹ ³

Laboratory Tests

Monitor laboratory parameters at regular intervals in patients receiving long-term oral therapy.² ⁴

Routine laboratory tests are usually not required before or after IV administration.¹ ³

In patients with concomitant illnesses (e.g., impaired renal function), perform appropriate tests to monitor these conditions.¹ ² ³ ⁴

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of labetalol hydrochloride and Lamictal (lamotrigine, an anticonvulsant agent) has resulted in dispensing errors.³¹⁹ ³²⁰ Errors may be associated with serious adverse events (e.g., status epilepticus, serious lamotrigine rash) in patients receiving the wrong drug.³¹⁹ ³²⁰

History of Anaphylactic Reactions

Possible increased reactivity to a variety of allergens;¹ patients may be less responsive to usual doses of epinephrine used to treat anaphylactic reactions.¹ ³ ⁴

Other Precautions

Shares the toxic potentials of β-adrenergic and postsynaptic α₁-adrenergic blocking agents;¹ ² ³ ⁴ ⁷ ⁸ ⁹ observe the usual precautions of these agents.¹ ² ³ ⁴ ⁷

Specific Populations

Pregnancy

Category C.¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸ ^a

Lactation

Distributed into milk.¹ ² ³ ⁴ ⁶ ⁷ ⁶⁴ ⁶⁸ ⁶⁹ Caution if used in nursing women.¹ ² ³ ⁴

Pediatric Use

Safety and efficacy not fully established;¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸ however, some experts have recommended dosages for hypertension based on clinical experience.¹¹⁵⁰

Geriatric Use

Orthostatic symptoms (e.g., orthostatic hypotension, dizziness, lightheadedness) are more likely in geriatric individuals than in younger adults; caution geriatric patients about the possibility of such symptoms.⁴

A lower maintenance dosage may be required because of reduced elimination in geriatric patients.⁴ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution; metabolism of the drug may be decreased.¹ ² ³ ⁴ ⁷ ³⁹ ²⁴⁷ ²⁴⁸ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Elimination half-life may be increased in patients with severe renal impairment undergoing dialysis; once-daily dosing may be possible in these patients.²⁴¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Symptomatic orthostatic hypotension,¹ ² ³ ⁴ ⁷ ⁸ ⁹ ¹⁹ ²³ ⁴⁶ ⁵¹ ⁵⁴ ⁵⁵ ⁷⁹ ⁸¹ ⁸³ ⁸⁸ ⁹¹ ⁹⁴ ⁹⁶ ¹⁰⁰ ¹⁰⁸ ¹²² ¹²⁹ ¹³² ¹⁵⁸ ¹⁵⁹ ²⁴⁷ ²⁴⁸ dizziness¹ ² ³ ⁴ ⁸ ²³ ⁷⁴ ⁷⁵ ⁷⁶ ⁷⁹ ⁸⁰ ⁸¹ ⁸² ⁸⁸ ⁹⁰ ¹⁵⁸ ¹⁵⁹ or lightheadedness,²³ ⁵¹ ⁵³ ⁸⁵ fatigue,¹ ² ³ ⁴ ²³ ⁷⁵ ⁷⁶ ⁷⁸ ⁸⁷ ¹⁵⁹ 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

Interactions for Labetalol

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
β-Adrenergic agonists	Labetalol may antagonize bronchodilating effects¹ ² ³ ⁴	Greater than usual dosages of β-adrenergic agonist bronchodilators may be required¹ ² ³ ⁴
Calcium-channel blocking agents (e.g., verapamil, diltiazem)	Possible additive therapeutic²⁵⁶ ²⁵⁷ ²⁵⁸ ²⁵⁹ ²⁶⁰ ²⁶¹ ²⁶² ²⁶³ ²⁶⁴ ²⁶⁵ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ ²⁷¹ ²⁷² ²⁷³ and adverse effects²⁵⁷ ²⁶¹ ²⁶⁴ ²⁶⁶ ²⁶⁷ ²⁶⁸ ²⁷¹ ²⁷² ²⁷³	Use concomitantly with caution¹ ³ ⁴ ²⁴⁷ ²⁵⁸ ²⁵⁹ ²⁶⁰ ²⁶¹ ²⁶⁴ ²⁶⁶ ²⁶⁸ ²⁷¹ ²⁷² ²⁷³ ²⁹⁰ ²⁹¹
Cimetidine	Absolute bioavailability of oral labetalol substantially increased, possibly via enhanced absorption or decreased first-pass hepatic metabolism ¹ ² ³ ⁴ ¹⁸⁰ ²²⁹	Carefully adjust labetalol dosage for optimal BP control with concomitant use¹ ² ³ ⁴ ²²⁹
Diuretics	Increased hypotensive effect ² ⁴ ⁷ ⁸ ⁹ ¹⁵ ¹⁹ ⁷² ⁷⁶ ⁷⁷ ⁷⁸ ⁸⁰ ⁸¹ ⁸² ⁸³ ⁸⁵ ⁸⁷ ⁹⁰ ⁹¹ ⁹⁶ ⁹⁷ ⁹⁹ ²³¹ ²³⁴	Usually used to therapeutic advantage; careful dosage adjustments recommended² ⁴ ⁷ ⁸ ⁹ ¹⁵ ¹⁹ ⁷² ⁷⁶ ⁷⁷ ⁷⁸ ⁸⁰ ⁸¹ ⁸² ⁸³ ⁸⁵ ⁸⁷ ⁹⁰ ⁹¹ ⁹⁶ ⁹⁷ ⁹⁹ ²³¹ ²³⁴
Glutethimide (no longer commercially available in the US)	Absolute bioavailability of oral labetalol decreased, possibly by increasing first-pass hepatic metabolism ²²⁹	Carefully adjust labetalol dosage for optimal BP control with concomitant use²²⁹
Halothane	Synergistic hypotensive effect; ¹⁸³ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵ may result in large reduction in cardiac output and increase in central venous pressure¹ ² ³ ⁴ ¹⁸³ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵	Adjust halothane concentration to control the degree and duration of hypotension;¹⁸³ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵ to minimize the risk of excessive hypotension, inspired halothane concentrations of ≥3% should not be used¹ ² ³ ⁴ Inform anesthesiologist if labetalol therapy is continued in a patient undergoing major surgery¹ ² ³ ⁴
Mibefradil (no longer commercially available in the US)	Slowing or complete suppression of SA node activity, with slow ventricular rates²⁹⁰ ²⁹¹
Nitroglycerin	Possible additive hypotensive effects¹ ² ³ ⁴ and antagonism of the reflex tachycardia produced by nitroglycerin¹ ² ³ ⁴
Tricyclic antidepressants	Possible increased incidence of tremor ¹ ² ³ ⁴
Tests for urinary catecholamines	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 methods¹ 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, use specific assay methods such as high-performance liquid chromatography (HPLC) with solid phase extraction¹ ² ³ ⁴ ²¹⁸ ²⁴⁸ ²⁵² to determine concentrations of catecholamines or their metabolites¹ ² ³ ⁴ ²¹⁶ ²¹⁷ ²¹⁸ ²⁴⁸

Labetalol Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed (i.e., 90–100%) from the GI tract following oral administration.² ⁴ ⁵ ⁶ ⁷ ⁸ ¹⁰ ³⁴ ⁵⁸ ⁵⁹

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 Absolute bioavailability is about 25%.² ⁴ ⁵ ⁶ ⁷ ³⁴ ³⁷

Onset

Following oral administration, hypotensive effect is generally apparent within 20 minutes to 2 hours,⁶ ¹⁰ ³⁴ ⁴³ ⁴⁸ ⁵⁶ ⁵⁷ and maximal within 1–4 hours.² ⁴ ⁵ ⁶ ⁷ ³⁴ ⁴³ ⁴⁸ ⁵⁶

Maximum, steady-state BP response with twice-daily dosing occurs within 1–3 days.² ⁴

Following slow, direct IV injection, hypotensive effect is apparent within 2–5 minutes,⁵ ⁶ ⁷ ³³ ⁴⁷ ⁵¹ ⁵² ⁵³ ⁵⁴ ⁵⁵ ²⁴⁰ and usually maximal within 5–15 minutes.¹ ³ ⁵³ ⁵⁴ ⁵⁵ ²⁴⁰

Duration

Dose dependent; about 8–12 or 12–24 hours after a single 200- or 300-mg dose, respectively.² ⁴ ⁵ ⁶ ⁴³ ⁵⁷

Following slow, direct IV injection, the hypotensive effect 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

Food

Delays absorption,³⁶ but increases absolute bioavailability.² ⁴ ⁵ ⁷ ¹⁰ ³⁶ ³⁷

Special Populations

Relative bioavailability is increased in hepatic impairment.^a ¹ ² ³ ⁴ ⁵ ¹⁰ ³⁹

First-pass metabolism may be reduced and bioavailability substantially increased in geriatric patients.⁷ ¹⁰ ³⁸

Distribution

Extent

Following IV administration, rapidly and widely distributed into the extravascular space.⁵ ⁷ ¹⁰ ³³ ³⁴ ³⁵

In animals, highest concentrations in 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

Crosses the placenta;¹ ² ³ ⁴ ⁵ ⁶ ⁵⁸ ⁶⁴ ⁶⁵ ⁶⁶ ⁶⁷ ⁷⁰ distributed into milk,¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁶⁴ ⁶⁸ ⁶⁹ principally as unbound labetalol.⁵

Plasma Protein Binding

Approximately 50%.¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ⁵⁸

Special Populations

In patients with impaired hepatic function, the apparent volume of distribution is decreased.³⁹

Elimination

Metabolism

Following oral administration, extensively metabolized in the liver and possibly in the GI mucosa principally by conjugation with glucuronic acid,¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ⁵⁸ principally to O-alkylglucuronide⁵ and smaller amounts of O-phenylglucuronide and N-glucuronide.⁵ ¹⁰ ⁵⁸

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

Elimination Route

Excreted in feces via biliary elimination (30% within 4 days) and in urine (55–60% within 24 hours), mainly as glucuronide conjugates.¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ⁵⁸ ¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ⁵⁸

Less than 5% of a dose is excreted unchanged in urine.⁷ ¹⁰ ⁵⁸

Half-life

Biphasic⁵ ⁷ ¹⁰ ³³ ³⁵ ⁴³ ⁵⁸ ⁵⁹ or possibly triphasic;¹⁰ ³³ ²⁴¹ terminal half-life averages 2.5–8 hours.¹ ² ³ ⁴ ⁵ ⁷ ¹⁰ ³³ ³⁵ ³⁷ ³⁸ ³⁹ ⁴¹ ⁴³ ⁵⁸ ⁶⁰ ⁶³ Manufacturers specify half-life of 5.5 or 6–8 hours following IV or oral administration, respectively.¹ ² ³ ⁴

Special Populations

Elimination may be reduced and half-life may be slightly increased in geriatric individuals.⁴ ⁷ ¹⁰ ³⁸

Half-life apparently 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., Cl_cr <10 mL/minute) undergoing dialysis.²⁴¹

Not appreciably removed (<1% of a dose) by hemodialysis²⁰³ ²⁰⁴ ²⁴¹ ²⁴² or peritoneal dialysis.²⁰³ ²²³ ²⁴¹ ²⁴²

Stability

Storage

Oral

Tablets

Well-closed containers²⁰ at 2–30°C.² ⁴ ⁵ ⁶

Protect tablets in unit-dose packages from excessive moisture.² ⁴ ⁵ ⁶

Parenteral

Injection

2–30°C; protect from light and freezing.¹ ³ ⁵ ⁶

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible
Dextrose 5% in Ringer’s injection
Dextrose 5% in Ringer’s injection, lactated
Dextrose 2.5% in sodium chloride 0.45%
Dextrose 5% in sodium chloride 0.2, 0.33, or 0.9%
Dextrose 5% in water
Polysal in dextrose 5%
Ringer’s injection
Ringer’s injection, lactated
Sodium chloride 0.9%
Incompatible
Sodium bicarbonate 5%

Drug Compatibility

Y-Site CompatibilityHID
Compatible
Amikacin sulfate
Aminophylline
Amiodarone HCl
Ampicillin sodium
Bivalirudin
Butorphanol tartrate
Calcium gluconate
Cefazolin sodium
Ceftazidime
Chloramphenicol sodium succinate
Clindamycin phosphate
Clonidine HCl
Co-trimoxazole
Dexmedetomidine HCl
Diltiazem HCl
Dobutamine HCl
Dopamine HCl
Doripenem
Enalaprilat
Epinephrine HCl
Erythromycin lactobionate
Esmolol HCl
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Gentamicin sulfate
Hetastarch in lactated electrolyte injection (Hextend)
Hydromorphone HCl
Hydroxyethyl starch 130/0.4 in sodium chloride 0.9%
Lidocaine HCl
Linezolid
Lorazepam
Magnesium sulfate
Meperidine HCl
Metronidazole
Micafungin sodium
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nicardipine HCl
Nitroglycerin
Norepinephrine bitartrate
Oxacillin sodium
Penicillin G potassium
Potassium chloride
Potassium phosphates
Propofol
Ranitidine HCl
Sodium acetate
Sodium nitroprusside
Telavancin HCl
Tobramycin sulfate
Vancomycin HCl
Vecuronium bromide
Incompatible
Amphotericin B cholesteryl sulfate complex
Ceftaroline fosamil
Ceftriaxone sodium
Furosemide
Nafcillin sodium
Warfarin sodium
Variable
Heparin sodium

Actions

Competitively blocks 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
Has some intrinsic β₂-agonist activity in animals,¹ ² ³ ⁴ ⁷ ³⁰ ⁶² ²²¹ ²²² but exerts little, if any, intrinsic β₁-agonist activity;¹ ² ³ ⁴ ⁷ ⁸ ⁹ ³⁰ ⁶² ¹⁰⁷ does not exhibit intrinsic α-adrenergic agonist activity.⁷ ²⁸ ³⁰
Unlike pure β-adrenergic blocking agents, produces a dose-dependent (at usual doses) decrease in systemic arterial BP 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
Effectively reduces BP in the standing or supine position, but because of the drug’s α₁-adrenergic blocking activity, the effect on BP is position dependent; labetalol-induced decreases in BP 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
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
May decrease conduction velocity through the AV node and increase the atrial effective refractory period (ERP), but the drug appears to have inconsistent effects on 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
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

Advice to Patients

Importance of taking medication exactly as prescribed.^a
Importance of not interrupting or discontinuing therapy without consulting clinician; patients should temporarily limit their physical activity when discontinuing therapy.¹ ² ³ ⁴
Importance of patients informing anesthesiologist or dentist about labetalol therapy before undergoing major surgery.¹ ² ³ ⁴
Importance of immediately informing clinician at the first sign or symptom of impending cardiac failure or if any difficulty in breathing occurs.¹ ² ³ ⁴
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹ ² ³ ⁴
Advise patients that transient scalp tingling may occur, usually during initiation of labetalol therapy.¹ ² ³ ⁴
Caution geriatric patients about the possibility of orthostatic symptoms (orthostatic hypotension, dizziness, lightheadedness).⁴
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ² ³ ⁴ ²⁴⁷ ²⁴⁸
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Labetalol Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names
Oral	Tablets, film-coated	100 mg*	Labetalol Hydrochloride Tablets
		200 mg*	Labetalol Hydrochloride Tablets
		300 mg*	Labetalol Hydrochloride Tablets
Parenteral	Injection, for IV use	5 mg/mL*	Labetalol Hydrochloride Injection

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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

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

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35. Kanto J, Allonen H, Kleimola T et al. Pharmacokinetics of labetalol in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1981; 19:41-4. http://www.ncbi.nlm.nih.gov/pubmed/7203731?dopt=AbstractPlus

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