Labetalol Hydrochloride

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
Brands: Normodyne, Trandate

Introduction

Selective α- and nonselective β-adrenergic blocking agent.^{1 2 3 4 5 6 7 8 9 19 21 22 23 32 336}

Uses for Labetalol Hydrochloride

Hypertension

Management of hypertension, alone or in combination with other classes of antihypertensive agents.^{2 4 13 253 293}

One of several preferred initial therapies in hypertensive patients with heart failure, post-MI, high coronary disease risk, or diabetes mellitus.³²⁶

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.³²⁶

Effective in controlling BP in pregnant women with moderate to severe hypertension,^{64 68 185 285 297} severe pregnancy-induced hypertension,^{64 68 95 185 244 285 297 298} or hypertension with superimposed pregnancy-induced hypertension.^{64 68 185 285} Has reduced proteinuria and prevented eclampsia in hypertensive pregnant women with proteinuria.^{64 65 68 185}

Severe Hypertension and Hypertensive Crisis

Used parenterally for immediate BP reduction in severe hypertension or in hypertensive crises when considered an emergency;^{1 3 7 8 13 14 15 16 51 52 53 73 79 93 94 152 197 198 209 210 235 236 240 293 331 336} generally suitable for most hypertensive emergencies except when acute cardiac failure is present.^{239 331}

Has been used for rapid reduction of BP in pediatric patients 1–17 years of age† with hypertensive urgencies or emergencies.†³³³

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.)

Preeclampsia

As an alternative to IV hydralazine, administered IV for controlling BP in pregnant women with preeclampsia† when delivery is imminent.³³¹

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}

Angina

Management of chronic stable angina pectoris†.^{7 17 18 127}

Tetanus

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

Labetalol Hydrochloride Dosage and Administration

General

Hypertension

• 
  

  Monitor BP during initial titration or subsequent upward dosage adjustment; large or abrupt reductions in BP generally should be avoided. With continued oral dosing, BP can be measured approximately 12 hours after a dose to determine if further dosage titration is necessary.^{2 4} (See Absorption under Pharmacokinetics.)

  
  


• 
  

  Adjust oral dosage according to standing BP.^{2 4 293} Adjust gradually (e.g., every 2–4 weeks)²⁰³ over a period of 4–12 weeks^{9 75 76 203} to minimize or avoid adverse effects (e.g., nausea, dizziness) and improve patient tolerance.²⁰³

  
  


• 
  

  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.)

  
  


• 
  

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

  
  

Severe Hypertension and Hypertensive Crisis

• 
  

  Adjust dosage according to the severity of hypertension and the patient’s supine BP response and tolerance.^{1 3 293}

  
  


• 
  

  Initial goal of IV therapy is to reduce mean arterial BP by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary insufficiency.²⁹³ If this BP is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24–48 hours.³³¹

  
  


• 
  

  Patients with aortic dissection should have systolic pressure reduced to <100 mm Hg if tolerated.³³¹

  
  

Preeclampsia

• 
  

  Administer antihypertensives before labor induction for persistent DBPs ≥105–110 mm Hg, aiming for levels of 95–105 mm Hg.³³¹

  
  


• 
  

  Monitor BP closely.³³¹

  
  

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 94 277 293 297 298}

Administer diluted solutions by slow, continuous IV infusion^{1 3 51 73 210 277 293 297} 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

Initially, 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 and Hypertensive Crisis†

IV Injection

Children 1–17 years of age: 0.2–1 mg/kg up to maximum of 40 mg per dose by direct IV injection.³³³

IV Infusion

Alternatively, 0.25–3 mg/kg per hour by continuous IV infusion.³³³

Adults

Hypertension

Monotherapy

Oral

Initially, 100 mg twice daily.^{2 4 277 293}

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

For maintenance, manufacturer recommends a usual dosage of 200–400 mg twice daily.^{2 4 277 293 326 331} Manufacturer states that some adults with severe hypertension may require up to 1.2 g–2.4 g administered in 2 or 3 divided doses daily.^{2 4 a}

JNC 7 recommends a usual range of 100–400 mg twice daily.³²⁶ JNC recommends adding another drug, if needed, rather than continuing to increase dosage.³²⁶

Combination Therapy

Oral

Initially, 100 mg twice daily, in combination with a diuretic.^{2 4 277 293}

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}

Severe Hypertension and Hypertensive Crisis

IV Injection

Initially, 20–80 mg by slow, direct IV injection.^{1 3 7 19 53 79 94 274 277 293 336}

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, usually 40–80 mg^{1 3 7 53 79 94} (range: 20–80 mg),^{19 73 79 274 277 293 336} at 10-minute intervals until the desired supine BP is achieved or up to a total cumulative dose of 300 mg.^{1 3 7 19 53 73 79 94 274 297 298 336}

IV Infusion

Alternatively, initial rate of 0.5–2 mg/minute by continuous IV infusion; adjust rate according to the BP response.^{1 3 7 19 52 73 210 274 277 293 297}

The usual effective, cumulative dose is 50–200 mg; up to 300 mg may be required.^{1 3}

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 when the DBP begins to increase.^{1 3}

Initially 200 mg, followed in 6–12 hours by an additional dose of 200 or 400 mg, depending on the BP response.^{1 3}

If necessary, oral dosage may be increased in usual increments at 1-day intervals while the patient is hospitalized.^{1 3}

Follow the usual oral dosage recommendations for subsequent outpatient dosage titration or maintenance dosing.^{1 3}

Preeclampsia

IV

Initially, 20 mg by slow, direct IV injection, followed by 40 mg IV 10 minutes later and then 80-mg doses at 10-minute intervals for 2 additional doses.³³¹

Prescribing Limits

Pediatric Patients

Hypertension

Oral

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

Severe Hypertension and Hypertensive Crisis†

IV Injection

Children 1–17 years of age: Maximum 40 mg per dose.³³³

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 94 274 297 298}

Preeclampsia

IV

Maximum cumulative dose of 220 mg.³³¹

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 Hydrochloride

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 CHF.^{1 2 3 4 7} Use contraindicated in patients with overt CHF;^{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 administration^{51 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} (See Hypertension and also see Preeclampsia under Uses.)

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 current limited clinical experience.³³³

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} dizziness^{1 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 Hydrochloride

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 13 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 recommended