Labetalol is available as an oral and intravenous formulation. It is a non-specific beta-adrenergic receptor blocker and has got alpha-blocking activity as well.

Labetalol Uses:

• Hypertension:

  • Management of hypertension (IV indicated for severe hypertension only [eg, hypertensive emergencies]).
  • Note: Beta-blockers are not recommended as first-line therapy.

• Off Label Use of Labetalol in Adults:

  • Acute aortic syndromes or Acute aortic dissection
  • For blood pressure management in patients with acute ischemic stroke.
  • Hypertensive emergency in pregnancy or postpartum (including acute-onset hypertension in preeclampsia/eclampsia)
  • For blood pressure management in patients with Intracerebral hemorrhage,
  • For the management of blood pressure in patients with subarachnoid hemorrhage

Labetalol dose in Adults:

Note:

• IV administration:

  • There is limited documentation of prolonged continuous infusions; most patients respond to initial IV bolus dosing and are then transitioned to an oral antihypertensive.
  • Accumulation can occur with high-dose continuous infusions and may result in severe hypotension and bradycardia.

Labetalol dose as an alternative agent in the treatment of Acute aortic syndromes/ Acute aortic dissection (off-label):

Note:

• Manage patients immediately (including operative assessment) by controlling heart rate (target <60 bpm), pain with IV opioids, and systolic BP (target 100 to 120 mm Hg or lowest tolerated pressure).
• Although the manufacturer's labeling recommends against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

• Intermittent IV Labetalol:

  • Initial:
    • 20 mg over 2 minutes;
    • This is followed by 20 to 80 mg every 10 minutes until the target heart rate and blood pressure is reached
    • May transition to continuous infusion if unable to obtain target goals.

• Continuous IV infusion of labetalol:

  • Initial loading dose:
    • 20 mg over 2 minutes (optional if intermittent dosing is used), followed by 0.5 to 2 mg/minute
    • Some patients may require titration up to 10 mg/minute for optimal response.

Labetalol Dose for blood pressure management in patients with acute ischemic stroke (off-label):

• Patient otherwise eligible for reperfusion treatment (eg, alteplase) except BP >185/110 mm Hg:

  • IV:
    • 10 to 20 mg over 1 to 2 minutes; may repeat once.
    • If BP remains >185/110 mm Hg, do not administer thrombolytic.

• Management of blood pressure during and after reperfusion treatment (eg, alteplase):

  • IV:
    • 10 mg given over 1 to 2 minutes, followed by a continuous infusion of 2 to 8 mg/minute.
    • Target BP <180/105 mm Hg for the first 24 hours after reperfusion treatment.
    • If hypertension is refractory or diastolic BP >140 mm Hg, consider alternative therapy.
    • Although the manufacturer's labeling recommends against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

Labetalol Dose in the treatment of acute/ severe hypertension (including perioperative hypertension):

Note:

• The benefit of using IV antihypertensive agents to treat acute severe asymptomatic hypertension is not well established
• In general, address underlying causes (eg, pain, agitation, withdrawal, hypervolemia) prior to initiating antihypertensive therapy.
• Rapid or excessive blood pressure reduction may be associated with severe adverse effects (eg, cerebral or myocardial ischemia).
• For patients with chronic hypertension before surgery, restart oral therapies as soon as appropriate once hemodynamically stable.

• Intermittent IV Labetalol:

  • Initial:
    • 5 to 20 mg given over 2 minutes;
    • The dose may be repeated every 10 minutes until target blood pressure is reached.
    • Although the manufacturer's labeling recommends against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

Labetalol dose in the treatment of chronic/ resistant hypertension:

Note:

• Not recommended for initial management of hypertension, but may be considered as additional therapy in patients who do not respond adequately to combination therapy with preferred agents.

• Oral:

  • Initial: 100 mg BD;
  • The dose may be increased as needed every 2 to 3 days by 100 mg twice daily (titration increments not to exceed 200 mg twice daily) until the desired response is obtained
  • Usual dosage range: 200 to 800 mg/day in 2 divided doses.
  • In patients with severe or resistant hypertension, doses up to 1.2 to 2.4 g/day in 2 or 3 divided doses may be required according to the manufacturer's labeling.
  • However, some experts prefer combinations of agents dosed within the usual range rather than further dose escalation.

Labetalol dose in patients with Hypertensive emergency:

Note:

• In general, reduce mean arterial BP ~10% to 20% over the first hour, then 5% to 15% over the next 23 hours, unless there is a compelling indication (eg, acute aortic dissection, severe preeclampsia, eclampsia) for more rapid blood pressure and heart rate control.
• Although the manufacturer's labeling has recommended against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

• Intermittent IV labetalol:

  • Initial: 10 to 20 mg given over 1 to 2 minutes; followed by 20 to 80 mg every 10 minutes until target blood pressure is reached
  • Consider a continuous infusion if unable to obtain target blood pressure.

• Continuous IV labetalol infusion:

  • Initial loading dose: 10 to 20 mg given over 2 minutes (optional if intermittent dosing is used), followed by 0.5 to 2 mg/minute; some patients may require titration up to 10 mg/minute.

Labetalol Dose in the Hypertensive emergency in pregnancy or postpartum (including acute-onset hypertension in preeclampsia/eclampsia) (off-label):

Note:

• For acute-onset, severe, persistent (eg, ≥15 minutes) hypertension.
• Although the manufacturer's labeling recommends against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

• Intermittent IV labetalol:

  • Initial: 20 mg given over 2 minutes; if blood pressure exceeds thresholds after 10 minutes, increase the dose in increments of 20 to 40 mg every 10 minutes.
  • Maximum single dose: 80 mg.

Note:

• If blood pressures remain above the threshold after several intermittent doses, another agent should be used.

• Continuous IV infusion:

  • Initial loading dose: 20 mg given over 2 minutes (optional if intermittent dosing is used), followed by 1 to 2 mg/minute titrated to response.

• Oral (alternative route):

  • Initial:
    • 200 mg every 12 hours.
    • The dose may be increased up to 800 mg every 8 to 12 hours as needed based on response and tolerability.
    • Maximum: 2.4 g/day.
    • IV therapy may be needed for acute treatment
    • Combination therapy with another agent may be needed if the maximum dose is ineffective or must be limited due to adverse effects.

Labetalol Dose for blood pressure management in patients with Intracerebral hemorrhage (off-label):

Note:

• In patients presenting within 6 hours of acute intracranial hemorrhage and having systolic BP between 150 and 220 mm Hg, decreasing systolic BP to <140 mm Hg is not beneficial and can be harmful.
• Although the manufacturer's labeling has recommended against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

• Patients who present with systolic BP >150 mm Hg:

  • Intermittent IV:
    • Initial: 5 to 20 mg IV push given over 2 minutes, followed by 20 to 80 mg every 10 to 15 minutes until recommended target systolic BP is reached
    • May consider a continuous infusion if unable to obtain target goals.

• Patients who present with systolic BP >220 mm Hg:

  • Continuous IV infusion:
    • Initial loading dose: 20 mg given over 2 minutes, followed by 0.5 to 2 mg/minute, titrate to recommended target systolic BP.

Labetalol Dose for blood pressure management in patients with subarachnoid hemorrhage  (off-label):

Note:

• • Optimal therapy is not well established.
  • Cautious use of antihypertensive therapy to decrease the risk of rebleeding may be appropriate in some patients with systolic BP >160 mm Hg or mean arterial pressure >110 mm Hg with adequate cerebral perfusion pressures.
  • Although the manufacturer's labeling has recommended against exceeding a cumulative IV dose of 300 mg, it may be reasonable to exceed this dose in selected patients, while monitoring for accumulation.

• Intermittent IV:

  • Initial:
    • 10 to 20 mg given over 2 minutes
    • Followed by 20 to 80 mg every 10 to 15 minutes until systolic BP <160 mm Hg or mean arterial pressure <100 mm Hg.

• Continuous IV infusion:

  • 5 to 2 mg/minute titrated to response; based on very limited data.

• IV to oral conversion:

  • Upon discontinuation of continuous IV infusion, may initiate oral dose of 200 mg followed in 6 to 12 hours with an additional dose of 200 to 400 mg
  • The dose should be adjusted based on the response at ≥1-day intervals to a range of 400 mg/day to 2.4 g/day in 2 to 3 divided doses.
  • Note: For hypertension, the usual dosage range is 200 to 800 mg/day in 2 divided doses.

Labetalol dose in Childrens:

Note:

• Use care with labetalol continuous IV infusions; the rate of administration is different for pediatric patients (mg/kg/hour) versus adult patients (mg/minute).

Labetalol Dose in the treatment of Hypertension:

• Children and Adolescents: Limited data available:

  • Oral:
    • Initial: 1 to 3 mg/kg/day in 2 divided doses
    • Maximum daily dose: 10 to 12 mg/kg/day, up to 1,200 mg/day
  • IV (intermittent bolus):
    • 0.2 to 1 mg/kg/dose
    • Maximum dose: 40 mg/dose; use should be reserved for severe hypertension

Labetalol Dose in patients with Hypertensive emergency or urgency: Limited data available:

• Infants, Children, and Adolescents:

  • IV (intermittent bolus):
    • 0.2 to 1 mg/kg/dose
    • Maximum dose: 40 mg/dose
  • Continuous IV infusion:
    • 25 to 3 mg/kg/hour
    • Initiate at the lower end of the range, and titrate up slowly.

Pregnancy Risk Factor C

• Labetalol crosses over the placenta.
• The risk of adverse reactions in the neonate may be increased by exposure to labetalol while pregnant.
• If beta-blocker use by mothers is necessary, it is important to monitor fetal growth during pregnancy and for 48 hours after birth for hypoglycemia, bradycardia, and respiratory depression.
• Chronic maternal hypertension can also be associated with adverse events for the infant/fetus.
• Chronic maternal hypertension can increase the likelihood of low birth weight, birth defects, stillbirths, premature births, and even neonatal deaths.
• The severity and duration of maternal hypertension may have an impact on the actual fetal/neonatal risk.
• Chronic hypertension, if left untreated can also increase the risk of adverse maternal outcomes such as preeclampsia and gestational diabetes, stroke, and myocardial injury.
• Pregnancy does not affect the pharmacokinetic properties or labetalol in any significant way.
• For the treatment of pregnancy-related hypertension, oral labetalol may be used.
• For the treatment of severe hypertension, intravenous labetalol should be used.
• Avoid the use of labetalol by women suffering from asthma or heart disease.

Labetalol use during breastfeeding:

• Breast milk contains labetalol.
• Based on the highest breastmilk concentration, the relative infant dose (RID), of labetalol was 3.6%. This is compared to a therapeutic infant dose of 3 mg/kg/day.
• When the RID is less than 10%, breastfeeding is generally acceptable.
• The highest possible milk concentration (0.71 mg/mL) is used to estimate the daily infant dose via breastmilk at 0.1065 mg/kg/day.
• This was achieved after maternal administration of oral lebetalol 300mg BD.
• It has not been proven that milk concentrations correspond to maternal serum levels.
• Peak milk concentrations can occur between 1 and 3 hours after the maternal dose.
• Asymptomatic bradycardia in a preterm infant who was exclusively breastfed was seen after maternal use of labetalol.
• In case reports, labetalol has been linked to nipple pain and Raynaud phenomenon in the nipple.
• The manufacturer suggests being cautious when administering labetalol breastfeeding women.
• Labetalol is a preferred beta-blocker for breastfeeding women.

Labetalol Dose in Kidney Disease:

• No dosage adjustments provided in the manufacturer’s labeling.
• Not removed by hemodialysis or peritoneal dialysis.
• Supplemental dose is not necessary.

Labetalol Dose in Liver disease:

• No dosage adjustments provided in the manufacturer’s labeling.
• However, dosage reduction may be necessary in patients with hepatic impairment due to decreased metabolism and increased oral bioavailability, use cautiously.

Common Side Effects of Labetalol:

• Cardiovascular:

  • Orthostatic hypotension

• Central nervous system:

  • Dizziness
  • Fatigue

• Gastrointestinal:

  • Nausea

Less Common Side Effects of Labetalol:

• Cardiovascular:

  • Edema
  • Flushing
  • Hypotension
  • Ventricular Arrhythmia

• Central Nervous System:

  • Paresthesia
  • Drowsiness
  • Yawning
  • Headache
  • Vertigo
  • Hypoesthesia

• Dermatologic:

  • Diaphoresis
  • Pruritus
  • Skin Rash

• Gastrointestinal:

  • Dyspepsia
  • Vomiting
  • Dysgeusia

• Genitourinary:

  • Ejaculatory Failure
  • Impotence

• Hepatic:

  • Increased Serum Transaminases

• Neuromuscular & Skeletal:

  • Asthenia

• Ophthalmic:

  • Visual Disturbance

• Renal:

  • Increased Blood Urea Nitrogen
  • Increased Serum Creatinine

• Respiratory:

  • Nasal Congestion
  • Dyspnea
  • Wheezing

Contraindications to Labetalol:

• Hypersensitivity to labetalol and any component of the formulation
• Bradycardia severe
• Heart block of greater than the first degree is possible (except for patients who have a working artificial pacemaker).
• Cardiogenic shock
• Bronchial asthma, obstructive or chronic airway disease.
• Uncompensated cardiac Failure
• Conditions associated with severe and prolonged hypotension Documentation of allergenic cross-reactivity for alpha/beta-adrenergic blocking agents are limited.
• Cross-sensitivity can be possible due to similarities in chemical structure or pharmacologic effects.

Warnings and precautions

• Anaphylactic reactions

  • Avoid using this product if you have had severe allergic reactions to allergens.
  • Beta-blockers can make patients more sensitive to repeated challenges.
  • Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

• Floppy iris syndrome:

  • Patients who had cataract surgery were treated with alpha blockers have been known to develop intraoperative floppy-iris syndrome.
  • It does not appear to be beneficial to stop taking alpha-blocker before surgery.

• Hepatic injury:

  • Rarely have we seen severe hepatocellular injuries.
  • Although the hepatic injury can usually be reversed, reports of hepatic necrosis and death have been made.
  • Injuries can occur after both short-term and long-term treatment. They may progress slowly despite having minimal symptoms.
  • Regularly monitor the liver functions.
  • Stop taking labetalol when you have liver injury or jaundice.

• Syncope and hypotension:

  • Labetalol may cause hypotension symptoms with or without syncope.
  • Particularly with the initial dose and subsequent dosing increases, close monitoring is necessary.
  • The patient's clinical condition dictates that blood pressure should be reduced at an appropriate rate.
  • Hypotension and syncope may be reduced by starting with a low dose and gradually increasing the dosage.
  • Patients should avoid driving and other dangerous tasks during the initiation of therapy because of the risk of developing syncope.
  • Intravenous administration may cause orthostatic hypotension.
  • Patients should remain upright for at least three hours following IV administration.

• Bronchospastic Disease:

  • Patients with bronchospastic diseases should not be given beta-blockers.
  • You should use caution if you are going to use it.

• Diabetes:

  • Patients with diabetes mellitus should be cautious.
  • Could cause hypoglycemia and/or mask symptoms.
  • Also, may reduce insulin release in hyperglycemia.
  • You may need to adjust the dosage of anti-diabetic drugs.

• Heart failure (HF):

  • Patients with compensated cardiac failure should be used with caution and monitored for any deterioration.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious
  • Due to a decreased first-pass metabolism, bioavailability increases.

• Myasthenia gravis:

  • Patients with myasthenia gravis should be treated with caution.

• Raynaud and peripheral vascular disease:

  • Patients with Raynaud disease or peripheral vascular disease may experience arterial insufficiency. Beta-blockers can cause or exacerbate symptoms.
  • Be cautious and monitor for arterial obstruction.

• Pheochromocytoma:

  • Patients with pheochromocytoma may find labetalol helpful in lowering blood pressure or relieving symptoms.
  • Patients may also experience paradoxical hypertensive reactions due to insufficient alpha-1 blocking.
  • Before any beta-blocker is used in this setting, it is important to have an adequate alpha-1 blockade.
  • Patients with pheochromocytoma should not use it. Alternate therapies should be considered.
  • Before using labetalol, it is important to have any diagnostic tests done.
  • This is because falsely high levels of plasma and urinary catecholamines can be caused by the drug.

• Psoriasis:

  • Although beta-blocker usage has been linked to the induction or exacerbation psoriasis symptoms, cause and effect are not clear.

• Thyroid disease:

  • Beta-blockers can mask symptoms of hyperthyroidism like tachycardia.
  • Hyperthyroidism should be suspected and treated with care.
  • Rapid withdrawal of beta-blockers can worsen hyperthyroidism symptoms or cause a thyroid storm.

Labetalol: Drug Interaction

Monitoring parameters:

• BP, standing and sitting/supine, pulse, cardiac monitor & BP monitor recommended for IV administration.

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults :

• Confirmed hypertension and known cardiovascular disease or 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥10%:

  • Target BP <130/80 mm Hg is recommended.

• Confirmed hypertension without markers of increased ASCVD risk:

  • Target BP <130/80 mm Hg may be reasonable.

• Hypertension, acute in pregnancy (hypertensive emergency/urgency):

  • Once the target BP is achieved, monitor every 10 minutes for the first hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, then every hour for 4 hours.

How to administer Labetalol?

• Oral:
  • Administer without regard to food
  • However, the absolute bioavailability of labetalol is increased when administered with food.
  • Administer in a consistent manner with regards to meals.

• Parenteral:

  • It may be administered as an intravenous bolus at a rate of 10 mg per minute followed by a continuous intravenous infusion.

Mechanism of action of Labetalol:

• It blocks beta-1 and beta-2 alpha-receptors.
• It also lowers the levels of renin.
• The route of administration will affect the ratio of beta- to alpha-blockade. 
• It is 1:3 for oral administration (alpha/beta). It is 1:3 (alpha-beta) when intravenous administration is used.

The onset of action:

• Oral: 20 minutes to 2 hours
• IV: Within 5 minutes

Peak effect:

• Oral: 2 to 4 hours
• IV: 5 to 15 minutes

Duration: Blood pressure response:

• Oral: 8 to 12 hours (dose-dependent)
• IV: Average: 16 to 18 hours (dose-dependent)

Absorption:

• Complete

Protein binding:

• ~50%

Metabolism:

• Hepatic, primarily via glucuronide conjugation
• Extensive first-pass effect

Bioavailability:

• Oral:
  • 25%
  • Increased with liver disease, elderly, and concurrent cimetidine

Half-life elimination:

• Oral: 6 to 8 hours
• IV: ~5.5 hours

Time to peak plasma:

• Oral: 1 to 2 hours

Excretion:

• Urine (55% to 60% as glucuronide conjugates, <5% as unchanged drug
• feces (12% to 27% as metabolites)

International Brands of Labetalol:

• APO-Labetalol
• RIVA-Labetalol
• Trandate
• Albetol
• Biascor
• Blocamine
• Chenday
• Hybloc
• Ipolab
• Labecard
• Labedin
• Labesin
• Labesol
• Labeta
• Labipress
• Lamitol
• Normadate
• Presolol
• Pressocard
• Trandate
• Trantalol
• Xin Yu Sen

Labetalol Brand Names in Pakistan: