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Labetalol


Pronunciation

 (la BET a lole)


U.S. Brand Names

 Normodyne®; Trandate®


Synonyms

 Ibidomide Hydrochloride; Labetalol Hydrochloride


Generic Available

 Yes


Canadian Brand Names

 Apo-Labetalol®; Normodyne®; Trandate®


Use

 Treatment of mild to severe hypertension; I.V. for hypertensive emergencies


Pregnancy Risk Factor

 C (manufacturer); D (2nd and 3rd trimesters - expert analysis)


Pregnancy Implications

 Labetalol crosses the placenta. Beta-blockers have been associated with persistent bradycardia, hypotension, and IUGR; IUGR is probably related to maternal hypertension. Available evidence suggests beta-blockers are generally safe during pregnancy (JNC 7). Cases of neonatal hypoglycemia have been reported following maternal use of beta-blockers at parturition or during breast-feeding. Monitor breast-fed infant for symptoms of beta-blockade.


Lactation

 Enters breast milk/use caution (AAP rates "compatible")


Contraindications

 Hypersensitivity to labetalol or any component of the formulation; sinus bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; bronchial asthma; uncompensated cardiac failure; pregnancy (2nd and 3rd trimesters)


Warnings/Precautions

 Use only with extreme caution in compensated heart failure and monitor for a worsening of the condition. Avoid abrupt discontinuation in patients with a history of CAD; slowly wean while monitoring for signs and symptoms of ischemia. Use caution with concurrent use of beta-blockers and either verapamil or diltiazem; bradycardia or heart block can occur. Avoid concurrent I.V. use of both agents. Patients with bronchospastic disease should not receive beta-blockers. Labetalol may be used with caution in patients with nonallergic bronchospasm (chronic bronchitis, emphysema). Use cautiously in diabetics because it can mask prominent hypoglycemic symptoms. Can mask signs of thyrotoxicosis. Can cause fetal harm when administered in pregnancy. Use cautiously in the hepatically impaired. Use caution when using I.V. labetalol and inhalational anesthetics concurrently (significant myocardial depression).


Adverse Reactions

>10%:

Central nervous system: Dizziness (1% to 16%)

Gastrointestinal: Nausea (0% to 19%)

1% to 10%:

Cardiovascular: Edema (0% to 2%), hypotension (1% to 5%); with IV use, hypotension may occur in up to 58%

Central nervous system: Fatigue (1% to 10%), paresthesia (1% to 5%), headache (2%), vertigo (2%)

Dermatologic: Rash (1%), scalp tingling (1% to 5%)

Gastrointestinal: Vomiting (<1% to 3%), dyspepsia (1% to 4%)

Genitourinary: Ejaculatory failure (0% to 5%), impotence (1% to 4%)

Hepatic: Transaminases increased (4%)

Neuromuscular & skeletal: Weakness (1%)

Respiratory: Nasal congestion (1% to 6%), dyspnea (2%)

Miscellaneous: Taste disorder (1%), abnormal vision (1%)

<1% (Limited to important or life-threatening): Hypotension, syncope, bradycardia, heart block, fever, diaphoresis increased, diarrhea, drowsiness, systemic lupus erythematosus, positive ANA, dry eyes, antimitochondrial antibodies, hepatic necrosis, hepatitis, cholestatic jaundice, muscle cramps, toxic myopathy, bronchospasm, Peyronie's disease, alopecia (reversible), micturition difficulty, urinary retention, hypersensitivity, urticaria, angioedema, pruritus, anaphylactoid reaction, Raynaud's syndrome, claudication, CHF, ventricular arrhythmia (I.V.)

Postmarketing and/or case reports: Fever, toxic myopathy, muscle cramps, systemic lupus erythematosus, diabetes insipidus

Other adverse reactions noted with beta-adrenergic blocking agents include mental depression, catatonia, disorientation, short-term memory loss, emotional lability, clouded sensorium, intensification of pre-existing AV block, laryngospasm, respiratory distress, agranulocytosis, thrombocytopenic purpura, nonthrombocytopenic purpura, mesenteric artery thrombosis, and ischemic colitis.


Overdosage/Toxicology

 Symptoms of intoxication include cardiac disturbances, CNS toxicity, bronchospasm, hypoglycemia, and hyperkalemia. The most common cardiac symptoms include hypotension and bradycardia. Atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membrane-depressant drugs (eg, propranolol). CNS effects include convulsions, coma, and respiratory arrest and are commonly seen with propranolol and other membrane-depressant and lipid-soluble drugs. Treatment is symptomatic. Glucagon may be administered to improve cardiac function.


Drug Interactions

 Substrate of CYP2D6 (major); Inhibits CYP2D6 (weak)

Alpha-blockers (prazosin, terazosin): Concurrent use of beta-blockers may increase risk of orthostasis.

Cimetidine increases the bioavailability of labetalol.

CYP2D6 inhibitors: May increase the levels/effects of labetalol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Halothane, isoflurane, enflurane (possibly other inhalational anesthetics): Excessive hypotension may occur.

NSAIDs may reduce antihypertensive efficacy of labetalol.

Salicylates may reduce the antihypertensive effects of beta-blockers.

Sulfonylureas: Effects may be decreased by beta-blockers.

Verapamil or diltiazem may have synergistic or additive pharmacological effects when taken concurrently with beta-blockers; avoid concurrent I.V. use.


Ethanol/Nutrition/Herb Interactions

Food: Labetalol serum concentrations may be increased if taken with food.

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid natural licorice (causes sodium and water retention and increases potassium loss). Avoid garlic (may have increased antihypertensive effect).


Stability

Labetalol should be stored at room temperature or under refrigeration and should be protected from light and freezing; the solution is clear to slightly yellow

Stability of parenteral admixture at room temperature (25°C) and refrigeration temperature (4°C): 3 days

Standard diluent: 500 mg/250 mL D5W

Minimum volume: 250 mL D5W

Incompatible with sodium bicarbonate, most stable at pH of 2-4; incompatible with alkaline solutions


Compatibility

 Stable in D5LR, D5 1 /4NS, D5 1 /3NS, D5NS, D5W, LR, NS; not stable in sodium bicarbonate 5%

Y-site administration: Compatible: Amikacin, aminophylline, amiodarone, ampicillin, butorphanol, calcium gluconate, cefazolin, ceftazidime, ceftizoxime, chloramphenicol, cimetidine, clindamycin, diltiazem, dobutamine, dopamine, enalaprilat, epinephrine, erythromycin lactobionate, esmolol, famotidine, fentanyl, gatifloxacin, gentamicin, hydromorphone, lidocaine, linezolid, lorazepam, magnesium sulfate, meperidine, metronidazole, midazolam, milrinone, morphine, nicardipine, nitroglycerin, norepinephrine, oxacillin, penicillin G potassium, piperacillin, potassium chloride, potassium phosphates, propofol, ranitidine, sodium acetate, sodium nitroprusside, tobramycin, trimethoprim/sulfamethoxazole, vancomycin, vecuronium. Incompatible: Amphotericin B cholesteryl sulfate complex, cefoperazone, ceftriaxone, nafcillin, thiopental, warfarin. Variable (consult detailed reference): Furosemide, heparin, insulin (regular)

Compatibility when admixed: Incompatible: Sodium bicarbonate


Mechanism of Action

 Blocks alpha-, beta1-, and beta2-adrenergic receptor sites; elevated renins are reduced


Pharmacodynamics/Kinetics

Onset of action: Oral: 20 minutes to 2 hours; I.V.: 2-5 minutes

Peak effect: Oral: 1-4 hours; I.V.: 5-15 minutes

Duration: Oral: 8-24 hours (dose dependent); I.V.: 2-4 hours

Distribution: Vd: Adults: 3-16 L/kg; mean: <9.4 L/kg; moderately lipid soluble, therefore, can enter CNS; crosses placenta; small amounts enter breast milk

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: Normal renal function: 2.5-8 hours

Excretion: Urine (<5% as unchanged drug)

Clearance: Possibly decreased in neonates/infants


Dosage

 Due to limited documentation of its use, labetalol should be initiated cautiously in pediatric patients with careful dosage adjustment and blood pressure monitoring.

Children:

Oral: Limited information regarding labetalol use in pediatric patients is currently available in literature. Some centers recommend initial oral doses of 4 mg/kg/day in 2 divided doses. Reported oral doses have started at 3 mg/kg/day and 20 mg/kg/day and have increased up to 40 mg/kg/day.

I.V., intermittent bolus doses of 0.3-1 mg/kg/dose have been reported.

For treatment of pediatric hypertensive emergencies, initial continuous infusions of 0.4-1 mg/kg/hour with a maximum of 3 mg/kg/hour have been used. Administration requires the use of an infusion pump.

Adults:

Oral: Initial: 100 mg twice daily, may increase as needed every 2-3 days by 100 mg until desired response is obtained; usual dose: 200-400 mg twice daily; may require up to 2.4 g/day.

Usual dose range (JNC 7): 200-800 mg/day in 2 divided doses

I.V.: 20 mg (0.25 mg/kg for an 80 kg patient) IVP over 2 minutes; may administer 40-80 mg at 10-minute intervals, up to 300 mg total dose.

I.V. infusion: Initial: 2 mg/minute; titrate to response up to 300 mg total dose, if needed. Administration requires the use of an infusion pump.

I.V. infusion (500 mg/250 mL D5W) rates:

1 mg/minute: 30 mL/hour

2 mg/minute: 60 mL/hour

3 mg/minute: 90 mL/hour

4 mg/minute: 120 mL/hour

5 mg/minute: 150 mL/hour

6 mg/minute: 180 mL/hour

Dialysis: Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.

Dosage adjustment in hepatic impairment: Dosage reduction may be necessary.


Administration

 Bolus administered over 2 minutes.


Monitoring Parameters

 Blood pressure, standing and sitting/supine, pulse, cardiac monitor and blood pressure monitor required for I.V. administration


Test Interactions

 False-positive urine catecholamines, VMA if measured by fluorometric or photometric methods; use HPLC or specific catecholamine radioenzymatic technique


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, with meals. Do not skip dose or discontinue without consulting prescriber. This medication does not replace other antihypertensive interventions; follow prescriber's instructions for diet and lifestyle changes. If you have diabetes, monitor serum glucose closely and notify prescriber of changes (this medication can alter hypoglycemic requirements). You may experience drowsiness, dizziness, or impaired judgment (use caution when driving or engaging in tasks that require alertness until response to drug is known); postural hypotension (use caution when rising from sitting or lying position or when climbing stairs); dry mouth, nausea, or loss of appetite (frequent mouth care or sucking lozenges may help); or sexual dysfunction (reversible, may resolve with continued use). Report altered CNS status (eg, fatigue, depression, numbness or tingling of fingers, toes, or skin); palpitations or slowed heartbeat; respiratory difficulty; edema or cold extremities; or other persistent side effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.


Nursing Implications

 Instruct patient regarding compliance


Anesthesia and Critical Care Concerns/Other Considerations

 Due to alterations in the beta-adrenergic autonomic nervous system, beta-adrenergic blockade may result in less hemodynamic response in the elderly than seen in younger adults. Despite decreased sensitivity to the chronotropic effects of beta blockade with age, there appears to be an increased myocardial sensitivity to the negative inotropic effect during stress (eg, exercise).


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Taste disorder.

Noncardioselective beta-blockers enhance the pressor response to epinephrine, resulting in hypertension and bradycardia. Many nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can reduce the hypotensive effect of beta-blockers after 3 or more weeks of therapy with the NSAID. Short-term NSAID use (ie, 3 days) requires no special precautions in patients taking beta-blockers.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Use with caution; epinephrine has interacted with nonselective beta-blockers to result in initial hypertensive episode followed by bradycardia


Mental Health: Effects on Mental Status

 Dizziness is common; may cause sedation


Mental Health: Effects on Psychiatric Treatment

 Barbiturates may decrease effects of beta-blockers; low potency antipsychotic and TCAs may potentiate the hypotensive effects of beta-blockers


Dosage Forms

Injection, solution, as hydrochloride (Normodyne®): 5 mg/mL (20 mL, 40 mL)

Injection, solution, as hydrochloride [prefilled syringe]: 5 mg/mL (4 mL)

Normodyne®: 5 mg/mL (4 mL, 8 mL)

Tablet, as hydrochloride: 100 mg, 200 mg, 300 mg

Normodyne®: 100 mg, 200 mg, 300 mg

Trandate®: 100 mg, 200 mg [contains sodium benzoate], 300 mg


Extemporaneously Prepared

 A 40 mg/mL suspension of labetalol hydrochloride can be made by first crushing sixteen 300 mg labetalol hydrochloride tablets into a fine powder. Using equal amounts of Ora-Sweet® and Ora-Plus® as a vehicle, add a small amount to make a paste; add additional amounts of the vehicle to qs to 120 mL. Suspension is stable for 60 days when stored in the refrigerator. Shake well before using.

Nahata MC and Hipple TF, Pediatric Drug Formulations , 4th ed, Cincinnati, OH: Harvey Whitney Books Co, 2000.


References

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

Erstad BL and Barletta JF, "Treatment of Hypertension in the Perioperative Patient," Ann Pharmacother , 2000, 34(1):66-79.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.


International Brand Names

 Albetol® (FI); Apo-Labetalol® (CA); Biascor® (AR); Coreton® (CZ); Hybloc® (NZ); Ipolab® (IT); Labetalol® (CY); Labetalol Hydrochloride® (GB); Liondox® (AR); Normodyne® (CA); Presolol® (AU); Pressocard® (PL); Trandate® (AT, AU, BE, CA, CH, CL, CY, DK, ES, FR, GB, HK, IE, IL, IT, JO, KW, LB, LU, NL, NO, NZ, PL, SE, SY, ZA)


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