These Highlights Do Not Include All The Information Needed To Use Labetalol Hydrochloride Tablets, Usp Safely And Effectively. See Full Prescribing Information For Labetalol Hydrochloride Tablets, Usp. Labetalol Hydrochloride Tablets, Usp For Oral Use. Initial U.s. Approval: 1984

Labetalol Hydrochloride is indicated in the management of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including beta adrenergic blockers.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Labetalol Hydrochloride Tablets, USP may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.

• The recommended initial dosage is 100 mg twice daily, alone or added to a diuretic regimen. Titrate in increments of 100 mg twice daily every 2 or 3 days. Maintenance dosage is between 200 and 400 mg twice daily. (2.1)
• Severe Hypertension: May require from 1,200 to 2,400mg per day, with or without thiazide diuretics. Titrate in increments not to exceed 200 mg twice daily. (2.2)
• Elderly patients: Initiate at 100 mg twice daily. Titrate in increments of 100 mg twice daily as required for blood pressure control. Many elderly patients will require between 100 and 200 mg twice daily. (2.3)

Labetalol Hydrochloride Tablets USP, 100 mg, White to off-white, biconvex, film coated tablets with “ET20” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-035-12) and bottles of 500 (NDC 71930-035-52).

Labetalol Hydrochloride Tablets USP, 200 mg, White to off-white, biconvex, film coated tablets with “ET21” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-036-12) and bottles of 500 (NDC 71930-036-52).

Labetalol Hydrochloride Tablets USP, 300 mg, White to off-white, biconvex, film coated tablets with “ET22” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-037-12) and bottles of 500 (NDC 71930-037-52).



Storage

Store Labetalol Hydrochloride Tablets, USP between 2° and 30°C (36° and 86°F).

Labetalol Hydrochloride Tablets are contraindicated in patients with:

• bronchial asthma or obstructive airway disease
• decompensated heart failure
• greater than first degree heart block
• cardiogenic shock
• severe bradycardia
• Hypersensitivity reactions, including anaphylaxis, to labetalol
• non-dihydropyridine calcium-channel antagonists

Labetalol Hydrochloride Tablets, USP contain labetalol hydrochloride, an adrenergic receptor blocking agent that has both selective alpha₁ adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance.  

Labetalol hydrochloride is a racemate chemically designated as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] benzamide monohydrochloride, and it has the following structural formula:

Labetalol hydrochloride has the empirical formula C₁₉H₂₄N₂O₃•HCl and a molecular weight of 364.9. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic labetalol.

Labetalol hydrochloride is a white or off-white crystalline powder, soluble in water.

Labetalol Hydrochloride Tablets, USP contain 100 mg, 200 mg, or 300 mg of labetalol hydrochloride and are for oral administration. The tablets also contain the inactive ingredients lactose monohydrate, magnesium stearate, pregelatinized corn starch, sodium starch glycolate.

FDA approved dissolution test specifications differ from USP.

• Concomitant use with negative chronotropes can increase risk of bradycardia (7.1)
• Beta blockers antagonize the bronchodilator effect of beta-receptor agonists. (7.2)
• Increase hypotension may occur with halothane anesthesia. (7.3)
• Nitroglycerin may result in additional hypotensive effects. (7.4)

• Advise patients to not interrupt or discontinue using Labetalol Hydrochloride Tablets without advice from their healthcare provider
• Advise patients to contact their healthcare provider about any signs or symptoms of impending cardiac failure or hepatic dysfunction [see Warnings and Precautions (5.3,5.8)]
• Inform patients or caregivers that there is a risk of hypoglycemia when Labetalol Hydrochloride Tablets is given to patients who are fasting or who are vomiting. Monitor for symptoms of hypoglycemia [see Warnings and Precautions (5.6)].  

Manufactured for:

Eywa-Hibrow Pharma

908 Oak Tree Road, Suite O

South Plainfield, NJ 07080



Made in India



Revised: 04/2025

Risk Summary

Available published data report the presence of labetalol in human milk at low levels. There are no data on the effects on the breastfed infant and on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for labetalol and any potential adverse effects on the breastfed infant from labetalol or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

Pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Although elderly patients may initiate therapy at the currently recommended dosage of 100 mg twice daily, elderly patients will generally require lower maintenance dosages than nonelderly patients.

Long-term oral dosing studies with labetalol hydrochloride for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol hydrochloride using dominant lethal assays in rats and mice and exposing microorganisms according to modified Ames tests showed no evidence of mutagenesis.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypotension [see Warnings and Precautions (5.1)
• Bradycardia [see Warnings and Precautions (5.2)
• Cardiac failure [see Warnings and Precautions (5.3)
• Ischemic heart disease [see Warnings and Precautions (5.4)]
• Nonallergic bronchospasm [see Warnings and Precautions (5.5)]
• Use in patients with pheochromocytoma [see Warnings and Precautions (5.7)]
• Hepatic injury [see Warnings and Precautions (5.8)]
• Risk of severe acute hypersensitivity reaction [see Warnings and Precautions (5.9)]

Overdosage with labetalol hydrochloride causes excessive hypotension that is posture sensitive and, sometimes, excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. Treat symptoms of overdose with standard supportive care. If overdosage with labetalol hydrochloride follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. Treat symptoms of overdose with standard supportive care.

Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (<1%).

The oral LD₅₀ value of labetalol hydrochloride in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD₅₀in these species is 50 mg/kg to 60 mg/kg.

Risk Summary 

The extensive experience with use of labetalol in pregnant women, based on published interventional and observational studies, has not identified a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Untreated hypertension during pregnancy can lead to serious adverse outcomes for the mother and the fetus (see Clinical Considerations). In animal reproductive studies, oral administration of labetalol to pregnant rats and rabbits during organogenesis at doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively, resulted in no fetal malformations; however, increased fetal resorptions were seen in both species at doses approximating the MRHD (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Consideration

Disease-Associated Materanl and/or Embryo/Fetal Risk  

Hypertension in pregnancy increase the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions  

Labetalol crosses the placenta. Newonates born to mothers who are receiving labetalol during pregnancy, may be at risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Neonates should be monitored for symptoms of hypotension, bradycardia, hypoglycemia and respiratly depression and mange accordingly.

Data

Human Data

Data from published interventional and observational studies did not demonstrate an association between major congenital malformations and the use of labetalol in pregnancy, however, most studies reported the maternal use of intravenous labetalol occurring after 20 weeks gestation. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of labetalol during pregnancy; however, these studies have methodological limitations hindering interpretation. These studies cannot definitively establish the absence of risk during pregnancy.

Animal Data  

Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD.

A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus.

Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Labetalol Hydrochloride dosage must be individualized.

The recommended initial dosage of labetalol hydrochloride is 100 mg twice daily. Adjust dosage in increments of 100 mg twice daily at 2-to 3-day intervals based on response. The recommended maintenance dosage of labetalol hydrochloride is between 200 and 400 mg twice daily.

Labetalol Hydrochloride Tablets, USP are available in the following strengths:

• 100 mg - White to off-white, biconvex, film coated tablets with “ET20” debossed on one side and non-functional scoring on the other side

• 200 mg - White to off-white, biconvex, film coated tablets with “ET21” debossed on one side and non-functional scoring on the other side

• 300 mg - White to off-white, biconvex, film coated tablets with “ET22” debossed on one side and non-functional scoring on the other side

Labetalol hydrochloride combines both selective, competitive, alpha₁-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity. The ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively.

The capacity of labetalol hydrochloride to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice cold water ("cold pressor test"). Labetalol hydrochloride's beta₁ receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta₂ receptor blockade was demonstrated by inhibition of the isoproterenol induced fall in diastolic blood pressure. Both the alpha- and beta blocking actions of orally administered labetalol hydrochloride contribute to a decrease in blood pressure in hypertensive patients. Labetalol hydrochloride consistently, in dose related fashion, blunted increases in exercise induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol hydrochloride dosing.

The effects on A-V nodal refractoriness were inconsistent. Single oral doses of labetalol hydrochloride administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV labetalol hydrochloride slightly prolonged A V nodal conduction time and atrial effective refractory period with only small changes in heart rate.

Labetalol hydrochloride produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.

Due to the alpha₁- receptor blocking activity of labetalol hydrochloride, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2.1)]. Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.

The peak effects of single oral doses of labetalol hydrochloride occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.

The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise induced tachycardia occurring at 2 hours after oral administration of labetalol hydrochloride and the logarithm of the plasma concentration.

About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.

Absorption  

Labetalol hydrochloride is absorbed with peak plasma levels occurring 1 to 2 hours after oral administration.

The relative bioavailability of Labetalol Hydrochloride Tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an IV infusion is 25%; this is due to extensive "first-pass" metabolism. There is a linear relationship between oral doses of 100 mg to 3,000 mg and peak plasma levels.

Effect of Food  

The absolute bioavailability of labetalol is increased when administered with food.

Distribution  

Labetalol has been shown to cross the placental barrier in humans. Labetalol is approximately 50% protein bound.

Elimination  

The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol are reached by about the third day of dosing.

Metabolism

Metabolism of labetalol is mainly through conjugation to glucuronide metabolites.

Excretion  

Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (<1%).

Specific Populations

Patients with Renal or Hepatic Impairment

In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased "first pass" metabolism.

Drug Interaction Studies

Tricyclic Antidepressants  

In one survey, 2.3% of patients taking labetalol hydrochloride in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol hydrochloride alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded.

Cimetidine  

Cimetidine has been shown to increase the bioavailability of labetalol hydrochloride. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol hydrochloride, special care should be used in establishing the dose required for blood pressure control in such patients.

• Monitor patients for symptomatic postural hypotension and syncope after initial dosing or dose increments. (5.1)
• Monitor heart rate and rhythm for bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest in patients receiving Labetalol Hydrochloride Tablets. (5.2)
• Beta-blockade can depress myocardial contractility and precipitating more severe failure. Avoid use in patients with overt heart failure. (5.3)
  
  Acute exacerbation of coronary artery disease upon cessation of therapy. Do not abruptly discontinue. (5.4)
• Avoid use in patients with bronchospastic disease. (5.5)
• Beta‑adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. (5.6)
• Exacerbation of pheochromocytoma: Paradoxical increases in blood pressure may occur. (5.7)
• Hepatic necrosis and death have been reported. If the patient develops signs or symptoms of liver injury, institute appropriate treatment and investigate the probable cause. (5.8)
• Do not routinely withdraw chronic beta blocker therapy prior to surgery. (5.10)

NDC 71930-035-12

Labetalol Hydrochloride Tablets, USP

100 mg

Rx only

100 tablets

Eywa-Hibrow Pharma

NDC 71930-036-12

Labetalol Hydrochloride Tablets, USP

200 mg

Rx only

100 tablets

Eywa-Hibrow Pharma

NDC 71930-037-12

Labetalol Hydrochloride Tablets, USP

300 mg

Rx only

100 tablets

Eywa-Hibrow Pharma

Labetalol Hydrochloride is indicated in the management of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including beta adrenergic blockers.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Labetalol Hydrochloride Tablets, USP may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.

• The recommended initial dosage is 100 mg twice daily, alone or added to a diuretic regimen. Titrate in increments of 100 mg twice daily every 2 or 3 days. Maintenance dosage is between 200 and 400 mg twice daily. (2.1)
• Severe Hypertension: May require from 1,200 to 2,400mg per day, with or without thiazide diuretics. Titrate in increments not to exceed 200 mg twice daily. (2.2)
• Elderly patients: Initiate at 100 mg twice daily. Titrate in increments of 100 mg twice daily as required for blood pressure control. Many elderly patients will require between 100 and 200 mg twice daily. (2.3)

Labetalol Hydrochloride Tablets USP, 100 mg, White to off-white, biconvex, film coated tablets with “ET20” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-035-12) and bottles of 500 (NDC 71930-035-52).

Labetalol Hydrochloride Tablets USP, 200 mg, White to off-white, biconvex, film coated tablets with “ET21” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-036-12) and bottles of 500 (NDC 71930-036-52).

Labetalol Hydrochloride Tablets USP, 300 mg, White to off-white, biconvex, film coated tablets with “ET22” debossed on one side and nonfunctional scoring on the other side, bottles of 100 (NDC 71930-037-12) and bottles of 500 (NDC 71930-037-52).



Storage

Store Labetalol Hydrochloride Tablets, USP between 2° and 30°C (36° and 86°F).

Labetalol Hydrochloride Tablets are contraindicated in patients with:

• bronchial asthma or obstructive airway disease
• decompensated heart failure
• greater than first degree heart block
• cardiogenic shock
• severe bradycardia
• Hypersensitivity reactions, including anaphylaxis, to labetalol
• non-dihydropyridine calcium-channel antagonists

• Concomitant use with negative chronotropes can increase risk of bradycardia (7.1)
• Beta blockers antagonize the bronchodilator effect of beta-receptor agonists. (7.2)
• Increase hypotension may occur with halothane anesthesia. (7.3)
• Nitroglycerin may result in additional hypotensive effects. (7.4)

• Advise patients to not interrupt or discontinue using Labetalol Hydrochloride Tablets without advice from their healthcare provider
• Advise patients to contact their healthcare provider about any signs or symptoms of impending cardiac failure or hepatic dysfunction [see Warnings and Precautions (5.3,5.8)]
• Inform patients or caregivers that there is a risk of hypoglycemia when Labetalol Hydrochloride Tablets is given to patients who are fasting or who are vomiting. Monitor for symptoms of hypoglycemia [see Warnings and Precautions (5.6)].  

Manufactured for:

Eywa-Hibrow Pharma

908 Oak Tree Road, Suite O

South Plainfield, NJ 07080



Made in India



Revised: 04/2025

Risk Summary

Available published data report the presence of labetalol in human milk at low levels. There are no data on the effects on the breastfed infant and on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for labetalol and any potential adverse effects on the breastfed infant from labetalol or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

Pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Although elderly patients may initiate therapy at the currently recommended dosage of 100 mg twice daily, elderly patients will generally require lower maintenance dosages than nonelderly patients.

Long-term oral dosing studies with labetalol hydrochloride for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol hydrochloride using dominant lethal assays in rats and mice and exposing microorganisms according to modified Ames tests showed no evidence of mutagenesis.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypotension [see Warnings and Precautions (5.1)
• Bradycardia [see Warnings and Precautions (5.2)
• Cardiac failure [see Warnings and Precautions (5.3)
• Ischemic heart disease [see Warnings and Precautions (5.4)]
• Nonallergic bronchospasm [see Warnings and Precautions (5.5)]
• Use in patients with pheochromocytoma [see Warnings and Precautions (5.7)]
• Hepatic injury [see Warnings and Precautions (5.8)]
• Risk of severe acute hypersensitivity reaction [see Warnings and Precautions (5.9)]

Overdosage with labetalol hydrochloride causes excessive hypotension that is posture sensitive and, sometimes, excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. Treat symptoms of overdose with standard supportive care. If overdosage with labetalol hydrochloride follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. Treat symptoms of overdose with standard supportive care.

Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (<1%).

The oral LD₅₀ value of labetalol hydrochloride in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD₅₀in these species is 50 mg/kg to 60 mg/kg.

Labetalol Hydrochloride Tablets, USP contain labetalol hydrochloride, an adrenergic receptor blocking agent that has both selective alpha₁ adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance.  

Labetalol hydrochloride is a racemate chemically designated as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] benzamide monohydrochloride, and it has the following structural formula:

Labetalol hydrochloride has the empirical formula C₁₉H₂₄N₂O₃•HCl and a molecular weight of 364.9. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic labetalol.

Labetalol hydrochloride is a white or off-white crystalline powder, soluble in water.

Labetalol Hydrochloride Tablets, USP contain 100 mg, 200 mg, or 300 mg of labetalol hydrochloride and are for oral administration. The tablets also contain the inactive ingredients lactose monohydrate, magnesium stearate, pregelatinized corn starch, sodium starch glycolate.

FDA approved dissolution test specifications differ from USP.

Risk Summary 

The extensive experience with use of labetalol in pregnant women, based on published interventional and observational studies, has not identified a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Untreated hypertension during pregnancy can lead to serious adverse outcomes for the mother and the fetus (see Clinical Considerations). In animal reproductive studies, oral administration of labetalol to pregnant rats and rabbits during organogenesis at doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively, resulted in no fetal malformations; however, increased fetal resorptions were seen in both species at doses approximating the MRHD (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Consideration

Disease-Associated Materanl and/or Embryo/Fetal Risk  

Hypertension in pregnancy increase the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions  

Labetalol crosses the placenta. Newonates born to mothers who are receiving labetalol during pregnancy, may be at risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Neonates should be monitored for symptoms of hypotension, bradycardia, hypoglycemia and respiratly depression and mange accordingly.

Data

Human Data

Data from published interventional and observational studies did not demonstrate an association between major congenital malformations and the use of labetalol in pregnancy, however, most studies reported the maternal use of intravenous labetalol occurring after 20 weeks gestation. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of labetalol during pregnancy; however, these studies have methodological limitations hindering interpretation. These studies cannot definitively establish the absence of risk during pregnancy.

Animal Data  

Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD.

A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus.

Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Labetalol Hydrochloride dosage must be individualized.

The recommended initial dosage of labetalol hydrochloride is 100 mg twice daily. Adjust dosage in increments of 100 mg twice daily at 2-to 3-day intervals based on response. The recommended maintenance dosage of labetalol hydrochloride is between 200 and 400 mg twice daily.

Labetalol Hydrochloride Tablets, USP are available in the following strengths:

• 100 mg - White to off-white, biconvex, film coated tablets with “ET20” debossed on one side and non-functional scoring on the other side

• 200 mg - White to off-white, biconvex, film coated tablets with “ET21” debossed on one side and non-functional scoring on the other side

• 300 mg - White to off-white, biconvex, film coated tablets with “ET22” debossed on one side and non-functional scoring on the other side

Labetalol hydrochloride combines both selective, competitive, alpha₁-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity. The ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively.

The capacity of labetalol hydrochloride to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice cold water ("cold pressor test"). Labetalol hydrochloride's beta₁ receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta₂ receptor blockade was demonstrated by inhibition of the isoproterenol induced fall in diastolic blood pressure. Both the alpha- and beta blocking actions of orally administered labetalol hydrochloride contribute to a decrease in blood pressure in hypertensive patients. Labetalol hydrochloride consistently, in dose related fashion, blunted increases in exercise induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol hydrochloride dosing.

The effects on A-V nodal refractoriness were inconsistent. Single oral doses of labetalol hydrochloride administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV labetalol hydrochloride slightly prolonged A V nodal conduction time and atrial effective refractory period with only small changes in heart rate.

Labetalol hydrochloride produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.

Due to the alpha₁- receptor blocking activity of labetalol hydrochloride, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2.1)]. Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.

The peak effects of single oral doses of labetalol hydrochloride occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.

The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise induced tachycardia occurring at 2 hours after oral administration of labetalol hydrochloride and the logarithm of the plasma concentration.

About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.

Absorption  

Labetalol hydrochloride is absorbed with peak plasma levels occurring 1 to 2 hours after oral administration.

The relative bioavailability of Labetalol Hydrochloride Tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an IV infusion is 25%; this is due to extensive "first-pass" metabolism. There is a linear relationship between oral doses of 100 mg to 3,000 mg and peak plasma levels.

Effect of Food  

The absolute bioavailability of labetalol is increased when administered with food.

Distribution  

Labetalol has been shown to cross the placental barrier in humans. Labetalol is approximately 50% protein bound.

Elimination  

The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol are reached by about the third day of dosing.

Metabolism

Metabolism of labetalol is mainly through conjugation to glucuronide metabolites.

Excretion  

Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (<1%).

Specific Populations

Patients with Renal or Hepatic Impairment

In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased "first pass" metabolism.

Drug Interaction Studies

Tricyclic Antidepressants  

In one survey, 2.3% of patients taking labetalol hydrochloride in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol hydrochloride alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded.

Cimetidine  

Cimetidine has been shown to increase the bioavailability of labetalol hydrochloride. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol hydrochloride, special care should be used in establishing the dose required for blood pressure control in such patients.

• Monitor patients for symptomatic postural hypotension and syncope after initial dosing or dose increments. (5.1)
• Monitor heart rate and rhythm for bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest in patients receiving Labetalol Hydrochloride Tablets. (5.2)
• Beta-blockade can depress myocardial contractility and precipitating more severe failure. Avoid use in patients with overt heart failure. (5.3)
  
  Acute exacerbation of coronary artery disease upon cessation of therapy. Do not abruptly discontinue. (5.4)
• Avoid use in patients with bronchospastic disease. (5.5)
• Beta‑adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. (5.6)
• Exacerbation of pheochromocytoma: Paradoxical increases in blood pressure may occur. (5.7)
• Hepatic necrosis and death have been reported. If the patient develops signs or symptoms of liver injury, institute appropriate treatment and investigate the probable cause. (5.8)
• Do not routinely withdraw chronic beta blocker therapy prior to surgery. (5.10)

NDC 71930-035-12

Labetalol Hydrochloride Tablets, USP

100 mg

Rx only

100 tablets

Eywa-Hibrow Pharma

NDC 71930-036-12

Labetalol Hydrochloride Tablets, USP

200 mg

Rx only

100 tablets

Eywa-Hibrow Pharma

NDC 71930-037-12

Labetalol Hydrochloride Tablets, USP

300 mg

Rx only

100 tablets

Eywa-Hibrow Pharma