Labetalol Hcl In Sodium Chloride Injection
FDA Label NDC 0143-9365

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are indicated in severe hypertension, to lower blood pressure.

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are ready-to-use solutions and do not require further dilution. Check for leaks by squeezing the bag firmly. If leaks are found, discard solution, as sterility may be impaired. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the content of the bag unless the solution is clear (colorless to light yellow) and the seal is intact. Do not add any additional medications to the bag.

Once infusion has started, discard any remaining at 24 hours.

The recommended initial dosage is 2 mg/minute by continuous intravenous infusion, which is 2 mL/minute. Monitor blood pressure and adjust the dosage and duration of infusion accordingly.

Once supine diastolic blood pressure has begun to rise, transition to oral labetalol HCl.

The usual intravenous dose is in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients, but the safety of doses above 300 mg has not been established.

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are available as a 1 mg/mL, preservative-free, clear, colorless to light yellow solution in single-dose bags in the following configurations;

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are contraindicated in patients with:

• Bronchial asthma or obstructive airway disease.
• Severe sinus bradycardia:
• Heart block greater than first degree.
• Cardiogenic shock.
• IV administration of non-dihydropyridine calcium-channel antagonists (e.g., verapamil)
• Hypersensitivity reactions, including anaphylaxis, to labetalol

Symptomatic postural hypotension (incidence, 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol HCl injection. Before permitting any ambulation, establish patient’s ability to tolerate an upright position and observe the patient at the time of first ambulation.

Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of beta blockers. Monitor heart rate and rhythm in patients receiving labetalol hydrochloride injection.

Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Avoid labetalol HCl injection in patients with overt congestive heart failure. If patients develop signs or symptoms of heart failure during administration, discontinue labetalol and treat appropriately.

Abrupt cessation of therapy with beta blocking agents in patients with coronary artery disease, can cause exacerbations of angina pectoris and, in some cases, myocardial infarction has been reported. Therefore, even in the absence of overt angina pectoris, after the discontinuation of labetalol HCl injection observe patients for development or worsening of angina. If patient experiences angina or angina markedly worsens or if acute coronary insufficiency develops, promptly reinstitute labetalol HCl injection and manage as unstable angina.

Patients with reactive airways disease should, in general, not receive beta blockers. Labetalol HCl at the usual intravenous therapeutic doses has not been studied in patients with nonallergic bronchospastic disease. In the event of bronchospasm, stop the infusion immediately, and treat as appropriate.

In patients with hypoglycemia, or diabetic patients (especially those with labile diabetes) who are receiving insulin or other hypoglycemic agents, beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be masked. Concomitant use of beta-blockers and antidiabetic agents can enhance the glucose-lowering effect of antidiabetic agents. Monitor glycemic levels in patients receiving labetalol HCl injection.

Intravenous labetalol has been shown to lower blood pressure and relieve symptoms in patients with pheochromocytoma; higher than usual doses may be required. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, monitor blood pressure when administering intravenous labetalol HCl to patients with pheochromocytoma.

Severe hepatocellular injury occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but 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. Do not restart labetalol in patients without another explanation for the observed liver injury.

Patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions. Avoid labetalol HCl injection in patients at high risk of anaphylactic reactions.

IFIS has been observed during cataract surgery in some patients treated with alpha-1 blockers (labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. Inform the patient’s ophthalmologist to be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

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)]
• Depression of myocardial contractility in patients with overt congestive heart failure [see Warnings and Precautions (5.3)]
• Aggravation of angina [see Warnings and Precautions (5.4)]
• Significant decline in cardiac output following coronary bypass [see Warnings and Precautions (5.3)]
• Bronchospasm in patients with reactive airway disease [see Warnings and Precautions (5.5)]
• Paradoxical hypertensive responses in patients with pheochromocytoma [see Warnings and Precautions (5.7)]
• Hepatic injury [see Warnings and Precautions (5.8)]
• Acute hypersensitivity reaction [see Warnings and Precautions (5.9)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Most adverse effects have been mild and transient and, in controlled trials involving 92 patients, did not require labetalol withdrawal. Symptomatic postural hypotension (incidence, 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol HCl. Moderate hypotension occurred in 1 of 100 patients while supine. Increased sweating was noted in 4 of 100 patients, and flushing occurred in 1 of 100 patients.

The following also were reported with labetalol HCl with the incidence as noted:

Central and Peripheral Nervous Systems

Dizziness in 9%

Paresthesia, most frequently described as tingling of the scalp/skin in 7%

Gastrointestinal System

Nausea in 13%

Vomiting in 4%

Metabolic Disorders

Transient increases in blood urea nitrogen and serum creatinine levels occurred in 8%; these were associated with drops in blood pressure, generally in patients with prior renal insufficiency.

Respiratory System

Bronchospasm

In addition, a number of other less common adverse events have been reported:

Cardiovascular:

Hypotension, and rarely, syncope, bradycardia, heart block.

Liver and Biliary System

Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.

Hypersensitivity

Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions.

The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with labetalol HCl during investigational use and extensive foreign marketing experience.

Clinical Laboratory Tests

Among patients dosed with labetalol tablets, there have been reversible increases of serum transaminases in 4% of patients tested and, more rarely, reversible increases in blood urea.

Labetalol HCl antagonizes the bronchodilatory effect of beta-receptor agonist drugs; therefore, labetalol HCl is contraindicated in patients with bronchial asthma [see Contraindications (4)].

Synergism has been shown between halothane anesthesia and intravenously administered labetalol. During controlled hypotensive anesthesia using labetalol in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure.

Coadministration of labetalol HCl and nitroglycerine will have an additive effect in lowering blood pressure. Additionally, labetalol HCl blunts the reflex tachycardia produced by nitroglycerin. If labetalol is used in patients with angina pectoris on nitroglycerine, monitor patients’ blood pressure and adjust labetalol HCl injection dose as needed. In these patients, avoid initiating labetalol HCl tablets.

Coadministration of labetalol HCl with non-dihydropyrindine calcium-channel antagonists (e.g., verapamil) is contraindicated [see Contraindications (4)]. Avoid the use of labetalol in patients receiving calcium-channel antagonists.

The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol, a specific method, such as a high-performance liquid chromatographic assay with solid phase extraction should be employed in determining levels of catecholamines.

Labetalol has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods. When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirm using more specific methods, such as a gas chromatographic-mass spectrometer technique.

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 reproduction 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. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases 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. Neonates 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 respiratory depression and manage 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.

Risk Summary

Available published data report the presence oflabetalol 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.

Infertility

Based on the published literature, beta blockers, including labetalol, may cause erectile dysfunction and inhibit sperm motility.

Safety and effectiveness in pediatric patients have not been established.

Some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients [see Clinical Pharmacology (12.3)]. Geriatric patients treated with labetalol could initiate therapy at the currently recommended dose of 2 mg/minute by continuous intravenous infusion; however, lower maintenance dosages are generally required for elderly patients than nonelderly patients. Monitor blood pressure and adjust the dosage and duration of infusion accordingly until the desired response is obtained [see Dosage and Administration (2)].

Overdosage with labetalol HCl 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 HCl follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion.

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

The oral LD₅₀ value of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is greater than 2 g/kg. The intravenous LD₅₀ in these species is 50 to 60 mg/kg.

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection contain labetalol HCl an adrenergic receptor blocking agent that has both selective alpha₁-adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance. Labetalol hydrochloride (HCl) is a racemate chemically designated as 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-salicylamide monohydrochloride and it has the following structural formula:

Structural Formula (Labetalol HCl In Sodium Chloride Injection And Lab 1)

Labetalol HCl is a white or off-white crystalline powder, soluble in water. Labetalol HCl has the molecular formula C₁₉H₂₄N₂O₃•HCl and a molecular weight of 364.87. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. 

Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are two preservative-free, ready-to use formulations of labetalol. Labetalol HCl in Sodium Chloride Injection and Labetalol HCl in Dextrose Injection are clear, colorless to light yellow, aqueous, sterile, isotonic solution for intravenous injection.

Each milliliter of Labetalol HCl in Sodium Chloride Injection contains 1 mg of labetalol HCl, 7.2 mg sodium chloride, 9 mg of anhydrous dextrose, 0.02 mg of edetate disodium; and citric acid monohydrate and sodium hydroxide, as necessary, to bring the solution into the pH range of 3.5 to 4.5.

Each milliliter of Labetalol HCl in Dextrose Injection contains 1 mg of labetalol HCl, 45 mg of anhydrous dextrose, 0.02 mg of edetate disodium; and citric acid monohydrate and sodium hydroxide, as necessary, to bring the solution into the pH range of 3.5 to 4.5.

Labetalol has both competitive alpha₁-adrenergic blocking and competitive beta-adrenergic blocking activity. In man, the ratio of alpha- to beta-blockade has been estimated to be approximately 1:7 following intravenous administration. Beta₂-agonist activity has been demonstrated in animals with minimal beta₁-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane stabilizing effect has been demonstrated.

In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol HCl administered to patients in the supine position decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15-minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol HCl caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of intravenous treatment with labetalol HCl, the blood pressure rose gradually and progressively, approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients.

Similar results were obtained in the treatment of patients with severe hypertension who required urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 or 80 mg at 10 minute intervals to achieve the desired effect, or up to a cumulative dose of 300 mg.

Labetalol HCl administered as a continuous intravenous infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours (mean of 2 hours and 39 minutes), lowered the blood pressure by an average of 60/35 mmHg.

Distribution

Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the systemic circulation (<1%).

Elimination

Following intravenous infusion of labetalol, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min/kg. Steady-state plasma levels of labetalol during repetitive dosing are reached following 22 to 28 hours of continuous infusion.

Metabolism

The 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. The metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces.

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.

Geriatric Patients

Some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients.

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

Labetalol HCl in Sodium Chloride Injection is a preservative-free, clear, colorless to light yellow sterile solution that is available in a single-dose single-port bag with an aluminum overwrap. The container closure is not made with natural rubber latex. It is available in the following presentations:

Labetalol HCl in Dextrose Injection is a preservative-free, clear, colorless to light yellow sterile solution that is available in a single-dose single-port bag with an aluminum overwrap. The container closure is not made with natural rubber latex. It is available in the following presentations:

Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light. DO NOT REMOVE FROM OVERWRAP UNTIL READY TO USE.

• Advise patients to remain supine and to proceed gradually in becoming ambulatory during and immediately following infusion (for up to 3 hours) of labetalol HCl injection.
• Inform patient to notify their healthcare provider if they experience symptoms of hypotension.
  
• Advise patients to not interrupt or discontinue their labetalol HCl tablets without discussing with their healthcare provider and report any signs or symptoms of impending cardiac failure or hepatic dysfunction

Rx Only

Manufactured by

HIKMA FARMACÊUTICA (PORTUGAL), S.A.

Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL

Distributed by

Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922

PIN539-WES/2

NDC 0143-9363-01      Rx only    100 mL
Labetalol Hydrochloride
in 0.72% Sodium Chloride Injection
100 mg per 100 mL (1 mg/mL)
For Intravenous Infusion     Ready to Use
Sterile, nonpyrogenic     Single-Dose Flexible Container

Bag 9363 (Labetalol HCl In Sodium Chloride Injection And Lab 2)

NDC 0143-9364-01      Rx only      200 mL
Labetalol Hydrochloride
in 0.72% Sodium Chloride Injection
200 mg per 200 mL
(1 mg/mL)
For Intravenous Infusion     Ready to Use
Sterile, nonpyrogenic     Single-Dose Flexible Container

Bag 9364 (Labetalol HCl In Sodium Chloride Injection And Lab 3)

NDC 0143-9365-01      Rx only     300 mL
Labetalol Hydrochloride
in 0.72% Sodium Chloride Injection
300 mg per 300 mL
(1 mg/mL)
For Intravenous Infusion     Ready to Use
Sterile, nonpyrogenic     Single-Dose Flexible Container

5

Bag 9365 (Labetalol HCl In Sodium Chloride Injection And Lab 4)

NDC 0143-9366-01     Rx only    200 mL
Labetalol Hydrochloride
in 5% Dextrose Injection
200 mg per 200 mL
(1 mg/mL)
For Intravenous Infusion     Ready to Use
Sterile, nonpyrogenic     Single-Dose Flexible Container

Bag 9366 (Labetalol HCl In Sodium Chloride Injection And Lab 5)