Labetalol Hydrochloride

Labetalol HCl Injection is indicated in severe hypertension, to lower blood pressure. Labetalol Hydrochloride (HCl) is a beta-adrenergic blocker. Labetalol HCl injection is indicated in severe hypertension, to lower blood pressure. ( 1 )

Labetalol HCl in Sodium Chloride Injection is a clear, colorless to pale yellow solution available as: 100 mg/100 mL (1 mg/mL) in a single-dose bag 200 mg/200 mL (1 mg/mL) in a single-dose bag 300 mg/300 mL (1 mg/mL) in a single-dose bag Labetalol HCl in Dextrose Injection is a clear, colorless to pale yellow solution available as: 200 mg/200 mL (1 mg/mL) in a single-dose bag Labetalol HCl Injection is a clear, colorless to pale yellow solution available as: 10 mg/2 mL (5 mg/mL) in a single-dose prefilled syringe 20 mg/4 mL (5 mg/mL) in a single-dose vial Labetalol HCl Injection solution: 100 mg/100 mL (1 mg/mL) in sodium chloride in a single-dose bag ( 3 ) 200 mg/200 mL (1 mg/mL) in sodium chloride in a single-dose bag ( 3 ) 300 mg/300 mL (1 mg/mL) in sodium chloride in a single-dose bag ( 3 ) 200 mg/200 mL (1 mg/mL) in dextrose in a single-dose bag ( 3 ) 10 mg/2 mL (5 mg/mL) in a single-dose prefilled syringe ( 3 ) 20 mg/4 mL (5 mg/mL) in a single-dose vial ( 3 )

Labetalol Hydrochloride Injection is 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 Bronchial asthma ( 4 ) Overt cardiac failure ( 4 ) Greater-than-first-degree heart block ( 4 ) Cardiogenic shock ( 4 ) Severe bradycardia ( 4 )

Exacerbation of heart failure: Avoid use. ( 5.3 ) Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.4 ) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid since it has not been studied. ( 5.5 ) Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor ( 5.6 ) Exacerbation of pheochromocytoma: Paradoxical increases in blood pressure may occur. ( 5.7 ) Severe hepatocellular injury: Discontinue permanently for liver injury or jaundice ( 5.8 )

5.1 Hypotension 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.

5.2 Bradycardia 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.

5.3 Cardiac Failure 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.

5.4 Ischemic Heart Disease 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.

5.5 Reactive Airway Disease and Nonallergic Bronchospasm 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.

5.6 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to see medical treatment.

5.7 Use in Patients with Pheochromocytoma 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.

5.8 Hepatic Injury 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.

5.9 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions 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.

5.10 Intraoperative Floppy Iris Syndrome (IFIS) 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) ] Most common adverse events: Symptomatic postural hypotension. ( 6 ) Nausea13%, dizziness 9% ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For product Inquiry call 1-877-845-0689.

6.1 Clinical Trial Experience 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.

Beta blockers antagonize the bronchodilator effect of beta-receptor agonists. ( 7.1 ) Increase hypotension may occur with halothane anesthesia. ( 7.2 ) Nitroglycerin may result in additional hypotensive effects. ( 7.3 )

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

7.2 Anesthesia 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.

7.3 Nitroglycerin Coadministration of labetalol HCl and nitroglycerin 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 nitroglycerin, monitor patients’ blood pressure and adjust labetalol HCl injection dose as needed. In these patients, avoid initiating labetalol HCl tablets.

7.4 Calcium Channel Blockers 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.

7.5 Drug/Laboratory Test Interactions 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.

8.1 Pregnancy 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.

8.2 Lactation 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.

8.3 Females and Males of Reproductive Potential Infertility Based on the published literature, beta blockers, including labetalol, may cause erectile dysfunction and inhibit sperm motility.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use 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 ) ] .

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. Beta 2 -agonist activity has been demonstrated in animals with minimal beta 1 -agonist activity detected.