LABETALOL: 1,301 Adverse Event Reports & Safety Profile

Labetalol HCl in Sodium Chloride Injection, Labetalol HCl in Dextrose Injection and Labetalol Hydrochloride Injection, USP contain labetalol HCl an adrenergic receptor blocking agent that has both selective alpha1-adrenergic and nonselective beta-adrenergic receptor blocking actions. 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: 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 pale 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 Hydrochloride

Injection prefilled syringe and vial are two preservative-free, ready-to use formulations of labetalol.

Labetalol Hydrochloride

Injection is a clear, colorless to pale yellow, aqueous, sterile, isotonic solution for intravenous injection. Each milliliter of Labetalol Hydrochloride Injection, USP, contains 5 mg of labetalol HCI, 45 mg of anhydrous dextrose, 0.1 mg of edetate disodium, and citric acid monohydrate and sodium hydroxide, as necessary, to bring the solution into the pH range of 3.0 to 4.5. structural formula

AND USAGE 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.

Labetalol Hydrochloride

Tablets, USP are a beta adrenergic blocker indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1 )

DOSAGE AND ADMINISTRATION Labetalol hydrochloride injection is intended for intravenous use in hospitalized patients. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing. Patients should always be kept in a supine position during the period of intravenous drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient's ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities. Either of two methods of administration of labetalol hydrochloride injection may be used: a) repeated intravenous injections, b) slow continuous infusion.

Repeated Intravenous Injection

Initially, labetalol hydrochloride injection should be given in a dose of 20 mg labetalol HCl (which corresponds to 0.25 mg/kg for an 80 kg patient) by slow intravenous injection over a 2-minute period. Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 mg or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300 mg labetalol HCl has been injected. The maximum effect usually occurs within 5 minutes of each injection.

Slow Continuous Infusion

Labetalol hydrochloride injection is prepared for continuous intravenous infusion by diluting the contents with commonly used intravenous fluids (see below). Examples of methods of preparing the infusion solution are: The contents of either two 20 mL vials (40 mL), or one 40 mL vial, are added to 160 mL of a commonly used intravenous fluid such that the resultant 200 mL of solution contains 200 mg of labetalol hydrochloride, 1 mg per mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min. Alternatively, the contents of either two 20 mL vials (40 mL), or one 40 mL vial, of labetalol hydrochloride injection are added to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol hydrochloride, approximately 2 mg per 3 mL. The diluted solution should be administered at a rate of 3 mL/min to deliver approximately 2 mg/min. The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump. Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol hydrochloride started. The effective intravenous dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.

Blood Pressure Monitoring

The blood pressure should be monitored during and after completion of the infusion or intravenous injections. Rapid or excessive falls in either systolic or diastolic blood pressure during intravenous treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as indicator of effectiveness in addition to the response of the diastolic pressure. Initiation of Dosing with Labetalol Hydrochloride Tablets Subsequent oral dosing with labetalol hydrochloride tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with labetalol hydrochloride tablets may proceed as follows: * If needed, the total daily dose may be given in three divided doses.

Inpatient Titration Instructions Regimen Daily

Dose * 200 mg b.i.d. 400 mg 400 mg b.i.d. 800 mg 800 mg b.i.d. 1600 mg 1200 mg b.i.d. 2400 mg While in the hospital, the dosage of labetalol hydrochloride tablets may be increased at 1 day intervals to achieve the desired blood pressure reduction. For subsequent outpatient titration or maintenance dosing see Labetalol Hydrochloride Tablets Product Information DOSAGE AND ADMINISTRATION for additional recommendations. Compatibility with Commonly Used Intravenous Fluids Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Labetalol hydrochloride injection was tested for compatibility with commonly used intravenous fluids at final concentrations of 1.25 mg to 3.75 mg labetalol hydrochloride per mL of the mixture. Labetalol hydrochloride injection was found to be compatible with and stable (for 24 hours refrigerated or at room temperature) in mixtures with the following solutions: Ringers Injection, USP Lactated Ringers Injection, USP 5% Dextrose and Ringers Injection 5% Lactated Ringers and 5% Dextrose Injection 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.33% Sodium Chloride Injection, USP Labetalol hydrochloride injection was NOT compatible with 5% Sodium Bicarbonate Injection, USP. Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together.

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
• Bronchial asthma or obstructive airway disease ( 4 )
• Overt cardiac failure ( 4 )
• Greater‑than‑first‑degree heart block ( 4 )
• Cardiogenic shock ( 4 )
• Severe bradycardia ( 4 )
• Non-dihydropyridine calcium-channel antagonists ( 4 )

ADVERSE REACTIONS Most adverse effects are mild and transient and occur early in the course of treatment. In controlled clinical trials of 3 to 4 months' duration, discontinuation of labetalol HCl tablets due to one or more adverse effects was required in 7% of all patients. In these same trials, other agents with solely beta-blocking activity used in the control groups led to discontinuation in 8% to 10% of patients, and a centrally acting alpha-agonist led to discontinuation in 30% of patients. The incidence rates of adverse reactions listed in the following table were derived from multicenter, controlled clinical trials comparing labetalol HCl, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol HCl and placebo is similar, causal relationship is uncertain. The rates are based on adverse reactions considered probably drug related by the investigator. If all reports are considered, the rates are somewhat higher (e.g., dizziness, 20%, nausea, 14%, fatigue, 11%), but the overall conclusions are unchanged. Labetalol HCl (n= 227) % Placebo (n= 98) % Propranolol (n= 84) % Metoprolol (n= 49) % Body as a whole Fatigue 5 0 12 12 Asthenia 1 1 1 0 Headache 2 1 1 2 Gastrointestinal Nausea 6 1 1 2 Vomiting <1 0 0 0 Dyspepsia 3 1 1 0 Abdominal pain 0 0 1 2 Diarrhea <1 0 2 0 Taste distortion 1 0 0 0 Central and Peripheral Nervous Systems Dizziness 11 3 4 4 Paresthesias <1 0 0 0 Drowsiness <1 2 2 2 Autonomic Nervous System Nasal stuffiness 3 0 0 0 Ejaculation failure 2 0 0 0 Impotence 1 0 1 3 Increased sweating <1 0 0 0 Cardiovascular Edema 1 0 0 0 Postural hypotension 1 0 0 0 Bradycardia 0 0 5 12 Respiratory Dyspnea 2 0 1 2 Skin Rash 1 0 0 0 Special Senses Vision abnormality 1 0 0 0 Vertigo 2 1 0 0 The adverse effects were reported spontaneously and are representative of the incidence of adverse effects that may be observed in a properly selected hypertensive patient population, i.e., a group excluding patients with bronchospastic disease, overt congestive heart failure, or other contraindications to beta-blocker therapy. Clinical trials also included studies utilizing daily doses up to 2,400 mg in more severely hypertensive patients. Certain of the side effects increased with increasing dose, as shown in the following table that depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related. Labetalol HCl Daily Dose (mg) 200 300 400 600 800 Number of patients 522 181 606 608 503 Dizziness (%) 2 3 3 3 5 Fatigue 2 1 4 4 5 Nausea <1 0 1 2 4 Vomiting 0 0 <1 <1 <1 Dyspepsia 1 0 2 1 1 Paresthesia 2 0 2 2 1 Nasal stuffiness 1 1 2 2 2 Ejaculation failure 0 2 1 2 3 Impotence 1 1 1 1 2 Edema 1 0 1 1 1 Labetalol HCl Daily Dose (mg) 900 1,200 1,600 2,400 Number of patients 117 411 242 175 Dizziness (%) 1 9 13 16 Fatigue 3 7 6 10 Nausea 0 7 11 19 Vomiting 0 1 2 3 Dyspepsia 0 2 2 4 Paresthesia 1 2 5 5 Nasal stuffiness 2 4 5 6 Ejaculation failure 0 4 3 5 Impotence 4 3 4 3 Edema 0 1 2 2 In addition, a number of other less common adverse events have been reported: Body as a Whole Fever.

Cardiovascular

Hypotension, and rarely, syncope, bradycardia, heart block. Central and Peripheral Nervous Systems Paresthesia, most frequently described as scalp tingling. In most cases, it was mild and transient and usually occurred at the beginning of treatment.

Collagen Disorders

Systemic lupus erythematosus, positive antinuclear factor.

Eyes

Dry eyes.

Immunological System

Antimitochondrial antibodies. Liver and Biliary System Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.

Musculoskeletal System

Muscle cramps, toxic myopathy.

Respiratory System

Bronchospasm. Skin and Appendages Rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriaform, and facial erythema; Peyronie's disease; reversible alopecia.

Urinary System

Difficulty in micturition, including acute urinary bladder retention.

Hypersensitivity

Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions. Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6,800 patients was conducted for further safety and efficacy evaluation of this product. Results of this survey indicate that the type, severity, and incidence of adverse effects were comparable to those cited above.

Potential Adverse

Effects In addition, other adverse effects not listed above have been reported with other beta-adrenergic blocking agents.

Central Nervous System

Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on psychometrics.

Cardiovascular

Intensification of A-V block (see CONTRAINDICATIONS ).

Allergic

Fever combined with aching and sore throat, laryngospasm, respiratory distress.

Hematologic

Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.

Gastrointestinal

Mesenteric artery thrombosis, ischemic colitis. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.

Clinical Laboratory Tests

There have been reversible increases of serum transaminases in 4% of patients treated with labetalol HCl and tested and, more rarely, reversible increases in blood urea. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS 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 ). 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 )

5.1 Hypotension Monitor patients for symptomatic postural hypotension and syncope after initial dosing or dose increments with Labetalol Hydrochloride Tablets. Elderly patients are generally more likely than younger patients to experience orthostatic symptoms <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Use in Specific Populations (8.5) , Clinical Pharmacology (12.2) ]</span>.

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 Tablets.

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 Hydrochloride

Tablets in patients with overt congestive heart failure. If patients develop signs or symptoms of heart failure during administration, discontinue Labetalol Hydrochloride Tablets 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 Hydrochloride Tablets 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 Hydrochloride Tablets and manage as unstable angina.

5.5 Reactive Airway Disease and Nonallergic Bronchospasm Avoid use in patients with reactive airways disease.

If Labetalol Hydrochloride

Tablets are used, use the smallest effective dose, to minimize inhibition of endogenous or exogenous beta agonists.

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 seek emergency treatment.

5.7 Use in Patients with Pheochromocytoma Labetalol hydrochloride has been shown to be effective in lowering blood pressure and relieving 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, blood pressure when administering labetalol hydrochloride 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 Hydrochloride

Tablets in patients at high risk of anaphylactic reactions.

5.10 Major Surgery Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of labetalol’s alpha adrenergic activity has not been evaluated in this setting. A synergism between labetalol hydrochloride and halothane anesthesia has been shown [ see Drug Interactions (7.3) ].

5.11 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 a 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.

5.1 Hypotension Monitor patients for symptomatic postural hypotension and syncope after initial dosing or dose increments with Labetalol Hydrochloride Tablets. Elderly patients are generally more likely than younger patients to experience orthostatic symptoms <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Use in Specific Populations (8.5) , Clinical Pharmacology (12.2) ]</span>.

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 Tablets.

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 Hydrochloride

Tablets in patients with overt congestive heart failure. If patients develop signs or symptoms of heart failure during administration, discontinue Labetalol Hydrochloride Tablets 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 Hydrochloride Tablets 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 Hydrochloride Tablets and manage as unstable angina.

5.5 Reactive Airway Disease and Nonallergic Bronchospasm Avoid use in patients with reactive airways disease.

If Labetalol Hydrochloride

Tablets are used, use the smallest effective dose, to minimize inhibition of endogenous or exogenous beta agonists.

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 seek emergency treatment.

5.7 Use in Patients with Pheochromocytoma Labetalol hydrochloride has been shown to be effective in lowering blood pressure and relieving 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, blood pressure when administering labetalol hydrochloride 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 Hydrochloride

Tablets in patients at high risk of anaphylactic reactions.

5.10 Major Surgery Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of labetalol’s alpha adrenergic activity has not been evaluated in this setting. A synergism between labetalol hydrochloride and halothane anesthesia has been shown [ see Drug Interactions (7.3) ].

5.11 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 a 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.

PRECAUTIONS General Impaired Hepatic Function Labetalol hydrochloride injection should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.

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 hydrochloride injection. Therefore, the patient's ability to tolerate an upright position should be established before permitting any ambulation.

Intraoperative Floppy Iris

Syndrome (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 a 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. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Following Coronary Artery Bypass

Surgery In one uncontrolled study, patients with low cardiac indices and elevated systemic vascular resistance following intravenous labetalol experienced significant declines in cardiac output with little change in systemic vascular resistance. One of these patients developed hypotension following labetalol treatment. Therefore, use of labetalol should be avoided in such patients. High-Dose Labetalol Administration of up to 3 g/d as an infusion for up to 2 to 3 days has been anecdotally reported; several patients experienced hypotension or bradycardia. Jaundice or Hepatic Dysfunction (See WARNINGS. ) Information for Patients The following information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. During and immediately following (for up to 3 hours) labetalol hydrochloride injection, the patient should remain supine. Subsequently, the patient should be advised on how to proceed gradually to become ambulatory, and should be observed at the time of first ambulation. When the patient is started on labetalol hydrochloride tablets following adequate control of blood pressure with labetalol hydrochloride injection, appropriate directions for titration of dosage should be provided (see DOSAGE AND ADMINISTRATION ). As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol is warranted: While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol, dosing with labetalol hydrochloride tablets should not be interrupted or discontinued without a physician's advice. Patients being treated with labetalol hydrochloride tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction (see WARNINGS ). Also, transient scalp tingling may occur, usually when treatment with labetalol hydrochloride tablets is initiated (see ADVERSE REACTIONS ).

Laboratory Tests

Routine laboratory tests are ordinarily not required before or after intravenous labetalol. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.

Drug Interactions

Since labetalol hydrochloride injection may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and treat promptly any undesired effect from concomitant administration. In one survey, 2.3% of patients taking labetalol orally in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol alone. The contribution of each of the treatments to this adverse reaction is unknown but the possibility of a drug interaction cannot be excluded. Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal antiasthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol administered orally. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol, special care should be used in establishing the dose required for blood pressure control in such patients. 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. The anesthesiologist should be informed when a patient is receiving labetalol. Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type. When drug products that are alkaline, such as furosemide, have been administered in combination with labetalol, a white precipitate has been noted. Therefore, these drugs should not be administered in the same infusion line. Risk of Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

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 (e.g., J Chromatogr . 385:241, 1987) 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 Toxi-Lab A ® (thin-layer chromatographic assay) and Emit-d.a.u. ® (radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique. Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

Pregnancy Teratogenic Effects

Teratogenic studies have been performed with labetalol in rats and rabbits at oral doses up to approximately 6 and 4 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. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of 2 to 4 times the MRHD caused a decrease in neonatal survival. Labor and Delivery Labetalol given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.

Nursing Mothers

Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol hydrochloride injection is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

DRUG INTERACTIONS 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. Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal anti-asthmatic dose of beta-agonist bronchodilator drugs may be required. 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. Synergism has been shown between halothane anesthesia and intravenously administered labetalol hydrochloride. During controlled hypotensive anesthesia using labetalol hydrochloride 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. The anesthesiologist should be informed when a patient is receiving labetalol hydrochloride. Labetalol hydrochloride blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Risk of Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

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 hydrochloride, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g. J.

Chromatogr

385:241, 1987) should be employed in determining levels of catecholamines. Labetalol hydrochloride 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 TOXI-Lab ® A (thin-layer chromatographic assay) and Emit-d.a.u. ® (radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique. Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

Pregnancy Teratogenic Effects Pregnancy

Category C 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. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Hypotension, bradycardia, hypoglycemia and respiratory depression have been reported in infants of mothers who were treated with labetalol hydrochloride for hypertension during pregnancy. 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. Labor and Delivery Labetalol hydrochloride given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.

Nursing Mothers

Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol hydrochloride tablets are administered to a nursing woman..

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Elderly

Patients As in the general population, some elderly patients (60 years of age and older) have experienced orthostatic hypotension, dizziness or lightheadedness during treatment with labetalol. Because elderly patients are generally more likely than younger patients to experience orthostatic symptoms, they should be cautioned about the possibility of such side effects during treatment with labetalol.