LABETALOL HYDROCHLORIDE

Labetalol Hydrochloride Tablets 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 C 19 H 24 N 2 O 3 •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 contain 100 mg, 200 mg, or 300 mg of labetalol hydrochloride and are for oral administration. The tablets also contain the inactive ingredients ingredients lactose monohydrate, corn starch, colloidal silicon dioxide, magnesium stearate, sodium starch glycolate, hypromellose, titanium dioxide, macrogol and polysorbate 80. FDA approved dissolution test specifications differ from USP. 111

INDICATIONS & 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 may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics. Labetalol Hydrochloride Tablets 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 & ADMINISTRATION • 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) 2.1 Recommended Dosage 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 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 )

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 ) ] • Most commonly observed adverse reactions: fatigue, nausea, dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. In controlled clinical trials of 3 to 4 months' duration, discontinuation of Labetalol Hydrochloride Tablets due to one or more adverse effects was required in 7% of all patients. The incidence rates of adverse reactions listed in Table 1 were derived from multicenter, controlled clinical trials comparing labetalol hydrochloride and placebo over treatment periods of 3 and 4 months. Table 1: Adverse Reactions Occurring in at Least 2% of Patients and More Frequent on Labetalol Labetalol HCl (n = 227) Placebo (n = 98) Body as a whole Fatigue 5% 0% Headache 2% 1% Gastrointestinal Nausea 6% 1% Dyspepsia 3% 1% Central and peripheral nervous systems Dizziness 11% 3% Autonomic nervous system Nasal stuffiness 3% 0% Respiratory Dyspnea 2% 0% Special senses Vertigo 2% 1% 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 Table 2 that depicts the entire US therapeutic trials data base for adverse reactions that are clearly or possibly dose related.

• 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 ) See 17 for PATIENT COUNSELING INFORMATION. 7.1 Negative Chronotropes Digitalis glycosides, diltiazem, verapamil, and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use with negative chronotropes can increase the risk of bradycardia or hypotension [see Warnings and Precautions (5.2)]. Coadministration of labetalol HCl with non-dihydropyridine calcium-channel antagonists (e.g., verapamil) is contraindicated [see Contraindications (4)]. 7.2 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)]. 7.3 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. 7.4 Nitroglycerin 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 HCl is used in patients with angina pectoris on nitroglycerin, monitor patients’ blood pressure and adjust labetalol dose as needed. In these patients, avoid initiating Labetalol Hydrochloride Tablets. 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.