Labetalol Hydrochloride

1 INDICATIONS 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 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 AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. (twice daily) every 2 or 3 days. The usual maintenance dosage of labetalol hydrochloride tablets, USP is between 200 mg and 400 mg twice daily. Since the full antihypertensive effect of labetalol hydrochloride tablets, USP is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary. Patients with severe hypertension may require from 1200 mg to 2400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered b.i.d. (twice daily), the same total daily dose administered t.i.d. (three times daily) may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg b.i.d. (twice daily). When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol hydrochloride tablets, USP dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets, USP are usually lower in patients also receiving a diuretic. When transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets, USP should be introduced as recommended and the dosage of the existing therapy progressively decreased. Elderly Patients As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. (twice daily) as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 mg and 200 mg b.i.d. (twice daily).

3 DOSAGE FORMS & STRENGTHS Labetalol Hydrochloride Tablets, USP are available in the following strengths: • Labetalol hydrochloride tablets, USP 100 mg, White to off white colored, round shape, biconvex film coated tablets debossed with 'I 33' on one side and score line on other side. • Labetalol hydrochloride tablets, USP 200 mg, White to off white colored, round shape, biconvex film coated tablets debossed with 'I 34' on one side and score line on other side. • Labetalol hydrochloride tablets, USP 300 mg, White to off white colored, round shape, biconvex film coated tablets debossed with 'I 35' on one side and score line on other side. Tablets: 100 mg, 200 mg, and 300 mg tablets ( 3 )

4 CONTRAINDICATIONS 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 Paresthesia <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) 200 300 400 600 800 900 1,200 1,600 2,400 Number of patients 522 181 606 608 503 117 411 242 175 Dizziness (%) 2 3 3 3 5 1 9 13 16 Fatigue 2 1 4 4 5 3 7 6 10 Nausea <1 0 1 2 4 0 7 11 19 Vomiting 0 0 <1 <1 <1 0 1 2 3 Dyspepsia 1 0 2 1 1 0 2 2 4 Paresthesia 2 0 2 2 1 1 2 5 5 Nasal stuffiness 1 1 2 2 2 2 4 5 6 Ejaculation failure 0 2 1 2 3 0 4 3 5 Impotence 1 1 1 1 2 4 3 4 3 Edema 1 0 1 1 1 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, psoriasform, 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 anaphylact …

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-LabA ® (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), r …

8 USE IN SPECIFIC POPULATIONS 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 reproductive studies, oral administration of labetalol to pregnant rats and rabbits during organogenesis at doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively, resulted in no fetal malformations; however, increased fetal resorptions were seen in both species at doses approximating the MRHD (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Consideration Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increase the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Labetalol crosses the placenta. Newonates born to mothers who are receiving labetalol during pregnancy, may be at risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Neonates should be monitored for symptoms of hypotension, bradycardia, hypoglycemia and respiratly depression and mange accordingly. Data Human Data Data from published interventional and observational studies did not demonstrate an association between major congenital malformations and the use of labetalol in pregnancy, however, most studies reported the maternal use of intravenous labetalol occurring after 20 weeks gestation. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of labetalol during pregnancy; however, these studies have methodological limitations hindering interpretation. These studies cannot definitively establish the absence of risk during pregnancy. Animal Data Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival. 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Although elderly patients may initiate therapy at the currently recommended dosage of 100 mg twice daily, elderly patients will generally require lower maintenance dosages than nonelderly patients.

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

DESCRIPTION Labetalol hydrochloride tablets, USP are an adrenergic receptor blocking agent that has both selective alpha 1 -adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance. Labetalol hydrochloride, USP 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 structure: Labetalol hydrochloride, USP has the molecular formula C 19 H 24 N 2 O 3 •HCl and a molecular weight of 364.87. 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, USP is a white or off-white crystalline powder, soluble in water. Labetalol hydrochloride tablets, USP, for oral administration, contain 100 mg, 200 mg or 300 mg labetalol hydrochloride, USP. In addition, each 100 mg tablet contains the following inactive ingredients: anhydrous lactose, carnauba wax, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch (corn), red iron oxide, titanium dioxide and yellow iron oxide. In addition, each 200 mg tablet contains the following inactive ingredients: anhydrous lactose, carnauba wax, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, pregelatinized starch (corn), titanium dioxide and triacetin. In addition, each 300 mg tablet contains the following inactive ingredients: anhydrous lactose, carnauba wax, FD&C Blue #2, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch (corn), titanium dioxide. Labetalol hydrochloride, USP 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 structur

OVERDOSAGE Overdosage with labetalol hydrochloride causes excessive hypotension that is posture sensitive and, sometimes, excessive bradycardia. Patients should be placed supine and their legs raised, if necessary, to improve the blood supply to the brain. If overdosage with labetalol hydrochloride follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. The following additional measures should be employed if necessary: Excessive bradycardia Administer atropine or epinephrine. Cardiac failure Administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. Hypotension Administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. Bronchospasm Administer epinephrine and/or an aerosolized beta 2 -agonist. Seizures Administer diazepam. In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 mg to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg per hour that can be reduced as the patient improves). Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (less than 1%). The oral LD 50 value of labetalol hydrochloride in the mouse is approximately 600 mg/kg and in the rat is greater than 2 g/kg. The intravenous LD 50 in these species is 50 mg/kg to 60 mg/kg.

HOW SUPPLIED Labetalol Hydrochloride Tablets USP for oral administration are available as: Labetalol Hydrochloride Tablets USP, 100 mg are yellow colored, round, biconvex, film-coated tablets debossed with "7" and "98" on either side of score line on one side and plain on other side and are supplied as: NDC 68382-798-06 in bottle of 30 tablets NDC 68382-798-16 in bottle of 90 tablets NDC 68382-798-01 in bottle of 100 tablets NDC 68382-798-05 in bottle of 500 tablets Labetalol Hydrochloride Tablets USP, 200 mg are white to off white colored, round, biconvex, film-coated tablets debossed with "7" and "99" on either side of score line on one side and plain on other side and are supplied as: NDC 68382-799-06 in bottle of 30 tablets NDC 68382-799-16 in bottle of 90 tablets NDC 68382-799-01 in bottle of 100 tablets NDC 68382-799-05 in bottle of 500 tablets Labetalol Hydrochloride Tablets USP, 300 mg are light green colored, round, biconvex, beveled edge, film-coated tablets debossed with "800" on one side and plain on other side and are supplied as: NDC 68382-800-06 in bottle of 30 tablets NDC 68382-800-16 in bottle of 90 tablets NDC 68382-800-01 in bottle of 100 tablets NDC 68382-800-05 in bottle of 500 tablets Labetalol Hydrochloride Tablets USP should be Stored at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure as required. To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. This product's package insert may have been updated. For current package insert, please visit www.zydususa.com Manufactured by: Zydus Lifesciences Ltd. Matoda, Ahmedabad, India Distributed by: Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 Rev.: 03/26