`
`PHYSICIANS
`See
`RsrareNe=
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 001
`
`

`

`2000
`
`
`
`
` PDR
`eh
`
`EDITION
`
`
`
`
`PHYSICIANS
`OK
`REFERENCE
`
`
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`Director of Sales: Dikran N. Barsamian
`
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales:Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Managerof Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy,Ill
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`
`
`oe Copyright©2000 and published by Medical Economics Company,Inc. at Montvale, NJ 07645-1742. All rights reserved. Noneofthe contentofthis publication may
`
`be reproduced, stored in a retrieval system, resold,redistributed, or transmitted in any form or by any means(electronic, mechanical, photocopying, recording, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDR For Ophthalmology®, Pocket PDR®, and The PDR® Family
`Guide to Prescription Drugs® are registered trademarks used herein underlicense. PDR For Nonprescription Drugs and Dietary Supplements™, PDR Companion Guide™,
`PDR?for Herbal Medicines™, PDR® Medical Dictionary™, PDR® Nurse's Drug Handbook™, PDR® Nurse's Dictionary™, The PDR® Family Guide Encyclopedia of Medical
`Care™, The PDR® Family Guide to Natural Medicines and Healing Therapies™, The PDR® Family Guide to CommonAilments™, The PDR® Family Guide to Over-the-
`Counter Drugs™, and PDR?® Electronic Library™ are trademarks used herein underlicense.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler; Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: Jonn R. Ware; Senior Vice President, Internet Strategies: Raymond Zoeller
`
`3) Printed on recycled paper
`
`ISBN: 1-56363-330-2
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 002
`
`

`

`572/ASTRAZENECA
`PHYSICIANS’ DESK REFERENCE®
`ee
`Tenoretic—Cont.
`
`DESCRIPTION
`TENORMIN (atenolol), a synthetic, beta,-selective (cardi-
`oselective) adrenoreceptor blocking agent, may be chemi-
`cally described as benzeneacetamide, 4-[2'-hydroxy-3'-[(1-
`methylethyl)amino]propoxy]-. The molecular and structural
`formulasare:
`C,,H2,N203
`
`OH
`
`OCH2CHCHNHCH (CHs)2
`
`CH2CONH2
`
`
`
`Cessation of Therapy with TENORMIN: Patients j
`with coronary artery disease, who are being treated |
`with TENORMIN,should be advised against abrupt
`|
`discontinuation oftherapy. Severe exacerbation of an-
`|
`gina and the occurrence of myocardial infarction and |
`ventricular arrhythmias have been reported in an- |
`ginapatients following the abrupt discontinuation of —
`therapy with beta blockers. The last two complica-
`}
`tions may occur with or without preceding exacerba-
`—
`tion of the angina pectoris. As with other beta block-
`|
`ers, when discontinuation of TENORMINis planned,
`_
`the patients should be carefully observed and advised
`to limit physical activity to a minimum.If the angina i
`worsensor acute coronary insufficiency develops,it is
`recommenced that TENORMINbe promptly reinsti-
`tuted, at least temporarily. Because coronary artery —
`disease is common and maybe unrecognized, it may _
`be prudent not to discontinue TENORMIN therapy —
`abruptly even in patients treated only for hyperten- |
`sion. (See DOSAGE AND ADMINISTRATION.)
`
`Concomitant Use of Calcium Channel Blockers: Bradycar-
`dia and heart block can occur and theleft ventricular end
`diastolic pressure can rise when beta blockers are adminis-
`tered with verapamil or diltiazem. Patients with pre-exist-
`ing conduction abnormalities or left ventricular dysfunction
`are particularly susceptible. (See PRECAUTIONS.)
`Bronchospastic Diseases:
`PATIENTS WITH BRONCHO-
`SPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE
`BETA BLOCKERS.Becauseofits relative beta, selectivity.
`however, TENORMIN maybeusedwith cautionin patients
`with bronchospastic disease who do not respond to, or
`cannottolerate, other antihypertensive treatment. Since
`beta, selectivity is not absolute, the lowest possible dose
`of TENORMINshould be used with therapyinitiated at 50
`mg and a beta,-stimulating agent (bronchodilator) should
`be madeavailable. If dosage must be increased, dividing
`the dose should be considered in order to achieve lower
`peakbloodlevels.
`It is not advisable to with
`Anesthesia and Major Surgery:
`draw beta-adrenoreceptor blocking drugs prior to surgery i=
`Information will be superseded by supplements and u>SBTAICON PHARMA LTD (IPR2020-0 ] 263) Ex. ] 020, p. 003
`
`
`
`—
`
`HOW SUPPLIED
`TENORETIC 50 Tablets (atenolol 50 mg and chlorthalidone
`25 mg), NDC 0310-0115, (white, round, biconvex, uncoated
`tablets with TENORETICon one side and 115 on the other
`side, bisected) are supplied in bottles of 100 tablets.
`TENORETIC 100 Tablets (atenolol 100 mg and chlorthali-
`done 25 mg), NDC 0310-0117, (white, round, biconvex, un-
`coated tablets with TENORETICon oneside and 117 on the
`other side) are supplied in bottles of 100 tablets.
`Store at controlled room temperature, 20-25°C (68-77°F)
`[see USP]. Dispense in well-closed, light-resistant contain-
`ers.
`ZENECA
`Manufacturedfor:
`Zeneca Pharmaceuticals
`A Business Unit of Zeneca Inc.
`Wilmington, Delaware 19850-5437
`By: IPR Pharmaceuticals, Inc.
`Carolina, Puerto Rico 00984-1967
`SIC 64112-01
`Rev D 01/99
`Shown in Product Identification Guide, page 305
`
`TENORMIN® Tablets
`TENORMINGI.V.Injection
`[ten-or 'min ]
`(atenolol)
`
`R
`
`macological tests, beta-adrenoreceptor blocking activity of TENORMIN has been demonstrated by: (1) reduction in
`clinical judgment suggests, however, that patients who are dependent on sympathetic stimulation for maintenance of
`
`adequate cardiac output and blood pressure are not good
`resting and exercise heart rate and cardiac output, (2) re-
`candidates for beta blockade. Indeed, the trial protocol re-
`duction of systolic and diastolic blood pressure at rest and
`flected that judgment by excluding patients with blood pres-
`on exercise, (3) inhibition of isoproterenol induced tachycar-
`sure consistently below 100 mm Hgsystolic. Theoverall re-
`dia, and (4) reduction in reflex orthostatic tachycardia.
`sults of the study are compatible with the possibility that
`A significant beta-blocking effect of TENORMIN,as mea-
`patients with borderline blood pressure (less than 120 mm
`sured by reduction of exercise tachycardia, is apparent
`Hgsystolic), especially if over 60 years ofage, arelesslikely
`within one hour following oral administration of a single
`to benefit.
`-
`dose. This effect is maximal at about 2 to 4 hours, and per-
`The mechanism through which atenolol improves survival
`sists for at least 24 hours. Maximum reduction in exercise
`in patients with definite or suspected acute myocardial in-
`tachycardia occurs within 5 minutes of an intravenous dose.
`farction is unknown,as is thecasefor other beta blockers in
`For both orally and intravenously administered drug, the _
`the postinfarction setting. Atenolol, in addition to its effects
`duration of action is dose related and also bears a linear
`on survival, has shown otherclinical benefits including re-
`relationship to the logarithm of plasma TENORMIN con-
`duced frequency of ventricular premature beats, reduced
`centration. The effect on exercise tachycardia of a single 10
`chest pain, and reduced enzymeelevation.
`mg intravenous dose is largely dissipated by 12 hours,
`INDICATIONS AND USAGE
`whereasbeta-blocking activity of single oral doses of 50 mg
`Hypertension: TENORMINis indicated in the manage-
`and 100 mgis still evident beyond 24 hours following ad-
`ment of hypertension. It may be used alone or concomi-
`ministration. However, as has been shown forall beta-
`tantly with other antihypertensive agents, particularly with
`blocking agents, the antihypertensive effect does not appear
`a thiazide-type diuretic.
`to be related to plasmalevel.
`Angina Pectoris Due to Coronary Atherosclerosis:
`In normalsubjects, the beta,-selectivity of TENORMINhas
`TENORMINis indicated for the long-term management of
`been shown by its reduced ability to reverse the beta,-
`patients with anginapectoris.
`mediated vasodilating effect of isoproterenol as compared to
`Acute Myocardial Infarction: TENORMINis indicated in
`equivalent beta-blocking doses of propranolol. In asthmatic
`the management of hemodynamically stable patients with
`patients, a dose of TENORMINproducing a greater effect
`definite or suspected acute myocardial infarction to reduce
`cardiovascular mortality. Treatment can beinitiated as soon
`on resting heart rate than propranolol resulted in muchless
`as the patient’s clinical condition allows. (See DOSAGE
`increase in airway resistance. In a placebo controlled com-
`AND ADMINISTRATION, CONTRAINDICATIONS, AND
`parison of approximately equipotent oral doses of several
`WARNINGS.) In general, there is no basis for treating pa-
`beta blockers, TENORMINproduceda significantly smaller
`tients like those who were excluded from the ISIS-1 trial
`decrease of FEV, than nonselective beta blockers such as
`(blood pressure less than 100 mm Hgsystolic, heart rate
`propranolol and, unlike those agents, did not inhibit bron-
`less than 50 bpm)or have other reasonsto avoid beta block-
`chodilation in response to isoproterenol.
`ade. As noted above, some subgroups(eg, elderly patients
`Consistent with its negative chronotropiceffect due to beta
`with systolic blood pressure below 120 mm Hg) seemed less
`blockade of the SA node, TENORMINincreases sinuscycle
`likely to benefit.
`length and sinus node recovery time. Conduction in the AV
`CONTRAINDICATIONS
`node is also prolonged. TENORMINis devoid of membrane
`stabilizing activity, and increasing the dose well beyond
`TENORMINis contraindicated in sinus bradycardia, heart
`that producing beta blockade does not further depress my-
`block greater than first degree, cardiogenic shock, and overt
`ocardial contractility. Several studies have demonstrated a
`cardiac failure. (See WARNINGS.)
`moderate (approximately 10%) increase in stroke volume at
`WARNINGS
`rest and during exercise.
`Cardiac Failure: Sympathetic stimulation is necessary in
`In controlled clinical trials, TENORMIN,given as a single
`supporting circulatory function in congestive heart failure,
`daily oral dose, was aneffective antihypertensive agent pro-
`and beta blockadecarries the potential hazard of further de-
`viding 24-hour reduction of blood pressure. TENORMIN
`pressing myocardial contractility and precipitating more se-
`has been studied in combination with thiazide-type diuret-
`vere failure. In patients who have congestive heart failure
`ics, and the blood pressure effects of the combination are
`controlled by digitalis and/or diuretics, TENORMINshould
`approximately additive. TENORMIN is also compatible
`be administered cautiously. Both digitalis and atenolol slow
`with methyldopa, hydralazine, and prazosin, each combina-
`AV conduction:
`tion resulting in a larger fall in blood pressure than with the
`In patients with acute myocardialinfarction, cardiac failure
`single agents. The dose range of TENORMIN is narrow and
`Atenolol (free base) has a molecular weight of 266. It is a
`increasing the dose beyond 100 mgoncedailyis not associ-
`which is not promptly and effectively controlled by 80 mg of
`relatively polar hydrophilic compound with a watersolubil-
`ated with increased antihypertensive effect. The mecha-
`intravenous furosemide or equivalent therapyis a contrain-
`ity of 26.5 mg/mL at 37°C andalogpartition coefficient (oc-
`dication to beta-blocker treatment.
`nisms of the antihypertensive effects of beta-blocking
`tanol/ water) of 0.23. It is freely soluble in IN HCl (300
`In Patients Without a History of Cardiac Failure: Contin-
`agents have not been established. Several possible mecha-
`mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at
`25°C).
`nisms have been proposed and include: (1) competitive an-
`ued depression of the myocardium with beta-blocking
`agents over a period of time can, in somecases, lead to car-
`tagonism of catecholamines at peripheral (especially car-
`TENORMINis available as 25, 50 and 100 mgtablets for
`diac) adrenergic neuronsites, leading to decreased cardiac
`diac failure. At the first sign or symptom of impendingcar-
`oral administration. TENORMIN for parenteral adminis-
`diac failure, patients should be fully digitalized and/or be
`output, (2) a central effect leading to reduced sympathetic
`tration is available as TENORMINLV. Injection containing
`outflow to the periphery, and (3) suppression of renin activ-
`given a diuretic and the responseobservedclosely. If cardiac
`5 mgatenolol in 10 mLsterile, isotonic, citrate-buffered,
`failure continues despite adequate digitalization and diure-
`aqueous solution. The pH ofthe solution is 5.5-6.5.
`ity. The results from long-term studies have not shown any
`sis, TENORMINshould be withdrawn. (SEE DOSAGE AND
`diminution of the antihypertensive efficacy of TENORMIN
`Tnactive Ingredients: TENORMIN Tablets: Magnesium
`ADMINISTRATION.)
`with prolonged use.
`stearate, microcrystalline cellulose, povidone, sodium
`By blocking the positive chronotropic and inotropiceffects of
`starch glycolate. TENORMIN L.V. Injection: Sodium chlo-
`catecholamines and by decreasing blood pressure, atenolol
`ride for isotonicity andcitric acid and sodium hydroxide to
`adjust pH.
`generally reduces the oxygen requirementsof the heart at
`any givenlevel of effort, making it useful for many patients
`CLINICAL PHARMACOLOGY
`in the long-term management of angina pectoris. On the
`TENORMINis a beta,-selective (cardioselective) beta-ad-
`other hand, atenolol can increase oxygen requirements by
`renergic receptor blocking agent without membranestabi-
`increasing left ventricular fiber length and end diastolic
`lizing or intrinsic sympathomimetic (partial agonist) activi-
`pressure, particularly in patients with heart failure.
`ties. This preferential effect is not absolute, however, and at
`In a multicenterclinical trial (ISIS-1) conducted in 16,027
`higher doses, TENORMINinhibits beta,-adrenoreceptors,
`patients with suspected myocardial infarction, patients
`chiefly located in the bronchial and vascular musculature.
`presenting within 12 hours (mean = 5 hours)after the onset
`Pharmacokinetics and Metabolism:
`In man,absorption of
`of pain were randomizedto either conventional therapy plus
`an oral doseis rapid and consistent but incomplete. Approx-
`TENORMIN(n = 8,037), or conventional therapy alone (n =
`imately 50% of an oral dose is absorbed from the gastroin-
`7,990). Patients with a heart rate of <50 bpm orsystolic
`testinal tract, the remainder being excreted unchanged in
`blood pressure <100 mm Hg, or with other contraindica-
`the feces. Peak bloodlevels are reached between two (2) and
`tions to beta blockade, were excluded. Thirty-eight percent
`four (4) hours after ingestion. Unlike propranolol or meto-
`of each group were treated within 4 hours of onset of pain.
`prolol, but like nadolol, TENORMIN undergoeslittle or no
`The mean time from onset of pain to entry was 5.0 + 2.7
`metabolism by theliver, and the absorbed portion is elimi-
`hours in both groups. Patients in the TENORMIN group
`nated primarily by renal excretion. Over 85% of an intrave-
`were to receive TENORMIN L.V. Injection 5-10 mg given
`nous dose is excreted in urine within 24 hours compared
`over 5 minutes plus TENORMIN Tablets 50 mg every 12
`with approximately 50% for an oral dose. TENORMINalso
`hoursorally on thefirst study day (the first oral dose ad-
`differs from propranolol in that only a small amount (6%
`ministered about 15 minutesafter the IV dose) followed by
`16%)is boundto proteins in the plasma. This kinetic profile
`either TENORMIN Tablets
`100 mg once daily or
`results in relatively consistent plasma drug levels with
`TENORMINTablets 50 mg twice daily on days 2-7. The
`about a fourfold interpatient variation.
`groups were similar in demographic and medical history.
`The elimination half-life of oral TENORMIN is approxi-
`characteristics and in electrocardiographic evidence of my-
`mately 6 to 7 hours, and there is no alteration of the kinetic
`ocardial infarction, bundle branch block, and first degree
`profile of the drug by chronic administration. Following in-
`atrioventricular block at entry.
`:
`travenous administration, peak plasma levels are reached
`During the treatment period (days 0-7), the vascular mor-
`within 5 minutes. Declines from peaklevels are rapid (5- to
`tality rates were 3.89% in the TENORMINgroup (313
`10-fold) during the first 7 hours; thereafter, plasma levels
`deaths) and 4.57% in the control group (365 deaths). This
`decay with a half-life similar to that of orally administered
`absolute difference in rates, 0.68%, is statistically signifi-
`cant at the P <0.05level. The absolute difference translates
`drug. Following oral doses of 50 mg or 100 mg,both beta-
`blocking and antihypertensive effects persist for at least 24
`into a proportional reduction of 15% (3.89-4.57/4.57 =
`—0.15). The 95% confidence limits are 1%-27%. Mostof the
`hours. When renal function is impaired, elimination of
`TENORMINis closely related to the glomerularfiltration
`difference was attributed to mortality in days 0-1
`rate; significant accumulation occurs when thecreatinine
`(TENORMIN—121 deaths; control—171 deaths).
`clearance falls below 35 mL/min/1.73m?. (See DOSAGE
`Despite the large size of the ISIS-1 trial, it is not possible to
`AND ADMINISTRATION).
`identify clearly subgroups of patients most likely or least
`Pharmacodynamics:
`In standard animal or human phar-
`likely to benefit from early treatment with atenolol. Good
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 003
`
`

`

`Volunteered
`(US Studies)
`:
`
`Placebo
`(n = 206)
`%
`
`Atenolol
`(n = 164)
`%
`
`OO
`
`ASTRAZENECA/573
`Total—Volunteered
`and Elicited
`(Foreign + US Studies)
`Atenolol
`Placebo
`(n = 399)
`(n.= 407)
`%
`%
`
`00
`
`1 0
`
`1
`
`oNow
`DSOSKWORNAa
`
`
`
`pertensive dose*) resultedin increased incidences of benign
`
`PRODUCT INFORMATION
`the majority of patients. However, care should be taken
`when using anesthetic agents such as those which may de-
`press the myocardium.Vagal dominance,ifit occurs, may be
`corrected with atropine (1-2 mg IV).
`Additionally, caution should be used when TENORMINLV.
`Injection is administered concomitantly with such agents.
`TENORMIN,like. other beta blockers, is a competitive in-
`hibitor of beta-receptor agonists andits effects on the heart
`can be reversed by administration of such agents: eg, dob-
`utamine or isoproterenol with caution (see section on
`OVERDOSAGE).
`Diabetes and Hypoglycemia: TENORMINshould be used
`with caution in diabetic patients if a beta-blocking agent is
`required. Beta blockers may mask tachycardia occurring
`with hypoglycemia, but other manifestations such as dizzi-
`ness and sweating maynot be significantly affected. At rec-
`ommended doses TENORMIN does not potentiate insulin-
`induced hypoglycemia and, unlike nonselective beta block-
`ers, does not delay recovery of blood glucose to normal
`levels.
`Thyrotoxicosis: Beta-adrenergic blockade may. mask cer-
`tain clinical signs(eg, tachycardia) of hyperthyroidism, Pa-
`tients suspected of having thyroid disease should be moni-
`tored closely when adminstering TENORMINLV. Injection.
`Abrupt withdrawalofbeta blockade mightprecipitate a thy-
`roid storm; therefore, patients suspected of developing thy-
`rotoxicosis from whom TENORMIN therapy is to be with-
`drawn should be monitored closely. (See DOSAGE AND AD-
`MINISTRATION.)
`PregnancyandFetal Injury: Atenolol can causefetal harm
`when administered to a pregnant woman.Atenolol crosses
`theplacental barrier and appearsin cord blood. Administra-
`tion ofatenolol, starting in the second trimester of preg-
`nancy, hasbeen associated with the birth ofinfants that are
`small for gestational age. No studies have been performed
`on theuseof atenololin the first trimester and the possibil-
`ity of fetal injury cannot be excluded. If this drug is used
`during pregnancy, orif the patient becomes pregnant while
`taking this drug, the patient should be apprised of the po-
`tential hazard to the fetus.
`Atenolol has been shown to produce a dose-related increase
`in embryo/fetal resorptions in rats at doses equal to or
`greater than 50 mg/kg/day or 25 or more times the maxi-
`mum recommended human antihypertensive dose*. Al-
`though similar effects were not seen in rabbits, the com-
`pound was not evaluated in rabbits at doses above 25 mg/
`ke/day or 12.5 times the maximum recommended human
`antihypertensive dose*,
`*Based on the maximum doseof 100 mg/day ina 50 kg pa-
`tient.
`PRECAUTIONS
`General: Patients already on a beta blocker must be eval-
`uated carefully before TENORMINis administered. Initial
`and subsequent TENORMIN dosages can be adjusted down-
`ward depending on clinical observations including pulse
`and blood pressure. TENORMIN may aggravateperipheral
`arterial circulatory disorders.
`impaired Renal Function: The drug should be used with
`caution in patients with impaired renal function. (See DOS-
`AGE AND ADMINISTRATION.)
`DrugInteractions: Catecholamine-depleting drugs(eg, re-
`serpine) may have an additive effect whengiven with beta-
`blocking agents. Patients treated with TENORMIN plus a
`catecholamine depletor should therefore be closely observed
`for evidence of hypotension and/or marked bradycardia
`which may produce vertigo, syncope or postural hypo-
`tension.
`Calcium channel blockers may also have an additiveeffect
`when given with TENORMIN (See WARNINGS.).
`Beta blockers may exacerbate the rebound hypertension
`which can follow the withdrawal of clonidine. If the two
`drugs are coadministered, the beta blocker should be with-
`drawn several days before the gradual withdrawalofcloni-
`dine. If replacing clonidine by beta-blocker therapy, the in-
`troduction of beta blockers should be delayed for several
`days after clonidine administration has stopped.
`Caution should be exercised with TENORMINLV. Injection
`when given in close proximity with drugs that may also
`have a depressanteffect on myocardial contractility. On rare
`occasions, concomitantuse ofintravenous beta blockers and
`intravenous verapamil hasresulted in serious adverse reac-
`tions, especially in patients with severe cardiomyopathy,
`congestive heart failure, or recent myocardial infarction,
`Information on concurrent usage ofatenolol andaspirin is
`limited. Data from several studies, ie, TIMI-II, ISIS-2, cur-
`rently do not suggest any clinical interaction between as-
`pirin andbeta blockers in the acute myocardial infarction
`setting.
`While taking beta blockers, patients with a history of ana-
`phylactic reaction toa variety of allergens may have a more
`severe reaction on repeated challenge, either accidental, di-
`agnostic or therapeutic. Such patients may be-unresponsive
`to the usual doses of epinephrine used to treat the allergic
`reaction.
`:
`v2
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`Two long-term (maximum dosing duration. of 18 or 24
`months) rat studies and one long-term. (maximum. dosing
`duration of 18 months) mouse study, each employing dose
`levels as high as 300 mg/kg/day or 150 times the maximum
`recommended human antihypertensive dose,* did not. indi-
`cate a carcinogenic potential of atenolol. A third (24 month)
`rat study, employing doses of 500 and 1,500 mg/kg/day (250
`and 750 times the maximum recommended human antihy-
`
`CARDIOVASCULAR
`Bradycardia
`Cold Extremities
`Postural
`Hypotension
`Leg Pain
`CENTRAL NERVOUS
`SYSTEM/NEUROMUSCULAR
`Dizziness
`Vertigo
`Light-headedness
`Tiredness
`Fatigue
`Lethargy
`Drowsiness
`Depression
`Dreaming
`GASTROINTESTINAL
`Diarrhea
`wmdO
`Nausea
`RESPIRATORY(see WARNINGS)
`0
`Wheeziness
`0.6
`Dyspnea
`adrenal medullary tumors in males and females, mammary
`fibroadenomasin females, and anterior pituitary adenomas
`and thyroid parafollicular cell carcinomasin males. No evi-
`dence of a mutagenic potential of atenolol was uncoveredin
`the dominantlethal test (mouse), in vivo cytogenetics test
`(Chinese hamster) or Ames test (S typhimurium ).
`Fertility of male or female rats (evaluated at dose levels as
`high as 200 mg/kg/day or 100 times the maximum recom-
`mended human dose*) was unaffected by atenolol adminis-
`tration.
`Animal Toxicology: Chronic studies employing oral
`atenolol performedin animals have revealed the occurrence
`of vacuolation of epithelial cells of Brunner’s glandsin the
`duodenum of both male and female dogs atall tested dose
`levels of atenolol (starting at 15 mg/kg/day or 7.5 times the
`maximum recommended human antihypertensive dose*)
`and increased incidence ofatrial degeneration of hearts of
`malerats at 300 but not 150 mgatenolol/kg/day (150 and 75 ~
`times the maximum recommended human antihypertensive
`dose,* respectively).
`*Based on the maximum dose of 100 mg/dayin a 50 kg pa-
`tient.
`Usagein Pregnancy: Pregnancy Category D: See WARN-
`INGS—Pregnancyand Fetal Injury.
`:
`Nursing Mothers: Atenolol is excreted in human breast
`milk at a ratio of 1.5 to 6.8 when compared to the concen-
`tration in plasma. Caution should be exercised when
`TENORMINis administered to a nursing woman.Clinically
`significant bradycardia has been reported in breast fed in-
`fants. Premature infants, or infants with impaired renal
`function, may be-more likely to develop adverseeffects,
`Pediatric Use: Safety and effectiveness in pediatric pa-
`tients have not beenestablished.
`ADVERSE REACTIONS
`Most adverseeffects have been mild and transient.
`Thefrequency estimates in the following table were derived
`from controlled studies in hypertensive patients in which
`adverse reactions were either volunteered by the patient
`(US studies) or elicited, eg, by checklist (foreign: studies).
`The reported frequency of elicited adverse effects was
`higher for both TENORMIN and placebo-treated patients
`than when these reactions were volunteered. Wherefre-
`quencyofadverseeffects ofTENORMINand placebois sim-
`ilar, causal relationship to TENORMINis uncertain.
`[See table above]
`Acute MyocardialInfarction:
`In a series of investigations
`in the treatment ofacute myocardialinfarction, bradycardia
`and hypotension occurred more commonly, as expected for
`any betablocker, in atenolol-treated patients than in control
`patients. However, these usually responded to atropine
`and/or to withholding further dosage of atenolol. The inci-
`denceofheart failure was not increased byatenolol. Inotro-
`pic agents were infrequently used. The reported frequency
`of these and other events occurring during these investiga-
`tions is given in the following table.
`In a study of 477 patients, the following adverse events
`were reported during either intravenous and/or oral
`atenolol administration:
`[See first table at bottom of next page]
`In the subsequent International Study of Infarct Survival
`(ISIS-1) including over 16,000 patients of whom 8,037 were
`randomized to receive TENORMIN treatment, the dosage of
`intravenous and subsequent oral TENORMIN was either
`discontinued or reduced for the following reasons:
`[See secondtable at bottom of next page]
`During postmarketing experience with TENORMIN, the
`following have been reported in temporal relationship to the
`use ofthe drug:elevatedliver enzymesand/orbilirubin, hal-
`lucinations, headache, impotence, Peyronie’s disease, postu-
`ral hypotension which maybe associated with syncope, pso-
`riasiform rash or exacerbation of psoriasis, psychoses, pur-
`pura,
`reversible
`alopecia,
`Continued on next page
`BIOCON PHARMALTD(IPR2020-61263)"EX?0202"OO»rovsions
`
`thrombocytopenia, visual disturbances, and dry mouth. TENORMIN,like other beta
`
`.5
`
`.5
`
`3
`12
`4
`
`3
`
`13
`2.
`3
`26
`6
`3
`2
`12
`3
`
`3
`3
`
`3
`6
`
`0
`5
`5
`
`1
`
`6
`0.2
`0.7
`13
`5
`0.7
`0.5
`9
`1
`
`2
`1
`3
`4
`
`:
`
`blockers, has been associated with the developmentof anti-
`nuclear antibodies (ANA) and lupus syndrome.
`POTENTIAL ADVERSE EFFECTS
`In addition, a variety of adverse effects have been reported
`with other beta-adrenergic blocking agents, and maybe con-
`sidered potential adverse effects of TENORMIN.
`Hematologic: Agranulocytosis.
`Allergic: Fever, combined with aching andsore throat, la-
`ryngospasm,andrespiratory distress.
`Central Nervous System: Reversible mental depression
`Progressing to catatonia; an acute reversible syndrome
`characterized by disorientation of time and place; short-
`term memory loss; emotional lability with slightly clouded
`rics.
`sensorium; and decreased performance on neuropsychomet-
`Gastrointestinal:
`Mesentericarterial thrombosis, ischemic
`colitis.
`Other: Erythematous rash, Raynaud’s phenomenon.
`Miscellaneous: There have been reports of skin rashes
`and/ or dry eyes associated with the use of beta-adrenergic
`blocking drugs. The reported incidenceis small, and in most
`cases, the symptoms have cleared when treatment was
`withdrawn. Discontinuance of the drug should be consid-
`ered if any such reaction is not otherwise explicable. Pa-
`tients should be closely monitored following cessation of
`therapy. (See DOSAGE AND ADMINISTRATION:)
`The oculomucocutaneous syndromeassociated with the beta
`blocker practolol has not been reported with TENORMIN.
`Furthermore, a numberof patients who had previously
`demonstrated established practolol reactions were trans-
`ferred to TENORMIN therapy with subsequentresolution
`or quiescenceofthe reaction.
`OVERDOSAGE
`Overdosage with TENORMIN has been reported with pa-
`tients surviving acute doses as high as 5 g. One death was
`reported in a man who mayhave taken as much as 10 g
`acutely.
`The
`predominant
`symptoms
`reported
`following
`TENORMINoverdose are lethargy, disorder of respiratory
`drive, wheezing, sinus pause and bradycardia. Additionally,
`common effects associated with overdosage of any beta-
`adrenergic blocking agent and which might also be expected
`in TENORMINoverdose are congestive heartfailure, hypo-
`tension, bronchospasm and/or hypoglycemia.
`Treatment of overdose should be directed to the removal of
`any unabsorbed drug by induced emesis, gastric lavage, or
`administration of activated charcoal. TENORMINcan be
`removed from the general circulation by hemodialysis.
`Other treatment modalities should be employed at the phy-
`sician’s discretion and mayinclude:
`BRADYCARDIA: Atropine intravenously. If there is no re-
`sponse to vagal blockade, give isoproterenol cautiously. In
`refractory cases, a transvenous cardiac pacemaker may be
`indicated.
`HEART BLOCK (SECOND OR: THIRD DEGREE); Isopro-
`terenol or transvenous cardiac pacemaker.
`CARDIACFAILURE:Digitalize the patient and administer
`a diuretic. Glucagon has been reported to be useful.
`HYPOTENSION: Vasopressors such as dopamineor nor-
`epinephrine (levarterenol). Monitor blood pressure con-
`tinuously.
`BRONCHOSPASM:A beta, stimulant such as isoproterenol
`or terbutaline and/or aminophylline.
`HYPOGLYCEMIA:Intravenous glucose.
`Based on the severity of symptoms, management mayre-
`quire intensive support care and facilities for applying car-
`diac and respiratory support.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 004
`
`

`

`PHYSICIANS’ DESK REFERENCE®
`574/ASTRAZENECA
`
`
`Tenormin—Cont.
`
`based entirely on data from the first seven postinfarction
`days, data from other betablockertrials suggest that treat-
`ment with beta blockers that areeffective in the postinfarc-
`tion setting may be continuedfor oneto three years if there
`are no contraindications.
`TENORMINis an additional treatment to standard coro-
`nary care unit the