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`PHYSIOANS’
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`#
`# DESK
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`PEEEEENCE‘
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`5.3
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`DESK
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 002
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`

`

`572lASTRAZENECA
`PHYSICIANS’ DESK REFERENCE®
`—————————v——__—_____—_—__v_—___—____—
`Tenoretic—Cont.
`
`HOW SUPPLIED
`TENORETIC 50 Tablets (atenolol 50 mg and chlorthalidone
`25 mg), NDC 0310-0115, (white, round, biconvex, uncoated
`tablets with TENORETIC on 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 TENORETIC on one side and 117 on the
`other side) are supplied in bottles of 100 tablets.
`Store at controlled room temperature, 20—25°C (GS—77°F)
`[see USP]. Dispense in well-closed, light-resistant contain-
`ers.
`ZENECA
`Manufactured for:
`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
`TENORMIN® I.V. Injection
`[ten-or ’min ]
`(atenolol)
`
`Ba
`
`DESCRIPTION
`TENORMIN (atenolol), a synthetic, betal—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
`formulas are:
`C14H22Nz°a
`
`OH
`
`OCHZCHCHZNHCH (CH3);
`
`CHZCONHg
`
`Atenolol (free base) has a molecular weight of 266. It is a
`relatively polar hydrophilic compound with a water solubil-
`ity of 26.5 mg/mL at 37°C and a log partition coefficient (oc-
`tanol/ water) of 0.23. It is freely soluble in IN H01 (300
`mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at
`25°C).
`TENORMIN is available as 25, 50 and 100 mg tablets for
`oral administration. TENORMIN for parenteral adminis»
`tration is available as TENORMIN I.V. Injection containing
`5 mg atenolol in 10 mL sterile, isotonic, citrate-bufl‘ered,
`aqueous solution. The pH of the solution is 5.5—6.5.
`Inactive Ingredients: TENORMIN Tablets: Magnesium
`stearate, microcrystalline cellulose, povidone, sodium
`starch glycolate. TENORMIN I.V. Injection: Sodium chlo‘
`ride for isotonicity and citric acid and sodium hydroxide to
`adjust pH.
`CLINICAL PHARMACOLOGY
`TENORMIN is a betel-selective (cardioselective) beta-ad-
`renergic receptor blocking agent without membrane stabi—
`lizing or intrinsic sympathomimetic (partial agonist) activi-
`ties. This preferential effect is not absolute, however, and at
`higher doses, TENORMIN inhibits betaz-adrenoreceptors,
`chiefly located in the bronchial and vascular musculature.
`Pharmacokinetics and Metabolism:
`In man, absorption of
`an oral dose is rapid and consistent but incomplete. Approx-
`imately 50% of an oral dose is absorbed from the gastroin-
`testinal tract, the remainder being excreted unchanged in
`the feces. Peak blood levels are reached between two (2) and
`four (4) hours after ingestion. Unlike propranolol or meto-
`prolol, but like nadolol, TENORMIN undergoes little or no
`metabolism by the liver, and the absorbed portion is elimi-
`nated primarily by renal excretion. Over 85% of an intrave-
`nous dose is excreted in urine within 24 hours compared
`with approximately 50% for an oral dose. TENORMIN also
`differs from propranolol in that only a small amount (6%—
`16%) is bound to proteins in the plasma. This kinetic profile
`results in relatively consistent plasma drug levels with
`about a fourfold interpatient variation.
`The elimination half-life of oral TENORMIN is approxi-
`mately 6 to 7 hours, and there is no alteration of the kinetic
`profile of the drug by chronic administration. Following in-
`travenous administration, peak plasma levels are reached
`within 5 minutes. Declines from peak levels are rapid (5- to
`10-fold) during the first 7 hours; thereafter, plasma levels
`decay with a half-life similar to that of orally administered
`drug. Following oral doses of 50 mg or 100 mg, both betav
`blocking and antihypertensive effects persist for at least 24
`hours. When renal function is impaired, elimination of
`TENORMIN is closely related to the glomerular filtration
`rate; significant accumulation occurs when the creatinine
`clearance falls below 35 mL/min/L73m2. (See DOSAGE
`AND ADMINISTRATION).
`Pharmacodynamics:
`In standard animal or human phar-
`macological tests, beta~adrenoreceptor blocking activity of
`
`
`
`TENORMIN has been demonstrated by: (1) reduction in
`resting and exercise heart rate and cardiac output, (2) re-
`duction of systolic and diastolic blood pressure at rest and
`on exercise, (3) inhibition of isoproterenol induced tachycar-
`dia, and (4) reduction in reflex orthostatic tachycardia.
`A significant betatblocking effect of TENORMIN, as mea-
`sured by reduction of exercise tachycardia, is apparent
`within one hour following oral administration of a single
`dose. This effect is maximal at about 2 to 4 hours, and per-
`sists for at least 24 hours. Maximum reduction in exercise
`tachycardia occurs within 5 minutes of an intravenous dose.
`For both orally and intravenously administered drug, the ,
`duration of action is dose related and also bears a linear
`relationship to the logarithm of plasma TENORMIN con-
`centration. The efl‘ect on exercise tachycardia of a single 10
`mg intravenous dose is largely dissipated by 12 hours,
`whereas beta-blocking activity of single oral doses of 50 mg
`and 100 mg is still evident beyond 24 hours following ad-
`ministration. However, as has been shown for all beta-
`blocking agents, the antihypertensive effect does not appear
`to be related to plasma level.
`In normal subjects, the betal-selectivity of TENORMIN has
`been shown by its reduced ability to reverse the betaf
`mediated vasodilating efiect of isoproterenol as compared to
`equivalent beta-blocking doses of propranolol. In asthmatic
`patients, a dose of TENORMIN producing a greater effect
`on resting heart rate than propranolol resulted in much less
`increase in airway resistance. In a placebo controlled com-
`parison of approximately equipotent oral doses of several
`beta blockers, TENORMIN produced a significantly smaller
`decrease of FEV1 than nonselective beta blockers such as
`propranolol and, unlike those agents, did not inhibit bron-
`chodilation in response to isoproterenol.
`Consistent with its negative chronotropic efiect due to beta
`blockade of the SA node, TENORMIN increases sinus cycle
`length and sinus node recovery time. Conduction in the AV
`node is also prolonged. TENORMIN is devoid of membrane
`stabilizing activity, and increasing the dose well beyond
`that producing beta blockade does not further depress my-
`ocardial contractility. Several studies have demonstrated a
`moderate (approximately 10%) increase in stroke volume at
`rest and during exercise.
`In controlled clinical trials, TENORMIN, given as a single
`daily oral dose, was an effective antihypertensive agent pro-
`viding 24-hour reduction of blood pressure. TENORMIN
`has been studied in combination with thiazide-type diuret—
`ics, and the blood pressure efi‘ects of the combination are
`approximately additive. TENORMIN is also compatible
`with methyldopa, hydralazine, and prazosin, each combina-
`tion resulting in a larger fall in blood pressure than with the
`single agents. The dose range of TENORMIN is narrow and
`increasing the dose beyond 100 mg once daily is not associ-
`ated with increased antihypertensive efi'ect. The mecha-
`nisms of the antihypertensive effects of beta-blocking
`agents have not been established. Several possible mecha-
`nisms have been proposed and include: (1) competitive an-
`tagonism of catecholamines at peripheral (especially car-
`diac) adrenergic neuron sites, leading to decreased cardiac
`output, (2) a central effect leading to reduced sympathetic
`outflow to the periphery, and (3) suppression of renin activ-
`ity. The results from long-term studies have not shown any
`diminution of the antihypertensive efficacy of TENORMIN
`with prolonged use.
`By blocking the positive chronotropic and inotropic efl'ects of
`catecholamines and by decreasing blood pressure, atenolol
`generally reduces the oxygen requirements of the heart at
`any given level of effort, making it useful for many patients
`in the long-term management of angina pectoris. On the
`other hand, atenolol can increase oxygen requirements by
`increasing left ventricular fiber length and end diastolic
`pressure, particularly in patients with heart failure.
`In a multicenter clinical trial (ISIS-1) conducted in 16,027
`patients with suspected myocardial infarction, patients
`presenting within 12 hours (mean = 5 hours) after the onset
`of pain were randomized to either conventional therapy plus
`TENORMIN (n = 8,037), or conventional therapy alone (n =
`7,990). Patients with a heart rate of <50 bpm or systolic
`blood pressure < 100 mm Hg, or with other contraindica—
`tions to beta blockade, were excluded. Thirty-eight percent
`of each group were treated within 4 hours of onset of pain.
`The mean time from onset of pain to entry was 5.0 i 2.7
`hours in both groups. Patients in the TENORMIN group
`were to receive TENORMIN I.V. Injection 5—10 mg given
`over 5 minutes plus TENORMIN Tablets 50 mg every 12
`hours orally on the first study day (the first oral dose ad-
`ministered about 15 minutes after the IV dose) followed by
`either TENORMIN Tablets
`100 mg once daily or
`TENORMIN Tablets 50 mg twice daily on days 2—7. The
`groups were similar in demographic and medical history
`characteristics and in electrocardiographic evidence of my-
`ocardial infarction, bundle branch block, and first degree
`atrioventricular block at entry.
`,
`During the treatment period (days 0—7), the vascular mor-
`tality rates were 3.89% in the TENORMIN group (313
`deaths) and 4.57% in the control group (365 deaths). This
`absolute difference in rates, 0.68%, is statistically signifi‘
`cant at the P <0.05 level. The absolute difference translates
`into a proportional reduction of 15% (3.89-4.57/4.57 =
`~0.15). The 95% confidence limits are 1%«27%. Most of the
`difference was attributed to mortality in days 0-1
`(TENORMIN—121 deaths; control—171 deaths).
`Despite the large size of the ISIS-1 trial, it is not possible to
`identify clearly subgroups of patients most likely or least
`likely to benefit from early treatment with atenolol. Good
`clinical judgment suggests, however, that patients who are
`
`'
`
`
`
`dependent on sympathetic stimulation for maintenance of
`adequate cardiac output and blood pressure are not good
`candidates for beta blockade. Indeed, the trial protocol re-
`flected that judgment by excluding patients with blood pres-
`sure consistently below 100 mm Hg systolic. The overall re«
`sults of the study are compatible with the possibility that
`patients with borderline'blood pressure (less than 120 mm
`Hg systolic), especially if over 60 years of age, are less likely
`to benefit.
`.
`The mechanism through which atenolol improves survival
`in patients with definite or suspected acute myocardial in-
`farction is unknown, as is the case for other beta blockers in
`the postinfarction setting. Atenolol, in addition to its effects
`on survival, has shown other clinical benefits including re-
`duced frequency of ventricular premature beats, reduced
`chest pain, and reduced enzyme elevation.
`INDICATIONS AND USAGE
`Hypertension: TENORMIN is indicated in the manage-
`ment of hypertension. It may be used alone or concomi-
`tantly with other antihypertensive agents, particularly with
`a thiazide—type diuretic.
`Angina Pectoris Due to Coronary Atherosclerosis:
`TENORMIN is indicated for the long-term management of
`patients with angina pectoris.
`Acute Myocardial Infarction: TENORMIN is indicated in
`the management of hemodynamically stable patients with
`definite or suspected acute myocardial infarction to reduce
`cardiovascular mortality. Treatment can be initiated as soon
`as the patient’s clinical condition allows. (See DOSAGE
`AND ADMINISTRATION, CONTRAINDICATIONS, AND
`WARNINGS.) In general, there is no basis for treating pa-
`tients like those who were excluded from the ISIS-1 trial
`(blood pressure less than 100 mm Hg systolic, heart rate
`less than 50 bpm) or have other reasons to avoid beta block-
`ade. As noted above, some subgroups (eg, elderly patients
`with systolic blood pressure below 120 mm Hg) seemed less
`likely to benefit.
`CONTRAINDICATIONS
`TENORMIN is contraindicated in sinus bradycardia, heart
`block greater than first degree, cardiogenic shock, and overt
`cardiac failure. (See WARNINGS.)
`WARNINGS
`Cardiac Failure: Sympathetic stimulation is necessary in
`supporting circulatory function in congestive heart failure,
`and beta blockade carries the potential hazard of further de<
`pressing myocardial contractility and precipitating more se-
`vere failure. In patients who have congestive heart failure
`controlled by digitalis and/or diuretics, TENORMIN should
`be administered cautiously. Both digitalis and atenolol slow
`AV conduction.
`In patients with acute myocardial infarction, cardiac failure
`which is not promptly and effectively controlled by 80 mg of
`intravenous furosemide or equivalent therapy is a contrain-
`dication to beta-blocker treatment.
`In Patients Without a History of Cardiac Failure: Contin-
`ued depression of the myocardium with beta-blocking
`agents over a period of time can, in some cases, lead to car-
`diac failure. At the first sign or symptom of impending car-
`diac failure, patients should be fully digitalized and/or be
`given a diuretic and the response observed closely. If cardiac
`failure continues despite adequate digitalization and diure-
`sis, TENORMIN should be withdrawn. (SEE DOSAGE AND
`ADMINISTRATION.)
`
`Cessation of Therapy with TENORMIN: Patients l
`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-
`gina patients 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 TENORMIN is planned,
`the patients should be carefully observed and advised
`to limit physical activity to a minimum. If the angina
`worsens or acute coronary insufficiency develops, it is
`recommenced that TENORMIN be promptly reinsti-
`tuted, at least temporarily. Because coronary artery
`disease is common and may be 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 the left ventricular end
`diastolic pressure can rise when beta blockers are adminis
`tered with verapamil or diltiazem. Patients with pro—exist—
`ing conduction abnormalities or left ventricular dysfunction
`are particularly susceptible. (See PRECAUTIONS.)
`Bronchospastic Diseases:
`PATIENTS WITH VBRONCHO—
`SPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE
`BETA BLOCKERS. Because of its relative beta, selectivity,
`however, TENORMIN may be used with caution in patients
`with bronchospastic disease who do not respond to, or
`cannot tolerate, other antihypertensive treatment. Since
`beta1 selectivity is not absolute, the lowest possible dose
`of TENORMIN should be used with therapy initiated at 50
`mg and a betaz-stimulating agent (bronchodilator) should
`be made available. If dosage must be increased, dividing
`the dose should be considered in order to achieve lower
`peak blood levels.
`It is not advisable to with—
`Anesthesia and Major Surgery:
`draw beta-adrenoreceptor blocking drugs prior to surgery '1:
`Information will be superseded by supplements and subsBmN PHARMA LTD (IPR2020_0 1263) EX. 1 020, p 003
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 003
`
`

`

`‘
`
`Volunteered
`(US Studies)
`'
`
`Placebo
`(n = 206)
`%
`
`ASTRAZENECA/573
`Total—Volunteered
`and Elicited
`(Forei
`+ US Studies)
`Atenolol
`Placebo
`(n = 399)
`(n = 407)
`%
`%
`
`Atenolol
`(n = 164)
`%
`
`3
`12
`4
`
`3
`
`13
`2
`3
`26
`6
`3
`2
`12
`3
`
`3
`3
`
`0:09
`
`0
`5
`5
`
`1
`
`6
`0.2
`0.7
`13
`5
`0.7
`0.5
`9
`1
`
`2
`1
`3
`4
`
`00
`
`l 0
`
`.5
`
`.5
`
`1
`
`_
`
`O[COCO
`oppwwpp—amuacam
`
`O:
`
`#10
`0
`0.6
`
`CARDIOVASCULAR
`Bradycardia
`Cold Extremities
`Postural
`Hypotension
`Leg Pain
`CENTRAL NERVOUS
`SYSTEM/NEUROMUSCULAR
`Dizziness
`Vertigo
`Light-headedness
`Tiredness
`Fatigue
`Lethargy
`Drowsiness
`Depression
`Dreaming
`GASTROINTESTINAL
`Diarrhea
`Nausea
`RESPIRATORY (see WARNINGS)
`Wheeziness
`Dyspnea
`
`adrenal medullary tumors in males and females, mammary
`fibroadenomas in females, and anterior pituitary adenomas
`and thyroid parafollicular cell carcinomas in males. No evi-
`dence of a mutagenic potential of atenolol was uncovered in
`the dominant lethal 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-
`tration.
`mended human dose*) was unaflected by atenolol adminis-
`
`disturbances, and dry mouth. TENORMIN, like other beta
`blockers, has been associated with the development of 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 may be con-
`sidered potential adverse effects of. TENORMIN.
`Hematologic: Agranulocytosis.
`Allergic: Fever, combined with aching and sore throat, la-
`ryngospasm, and respiratory 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:
`colitis.
`
`Mesenteric arterial thrombosis, ischemic
`
`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 incidence is 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 ADMWISTRATION.)
`The oculomucocutaneous syndrome asSociated with the beta
`blocker practolol has not been reported with TENORMIN.
`Furthermore, a number of patients who had previously
`demonstrated established practolol reactions were trans-
`ferred to TENORMIN therapy with subsequent resolution
`or quiescence of the reaction.
`OVERDOSAGE
`
`Overdosage with TENORMIN has been reported with pa-
`tients surviving acute doses as high as 5 g. One death was
`
`following
`reported
`symptoms
`predominant
`TENORMIN overdose 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 TENORMIN overdose are congestive heart failure, hypov
`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. TENORMIN can be
`removed from the general circulation by hemodialysis.
`Other treatment modalities should be employed at the phy-
`sician’s discretion and may include:
`BRADYCARDIA: Atropine intravenously. If there is no re-
`sponse to vagal blockade, give isoproterenol cautiously. In
`indicated.
`refractory cases, a transvenous cardiac pacemaker may be
`
`HEART BLOCK (SECOND ORV THIRD DEGREE): Isopro-
`terenol or transvenous cardiac pacemaker.
`CARDIAC FAILURE: Digitalize the patient and administer
`a diuretic. Glucagon has been reported to be useful.
`HYPOTENSION: Vasopressors such as dopamine or nor-
`epinephrine (levarterenol). Monitor blood pressure con-
`tinuously.
`
`BRONCHOSPASM: A betaz stimulant such as isoproterenol
`or terbutaline and/or aminophylline.
`HYPOGLYCEMIA: Intravenous glucose.
`Based on the severity of symptoms, management may re-
`quire intensive support care and facilities for applying car-
`diac and respiratory support.
`
`
`
`Continued on next page
`BIOCON PHARMA LTD (IPRzozo-omésjinwrororpeooemmm
`
`
`
`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 TENORMIN I.V.
`Injection is administered concomitantly with such agents.
`TENORMIN, like other beta blockers, is a competitive in-
`hibitor of beta-receptor agonists and its 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: TENORMIN should 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 may not be significantly affected. At rec-
`ommended doses TENORMIN does not potentiate insulin-
`induced hypoglycemia and, unlike nonselective beta block-
`levels.
`ers, does not delay recovery of blood glucose to normal
`
`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 TENORMIN I.V. Injection.
`Abrupt withdrawal ofbeta blockade might precipitate 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.)
`Pregnancy and Fetal Injury: Atenolol can cause fetal harm
`when administered to a pregnant woman. Atenolol crosses
`the placental barrier and appears in cord blood. Administra-
`tion of atenolol, starting in the second trimester of preg-
`nancy, has been associated with the birth of infants that are
`small for gestational age. No studies have been performed
`on the use of atenolol in the first trimester and the possibil-
`ity of fetal injury cannot be excluded. If this drug is used
`during pregnancy, or if the patient becomes pregnant while
`talfing 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 efl'ects were not seen in rabbits, the com-
`pound was not evaluated in rabbits at doses above 25 mg/
`kg/day or 12.5 times the maximum recommended human
`antihypertensive dose*.
`"Based on the maximum dose of 100
`tient.
`PRECAUTIONS
`
`General: Patients already on a beta blocker must be eval-
`uated carefully before TENORMIN‘ is administered. Initial
`and subsequent TENORMIN dosages can be adjusted down-
`ward depending on clinical observations including pulse
`and blood pressure. TENORMIN may aggravate peripheral
`arterial circulatory disorders.
`Impaired Renal Function: The drug should be used with
`caution in patients with impaired renal function. (See DOS-
`AGE AND ADMINISTRATION.)
`Drug Interactions: Catecholamine-depleting drugs (eg, re-
`serpine) may have an additive eflect when given 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
`tension.
`which may produce vertigo, syncope or postural hypo-
`Calcium channel blockers may also have an additive efl‘ect
`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 withdrawal of cloni-
`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 TENORMIN I.V. Injection
`when given in close proximity with drugs that may also
`have a depressant effect on myocardial contractility. On rare
`occasions, concomitant use of intravenous beta blockers and
`intravenous verapamil has resulted in serious adverse reac-
`tions, especially in patients with severe cardiomyopathy,
`congestive heart failure, or recent myocardial infarction.
`Information on concurrent usage of atenolol and aspirin is
`limited. Data from several studies, ie, TIMI-II, ISIS-2, cur—
`rently do not suggest any clinical interaction between as-
`pirin and beta blockers in the acute myocardial infarction
`setting.
`
`While taking beta blockers, patients with a history of ana-
`phylactic reaction to a 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.
`.
`.;
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`'IVvo 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-
`pertensive dose*) resultedin increased incidences of benign
`
`mg/day in a 50 kg pa-
`
`Animal Toxicology: Chronic studies employing oral
`atenolol performed in animals have revealed the occurrence
`of vacuolation of epithelial cells of Brunner’s glands in the
`duodenum of both male and female dogs at all tested dose
`levels of atenolol (starting at 15 mg/kg/day or 7.5 times the
`maximum recommended human antihypertensive dose*)
`and increased incidence of atrial degeneration of hearts of
`male rats at 300 but not 150 mg atenolol/kg/day (150 and 75 ‘-
`- times the maximum recommended human antihypertensive
`dose,* respectively).
`tient.
`*Based on the maximum dose of 100 mg/day in a 50 kg pa-
`Usage in Pregnancy: Pregnancy Category D: See WARN-
`INGS—Pregnancy and 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
`TENORMIN is 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 adverse effects.
`Pediatric Use: Safety and effectiveness in pediatric pa-
`tients have not been established.
`ADVERSE REACTIONS
`Most adverse effects have been mild and transient.
`The frequency 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. Where fre-
`quency of adverse effects of TENORMIN and placebo is sim-
`ilar, causal relationship to TENORMIN is uncertain
`[See table above]
`In a series of investigations
`Acute Myocardial Infarction:
`in the treatment of acute myocardial infarction, bradycardia
`and hypotension occurred more commonly, as expected for
`any beta blocker, in atenolol-treated patients than in control
`patients. However, these usually responded to atropine
`and/or to withholding further dosage of atenolol. The inci-
`dence of heart failure was not increased by atenolol. 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 second table at bottom of next page]
`During postmarketing experience with TENORMIN, the
`following have been reported in temporal relationship to the
`use ofthe drug: elevated liver enzymes and/or bilirubin, hal-
`lucinations, headache, impotence, Peyronie’s disease, postu-
`ral hypotension which may be associated with syncope, pso-
`riasiform rash or exacerbation of psoriasis, psychoses, pur-
`pura,
`reversible
`alopecia,
`thrombocytopenia, visual
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1020, p. 004
`
`

`

`PHYSICIANS' DESK REFERENCE®
`574/ASTRAZE N ECA
`
`
`l
`
`Tenormin—Cont.
`
`Although the demonstration of eflicacy of TENORMIN is
`based entirely on data from