TENORMIN®
`
`
` (atenolol) Tablets
`
`
`
`DESCRIPTION
`TENORMIN® (atenolol), a synthetic, beta1-selective (cardioselective) adrenoreceptor blocking
`
`agent, may be chemically described as benzeneacetamide, 4 -[2'-hydroxy-3'-[(1- methylethyl)
`amino] propoxy]-. The molecular and structural formulas are:
`
`
`
`
`
`
`
`C14H22N2O3
`
`
`Atenolol (free base) has a molecular weight of 266. It is a relatively polar hydrophilic compound
`with a water solubility of 26.5 mg/mL at 37°C and a log partition coefficient (octanol/water) of
`0.23. It is freely soluble in 1N HCl (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.
`
`Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch
`glycolate.
`
`CLINICAL PHARMACOLOGY
`TENORMIN is a beta1-selective (cardioselective) beta-adrenergic receptor blocking agent
`without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. This
`preferential effect is not absolute, however, and at higher doses, TENORMIN inhibits
`beta2-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. Approximately 50%
`of an oral dose is absorbed from the gastrointestinal 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 metoprolol, but like nadolol, TENORMIN undergoes little or
`no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion.
`Over 85% of an intravenous 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.
`
`
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`Reference ID: 3210443
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`The elimination half-life of oral TENORMIN is approximately 6 to 7 hours, and there is no
`alteration of the kinetic profile of the drug by chronic administration. Following intravenous
`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 beta-
`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/1.73m2.
`(See Dosage and administration.)
`
`Pharmacodynamics
`In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of
`TENORMIN has been demonstrated by: (1) reduction in resting and exercise heart rate and
`cardiac output, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3)
`inhibition of isoproterenol induced tachycardia, and (4) reduction in reflex orthostatic
`tachycardia.
`
`A significant beta-blocking effect of TENORMIN, as measured 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 persists 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 concentration. The effect 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 administration. 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 beta1 selectivity of TENORMIN has been shown by its reduced ability to
`reverse the beta2-mediated vasodilating effect 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 comparison 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 bronchodilation in response
`to isoproterenol.
`
`Consistent with its negative chronotropic effect 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 myocardial
`contractility. Several studies have demonstrated a moderate (approximately 10%) increase in
`stroke volume at rest and during exercise.
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`In controlled clinical trials, TENORMIN, given as a single daily oral dose, was an effective
`antihypertensive agent providing 24-hour reduction of blood pressure. TENORMIN has been
`studied in combination with thiazide type diuretics, and the blood pressure effects of the
`
` combination are approximately additive. TENORMIN is also compatible with methyldopa,
`
` hydralazine, and prazosin, each combination 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 associated with increased antihypertensive effect. The mechanisms of the
`antihypertensive effects of beta-blocking agents have not been established. Several possible
`mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at
`
` peripheral (especially cardiac) 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 activity. 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 effects 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 contraindications 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 ± 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 administered 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 myocardial infarction, bundle
`branch block, and first degree atrioventricular block at entry.
`
`
`During the treatment period (days 0-7), the vascular mortality 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 significant 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).
`
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`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 reflected that judgment by excluding patients with blood
`pressure consistently below 100 mm Hg systolic. The overall results 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 infarction 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 reduced frequency of ventricular premature beats, reduced chest pain, and
`reduced enzyme elevation.
`
`Atenolol Geriatric Pharmacology:
`In general, elderly patients present higher atenolol plasma levels with total clearance values
`about 50% lower than younger subjects. The half-life is markedly longer in the elderly
`compared to younger subjects. The reduction in atenolol clearance follows the general trend that
`the elimination of renally excreted drugs is decreased with increasing age.
`
`INDICATIONS AND USAGE
`Hypertension
`
`
`
`TENORMIN is indicated for the treatment of hypertension, to lower blood pressure. Lowering
`blood pressure lowers the risk of fatal and non-fatal 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 atenolol.
`
`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 1 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.
`
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`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 (eg,
`on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
`
`therapy.
`
`TENORMIN may be administered with other antihypertensive agents.
`
`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 patients 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
`blockade. 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.)
`
`
`
`TENORMIN is contraindicated in those patients with a history of hypersensitivity to the atenolol
`or any of the drug product’s components.
`
`WARNINGS
`Cardiac Failure
`Sympathetic stimulation is necessary in supporting circulatory function in congestive heart
`failure, and beta blockade carries the potential hazard of further depressing myocardial
`contractility and precipitating more severe failure.
`
`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 contraindication to
`beta-blocker treatment.
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`In Patients Without a History of Cardiac Failure
` Continued depression of the myocardium with beta-blocking agents over a period of time can, in
`
`some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure,
`patients should be treated appropriately according to currently recommended guidelines, and the
`response observed closely. If cardiac failure continues despite adequate treatment, TENORMIN
`should be withdrawn. (See Dosage and administration)
`
`Cessation of Therapy with TENORMIN
`Patients with coronary artery disease, who are being treated with TENORMIN, should be
`
`
`
`advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the
`occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina
`patients following the abrupt discontinuation of therapy with beta blockers. The last two
`
`
`
`complications may occur with or without preceding exacerbation of the angina pectoris. As
`
`with other beta blockers, 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 recommended that TENORMIN be
`promptly reinstituted, 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 hypertension. (See Dosage and administration.)
`
` Concomitant Use of Calcium Channel Blockers Bradycardia and heart block can occur
`
`and the left ventricular end diastolic pressure can rise when beta-blockers are administered with
`verapamil or diltiazem. Patients with pre-existing conduction abnormalities or left ventricular
`dysfunction are particularly susceptible. (See PRECAUTIONS.)
`
`Bronchospastic Diseases
`PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT
`RECEIVE BETA BLOCKERS. Because of its relative beta1 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 beta2-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.
`
`Major Surgery
`
`Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major
`surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may
`augment the risks of general anesthesia and surgical procedures.
`
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`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 dizziness and sweating may not be significantly affected. At recommended doses
`TENORMIN does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta
`blockers, does not delay recovery of blood glucose to normal levels.
`
`Thyrotoxicosis
`Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism.
`Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients
`suspected of developing thyrotoxicosis from whom TENORMIN therapy is to be withdrawn
`should be monitored closely. (See Dosage and administration.)
`
`Untreated Pheochromocytoma
`TENORMIN should not be given to patients with untreated pheochromocytoma.
`
`
`
`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. Administration of atenolol, starting in the second
`trimester of pregnancy, 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
`possibility of fetal injury cannot be excluded. If this drug is used during pregnancy, or if the
`patient becomes pregnant while taking this drug, the patient should be apprised of the potential
`hazard to the fetus.
`
`Neonates born to mothers who are receiving TENORMIN at parturition or breast-feeding may be
`
`at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORMIN is
`administered during pregnancy or to a woman who is breast-feeding. (See PRECAUTIONS,
`Nursing Mothers.)
`
`
`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 maximum recommended
`human antihypertensive dose.* Although similar effects were not seen in rabbits, the compound
`was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum
`recommended human antihypertensive dose.*
`
`
`
`
`
`PRECAUTIONS
`General
`
`Patients already on a beta blocker must be evaluated carefully before TENORMIN is
`
`Initial and subsequent TENORMIN dosages can be adjusted downward
`administered.
`depending on clinical observations including pulse and blood pressure. TENORMIN may
`aggravate peripheral arterial circulatory disorders.
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`Impaired Renal Function
`The drug should be used with caution in patients with impaired renal function. (See Dosage and
`administration.)
`
`*Based on the maximum dose of 100 mg/day in a 50 kg patient.
`Drug Interactions
`Catecholamine-depleting drugs (eg, reserpine) may have an additive effect 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 which may
`produce vertigo, syncope, or postural hypotension.
`
`Calcium channel blockers may also have an additive effect when given with TENORMIN (See
`WARNINGS).
`
`
`
`Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic
`
`effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure
`
` when administered with beta blockers.
`
`Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be
`
`additive to those seen with beta blockers.
`
`
`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 withdrawn several
`days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy,
`the introduction of beta blockers should be delayed for several days after clonidine
`administration has stopped.
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`
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`Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the
`hypotensive effects of beta blockers.
`
`Information on concurrent usage of atenolol and aspirin is limited. Data from several studies, ie,
`TIMI-II, ISIS-2, currently do not suggest any clinical interaction between aspirin and beta
`blockers in the acute myocardial infarction setting.
`
`While taking beta blockers, patients with a history of anaphylactic reaction to a variety of
`allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or
`
`therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
`the allergic reaction.
`
`
`
`Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart
`rate. Concomitant use can increase the risk of bradycardia.
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`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
`indicate 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
`antihypertensive dose*) resulted in increased incidences of benign adrenal medullary tumors in
`males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and
`thyroid parafollicular cell carcinomas in males. No evidence 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 recommended human dose*) was unaffected by atenolol administration.
`
`
`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).
`
`Usage in Pregnancy
`Pregnancy Category D
`
`See WARNINGS - Pregnancy and Fetal Injury.
`
`
`
`
`
`
`*Based on the maximum dose of 100 mg/day in a 50 kg patient.
`
`Nursing Mothers
`Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the
`concentration in plasma. Caution should be exercised when TENORMIN is administered to a
`
`nursing woman. Clinically significant bradycardia has been reported in breast-fed infants.
`
`Premature infants, or infants with impaired renal function, may be more likely to develop
`adverse effects.
`
`Neonates born to mothers who are receiving TENORMIN at parturition or breast-feeding may be
`
`at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORMIN is
`administered during pregnancy or to a woman who is breast-feeding (See WARNINGS,
`Pregnancy and Fetal Injury).
`
`Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
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`Geriatric Use
`Hypertension and Angina Pectoris Due to Coronary Atherosclerosis:
`Clinical studies of TENORMIN did not include sufficient number of patients aged 65 and over
`to determine whether they respond differently from younger subjects. Other reported clinical
`
` experience has not identified differences in responses between the elderly and younger patients.
`In general, dose selection for an elderly patient should be cautious, usually starting at the low end
`of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
`function, and of concomitant disease or other drug therapy.
`
`Acute Myocardial Infarction:
`Of the 8,037 patients with suspected acute myocardial infarction randomized to TENORMIN in
`the ISIS-1 trial (See CLINICAL PHARMACOLOGY), 33% (2,644) were 65 years of age and
`older. It was not possible to identify significant differences in efficacy and safety between older
`and younger patients; however, elderly patients with systolic blood pressure < 120 mmHg
`seemed less likely to benefit (See INDICATIONS AND USAGE).
`
`In general, dose selection for an elderly patient should be cautious, usually starting at the low end
`of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function,
`and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or
`myocardial infarction should always include assessment of renal function.
`
`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 frequency of adverse effects of TENORMIN and placebo is similar,
`
`causal relationship to TENORMIN is uncertain.
`
`
`
`Volunteered
`
`
`(US Studies)
`Atenolol
`Placebo
`
`(n=206)
`(n=164)
`%
`%
`
`3
`0
`2
`0
`
`0
`
`0.5
`1
`
`0.5
`
`Total - Volunteered
`and Elicited
`(Foreign+US Studies)
`Atenolol
`Placebo
`
`
`(n=399)
`(n=407)
`%
`%
`
`
`
`
`
`
`
`
`
`
`3
`12
`4
`3
`
`0
`5
`5
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`CARDIOVASCULAR
`Bradycardia
`
`Cold Extremities
`
`
`Postural Hypotension
`
`Leg Pain
`CENTRAL NERVOUS SYSTEM/
`NEUROMUSCULAR
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`
`
`6
`
`0.2
`0.7
`
` 13
`
`5
` 0.7
`
`0.5
`9
`1
`
`
`
`
`
`13
`2
`3
`
` 26
`6
`3
`2
`
` 12
`3
`
`3
`3
`
`3
`6
`
`1
`
` 0.5
`0
`
` 0.5
`1
`0
`0
`
` 0.5
`0
`
`0
`1
`
`0
`1
`
`4
`2
`1
`
` 0.6
`3
`1
`0.6
`0.6
`0
`
`
`
`2
`4
`
`0
`
` 0.6
`
`
`
`
`
`
`
`
`Dizziness
`Vertigo
`Light-headedness
`Tiredness
`Fatigue
`Lethargy
`Drowsiness
`Depression
`Dreaming
`
`GASTROINTESTINAL
`
`Diarrhea
`
`Nausea
`RESPIRATORY (see WARNINGS)
`
`
` Wheeziness
` Dyspnea
`
`
`Acute Myocardial Infarction
`In a series of investigations 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 incidence of heart failure was not increased by
`
`atenolol. Inotropic agents were infrequently used. The reported frequency of these and other
`events occurring during these investigations is given in the following table.
`
`
`2
`
`1
`
`
`3
`
`4
`
`
`
`In a study of 477 patients, the following adverse events were reported during either intravenous
`and/or oral atenolol administration:
`
`Conventional Therapy
`
`Plus Atenolol
`
`(n=244)
`
`Conventional
`
`Therapy Alone
`(n=233)
`
`
`
`
`
`
`(10%)
`(15%)
`(0.9%)
`
`(24%)
`(4.3%)
`
`
`(12%)
`(19%)
`(11%)
`(3%)
`(22%)
`(2.6%)
`(6.9%)
`(5.1%)
`(6.9%)
`
`(1.7%)
`
`
`24
`
`34
`
`2
`56
`
`10
`
`
`28
`
`45
`
`29
`7
`52
`
`6
`16
`12
`16
`
`4
`
`43
`
`60
`
`3
`46
`
`11
`
`
`16
`
`28
`
`12
`4
`39
`
`0
`4
`4
`7
`1
`
`(18%)
`(25%)
`(1.2%)
`
`(19%)
`(4.5%)
`
`
`(6.6%)
`
`(11.5%)
`(5%)
`(1.6%)
`(16%)
`(0%)
`(1.6%)
`(1.6%)
`(2.9%)
`
`(0.4%)
`
`
`
`
`
`
`
`Bradycardia
`Hypotension
`Bronchospasm
`Heart Failure
`Heart Block
`
`BBB + Major
`
`Axis Deviation
`
`Supraventricular Tachycardia
` Atrial Fibrillation
` Atrial Flutter
`Ventricular Tachycardia
`Cardiac Reinfarction
`Total Cardiac Arrests
`Nonfatal Cardiac Arrests
`
`Deaths
`Cardiogenic Shock
`
`
`Reference ID: 3210443
`
`
`11
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd.
`IPR2016-00379
`Patent Owner Forest Labs - Ex. 2005, p. 11
`
`
`
`

`
`Development of Ventricular
` Septal Defect
`Development of Mitral
`
`Regurgitation
`Renal Failure
`Pulmonary Emboli
`
`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:
`
`0
`
`0
`1
`3
`
`
`(0%)
`
`
`(0%)
`
`(0.4%)
`
`(1.2%)
`
`2
`
`2
`0
`0
`
`
`(0.9%)
`
`
`(0.9%)
`
`(0%)
`
`(0%)
`
`Reasons for Reduced Dosage
`
`IV Atenolol
` Reduced Dose
`
`(< 5 mg)*
`
`Oral Partial
`Dose
`
`
`
`
`(14.5%)
`(.44%)
`(.06%)
`(.34%)
`
`(1.7%)
`(2.9%)
`(.27%)
`
`(.62%)
`
`
`1168
`
`35
`5
`28
`143
`233
`
`22
`
`50
`
`
`
`
`105
`4
`0
`5
`5
`1
`3
`1
`
`
`(1.3%)
`(.04%)
`
`(0%)
`(.06%)
`(.06%)
`(.01%)
`(.04%)
`(.01%)
`
`
`
`
`
`
`
`
`Hypotension/Bradycardia
`
`Cardiogenic Shock
`Reinfarction
`Cardiac Arrest
`Heart Block (> first degree)
`Cardiac Failure
`Arrhythmias
`
`Bronchospasm
`
`
`
`*Full dosage was 10 mg and some patients received less than 10 mg but more than 5 mg.
`
`During postmarketing experience with TENORMIN, the following have been reported in
`temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin,
`hallucinations, headache, impotence, Peyronie's disease, postural hypotension which may be
`associated with syncope, psoriasiform rash or exacerbation of psoriasis, psychoses, purpura,
`reversible alopecia, thrombocytopenia, visual disturbance, sick sinus syndrome, and dry mouth.
`TENORMIN, like other beta blockers, has been associated with the development of antinuclear
`antibodies (ANA), lupus syndrome, and Raynaud’s phenomenon.
`
`POTENTIAL ADVERSE EFFECTS
`In addition,