Atenolol (Sivem Pharmaceuticals, 25 mg) Product Monograph

INDICATIONS AND CLINICAL USE

Hypertension

ATENOLOL (atenolol) tablets are indicated in patients with mild or moderate hypertension. It is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgement of the physician, treatment should be started with a beta-blocker rather than a diuretic. ATENOLOL may be used in combination with diuretics and/or vasodilators to treat severe hypertension.

The combination of atenolol with a diuretic or peripheral vasodilator has been found to be compatible. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with atenolol.

ATENOLOL is not recommended for the emergency treatment of hypertensive crises.

Angina Pectoris

ATENOLOL tablets are indicated in the long-term management of patients with angina pectoris due to ischemic heart disease.

CONTRAINDICATIONS

ATENOLOL (atenolol) should not be used in the presence of:

1. 1. sinus bradycardia, or bradycardia of other origin
2. 2. second and third degree A-V block
3. 3. sick sinus syndrome
4. 4. right ventricular failure secondary to pulmonary hypertension
5. 5. uncontrolled heart failure
6. 6. cardiogenic shock
7. 7. hypotension
8. 8. severe peripheral arterial disorders
9. 9. anesthesia with agents that produce myocardial depression
10. 10. pheochromocytoma, in the absence of alpha-blockade
11. 11. metabolic acidosis
12. 12. known hypersensitivity to the product

WARNINGS

1. a) Cardiac Failure

Special caution should be exercised when administering atenolol to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with beta blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Atenolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of atenolol when the two drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing A-V conduction. In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalised and/or given a diuretic and the response observed closely. If cardiac failure continues, despite adequate digitalisation and diuretic therapy, atenolol therapy should be immediately withdrawn.

1. b) Abrupt Cessation of Therapy with atenolol

Patients with angina should be warned against abrupt discontinuation of atenolol. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occuring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of atenolol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about two weeks and the patient should be carefully observed and advised to limit physical activity to a minimum. The same frequency of administration should be maintained. In situations of greater urgency, atenolol should be discontinued stepwise over a shorter time and under closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with atenolol be reinstituted promptly, at least temporarily.

1. c) Oculomucocutaneous Syndrome

Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including atenolol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed with atenolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.

1. d) Prinzmetal's Angina

Atenolol may increase the number and duration of angina attacks in patients with Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Atenolol, therefore, should only be used in these patients with the utmost care.

1. e) Sinus Bradycardia

Severe sinus bradycardia may occur with the use of atenolol treatment from unopposed vagal activity remaining after blockade of beta₁-adrenergic receptors; in such cases, dosage should be reduced.

1. f) Thyrotoxicosis

In patients with thyrotoxicosis, possible deleterious effects from long-term use of atenolol have not been adequately appraised. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or its complications and give a false impression of improvement. Therefore, abrupt withdrawal of atenolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

1. g) Pregnancy

Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in the cord blood.

No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age.

Studies in humans have shown that transplacental passage of atenolol does occur in pregnant women, with fetal drug serum levels equal to those of the mother. In a limited number of patients who were given the drug during the last trimester of pregnancy, low birth weight, neonatal hypoglycemia, bradycardia in the fetus/newborn, and placental insufficiency were observed.

Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding. (See PRECAUTIONS, Use in Lactating Women.)

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 dose.

PRECAUTIONS

1. a) Bronchospastic Disorders

Patients with bronchospastic diseases should, in general, not receive beta-blockers. Due to the relative beta1-selectivity of atenolol, atenolol 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, a beta₂-stimulating agent should be administered concomitantly, the lowest possible dose of atenolol should be used. Despite these precautions, the respiratory status of some patients may worsen, and, in such cases, atenolol should be withdrawn.

1. b) First Degree Heart Block

Due to its negative effect on A-V conduction time, atenolol should be used with caution in patients with first degree block.

1. c) Peripheral Arterial Circulatory Disorders

Atenolol may aggravate less severe peripheral arterial circulatory disorders (see CONTRAINDICATIONS).

1. d) Anaphylaxis - Epinephrine and Beta-Blockers

There may be increased difficulty in treating an allergic type reaction in patients on beta blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine included vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension.

1. e) Diabetes and Patients Subject to Hypoglycemia

Atenolol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs (e.g. tachycardia) and symptoms of acute hypoglycemia.

1. f) Impaired Renal Function

Atenolol should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

When renal function is impaired, clearance of atenolol is closely related to the glomerular filtration rate; however, significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73m².

1. g) Elective or Emergency Surgery

It is not advisable to withdraw beta-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using atenolol with anaesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg i.v.).

Some patients receiving beta-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.

In emergency surgery, since atenolol is a competitive inhibitor of beta-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or norepinephrine.

1. h) Ethnic Populations

Atenolol appears to be effective and well-tolerated in most ethnic populations, although the responses may be less in black patients than in Caucasians.

1. i) Use in Lactating Women

In humans, there is a significant accumulation of atenolol in the breast milk of lactating women. Neonates born to mothers who are breastfeeding may be at risk for hypoglycemia and bradycardia. If the use of atenolol is considered essential, then mothers should stop nursing.

1. j) Use in Children

There is no experience with atenolol in the treatment of pediatric age groups.

1. k) Activities Requiring Mental Alertness

Use of atenolol is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that dizziness or fatigue may occur.

1. l) Geriatric Use

Clinical studies of atenolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between 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 concomitant diseases or other drug therapy.

1. m) Drug Interactions

Clonidine

Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped. (Also see prescribing information for clonidine).

Reserpine or Guanethidine

Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added beta-adrenergic blocking action of atenolol may produce an excessive reduction of sympathetic activity. Atenolol should not be combined with other beta-blockers.

Antiarrhythmic Agents

Class I anti-arrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.

Calcium Channel Blockers

Combined use of beta-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of S-A and A-V conduction, particularly in patients with impaired ventricular function, conduction abnormalities, or diminished cardiac output. This may result in severe hypotension, bradycardia and cardiac failure. Concomitant therapy with dihydropyridines, e.g., nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Digitalis Glycosides

Digitalis glycosides may potentiate the bradycardia of beta1-blockade.

Non-Steroidal Anti-Inflammatory Agents

The concomitant use of non-steroidal anti-inflammatory agents may blunt the antihypertensive effects of beta-blockers.

Anaesthetic Agents

Anaesthetics can produce a hypotensive state with associated reflex tachycardia. Since beta-blockade will inhibit reflex tachycardia, the hypotensive potential of anaesthetic agents is increased with concomitant use of atenolol. The anaesthetist should be informed and the choice of anaesthetic should be an agent with as little negative inotropic activity as possible (see CONTRAINDICATIONS and PRECAUTIONS, Elective or Emergency Surgery).

ADVERSE REACTIONS

The most serious adverse reactions encountered are congestive heart failure, A-V block and bronchospasm. Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints.

The most common adverse reactions reported in clinical trials with oral atenolol in 2500 patients are bradycardia (3%), dizziness (3%), vertigo (2%), fatigue (3%), diarrhea (2%) and nausea (3%).

Adverse reactions occuring with an incidence of less than 1%, grouped by system, are as follows:

Cardiovascular

Heart failure deterioration (see WARNINGS)

Heart block

Palpitations

Lengthening of P-R interval

Chest pain

Lightheadedness

Postural hypotension which may be associated with syncope

Raynaud's phenomenon

Intermittent claudication, or worsening of pre-existing intermittent claudication

Leg pain and cold extremities

Edema

Respiratory

Dyspnea, wheeziness

Cough

Bronchospasm

Central Nervous System

Faintness

Ataxia

Tiredness

Lethargy

Nervousness

Depression

Drowsiness

Vivid dreams

Insomnia

Paresthesia

Headache

Tinnitus

Mood Changes

Visual disturbances

Psychoses and hallucinations

Gastrointestinal

Constipation

Anorexia

Abdominal discomfort, indigestion

Miscellaneous

Skin rash

Itchy and/or dry eyes

Psoriasiform skin reactions

Exacerbation of psoriasis

Decreased exercise tolerance

Alopecia

Epistaxis

Flushes

Impotence, decreased libido

Sweating

General body aches

Thrombocytopenia and purpura

POST MARKETING EXPERIENCE

During the post-marketing experience with atenolol, cold extremities, gastrointestinal disturbances and fatigue were commonly reported. The following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, headache, confusion, nightmares, impotence, Peyronie's disease, psoriasiform rash or exacerbation of psoriasis, purpura, reversible alopecia and thrombocytopenia. Rare cases of hepatic toxicity including intrahepatic cholestasis have been reported. Atenolol, like other beta blockers, has been associated with the development of antinuclear antibodies (ANA) and lupus syndrome.

In a long-term, well-controlled trial of 1,627 elderly patients with systolic hypertension, the incidence of dry mouth was significantly higher in patients taking atenolol (12.2%).

Potential Adverse Reactions

The following adverse reactions have occurred with other beta-blockers but have not been reported with atenolol:

Cardiovascular: pulmonary edema, cardiac enlargement, hot flushes and sinus arrest

Central Nervous System: aggressiveness, anxiety, short term memory loss, and emotional lability with slightly clouded sensorium

Allergic: laryngospasm, status asthmaticus and fever combined with aching and sore throat

Dermatological: exfoliative dermatitis

Ophthalmological: blurred vision, burning, and grittiness

Hematological: agranulocytosis

Gastrointestinal: mesenteric arterial thrombosis and ischemic colitis

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Limited information is available with regard to overdosage with ATENOLOL (atenolol) in humans. Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely.

The predominant symptoms reported following atenolol overdosage are lethargy, disorder of respiratory drive, wheezing, sinus pause, and bradycardia. Additionally, common effects associated with overdosage of any beta-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm, and/or hypoglycemia.

Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures.

Other treatment modalities should be employed at the physician's discretion and may include:

BRADYCARDIA: Atropine 1-2 mg intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated. Glucagon in a 10 mg intravenous bolus has been reported to be useful. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/h depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion or isoproterenol 10 to 25 micrograms given as an infusion at a rate not exceeding 5 micrograms/minute may be given, although larger doses may be required.

HEART BLOCK:

(second or third degree)

Isoproterenol, or transvenous pacemaker.

CONGESTIVE HEART FAILURE: Digitalize the patient and administer a diuretic.

Glucagon has been reported to be useful.

HYPOTENSION: Vasopressors such as dopamine or norepinephrine.

Monitor blood pressure continuously.

BRONCHOSPASM: A beta₂-stimulant such as isoproterenol or terbutaline and/or intravenous aminophylline.

HYPOGLYCEMIA: Intravenous glucose.

Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.

DOSAGE AND ADMINISTRATION

Hypertension

ATENOLOL (atenolol) is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic, but may be used alone (see INDICATIONS).

The dose of ATENOLOL should be administered in accordance with individual patient's needs.

The following guidelines are recommended:

The initial dose of ATENOLOL is 50 mg administered as one tablet a day either added to diuretic therapy or alone. The full effect of this dose will usually be seen within one to two weeks. If an adequate response is not achieved, the dose should be increased to ATENOLOL 100 mg once daily. Increasing the dose beyond 100 mg a day is unlikely to produce any further benefit.

If further lowering of the blood pressure is required, another antihypertensive agent should be added to the regimen.

Angina Pectoris

The initial dose of ATENOLOL is 50 mg given as one tablet a day. The full effect of this dose will usually be seen within one to two weeks. If an optimal response is not achieved within one week, the dosage should be increased to ATENOLOL 100 mg given as one tablet a day or 50 mg twice daily. Some patients may require a dosage of 200 mg a day for optimal effect.

Patients with Renal Impairment

Since atenolol is eliminated predominantly via the kidneys, dosage should be adjusted in patients with severe renal impairment. Significant accumulation of atenolol occurs when creatinine clearance falls below 35 mL/min/1.73m² (normal range is 100-150 mL/min/1.73m²).

The following maximum dosages are recommended for patients with renal impairment:

Dosage requirements may be reduced in the elderly, especially in patients with impaired renal function.

PHARMACEUTICAL INFORMATION

Composition

ATENOLOL 25 mg contains per tablet: Atenolol 25 mg, Croscarmellose Sodium, Hydroxypropyl Cellulose, Hydroxypropyl Methylcellulose, Magnesium Stearate, Magnesium Trisilicate, Microcrystalline Cellulose, Polyethylene Glycol, Talc and Titanium Dioxide.

ATENOLOL 50 mg contains per tablet: Atenolol 50 mg, Croscarmellose Sodium, Hydroxypropyl Cellulose, Hydroxypropyl Methylcellulose, Magnesium Stearate, Magnesium Trisilicate, Microcrystalline Cellulose, Polyethylene Glycol, Talc and Titanium Dioxide.

ATENOLOL 100 mg contains per tablet: Atenolol 100 mg, Croscarmellose Sodium, Hydroxypropyl Cellulose, Hydroxypropyl Methylcellulose, Magnesium Stearate, Magnesium Trisilicate, Microcrystalline Cellulose, Polyethylene Glycol, Talc and Titanium Dioxide.

Stability and Storage Recommendations

Store at room temperature (15-30 o C). Protect from light and moisture.

AVAILABILITY OF DOSAGE FORMS

ATENOLOL (atenolol) 25 mg tablets are white, round, biconvex, coated tablets, debossed with AA25@ on one side and plain on the other side. Available in white HDPE bottles of 100 and 500 tablets.

ATENOLOL (atenolol) 50 mg tablets are round, biconvex, film-coated white tablets, debossed AP@ logo with deep score over A50@ on one side and AATENOLOL@ on the other. Available in bottles of 100 and 500 tablets, and blister pack of 30 tablets.

ATENOLOL (atenolol) 100 mg tablets are round, biconvex, film-coated white tablets, debossed AP@ logo with deep score over A100" on one side and AATENOLOL@ on the other. Available in bottles of 100 and 500 tablets, and blister pack of 30 tablets.

* ATENOLOL, SIVEM Pharmaceuticals ULC. Canada

† Tenormin, ICI Pharma Canada Inc

^§ The Tmax and T_1/2 parameters are expressed as the arithmetic means.

Statistical results of the bioavailability demonstrate that ATENOLOL and ICI Pharma (Tenormin) 100 mg atenolol tablets are bioequivalent in the rates and extents of absorption.

PHARMACOLOGY

Animal Studies

Chronic studies 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 dose) and an 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 dose, respectively).

Effect on the Cardiovascular System

In anesthetized cats, atenolol infusion reduces the chronotropic response to isoproterenol and right cardiac sympathetic nerve stimulation.

In anesthetized dogs, atenolol 0.03 mg/kg i.v. depresses the heart rate by 22%, cardiac contractile force by 16% and diastolic blood pressure by 11%.

Studies in rats showed that atenolol was devoid of intrinsic sympathomimetic activity.

Atenolol in concentrations up to 10 mg/mL had no local anesthetic effect on the isolated sciatic nerve of the frog.

Atenolol (5-20 mg/kg i.v.) was without effect on the ventricular tachycardia produced by toxic levels of ouabain in anesthetized dogs. Atenolol (0.2 mg/kg i.v.) protected coronary ligated dogs from the arrhythmogenic activity of adrenaline on the fourth day after ligation (when the cardiac rhythm was predominantly sinus).

Single oral doses of 100 mg atenolol given to volunteers reduced exercise-induced tachycardia by 31% at 4 hours and by 15% at 24 hours after administration. The maximal suppression of the systolic blood pressure response to exercise was 21% at 4 hours.

Effects on Plasma Renin Activity

Studies in hypertensive patients have shown that the antihypertensive effect of atenolol is associated with a decrease in plasma renin activity.

Effects on Pulmonary Function

The effects of a single 100 mg dose of atenolol on forced expiratory volume (FEV₁) and airways resistance (AWR) were assessed in ten patients with labile asthma. The cardioselective agents tested in this comparative trial, including atenolol, usually had a lesser dose-related effect on airway function than non-selective beta-blockers. Atenolol produced a smaller decrease in FEV1 than did the non-selective agents and did not inhibit the bronchodilator response to isoprenaline. The decrease in FEV1 was 8-9%. Other studies in asthmatic patients have reported similar decreases in FEV1 with atenolol. Dose-effect comparisons with cardioselective agents have shown a fall in FEV1 values at the higher doses, indicating some beta₂-blocking effect.

Metabolic Effects

Atenolol did not potentiate the hypoglycemic effects of insulin in 12 patients with diabetes.

TOXICOLOGY

Acute Toxicity

Species Sex Concentration Route LD50 (mg/kg)

Mouse M/F 20% (1) Oral >2000 Mouse M/F 0.8-1.2% (2) i.v. 100 Rat M/F 30% (1) Oral >3000 Rat Male 21.3% (3) Oral 4960 Rat Female 21.3% (3) Oral 6600 Rat M/F 1.0-4.0% (2) i.v. 50-60 Rat Male 0.5% (2) i.v. 129(±25) Rat Female 0.5% (2) i.v. 114(±30) Rhesus Monkey M/F Variable (1) Oral >6000 (1) Suspension (2) Solution (3) Formulated Tablet

Toxic signs in rats were: depression, ataxia, labored respiration, cyanosis, tremors and convulsions. Effects occurred within 5 minutes following intravenous administration and surviving rats appeared normal after 2 hours. Effects following oral administration occurred within 1 hour and some persisted through 48 hours. Surviving rats appeared normal within 72 hours.

Following intravenous administration, all mice convulsed immediately and those animals dying did so within 5 minutes.

Toxic signs in monkeys following oral administration were emesis, lethargy, slight mydriasis, occasional ptosis, salivation and decreased respiration. Surviving monkeys appeared normal within 24 hours.

Subacute Toxicity

Dose Duration

Species Sex

Strain

M F mg/kg/day Route Route

(mo)

Effect

Rat Alderly

PK.

Strain 1

40 40 0, 5, 50, 200 oral 3 High and intermediate groups showed increased heart and spleen weights. High dose males (3/10) showed focal myocarditis. (1 male control showed focal myocardial necrosis.)

Dog Beagle 16 16 0, 5, 50, 100 oral 3 High and intermediate dose females showed increased liver weights. Mean heart rate and blood pressure decreased in high and inter-mediate dose animals.

Chronic Toxicity

Dose Duration

Species Sex

Strain

M F mg/kg/day Route Route

(mo)

Effect

Rat Alderly

PK.

Strain 1

80 80 0, 75, 150,

300

oral 6 Reduction in heart rate. High and intermediate dose showed decreased blood pressure. Spleen and heart weights increased. Chronic myocarditis was seen in all groups including controls. Three high dose and 2 mid-dose animals were killed in moribund state.

Dog Beagle 20 20 0, 50, 100,

200

oral 12 Decreased heart rate. Prolongation of PR interval on ECG. Vacuolation of epithelial cells of duodenal Brunner's glands: 5/10 low dose, 2/10 mid-dose, 7/10 high dose. One high dose female died.

Dog Beagle 15 15 0, 15, 200 oral 12 Vacuolation of epithelium of

Brunner's glands 9/10 high dose;

1/10 low dose.

Teratology and Reproduction Studies

Atenolol associated malformations were not observed when atenolol was administered at oral doses of up to 200 mg/kg/day, days 6-15 of gestation in rats or at doses of up to 25 mg/kg/day, days 6-18 of gestation in rabbits.

Dose levels of 50 or more mg/kg/day were, however, associated with an increased incidence of resorptions in rats. Although a similar effect was not seen in rabbits, it should be noted that the compound was not evaluated in rabbits at doses above 25 mg/kg/day. Atenolol, administered at doses of up to 200 mg/kg/day, for 11 weeks prior to mating in males or 2 weeks prior to mating in females, did not adversely affect fertility of male or female rats. Growth or survival of offspring were not affected when pregnant females were exposed at 200 mg/kg/day from day 15 of gestation to day 21 post partum.

Mutagenic Potential

Atenolol was negative in the mouse dominant lethal test, the Chinese hamster in vivo cytogenetic test and the Salmonella typhimurium back mutation test (Ames test), with or without metabolic activation.

Carcinogenicity Studies

Atenolol was administered to 3 groups of 65 male and 65 female CR7B1/10J mice at dietary levels of 0, 150 and 300 mg/kg/day for 18 months followed by the control diet for an additional three months. A fourth group received 2-AAF (positive control) and a fifth was the negative control group. Retardation in weight gain was observed. There was no statistically significant difference in mortality, number of tumor bearers, number of tumors in each animal or the total number of tumors in treated and negative control animals.

Two studies were conducted in Alderley Park Strain I rats. One study employed doses of 150 and 300 mg/kg/day for 18 months followed by the control diet for an additional six months, while the second study used doses of 75, 150 and 300 mg/kg/day for 24 months. Results from the two studies showed no significant difference in mortality for treated and control groups. No apparent carcinogenic potential was observed.

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TENORMIN, Product Monograph (AstraZeneca Canada Inc.), Revision Date: June 13, 2008, Control Number: 121387