Atenolol (Page 3 of 6)

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).

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

WARNINGS — 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 concentration in plasma. Caution should be exercised when atenolol 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.

WARNINGS, Pregnancy and Fetal Injury).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Hypertension and Angina Pectoris Due to Coronary Atherosclerosis

Clinical studies of atenolol 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 atenolol 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).

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 (U.S. studies) or elicited, e.g., by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of atenolol and placebo is similar, causal relationship to atenolol is uncertain.

	Volunteered(U.S. Studies)		Total — Volunteered and Elicited(Foreign+U.S. Studies)
	Atenolol(n=164)%	Placebo(n=206)%	Atenolol(n=399)%	Placebo(n=407)%
CARDIOVASCULAR
Bradycardia	3	0	3	0
Cold Extremities	0	0.5	12	5
Postural Hypotension	2	1	4	5
Leg Pain	0	0.5	3	1
CENTRAL NERVOUS SYSTEM/NEUROMUSCULAR
Dizziness	4	1	13	6
Vertigo	2	0.5	2	0.2
Lightheadedness	1	0	3	0.7
Tiredness	0.6	0.5	26	13
Fatigue	3	1	6	5
Lethargy	1	0	3	0.7
Drowsiness	0.6	0	2	0.5
Depression	0.6	0.5	12	9
Dreaming	0	0	3	1
GASTROINTESTINAL
Diarrhea	2	0	3	2
Nausea	4	1	3	1
RESPIRATORY (see WARNINGS)
Wheeziness	0	0	3	3
Dyspnea	0.6	1	6	4