Nadolol

Class: beta-Adrenergic Blocking Agents
VA Class: CV100
CAS Number: 42200-33-9
Brands: Corgard, Corzide

Introduction

Nonselective β-adrenergic blocking agent.^{a b}

Uses for Nadolol

Hypertension

Management of hypertension, alone or in combination with other antihypertensive agents.^{a b}

One of several preferred initial therapies in hypertensive patients with heart failure, post-MI, high coronary disease risk, or diabetes mellitus.¹⁵³

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC VII.¹⁵³

Angina

Long-term prophylactic management of chronic stable angina.^{a b}

A component of standard therapeutic measures for management of unstable angina and non-ST-segment elevation myocardial infarction†.^a

Supraventricular Tachyarrhythmias

Has been used for management of frequent VPCs, paroxysmal atrial tachycardia, and sinus tachycardia and to decrease heart rate in patients with atrial flutter or fibrillation†.^a

Vascular Headache

Prophylaxis of migraine headache†.^{100 101 148}

US Headache Consortium states there is evidence of efficacy and clinical experience suggests clinically important improvement in most patients.¹⁴⁸

Nadolol Dosage and Administration

General

• 
  

  Individualize dosage according to patient response.^{a b}

  
  


• 
  

  If long-term therapy is discontinued, reduce dosage gradually over 1–2 weeks.^{a b} (See Abrupt Withdrawal of Therapy under Cautions.)

  
  

Hypertension

• 
  

  Careful monitoring of BP during initial titration or subsequent upward adjustment in dosage is recommended.^{119 153} Large or abrupt reductions in BP generally should be avoided.¹¹⁹

  
  


• 
  

  Adjust antihypertensive dosage at approximately monthly intervals (more aggressively in high-risk patients) if response is inadequate.^{119 153}

  
  


• 
  

  Nadolol/bendroflumethiazide fixed combination is not recommended for initial combination therapy; adjust initial and subsequent dosages by administering each drug separately.^{a 135}

  
  


• 
  

  Bendroflumethiazide in the fixed-combination preparation with nadolol is about 30% more bioavailable than the drug alone.^{a 135}

  
  

Angina

• 
  

  Wide variation in individual dosage requirements; carefully titrate dosage to achieve optimum results.^a

  
  


• 
  

  Periodically evaluate chronic therapy for angina to determine need for dosage alteration or continued therapy.^a

  
  

Administration

Oral Administration

Administer orally once daily without regard to meals.^{a b 135}

Dosage

Adults

Hypertension

Monotherapy

Oral

Initially, 20–40 mg daily.^a

May gradually increase by 40–80 mg daily at 2- to 14-day intervals until optimum BP response is achieved.^a

Manufacturers recommend usual maintenance dosage of 40–80 mg daily; dosages up to 240 or 320 mg daily may be needed.^{a b}

JNC 7 currently recommends 40–120 mg daily.¹⁵³ It usually is preferable to add another antihypertensive agent to the regimen than to continue increasing nadolol dosage; continued increases may not be tolerated.¹⁵⁷

Combination Therapy

Oral

Nadolol in fixed combination with bendroflumethiazide: Initially 40 mg of nadolol and 5 mg of bendroflumethiazide once daily.¹³⁵ If needed, increase to 80 mg of nadolol and 5 mg of bendroflumethiazide once daily.¹³⁵

If BP is not adequately controlled with the fixed combination alone, may gradually add another nondiuretic hypotensive agent, starting with 50% of the usual recommended starting dosage to avoid excessive reduction in BP.¹³⁵

Use of fixed-combination preparations initially and for subsequent dosage adjustment generally is not recommended.^{a 135} Adjust by administering each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio in the combination preparation.^a Administer separately for subsequent dosage adjustment.^a

Angina

Chronic Stable Angina

Oral

Initially, 40 mg daily.^a Gradually increase by 40–80 mg daily at 3- to 7-day intervals until optimum control of angina is obtained or there is pronounced slowing of the heart rate (i.e., <55 bpm).^{a b}

Usual maintenance dosage is 40 or 80 mg daily.^{a b} Up to 160 or 240 mg daily may be needed.^{a b}

Supraventricular Tachyarrhythmias†

Various Cardiac Arrhythmias†

Oral

Maintenance dose: 60–160 mg daily in single or divided doses has been used.^a

Vascular Headache†

Prevention of Migraine†

Oral

Usual effective dosage: 80–240 mg daily.¹⁴⁸

Prescribing Limits

Adults

Angina

Oral

Safety and efficacy of dosages >240 mg daily not established.^{a b}

Special Populations

Renal Impairment

Adjust intervals for usual dosage of nadolol alone or in fixed combination with bendroflumethiazide:^b

Clcr (mL/minute per 1.73 m2)	Dosage Interval
>50	24 h
31–50	24–36 h
10–30	24–48 h
<10	40–60 h

Cautions for Nadolol

Contraindications

• 
  

  Bronchial asthma.^{a b}

  
  


• 
  

  Sinus bradycardia and heart block greater than first degree.^{a b}

  
  


• 
  

  Cardiogenic shock.^{a b}

  
  


• 
  

  Overt cardiac failure.^{a b}

  
  

Warnings/Precautions

Warnings

Cardiac Failure

Possible precipitation of CHF.^{a b} Avoid use in patients with overt CHF;^{a b} may use cautiously in patients with inadequate myocardial function and, if necessary, in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).^{a b} Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending cardiac failure occur; if cardiac failure continues, discontinue therapy, gradually if possible.^{a b}

Abrupt Withdrawal of Therapy

Abrupt withdrawal of nadolol not recommended as it may exacerbate angina symptoms or precipitate MI in patients with angina pectoris and/or CAD.^{a b} Avoid abrupt discontinuance, even when used only for hypertension.^{a b} Abrupt withdrawal may cause transient symptoms (e.g., tremulousness, sweating, palpitation, headache, malaise) in patients without CAD.^a Discontinue long-term therapy gradually (particularly in patients with myocardial ischemia); decrease dosage over 1–2 weeks and monitor carefully.^{a b} If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily, and initiate appropriate measures for the management of unstable angina.^{a b}

Bronchospastic Disease

Possible inhibition of bronchodilation produced by endogenous or exogenous catecholamines;^{a b} use not recommended in patients with bronchial asthma.^b (See Contraindications under Cautions.) Generally, β-adrenergic blocking agents should not be used in patients with bronchospastic disease.^{a b} Use with caution in patients with a history of nonallergic bronchospasm (e.g., chronic bronchitis, emphysema).^{a b}

Major Surgery

Possible increased risks associated with general anesthesia (e.g., severe hypotension, difficulty restarting or maintaining heart beat) due to decreased ability of the heart to respond to reflex β-adrenergic stimuli.^{a b} Use with caution in major surgery involving general anesthesia; if possible, withdraw drug before surgery.^{a b} If nadolol is continued during surgery, inform the anesthesiologist.^{a b}

Diabetes and Hypoglycemia

Possible masked signs and symptoms of acute hypoglycemia (e.g., tachycardia and BP changes but not sweating), impaired glucose tolerance, delayed rate of recovery of blood glucose concentration following drug-induced hypoglycemia, altered hemodynamic response to hypoglycemia (possibly resulting in an exaggerated hypertensive response), and impaired peripheral circulation.^{a b}

Use with caution in patients with diabetes mellitus (especially those with labile diabetes or those prone to hypoglycemia).^{a b} If used with hypoglycemic agents, may need to adjust hypoglycemic agent dosage.^a

Thyrotoxicosis

Signs of hyperthyroidism (e.g., tachycardia) may be masked.^{a b} Possible thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.^{a b}

General Precautions

History of Anaphylactic Reactions

Possible increased reactivity to a variety of allergens; patients may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.^{a b}

Other Precautions

Shares the toxic potentials of β-adrenergic blocking agents; observe usual precautions of these agents.^a In addition, when used in fixed-combination with bendroflumethiazide, consider the cautions, precautions, and contraindications associated with thiazide diuretics.^a

Specific Populations

Pregnancy

Category C.^{135 b}

Lactation

Distributed into milk.^{a b} Discontinue nursing or the drug.^{a b}

Pediatric Use

Safety and efficacy not established.^{a b}

Hepatic Impairment

Use with caution.^a

Renal Impairment

Use with caution.^b

Clearance may be decreased; dosage adjustments necessary depending on degree of renal impairment.^{a b} (See Renal Impairment under Dosage and Administration)

Common Adverse Effects

Bradycardia (heart rate <60 bpm), peripheral vascular insufficiency (usually Raynaud’s type), dizziness, fatigue.^a

Interactions for Nadolol

Specific Drugs

Drug	Interaction	Comments
Antidiabetic agents	Potential for altered antidiabetic responseb	Adjust antidiabetic agent dosage if neededb
Cardiovascular drugs (e.g., cardiac glycosides, nondihydropyridine calcium-channel blocking agents)	Possible additive negative effects on SA or AV nodal conduction116 117
Catecholamine-depleting drugs (e.g., reserpine)	Potential for additive effects (increased hypotension and marked bradycardia) a b	Monitor closely for symptoms (e.g., vertigo, syncope, postural hypotension)b
Diuretics	Possible increased hypotensive effecta	Careful dosage adjustments recommendeda
Drugs with anticholinergic effects	Potential for antagonism of cardiac β-adrenergic blocking effects
Hypotensive agents	Possible increased hypotensive effect a	Careful dosage adjustments recommendeda
Mibefradil (no longer commercially available in the US)	Slowing or complete suppression of SA node activity with development of slow ventricular rates116 117	Reported principally in geriatric patients with concomitant β-adrenergic blocker therapy116 117
Myocardial depressant general anesthetics	Increased risk of hypotension, myocardial depression, and heart failureb	See Major Surgery under Cautions
Neuromuscular blocking agents (e.g., tubocurarine chloride)	High doses of nadolol may increase effects of neuromuscular blocking agentsa
Phenothiazines	Possible additive hypotensive effect, especially when large phenothiazine doses are useda
Sympathomimetic agents (e.g., isopoterenol, epinephrine)	Possible antagonism of β-adrenergic stimulating effectsa	Administer epinephrine with caution; decreased pulse rate with first- and second-degree heart block and hypertension may occura Very large doses of isoproterenol may be needed to overcome β-adrenergic blocking effectsa

Nadolol Pharmacokinetics

Absorption

Bioavailability

Following oral administration, absorption is variable; averages about 30–40%.^{135 a b}

Duration

Following doses of 40–320 mg daily, duration of antihypertensive and antianginal effects is ≥24 hours.^a

Food

Food does not affect the rate or extent of absorption.^{a b}

Distribution

Extent

Widely distributed; minimal amounts detected in the brain of dogs.^a Distributed into bile.^a

Nadolol crosses the placenta in rats^a and is distributed into human milk.^b

Plasma Protein Binding

About 30%.^{135 a b}

Elimination

Metabolism

Not metabolized.^{a b}

Elimination Route

Excreted principally unchanged in feces (about 76.9%) and urine (about 24.6%) in 4 days.^a

Half-life

10–24 hours.^{135 a b}

Special Populations

Increased half-life in patients with renal impairment.^{a b} Removed by hemodialysis.^a

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at room temperature.^{a b}

ActionsActions

• 
  

  Inhibits response to adrenergic stimuli by competitively blocking β₁-adrenergic receptors within the myocardium and β₂-adrenergic receptors within bronchial and vascular smooth muscle.^{a b}

  
  


• 
  

  Decreases resting heart rate, inhibits exercise-induced increases in heart rate, and decreases cardiac output at rest and during exercise.^a

  
  


• 
  

  Decreases AV node conduction velocity and decreases myocardial automaticity.^a

  
  


• 
  

  No intrinsic sympathomimetic activity, little direct myocardial depressant activity, and no membrane-stabilizing effect on the heart.^a

  
  


• 
  

  Reduces BP by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.^a

  
  


• 
  

  Decreases BP in both supine and standing positions.^a

  
  


• 
  

  In patients with angina, blocks catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and BP resulting in a net decrease in myocardial oxygen consumption.^a

  
  


• 
  

  May increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure in patients with heart failure.^a

  
  


• 
  

  Increases airway resistance (especially in asthmatic patients) and inhibits the release of free fatty acids and insulin.^a

  
  

Advice to Patients

• 
  

  Importance of taking exactly as prescribed.^a

  
  


• 
  

  Importance of not interrupting or discontinuing therapy without consulting clinician.^a

  
  


• 
  

  Importance of immediately informing clinician at the first sign or symptom of impending cardiac failure or if any difficulty in breathing occurs.^a

  
  


• 
  

  Importance of patient informing anesthesiologist or dentist about nadolol therapy before undergoing major surgery.^a

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^a

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nadolol

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	20 mg*	Corgard (scored)	Monarch
			Nadolol Tablets	Mylan, Teva, UDL
		40 mg*	Corgard (scored)	Monarch
			Nadolol Tablets	Mylan, Sandoz, Teva, UDL
		80 mg*	Corgard (with povidone; scored)	Monarch
			Nadolol Tablets	Mylan, Sandoz, Teva, UDL
		120 mg*	Corgard (with povidone; scored)	Monarch
			Nadolol Tablets	Teva
		160 mg*	Corgard (with povidone; scored)	Monarch
			Nadolol Tablets	Sandoz, Teva, UDL

Nadolol Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	40 mg with Bendroflumethiazide 5 mg	Corzide (with povidone; scored)	Monarch
		80 mg with Bendroflumethiazide 5 mg	Corzide (with povidone; scored)	Monarch

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Corgard 20MG Tablets (KING PHARMA): 30/$93.99 or 90/$259.96

Corgard 40MG Tablets (KING PHARMA): 30/$109.99 or 90/$309.96

Corgard 80MG Tablets (KING PHARMA): 30/$129.99 or 90/$375.98

Corzide 40-5MG Tablets (KING PHARMA): 30/$109.99 or 90/$309.98

Corzide 80-5MG Tablets (KING PHARMA): 30/$119.99 or 90/$339.95

Nadolol 20MG Tablets (MYLAN): 30/$14.99 or 60/$19.97

Nadolol 40MG Tablets (MYLAN): 30/$15.99 or 90/$29.97

Nadolol 80MG Tablets (MYLAN): 30/$19.99 or 90/$39.97

Nadolol-Bendroflumethiazide 40-5MG Tablets (GLOBAL PHARMACEUTICAL CORP): 100/$219.99 or 300/$599.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Ryan RE Sr, Ryan RE Jr, Sudilovsky A. Nadolol: its use in the prophylactic treatment of migraine. Headache. 1983; 23:26-31. [PubMed 6131052]

101. Ryan RE Sr. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J. 1984; 108:1156-9. [IDIS 192098] [PubMed 6148878]

102. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the joint national committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

103. 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

104. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

105. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med. 1993; 153:149-52. [PubMed 8422205]

106. Collins R, Peto R, MacMahon S et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: an overview of randomized drug trials in their epidemiological context. Lancet. 1990; 335:827-38. [IDIS 264836] [PubMed 1969567]

107. Alderman MH. Which antihypertensive drugs first—and why! JAMA. 1992; 267:2786-7. Editorial.

108. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990; 335:765-74. [PubMed 1969518]

109. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991; 265:3255-64. [IDIS 282107] [PubMed 2046107]

110. Dahlof B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-hypertension). Lancet. 1991; 338:1281-5. [IDIS 289158] [PubMed 1682683]

111. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992; 304:405-12. [IDIS 292411] [PubMed 1445513]

112. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.

113. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.

114. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995; 274:620-5. [IDIS 352203] [PubMed 7637142]

115. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation. 1995; 92:1079-82. Editorial.

116. Roche. Posicor (mibefradil hydrochloride) tablets prescribing information. Nutley, NJ; 1997 Dec.

117. Ellison RH. Dear doctor letter regarding appropriate use of Posicor. Nutley, NJ: Roche Laboratories; 1997 Dec.

118. Mylan Pharmaceuticals. Nadolol tablets prescribing information. Morgantown, WV; 1993 Nov.

119. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

120. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [PubMed 8622249]

121. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997; 277:739-45. [IDIS 380501] [PubMed 9042847]

122. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996; 28:1328-428. [IDIS 376249] [PubMed 8890834]

123. Whelton PK, Appel LJ, Espeland MA et al. for the TONE COllaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA. 1998; 279:839-46. [PubMed 9515998]

124. American Diabetes Association. Clinical Practice Recommendations 2001. Position Statement. Diabetic nephropathy. Diabetes Care. 2001; 24(Suppl 1):S69-72.

125. Genuth S. United Kingdom prospective diabetes study results are in. J Fam Pract. 1998; 47:(Suppl 5):S27.

126. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2001; 24(Suppl 1):S33-43.

127. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med. 1998; 15:895-6. [PubMed 9827842]

128. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 1998; 106:369-72. [PubMed 9831300]

129. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703-13. [IDIS 412064] [PubMed 9732337]

130. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; 1998 Sep 15 from American Diabetes Association web site.

131. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998; 317:713-20. [IDIS 412065] [PubMed 9732338]

132. Davis TME. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust. 1998; 169:511-2.

133. American Diabetes Association. Clinical Practice Recommendations 1999. Position statement. Implications of the United Kingdom propective Diabetes Study. Diabetes Care. 1999; 22(Suppl 1):S27-31.

134. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: apporaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9A-38A.

135. Monarch. Corzide (40/5) and Corzide (80/5) (nadolol and bendroflumethazide) tablets prescribing information. Bristol, TN; 2001 Oct.

136. Lim PO, MacDonald TM. Antianginal and β-adrenergic blocking drugs. In: Dukes MNG, ed. Meyler’s side effects of drugs. 13th ed. New York: Elsevier/North Holland Inc; 1996:488-535.

137. Gress TW, Nieto FJ, Shahar E et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. N Engl J Med. 2000; 342:905-12. [IDIS 442916] [PubMed 10738048]

138. Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med. 2000; 342:969-70. [IDIS 442921] [PubMed 10738057]

139. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

140. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

141. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

142. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial Lancet. 1998; 351:1755-62.

143. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25(Suppl. 1):S71-S73.

144. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002; 25(Suppl 1):S33-43.

145. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol. 1999; 33:2092-7.

146. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). 2002. Available from ACC website. Accessed Sep. 10, 2002.

147. Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: a statement for health professional from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2002; 106:143-60. [PubMed 12093785]

148. Ramadan NM, Silberstein SD, Freitag FG et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of mirgaine. St. Paul, MN; 2001. From the American Academy of Neurology web site.

149. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From ACC website.

150. Antman EM, Fox KM et al. Guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction: proposed revisions. Am Heart J. 2000; 139:461-75. [IDIS 444999] [PubMed 10689261]

151. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-42. [IDIS 490723] [PubMed 12479770]

152. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-riskhypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97. [IDIS 490721] [PubMed 12479763]

153. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA. 2003; 289.

154. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163:525-41.

155. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26(Suppl 1):S80-2.

156. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension. 2003; 21:1011-53.

157. Carter B for the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Personal communication.

160. Thadani U. Beta blockers in hypertension. Am J Cardiol. 1983; 52:10-5D.

161. Conolly ME, Kersting F, Dollery CT. The clinical pharmacology of beta-adrenoceptor-blocking drugs. Prog Cardiovasc Dis. 1976; 19:203-34. [PubMed 10600]

162. Shand DG. State-of-the-art: comparative pharmacology of the β-adrenoceptor blocking drugs. Drugs. 1983; 25(Suppl 2):92-9.

163. Breckenridge A. Which beta blocker? Br Med J. 1983; 286:1085-8. (IDIS 169422)

164. Anon. Choice of a beta-blocker. Med Lett Drugs Ther. 1986; 28:20-2. [PubMed 2869400]

165. Wallin JD, Shah SV. β-Adrenergic blocking agents in the treatment of hypertension: choices based on pharmacological properties and patient characteristics. Arch Intern Med. 1987; 147:654-9. [IDIS 227948] [PubMed 2881524]

166. McDevitt DG. β-Adrenoceptor blocking drugs and partial agonist activity: is it clinically relevant? Drugs. 1983; 25:331-8.

167. McDevitt DG. Clinical significance of cardioselectivity: state-of-the-art. Drugs. 1983; 25(Suppl 2):219-26.

168. Frishman WH. β-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med. 1981; 305:500-6. [IDIS 136600] [PubMed 6114433]

169. Thadani U, Davidson C, Chir B et al. Comparison of the immediate effects of five β-adrenoceptor-blocking drugs with different ancillary properties in angina pectoris. N Engl J Med. 1979; 300:750-5. [PubMed 581782]

170. Lewis RV, McDevitt DG. Adverse reactions and interactions with β-adrenoceptor blocking drugs. Med Toxicol. 1986; 1:343-61. [IDIS 239050] [PubMed 2878346]

171. Frishman WH. Clinical differences between beta-adrenergic blocking agents: implications for therapeutic substitution. Am Heart J. 1987; 113:1190-8. [IDIS 229873] [PubMed 2883867]

a. AHFS Drug Information 2004. McEvoy GK, ed. Nadolol. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1770-3 .

b. Monarch Pharmaceuticals. Corgard (nadolol) tablets prescribing information. Bristol, TN; 2001 Oct.

More Nadolol resources

• Nadolol Side Effects (in more detail)
• Nadolol Dosage
• Nadolol Use in Pregnancy & Breastfeeding
• Drug Images
• Nadolol Drug Interactions
• Nadolol Support Group
• 11 Reviews for Nadolol - Add your own review/rating

• Nadolol MedFacts Consumer Leaflet (Wolters Kluwer)


• Nadolol Prescribing Information (FDA)


• Nadolol Professional Patient Advice (Wolters Kluwer)


• nadolol Concise Consumer Information (Cerner Multum)


• nadolol Advanced Consumer (Micromedex) - Includes Dosage Information


• Corgard Prescribing Information (FDA)

Compare Nadolol with other medications

• Angina
• Anxiety
• Benign Essential Tremor
• Esophageal Variceal Hemorrhage Prophylaxis
• Glaucoma
• High Blood Pressure
• Lithium Tremor
• Migraine Prevention
• Mitral Valve Prolapse
• Parkinsonian Tremor
• Supraventricular Tachycardia

YAZ

Pronunciation: droe-SPYE-re-none/ETH-i-nil ES-tra-DYE-ol
Generic Name: Drospirenone/Ethinyl Estradiol
Brand Name: YAZ

Cigarette smoking increases the risk of serious heart problems associated with use of YAZ. This risk increases with age and with heavy smoking (15 or more cigarettes per day). Women who are older than 35 years old have a greater risk. Women who use YAZ should not smoke.

YAZ is used for:

Preventing pregnancy. It is also used to treat premenstrual dysphoric disorder (PMDD) or certain types of acne in women who are using YAZ for birth control. It may also be used for other conditions as determined by your doctor.

YAZ is a progesterone and estrogen combination birth control pill. It works by preventing ovulation, thickening the mucus in the cervix, and changing the lining of the uterus.

Do NOT use YAZ if:

• you are allergic to any ingredient in YAZ


• you are pregnant or think you may be pregnant


• you have a history of blood clotting problems, severe blood clots (eg, in the lungs, legs, eyes), certain blood vessel problems (eg, bleeding in the brain, heart attack, stroke), or breast cancer


• you have certain heart problems (eg, heart valve problems, certain types of irregular heartbeat); chest pain caused by angina; certain blood problems (eg, porphyria); certain types of headaches or migraines with aura; severe or uncontrolled high blood pressure; diabetes that affects circulation; endometrial, cervical, or vaginal cancer; estrogen-dependent growths; or undiagnosed abnormal vaginal bleeding


• you have kidney disease, adrenal disease, liver disease or liver tumors, or a history of yellowing of the eyes or skin caused by pregnancy or prior birth control use


• you have had surgery and are or will be confined to a bed or a chair for an extended period of time


• you are older than 35 years old and you smoke 15 or more cigarettes per day

Contact your doctor or health care provider right away if any of these apply to you.

Before using YAZ:

Some medical conditions may interact with YAZ. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of endometriosis, growths in the uterus, abnormal mammogram, irregular menstrual periods, abnormal vaginal bleeding, a lump in the breast, or fibrocystic breast disease, or if a family member has had breast cancer


• if you have a history of diabetes or high blood sugar, gallbladder problems, migraines or severe or persistent headaches, heart problems, high blood pressure, high blood cholesterol or lipid levels, kidney or liver problems, blood or bleeding problems, mental or mood problems (eg, depression), lupus, high blood calcium or potassium levels, chorea (jerky, involuntary movements of the face, arms, or legs), varicose veins, yellowing of the eyes or skin, pancreas problems, or seizures


• if you smoke, are very overweight, have not yet had your first menstrual period, or have fluid retention or swelling problems


• if you will be having surgery or will be confined to a bed or a chair for a long period of time

Some MEDICINES MAY INTERACT with YAZ. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Aldosterone blockers (eg, eplerenone), angiotensin converting enzyme (ACE) inhibitors (eg, enalapril), angiotensin receptor blockers (eg, losartan), heparin, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, naproxen), potassium supplements, or potassium-sparing diuretics (eg, spironolactone) because the risk of high blood potassium levels may be increased


• Acetaminophen, ascorbic acid (vitamin C), or atorvastatin because they may increase the risk of YAZ's side effects


• Azole antifungals (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir) because they may decrease YAZ's effectiveness, resulting in pregnancy or breakthrough bleeding, or they may increase the risk of YAZ's side effects


• Aprepitant, barbiturates (eg, phenobarbital), bosentan, carbamazepine, felbamate, griseofulvin, hydantoins (eg, phenytoin), modafinil, nevirapine, penicillins (eg, ampicillin), phenylbutazone, rifampin, St. John's wort, tetracyclines (eg, doxycycline), topiramate, or troglitazone because they may decrease YAZ's effectiveness, resulting in breakthrough bleeding or pregnancy


• Beta-blockers (eg, propranolol), corticosteroids (eg, prednisolone), cyclosporine, theophylline, tizanidine, or troleandomycin because the risk of their side effects may be increased by YAZ


• Anticoagulants (eg, warfarin) because their effectiveness may be decreased or the risk of their side effects may be increased by YAZ


• Clofibric acid, lamotrigine, morphine, salicylic acid, or temazepam because their effectiveness may be decreased by YAZ

This may not be a complete list of all interactions that may occur. Ask your health care provider if YAZ may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use YAZ:

Use YAZ as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with YAZ. Talk to your pharmacist if you have questions about this information.


• Take YAZ by mouth with or without food.


• Talk with your doctor about how you should start to take your first pack of YAZ. If you begin to take YAZ during the first 24 hours of your period, you do not need to use an extra form of birth control. If you begin to take YAZ on the Sunday after your period starts, you will need to use an extra form of birth control for 7 days after you start taking YAZ.


• If you are switching from another birth control pill to YAZ, start YAZ on the same day that would have started a new pack of your previous birth control pills. Talk with your doctor if you have any questions about how to switch from another form of hormonal birth control to YAZ.


• Take YAZ at the same time every day, not more than 2 hours apart. After taking the last pill in the pack, start taking the first pill from a new pack the very next day.


• For YAZ to be effective, it must be taken every day. Do not skip doses even if you do not have sex very often. Do not skip pills if you are spotting, bleeding, or nauseated. If you have these side effects and they do not go away, check with your doctor.


• If you miss 1 dose of YAZ, take it as soon as you remember. Take your next dose at the regular time. This means you may take 2 doses on the same day. you do not need to use a backup form of birth control if you only miss 1 pill. If you miss more than 1 dose, read the extra patient leaflet that comes with YAZ or contact your doctor for instructions. You must use a backup form of birth control if you miss more than 1 dose. If you are not sure how to handle missed doses, use an extra form of birth control (eg, condoms) until you talk with your doctor.

Ask your health care provider any questions you may have about how to use YAZ.

Important safety information:

• YAZ may increase the risk of stroke, heart attack, blood clots, high blood pressure, or similar problems. The risk is greater if you smoke. Do not smoke or use other tobacco products while taking YAZ.


• Bleeding or spotting may occur while you are taking YAZ. Do not stop taking YAZ if this occurs. If bleeding or spotting continues or is heavy, contact your doctor.


• If your period does not occur when expected, or if you experience unusual breast tenderness or symptoms of morning sickness, call your doctor right away. These symptoms may indicate that you are pregnant.


• The effectiveness of YAZ may be decreased by certain medicines (eg, antibiotics, medicines for seizures, St. John's wort) or conditions (eg, vomiting or diarrhea). This could cause breakthrough bleeding or increase the risk of an unplanned pregnancy if you have sex. To prevent pregnancy, use an additional form of birth control (eg, condoms). Talk with your doctor or pharmacist for more information.


• Tell your doctor or dentist that you take YAZ before you receive any medical or dental care, emergency care, or surgery. If possible, YAZ should be stopped at least 4 weeks before surgery or any time you might be confined to a bed or chair for a long period of time (eg, long plane flight, bedrest, or lengthy illness).


• You should usually not take YAZ within 4 to 6 weeks after giving birth. Discuss any questions or concerns with your doctor.


• YAZ may cause dark skin patches on your face. Exposure to the sun may make these patches darker. If patches develop, use a sunscreen or protective clothing when exposed to the sun, sunlamps, or tanning booths.


• If you wear contact lenses and you develop problems with them or other vision changes, contact your doctor.


• You may experience a delay in being able to become pregnant after stopping YAZ. This effect may be greater in patients who had irregular periods before starting YAZ. Discuss any concerns with your doctor or pharmacist.


• YAZ does not stop the spread of HIV and other sexually transmitted diseases (STDs) to others through blood or sexual contact. Use barrier methods of birth control (eg, condoms) if you have an HIV infection or an STD.


• When your medicine supply is low, get more from your doctor or pharmacist as soon as you can. Do not run out of medicine. Your chance of becoming pregnant may be increased if you do not take YAZ every day as directed.


• Diabetes patients - YAZ may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including breast exams, Pap tests, physicals, and blood pressure, may be performed while you use YAZ. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Examine your breasts monthly as directed by your doctor. Report any lumps right away.


• YAZ may interfere with certain lab tests. Be sure your doctor and lab personnel know you are taking YAZ.


• YAZ should not be used in CHILDREN who have not yet had their first menstrual period; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not take YAZ if you are pregnant. If you think you may become pregnant, contact your doctor right away. YAZ is found in breast milk. Do not breast-feed while you are taking YAZ.

Possible side effects of YAZ:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Breast tenderness; bleeding or spotting between menstrual periods; nausea; stomach cramps or bloating; vomiting; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); breast lump or discharge; calf or leg pain, swelling, or tenderness; change in the amount of urine produced; chest pain or heaviness; confusion; coughing of blood; fainting; irregular heartbeat; left-sided jaw, neck, shoulder, or arm pain; mental or mood changes (eg, depression); migraines; missed menstrual period; numbness of an arm or leg; one-sided weakness; persistent, severe, or recurring headache or dizziness; persistent vaginal spotting; severe or persistent trouble sleeping; severe stomach pain or tenderness; shortness of breath; slurred speech; sudden severe vomiting; swelling of the fingers, hands, legs, or ankles; symptoms of liver problems (eg, yellowing of the skin or eyes, fever, dark urine, pale stools, loss of appetite); unusual or severe vaginal bleeding; unusual tiredness or weakness; vaginal irritation or discharge; vision changes (eg, sudden vision loss, double vision).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: YAZ side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include severe nausea; unexplained vaginal bleeding.

Proper storage of YAZ:

Store YAZ at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep YAZ out of the reach of children and away from pets.

General information:

• If you have any questions about YAZ, please talk with your doctor, pharmacist, or other health care provider.


• YAZ is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about YAZ. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More YAZ resources

• YAZ Side Effects (in more detail)
• YAZ Use in Pregnancy & Breastfeeding
• YAZ Drug Interactions
• YAZ Support Group
• 237 Reviews for YAZ - Add your own review/rating

• YAZ Advanced Consumer (Micromedex) - Includes Dosage Information


• Gianvi Prescribing Information (FDA)


• Loryna Prescribing Information (FDA)


• Ocella Prescribing Information (FDA)


• Syeda Prescribing Information (FDA)


• Yasmin Consumer Overview


• Yasmin Prescribing Information (FDA)


• Yaz Consumer Overview


• Yaz Prescribing Information (FDA)


• Zarah Prescribing Information (FDA)

Compare YAZ with other medications

• Acne
• Birth Control
• Menstrual Disorders
• Premenstrual Dysphoric Disorder

Nolvadex

tamoxifen citrate

Dosage Form: tablets

BOXED WARNING

For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer: Serious and life-threatening events associated with Nolvadex in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY-Clinical Studies − Reduction in Breast Cancer Incidence In High Risk Women). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for Nolvadex vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for Nolvadex vs 0.04 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for Nolvadex vs 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for Nolvadex versus 0.25 for placebo**.

Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.

Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering Nolvadex to reduce their risk of developing breast cancer.

The benefits of Nolvadex outweigh its risks in women already diagnosed with breast cancer.

*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.

**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies

Nolvadex Description

Nolvadex® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. Nolvadex Tablets are available as:

10 mg Tablets:

Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.

20 mg Tablets:

Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.

Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, Nolvadex is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:

Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.

Nolvadex - Clinical Pharmacology

Nolvadex is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.

In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.

Absorption and Distribution:

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg Nolvadex tablets given twice a day vs. a 20 mg Nolvadex tablet given once daily, the 20 mg Nolvadex tablet was bioequivalent to the 10 mg Nolvadex tablets.

Metabolism:

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion:

Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Special Populations:

The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Pediatric Patients:

The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of Nolvadex in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data.

In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of Nolvadex for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Nolvadex therapy in girls have not been established. In adults treated with Nolvadex an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING).

Drug-Drug Interactions:

In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.

Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

In the anastrozole adjuvant trial, co-administration of anastrozole and Nolvadex in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions). Nolvadex should not be co-administered with anastrozole.

Clinical Studies

Metastatic Breast Cancer:

Premenopausal Women (Nolvadex vs. Ablation):

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared Nolvadex to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (Nolvadex/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving Nolvadex, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during Nolvadex therapy responded to subsequent ovarian ablation.

Male Breast Cancer:

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with Nolvadex have shown that Nolvadex is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to Nolvadex which constitutes a 50% objective response rate.

Adjuvant Breast Cancer:

Overview:

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant Nolvadex using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing Nolvadex to no adjuvant therapy and 42% were entered into trials comparing Nolvadex in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for Nolvadex vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for Nolvadex vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for Nolvadex vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for Nolvadex versus 64.3% for control (logrank 2p < 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of Nolvadex, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of Nolvadex on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

Anastrozole Adjuvant ATAC Trial Study of Anastrozole compared to Nolvadex for Adjuvant Treatment of Early Breast Cancer:

An anastrozole adjuvant trial was conducted in 9366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, Nolvadex 20 mg daily, or a combination of these two treatments for five years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and Nolvadex did not demonstrate any efficacy benefit when compared with Nolvadex therapy alone, in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY-Special Populations-Drug-Drug Interactions, PRECAUTIONS-Laboratory Tests, PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections for safety information from this trial. Please refer to the full prescribing information for ARIMIDEX® (anastrozole) 1 mg Tablets for additional information on this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anatrozole arm compared to the Nolvadex arm.

Node Positive - Individual Studies:

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when Nolvadex was added to adjuvant cytotoxic chemotherapy. In the Hubay study, Nolvadex was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, Nolvadex was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of Nolvadex without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using Nolvadex adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

Node Negative - Individual Studies:

NSABP B-14, a prospective, double-blind, randomized study, compared Nolvadex to placebo in women with axillary node-negative, estrogen-receptor positive (≥10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving Nolvadex. This benefit was apparent both in women under age 50 and in women at or beyond age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for Nolvadex compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of Nolvadex appeared to be independent of estrogen receptor status.

Duration of Therapy:

In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional 5 years of Nolvadex or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of Nolvadex were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of Nolvadex (p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95% CI 0.87-1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant Nolvadex 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.

Contralateral Breast Cancer:

The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving Nolvadex compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with Nolvadex of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving Nolvadex were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of Nolvadex reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant Nolvadex 40 mg/day for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

Ductal Carcinoma in Situ:

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of Nolvadex or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.

In this trial 1,804 women were randomized to receive either Nolvadex or placebo for 5 years: 902 women were randomized to Nolvadex 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.

The Nolvadex and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to Nolvadex (44 cases - Nolvadex, 74 cases - placebo; p=0.004; relative risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

Table 1Major Outcomes of the NSABP B-24 Trial

Type of Event	Lumpectomy, radiotherapy and placebo		Lumpectomy, radiotherapy, and Nolvadex		RR	95% CI Limits
	No. of events	Rate per 1000 women per year	No. of events	Rate per 1000 women per year
* Updated follow-up data (median 8.1 years)
Invasive breast cancer (Primary endpoint)	74	16.73	44	9.60	0.57	0.39 to 0.84
-Ipsilateral	47	10.61	27	5.90	0.56	0.33 to 0.91
-Contralateral	25	5.64	17	3.71	0.66	0.33 to 1.27
-Side undetermined	2	--	0	--	--
Secondary Endpoints
DCIS	56	12.66	41	8.95	0.71	0.46 to 1.08
-Ipsilateral	46	10.40	38	8.29	0.88	0.51 to 1.25
-Contralateral	10	2.26	3	0.65	0.29	0.05 to 1.13
All Breast Cancer Events	129	29.16	84	18.34	0.63	0.47 to 0.83
-All ipsilateral events	96	21.70	65	14.19	0.65	0.47 to 0.91
-All contralateral events	37	8.36	20	4.37	0.52	0.29 to 0.92
Deaths	32		28
Uterine Malignancies*	4		9
Endometrial Adenocarcinoma*	4	0.57	8	1.15
Uterine Sarcoma*	0	0.0	1	0.14
Second primary malignancies (other than endometrial and breast)	30		29
Stroke	2		7
Thromboembolic events (DVT, PE)	5		15

Survival was similar in the placebo and Nolvadex groups. At 5 years from study entry, survival was 97% for both groups.

Reduction in Breast Cancer Incidence in High Risk Women:

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (See INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of Nolvadex, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation and surgery (See WARNINGS).

The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial.

In this trial, 13,388 women of at least 35 years of age were randomized to receive either Nolvadex or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to Nolvadex (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.

Table 2Demographic Characteristics of Women in the NSABP P-1 Trial

Characteristic	Placebo		Tamoxifen
	#	%	#	%
Age (yrs)
35-39	184	3	158	2
40-49	2,394	36	2,411	37
50-59	2,011	31	2,019	31
60-69	1,588	24	1,563	24
≥70	393	6	393	6
Age at first live birth (yrs.)
Nulliparous	1,202	18	1,205	18
12-19	915	14	946	15
20-24	2,448	37	2,449	37
25-29	1,399	21	1,367	21
≥30	606	9	577	9
Race
White	6,333	96	6,323	96
Black	109	2	103	2
Other	128	2	118	2
Age at menarche
≥14	1,243	19	1,170	18
12-13	3,610	55	3,610	55
≤11	1,717	26	1,764	27
# of first degree relatives with breast cancer
0	1,584	24	1,525	23
1	3,714	57	3,744	57
2+	1,272	19	1,275	20
Prior Hysterectomy
No	4,173	63.5	4,018	62.4
Yes	2,397	36.5	2,464	37.7
# of previous breast biopsies
0	2,935	45	2,923	45
1	1,833	28	1,850	28
≥2	1,802	27	1,771	27
History of atypical hyperplasia in the breast
No	5,958	91	5,969	91
Yes	612	9	575	9
History of LCIS at entry
No	6,165	94	6,135	94
Yes	405	6	409	6
5-year predicated breast cancer risk (%)
≤2.00	1,646	25	1,626	25
2.01-3.00	2,028	31	2,057	31
3.01-5.00	1,787	27	1,707	26
≥5.01	1,109	17	1,162	18
Total	6,570	100.0	6,544	100.0

Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to Nolvadex (86 cases-Nolvadex, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (≤ 49, 50-59, ≥ 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23-Nolvadex, 35-placebo; RR=0.66; 95% CI: 0.39-1.11).

There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61-Nolvadex, 59-placebo; RR=1.04, 95% CI: 0.73-1.49).

No overall difference in mortality (53 deaths in Nolvadex group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in Nolvadex group vs. 5 deaths in placebo group).

Although there was a non-significant reduction in the number of hip fractures (9 on Nolvadex, 20 on placebo) in the Nolvadex group, the number of wrist fractures was similar in the two treatment groups (69 on Nolvadex, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving Nolvadex. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, Nolvadex was associated with significant bone loss of the lumbar spine and hip in premenopausal women.

The risks of Nolvadex therapy include endometrial cancer, DVT, PE, stroke, cataract formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the Nolvadex group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27-4.92). Deep vein thrombosis was observed in 30 women receiving Nolvadex vs. 19 in women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the Nolvadex group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the Nolvadex arm and 24 on the placebo arm (RR=1.42; 95% CI: 0.82-2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking Nolvadex vs. 483 women receiving placebo (RR=1.13, 95% CI: 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking Nolvadex vs. 129 women receiving placebo (RR=1.51, 95% CI: 1.21-1.89) (See WARNINGS).

Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit (See INDICATIONS AND USAGE).

Table 3Major Outcomes of the NSABP P-1 Trial

	# of Events		Rate/1000 Women/Year		95% CI
Type of Event	Placebo	Nolvadex	Placebo	Nolvadex