Go the extra millimeter[TM].

National Health and Nutrition Examination Survey

*Non-placebo-corrected results of a systematic review of randomized, controlled clinical trials with at least 10 patients, one treatment arm of amlodipine monotherapy, minimum treatment duration of 8 weeks, reported baseline and end-point BP, and presence of baseline hypertension (defined as SBP >140 mm Hg, DBP >90 mm Hg, or both). All reduction, were calculated from baseline measurement. Out of 690 citations, 85 trials representing more than 5000 NORVASC, treated patients met all inclusion criteria. Comparable populations were pooled, and weighted means of efficacy results were calculated in 11 of the 85 trials there was a placebo group (n=639), and the the mean reduction in BP was 4.4/4.9 mm Hg. Mean baseline was 160.7/100.1 mm Hg for NORVASC treated patients and 153.7/98.2 mm Hg for patients in the placebo group (Adapted from levine et al, Clin Ther, 2003, Data on file.)

[ILLUSTRATION OMITTED]

P<.001 for all NORVASC patients vs placebo.

Please see brief summary of prescribing information on adjacent page.

[approximately equal to]60% of all African American hypertensive patients are not at goal systolic blood pressure (1,2) (NHANES* 1999-2000 data)

For proven efficacy in a broad range of patients, including African Americans:

GO TO NORVASC[R]

Reductions in DBP were 17.1, 12.3, and 10.8 mm Hg, respectively (4)

With NORVASC, the magnitude of BP reduction is correlated with the height of pretreatment elevation

In clinical trials, the most common side effects versus placebo were edema (8.3% vs 2.4%), headache (7.3% vs 7.8%), fatigue (4.5% vs 2.8%), and dizziness (3.2% vs 3.4%)

Brief Summary

NORVASC[R] (amlodipine besylate) Tablets

For Oral Use

CONTRAINDICATIONS: NORVASC is contraindicated in patients with known sensitivity to amlodipine.

WARNINGS: Increased Angina and/or Myocardial Infarction: Rarely, patients particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

PRECAUTIONS: General: Since the vasodilation induced by NORVASC is gradual in onset, acute hypotension has rarely been reported after oral administration of NORVASC. Nonetheless, caution should be exercised when administering NORVASC as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should be used with caution in patients with heart failure. NORVASC (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). NORVASC has been compared to placebo in four 8-12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance. NYHA classification, symptoms, or LVEF.

Beta-Blocker Withdrawal: NORVASC is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Patients with Hepatic Failure: Since NORVASC is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering NORVASC to patients with severe hepatic impairment.

Drug Interactions: In vitro data in human plasma indicate that NORVASC has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).

Special Studies: Effect of other agents on NORVASC: CIMETIDINE: co-administration of NORVASC with cimetidine did not alter the pharmacokinetics of NORVASC. GRAPEFRUIT JUICE: co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. MAALOX (antacid): co-administration of the antacid Maalox with a single dose of NORVASC had no significant effect on the pharmacokinetics of NORVASC. SILDENAFIL: a single 100 mg dose of sildenafil (Viagra[R]) in subjects with essential hypertension had no effect on the pharmacokinetic parameters of NORVASC. When NORVASC and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Special Studies: Effect of NORVASC on other agents: ATORVASTATIN: co-administration of multiple 10 mg doses of NORVASC with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin. DIGOXIN: co-administration of NORVASC with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers. ETHANOL (alcohol): single and multiple 10 mg doses of NORVASC had no significant effect on the pharmacokinetics of ethanol. WARFARIN: co-administration of NORVASC with warfarin did not change the warfarin prothrombin response time.

In clinical trials, NORVASC has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Drug/Laboratory Test Interactions: None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/[m.sup.2] basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/[m.sup.2] basis).

Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10 mg/kg amlodipine (respectively 8 times* and 23 times* the maximum recommended human dose of 10 mg on a mg/[m.sup.2] basis) during their respective periods or major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats administered 10 mg/kg amlodipine for 14 days before mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while NORVASC is administered.

Pediatric Use: Safety and effectiveness of NORVASC in children have not been established.

Geriatric Use: Clinical studies of NORVASC 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 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. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS: NORVASC has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with NORVASC was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with NORVASC were of mild or moderate severity. In controlled clinical trials directly comparing NORVASC (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of NORVASC due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects which occurred in a dose related manner are as follows: edema (1.8% at 2.5 mg, 3.0% at 5.0 mg, and 10.8% at 10.0 mg, compared with 0.6% placebo); dizziness (1.1% at 2.5 mg, 3.4% at 5.0 mg, and 3.4% at 10.0 mg, compared with 1.5% placebo); flushing (0.7% at 2.5 mg, 1.4% at 5.0 mg, and 2.6% at 10.0 mg, compared with 0.0% placebo); and palpitation (0.7% at 2.5 mg, 1.4% at 5.0 mg, and 4.5% at 10.0 mg, compared with 0.6% placebo).

Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: headache (7.3%, compared with 7.8% placebo); fatigue (4.5%, compared with 2.8% placebo); nausea (2.9%, compared with 1.9% placebo); abdominal pain (1.6%, compared with 0.3% placebo); and somnolence (1.4%, compared with 0.6% placebo).

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as follows: edema (5.6% in men, 14.6% in women, compared with a placebo incidence in men of 1.4% and 5.1% in women); flushing (1.5% in men, 4.5% in women, compared with a placebo incidence of 0.3% in men and 0.9% in women); palpitations (1.4% in men, 3.3% in women, compared with a placebo incidence of 0.9% in men and 0.9% in women); and somnolence (1.3% in men, 1.6% in women, compared with a placebo incidence of 0.8% in men and 0.3% in women).

The following events occurred in [less than or equal to]1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis; central and peripheral nervous system: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo; gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia; general: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease; musculoskeletal system: arthralgia, arthrosis, muscle cramps,** myalgia; psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization; respiratory system: dyspnea,** epistaxis; skin and appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular; special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus; urinary system: micturition frequency, micturition disorder, nocturia; autonomic nervous system: dry mouth, sweating increased; metabolic and nutritional: hyperglycemia, thirst; hemopoietic: leukopenia, purpura, thrombocytopenia.

The following events occurred in [less than or equal to]0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

NORVASC therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis) in some cases severe enough to require hospitalization have been reported in association with use of amlodipine.

NORVASC has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

OVERDOSAGE: Single oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively, caused deaths. A single oral dose of 4 mg/kg or higher in dogs caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of NORVASC is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who took 70 mg amlodipine and an unknown quantity of benzodiazepine in a suicide attempt developed shock which was refractory to treatment and died the following day with abnormally high benzodiazepine plasma concentration. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As NORVASC is highly protein bound, hemodialysis is not likely to be of benefit.

* Based on patient weight of 50 kg.

** These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

More detailed professional information available on request.

Rev. O December 2001

For clinical information clickety split visit NORVASC.com

References: 1. National Center for Health Statistics. National Health and Nutrition Examination Survey; 1999-2000 (CD-ROM). 2. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446. 3. Levine CB, Fahrbach KR, Frame D, et al. Effect of amlodipine on systolic blood pressure. Clin Ther. 2003;25:35-57. 4. Data on file. Pfizer Inc. New York, NY. 5. IMS International Prescription Data (total prescriptions based on 35 countries moving annual total), September 2002; IMS National Prescription Audit (total prescriptions), 2002; IMS Health Services MIDAS Data (cumulative patient-days total), 1990-September 2002.