NORVASC Rx

Effects in Chronic Stable Angina

• The effectiveness of 5–10 mg/day of Norvasc in exercise-induced angina was evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (Norvasc: n=684; placebo: n=354) with chronic stable angina.
• In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose.
• Increases in symptom-limited exercise time averaged 12.8% (63 sec) for Norvasc 10 mg, and averaged 7.9% (38 sec) for Norvasc 5 mg.
• Norvasc 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate.
• The sustained efficacy of Norvasc in angina patients has been observed over long-term dosing.
• In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Effects in Vasospastic Angina

• In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, Norvasc treatment decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (P <0.01). 
• Two of 23 Norvasc and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

Effects in Documented Coronary Artery Disease

In PREVENT (n=825), patients with angiographically documented coronary artery disease (CAD) were randomly assigned to Norvasc (5–10 mg once daily) or placebo; then followed for 3 years.

• Although the study did not show significance on the primary objective of change in coronary luminal diameter (assessed by quantitative coronary angiography), the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%.

• Patients were randomly assigned to double-blind treatment with either Norvasc (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers.
• The mean duration of follow-up was 19 months.
• The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease.
• A total of 110 (16.6%) and 151 (23.1%) first events occurred in the Norvasc and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI, 0.540–0.884; P =0.003).
• The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (for clinical trial data, see full labeling).
• In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Studies in Patients with Heart Failure

Norvasc was 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 left ventricular ejection fraction. 

In a long-term (follow-up ≥6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of Norvasc 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, Norvasc had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Norvasc and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2; followed for a mean 33 months) randomly assigned patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or Norvasc (n=827). There was no statistically significant difference between Norvasc and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on Norvasc). With Norvasc there were more reports of pulmonary edema.

Effects in Hypertension

Adults

• The antihypertensive efficacy of Norvasc has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving patients on Norvasc (n=800) and placebo (n=538). 
• Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. 
• Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. 
• Tolerance was not seen in patients studied for up to 1 year.
• The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. 
• Effects on diastolic pressure were similar in young and older patients.
• The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure.
• Effects were similar in black patients and in white patients.

Pediatrics

• Two hundred sixty-eight hypertensive patients aged 6–17 years were randomly assigned first to Norvasc 2.5 or 5 mg once daily for 4 weeks, and then randomly assigned again to the same dose or to placebo for another 4 weeks. 
• Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. 
• The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose.
• Adverse events were similar to those seen in adults.