General: Since the vasodilation induced by NORVASC is gradual in onset, acute
hypotension has rarely been reported after oral administration. Nonetheless, caution,
as with any other peripheral vasodilator, should be exercised when administering
NORVASC, 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 (see CLINICAL PHARMACOLOGY) 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 ½) 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 indicate that NORVASC has no
effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and
indomethacin.
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®)
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.
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 maleate in the diet for up to two years, at concentrations calculated
to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day showed
no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose
was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day*.
For the rat, the highest dose was, on a mg/m² basis, about twice the maximum recommended
human dose*.
Mutagenicity studies conducted with amlodipine maleate revealed no drug related
effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate
(males for 64 days and females for 14 days prior to mating) at doses up to 10 mg
amlodipine/kg/day (8 times* the maximum recommended human dose of 10 mg/day on a
mg/m² basis).
Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats and rabbits were treated orally with amlodipine
maleate at doses up to 10 mg amlodipine/kg/day (respectively 8 times* and 23 times*
the maximum recommended human dose of 10 mg on a mg/m² basis) during their respective
periods of 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 receiving amlodipine maleate at a dose equivalent to 10 mg
amlodipine/kg/day for 14 days before mating and throughout mating and gestation.
Amlodipine maleate 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.
*Based on patient weight of 50 kg.
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: The effect of NORVASC on blood pressure in patients less than
6 years of age is not known.
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).