CONTRAINDICATIONS
Amlodipine besylate 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 amlodipine besylate is gradual in onset, acute hypotension has
rarely been reported after oral administration of amlodipine besylate. Nonetheless, caution should be
exercised when administering amlodipine besylate 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.
amlodipine besylate (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). Amlodipine besylate 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
Amlodipine besylate 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 amlodipine besylate is extensively metabolized by the liver and the plasma elimination half-life
(t½) is 56 hours in patients with impaired hepatic function, caution should be exercised when
administering amlodipine besylate to patients with severe hepatic impairment.
Drug/Laboratory Test Interactions
None known.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Rats and mice treated with amlodipine in the diet for 2 years, at concentrations calculated to provide
daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence carcinogenicity. The highest
dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on
a mg/m2 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/m2 basis).
*Based on patient weight of 50 kg.
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/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 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.
*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 amlodipine besylate is administered.
Pediatric Use
Safety and effectiveness of amlodipine besylate in children have not been established.
Geriatric Use
Clinical studies of amlodipine besylate 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).