Amlodipine precautions

General
Since the vasodilation induced by Amlodipine 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 Amlodipine besylate tablets, 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 tablets (5 to 10 mg per day) have been studied in a placebo-controlled trial of 1,153 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 tablets have been compared to placebo in four 8 to 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 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 is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering Amlodipine to patients with severe hepatic impairment.

Drug Interactions
In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Effect of Other Agents on Amlodipine Besylate Tablets
Cimetidine: Coadministration of Amlodipine besylate tablets with cimetidine did not alter the pharmacokinetics of Amlodipine.

Grapefruit juice: Coadministration 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.

Antacid: Coadministration of the antacid with a single dose of Amlodipine besylate tablets had no significant effect on the pharmacokinetics of Amlodipine.

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlodipine. When Amlodipine besylate tablets and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Effect of Amlodipine Besylate Tablets on Other Agents
Atorvastatin: Coadministration of multiple 10 mg doses of Amlodipine besylate tablets with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of Amlodipine besylate tablets with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of Amlodipine besylate tablets had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of Amlodipine besylate tablets with warfarin did not change the warfarin prothrombin response time.

In clinical trials, Amlodipine besylate tablets have 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
Teratogenic Effects: 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 Amlodipine is administered.

Pediatric Use
The effect of Amlodipine on blood pressure in patients less than 6 years of age is not known.

Geriatric Use
Clinical studies of Amlodipine besylate tablets 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 to 60%, and a lower initial dose may be required.