Norvasc Description

NORVASC® is the besylate salt of amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C 20 H 25 CIN 2 O 5 ?C 6 H 6 O 3 S, and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. NORVASC (amlodipine besylate) tablets are formulated as white tablets equivalent to 2.5, 5 and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

Norvasc Indications And Usage

1. Hypertension

NORVASC is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

2. Coronary Artery Disease (Cad)

Chronic Stable Angina

NORVASC is indicated for the symptomatic treatment of chronic stable angina. NORVASC may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinzmetal's Or Variant Angina)

NORVASC is indicated for the treatment of confirmed or suspected vasospastic angina. NORVASC may be used as monotherapy or in combination with other antianginal drugs.

Angiographically Documented Cad

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, NORVASC is indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.

Norvasc Contraindications

NORVASC is contraindicated in patients with known sensitivity to amlodipine.

Norvasc Side Effects

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.

Norvasc Precautions

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 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 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.

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 ).

Norvasc Overdosage

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) 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 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.