Amlodipine (Norvasc): Drug Whys
By Mike McEvoy
Generic Name: Amlodipine (multiple manufacturers)
Common Brand Name: Norvasc (Pfizer – U.S.)
Popularity: 14th most commonly prescribed drug between 2002 – 2007 (U.S.)
Class: Calcium channel blocker
Treatment Uses – Mild to moderate hypertension (primarily systolic hypertension), angina, prevention of migraine headaches (not effective for stopping a migraine in progress), and treatment of pulmonary hypertension. Amlodipine is the drug of choice for treatment of Raynaud’s disease in adults. Controls blood pressure, maintains kidney function, and reduces rejection rates in certain transplant patients. Evidence suggests amlodipine may be useful in treatment of preterm labor. Previously used for treatment of congestive heart failure but potential risks are now thought to outweigh benefits.
Dosing and Administration – Initial oral dosing in adults is 5 milligrams daily, adjusted at one to two week intervals up to a maximum of 10 milligrams daily. Lower doses are recommended for those who are small, frail or geriatric, and patients with liver dysfunction (hepatic insufficiency). For these patients, a starting dose of 2.5 milligrams daily is recommended. The minimum effective dose of amlodipine appears to be 2.5 milligrams in adult patients. Treatment of Raynaud’s disease typically requires a 10 milligram daily dose.
In pediatric patients between 6 and 17 years old, the dose range is 2.5 to 5 milligrams daily. Children seem to require higher doses of amlodipine on a milligram per kilogram basis than adults and often require a twice-daily dosing schedule to maintain blood pressure control. The younger the child, the higher the (weight adjusted) dosing requirements seem to be. Adjustments can be made more frequently in children, recommended at five to seven-day intervals.
Food does not affect amlodipine absorption – it can be taken without regard to meals. Amlodipine is usually taken as a single daily dose in the morning.
Dosage adjustments are not necessary in patients with kidney disease, but are highly recommended in patients with liver disease because it is extensively metabolized in the liver. Dose reductions are also recommended in the geriatric population due to their decreased clearance of this drug.
Intravenous (IV) amlodipine is available in some countries, but not the United States. Oral suspensions can be prepared by a pharmacy and when refrigerated, have a shelf life of up to 90 days.
Overdoses result in hypotension (duh) and possible reflex tachycardias. It would appear that the lethal level of amlodipine is in the range of 40 milligrams per kilogram based on animal studies. Adults taking up to 250 milligrams have remained asymptomatic. Survival following a 560 milligram overdose has been reported. Children ingesting 2 milligrams per kilogram have exhibited marked hypotension requiring hospital admission and treatment. Use of calcium chloride or gluconate is recommended (and quite helpful) in any calcium channel blocker overdose; atropine is not usually effective. Pressors may be required. Hemodialysis is not helpful in removing the drug from the body. Dose adjustments do not appear necessary for patients on dialysis although studies to date have involved relatively small numbers of patients.
Pharmacology/Pharmacokinetics/Stability – After oral administration of amlodipine, peak concentrations are reached in the bloodstream between six and nine hours. Effects on blood pressure take from 24 to 96 hours to appear with initial dosing and 24 to 48 hours with subsequent dose titrations. Steady blood plasma levels are usually achieved after seven to eight days of consecutive dosing and drug effects last for about 24 hours after treatment is discontinued. The liver metabolizes 90 percent of each amlodipine dose. Kidneys excrete 60 percent and feces carry away 20 to 25 percent.
There are not sufficient data to establish the safety of using calcium channel blockers during pregnancy. It is unknown whether amlodipine is excreted in breast milk.
The mechanism of action of amlodipine is similar to other calcium channel blockers: preferential blockade of calcium channels in depolarized cells. Translated into non-chemist terms, amlodipine is a peripheral arterial vasodilator acting directly on arterial smooth muscle walls resulting in a reduced peripheral vascular resistance and reduced blood pressure.
Amlodipine tablets vary in size and shape by manufacturer. They should be kept at room temperature between 59 and 86 F and protected from light and moisture using a tight, light-resistant container.
Cautions and Warnings – Patients starting amlodipine should be advised not to change their position suddenly because of the possibility of dizziness or syncope induced by postural hypotension. Amlodipine, like all calcium channel blockers, should be used cautiously in patients with congestive heart failure because of a tendency to worsen heart failure. Rarely, patients with significant coronary artery disease have developed increased frequency or severity of angina when starting or increasing their dose of amlodipine.
Important Side Effects and Interactions – The arteriolar dilating effects of amlodipine produce the majority of the drug’s side effects. Dose dependent peripheral edema is the most frequent adverse effect reported, with an incidence ranging from 1.8 percent at doses of 2.5 milligrams daily to 10.8 percent at 10 milligrams daily. Significantly more women than men (3:1) develop edema, and the incidence is also higher in the over 65-year-old age group. Amlodipine dose related dizziness has a reported incidence ranging from 1 to 3 percent. Palpitations (with accompanying tachycardia) have been observed in up to 5 percent of patients taking amlodipine and, like edema, are dose related and more common in women than men. Dose related flushing is reported with all calcium channel blockers; amlodipine has an overall 2 percent reported incidence of flushing. All of these peripheral effects diminish in intensity with continued treatment.
A poorly understood calcium channel blocker side effect called gingival hyperplasia involves overgrowth of the gum tissues in the mouth. While seemingly common with other calcium channel blockers, it is rarely reported in patients taking amlodipine.
Eighty-one drugs are reported to interact with amlodipine. Of these, the most significant involves patients also taking cyclosporine (typically transplant patients). The combination of amlodipine and cyclosporine has been known to raise cyclosporine blood levels by 25 to 40 percent, which leads to prescribing specifically for the purpose of elevating cyclosporine levels (amlodipine is much cheaper than cyclosporine and many transplant patients need antihypertensive therapy). Despite this, the interaction is important not to overlook.
Rarely, some of the antifungal drugs have been reported to increase blood amlodipine concentrations, leading to increased dose dependent side effects (edema, dizziness, palpitations, flushing).
Licorice is reported to reduce the effectiveness of amlodipine. No surprise there -- licorice consumption in various doses has been shown to increase systolic blood pressure in healthy normotensive people as well. Separate studies of alcohol and grapefruit juice have both demonstrated no clinically significant interactions with amlodipine. Other than licorice, there have been no significant reports of amlodipine-food interactions.
Average Costs – U.S.
• 5 mg tablet/10 mg tablet (generic)
Patient cost: $1.13/1.17 each*
Large Hospital cost: $0.07/0.08 each
*(Wal Mart® and Target don’t include amlodipine in their $4/month programs)
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed March, 2009).
2. Albany Medical Center Pharmacy, Albany, New York.