The Food and Drug Administration (FDA) considers a side effect serious if it is life-threatening, requires a hospital stay, or causes permanent damage or disability.1 The FDA requires medication guides be issued when, in their view, serious side effects could occur while taking a medication. There is no medication guide issued for amlodipine.2
The manufacturer’s drug information reports combined side effect rates in controlled clinical trials comparing amlodipine (n=1,730) to placebo (n=1,250).3 It warns that worsening angina and acute myocardial infarction can occur in patients with severe obstructive coronary artery disease when increasing the dosage of amlodipine.
Osterloh et al. examined the safety profile of amlodipine utilizing a data-base of Pfizer-sponsored clinical research trials.4 The safety assessment suggests that serious adverse events are not common with amlodipine. In both the placebo-controlled and comparative studies, edema was the most frequently reported side effect. However, the edema was mild to moderate in nature.
An analysis of data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) evaluated the safety and efficacy of various drugs, including data from 460 patients taking amlodipine.5,6 Adverse events that occurred in more than 1% of patients taking amlodipine included edema (8.7%), headache (7.6%), nasopharyngitis (3.5%), upper respiratory infection (3.5%), potassium abnormalities (2.0%), and dizziness (1.5%). These adverse events occurred more often than in patients taking placebo, although a statistical analysis was not done for this comparison. Authors determined that amlodipine users in the ALLHAT study did not have an increased risk of gastrointestinal bleeding compared to users of lisinopril or chlorthalidone.
High and low potassium levels are associated with adverse cardiac events and can result from the use of medications used to treat hypertension.6 Because baseline and one-year potassium levels were available in the data from the ALLHAT study, researchers compared rates of hyper- and hypokalemia in patients taking amlodipine (2.5 – 10 mg/day), lisinopril, and chlorthalidone.7 Modest hypokalemia (3.2 – 3.4 mmol/L) occurred in 91 (1.7%) of 5,371 amlodipine users in the ALLHAT study when measured after one year of use. Severe hypokalemia (potassium < 3.2 mmol/L) occurred in 17 (0.3%) amlodipine users. These rates were lower than in those taking the diuretic chlorthalidone and higher than the rates among lisinopril users. Hypokalemic patients taking amlodipine had significantly increased risk of subsequent coronary heart disease (hazard ratio [HR] 2.41), heart failure (HR 2.19), combined cardiovascular disease (HR 1.48) and cardiovascular disease death (HR 2.10) compared to amlodipine users whose potassium levels remained normal. Because this data was evaluated after the study was concluded, it is not clear if the rates of cardiovascular events were associated with the use of amlodipine or other causes. Hyperkalemia occurred in 102 (1.9%) patients taking amlodipine. This rate was lower than that in the patients taking lisinopril. Hyperkalemic patients in all treatment groups were at significantly increased risk of subsequent cardiovascular disease compared to patients whose potassium levels remain normal (HR 1.58).
Another measure of the seriousness of a side effect is the patient’s decision to discontinue a drug because of the unacceptability of its effects. Although real-life clinical conditions may differ from study conditions, seven of 79 hypertensive patients taking amlodipine in a 12-week study were prematurely terminated from the study due to adverse events.8 One study participant had an unspecified serious adverse event.
In a multicenter, double-blinded clinical trial, 825 participants with evidence of coronary artery disease were randomized to receive either amlodipine or placebo.9 Those randomized to the amlodipine group were given 5 mg daily. The amlodipine dose was increased to 10 mg after two weeks if tolerated. Throughout the three-year study, adverse events were reported in both the amlodipine (n=417) and the placebo (n=408) group. The incidence of edema, vertigo, constipation, erythematous rash, and dry mouth occurred more often among amlodipine users compared to placebo (HR > 1).
Drug effects may not occur immediately. A 2013 case-control study linked long-term calcium channel blocker (CCB) use with an increased risk of breast cancer.10 Current use of CCBs (including amlodipine) for ten or more years was associated with higher risks of ductal breast cancer (odds ratio [OR] 2.4, 95% confidence interval [CI] [1.2 – 4.9], p=0.04 for trend) and lobular breast cancer (OR 2.6, 95% CI [1.3 – 5.3], p=0.01 for trend). Use of other antihypertensive medication (diuretics, beta-blockers, and angiotensin receptor blockers) was not associated with risk. Since then, other researchers have studied this effect, and the results have been inconclusive. Wright et al. conducted a systematic review and meta-analysis of these studies.11 The association appears to be unlikely, but the authors felt that uncertainty remains, and further study was needed to refute the association between the use of CCBs and breast cancer risk.
According to the package insert, side effects of amlodipine observed in less than 1.0% of patients but greater than 0.1% were:3
- cardiovascular (arrhythmia, bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis)
- neurologic (hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo, dry mouth, increased sweating)
- gastrointestinal (anorexia, constipation, dyspepsia, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia)
- musculoskeletal (arthralgia, arthrosis, muscle cramps, myalgia)
- psychiatric (sexual dysfunction in men and women, insomnia, depression, nervousness, depression, abnormal dreams, anxiety, depersonalization)
- respiratory (dyspnea, epistaxis)
- dermatological (angioedema, erythema multiforme, pruritis, rash)
- ocular (abnormal vision, conjunctivitis, diplopia, eye pain)
- urinary (nocturia, alterations in urinary frequency)
- metabolic (hyperglycemia, thirst)
- hematopoietic (leukopenia, purpura, thrombocytopenia)
- other (tinnitus, allergic reactions, back pain, hot flashes, malaise, pain, weight gain, weight decrease, rigors).
Side effects observed in less than 0.1% of patients were cardiac failure, pulse irregularity, extra systoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parasomnia, taste perversion, abnormal visual accommodation, and xerophthalmia.3
- Food and Drug Administration. What is a serious adverse event? https://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm. Accessed July 14, 2018.
- Food and Drug Administration. Medication guides. https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Accessed July 14, 2018.
- Norvasc [package insert]. Kirkland, Quebec: Pfizer Labs; 2016.
- Osterloh I. The safety of amlodipine. Am Heart J 1989; 118 (5 part 2): 1114-1120.
- Phillips W, Piller LB, Williamson JD, et al. Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE-inhibitor, or calcium-channel blocker in ALLHAT. J Clin Hypertens2013; 15 (11): 825-832.
- Cohen HW, Madhavan S, Alderman MH. High and low serum potassium associated with cardiovascular events in diuretic-treated patients. J Hypertens 2001; 19 (7): 1315-1323.
- Alderman MH, Piller LB, Ford CE, et al. Clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2012; 59 (5): 926-933.
- Kes S, Caglar N, Canberk A, et al. Treatment of mild-to-moderate hypertension with calcium channel blockers: a multicentre comparison of once-daily nifedipine GITS with once-daily amlodipine. Curr Med Res Opin 2003; 19 (3): 226-237.
- Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102 (13): 1503-1510.
- Li CI, Daling J, Tang M, et al. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med 2013; 173 (17): 1629-1637.
- Wright CM, Moorin RE, Chowdhury EK, et al. Calcium channel blockers and breast cancer incidence: an updated systematic review and meta-analysis of the evidence. Cancer Epidemiol 2017; 50 (May 2017): 113-124.