Amlodipine
Classification: AATC code: C08CA01, C09DB01
Summary
Clinical studies have shown contradictory results whether there are sex differences or not in blood pressure reduction by amlodipine.
A common adverse effect of amlodipine is edema, mainly peripheral edema, and occurs more often among women.
Additional information
Pharmacokinetics and dosing
In a single-dose bioequivalence study comparing two forms of amlodipine in healthy volunteers (18 men, 18 women), women had a slightly higher bioavailability compared with men. The difference disappeared after adjusting for weight [7]. The clinical studies have shown effect with similar doses in men and women and no sex differentiation in dosing has been suggested [8].
Effects
Studies analyzing sex differences in blood pressure reduction (BP) after amlodipine treatment report contradictory results. Clinical trials have reported a greater BP reduction with amlodipine in women compared with men [9-12]. The Amlodipine Community Trial (702 men, 382 women) observed that women had a greater absolute decrease in BP compared with men following amlodipine therapy (5-10 mg/day for 12 weeks). The percentage of patients achieving goal BP was higher in women than in men (91.4% vs. 83.0%). Reasons for these sex differences could be due to several mechanisms [9]. Also in the bioequivalence study mentioned earlier [8], women demonstrated a more pronounced reduction in systolic BP than men. The clinical significance of the sex difference remains to be determined.
Contrary to these findings, the large randomized double-blind ALLHAT study (17 719 men, 15 638 women) reported that the achieved BP reductions from amlodipine therapy (20 mg/day) were comparable in men and women, although decreases in systolic BP were more pronounced in men [5, 13]. Also, another clinical trial found a slightly less BP reduction in women compared with men [14].
Adverse effects
Clinical trials have report similar incidence of adverse events in men and women [7, 11]. In the Amlodipine Cardiovascular Community Trial [9], the most common adverse event was edema (mainly peripheral edema) which occurred in 24% of treated patients and was more common in women. Mainly peripheral edema is associated with amlodipine treatment [15]. A few cases, most men, of gingival overgrowth have been reported [16], but no significant difference between men and women has been shown [17].There are conflicting results from studies reporting that calcium channel blockers could be associated with cancer [1-5]. One case-control study has reported suspected increase in breast cancer in women taking calcium channel blockers [6], however the study was criticized due to methodological problems.
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Other information
A randomized clinical trial (76 men, 61 women) found that BP response to amlodipine among African-American men and women with early hypertensive nephrosclerosis appears to be determined by CYP4A4 genotypes and sex specificity may be an important consideration [11].
Updated: 2020-10-13
Date of litterature search: 2019-04-25
References
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- Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?. J Am Coll Cardiol. 1999;34(7):1857-66. PubMed
- Fryzek JP, Poulsen AH, Lipworth L, Pedersen L, Nørgaard M, McLaughlin JK et al. A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res Treat. 2006;97(3):231-6. PubMed
- Bangalore S, Kumar S, Kjeldsen SE, Makani H, Grossman E, Wetterslev J et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011;12(1):65-82. PubMed
- Oparil S, Davis BR, Cushman WC, Ford CE, Furberg CD, Habib GB et al. Mortality and morbidity during and after Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: results by sex. Hypertension. 2013;61:977-86. PubMed
- Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med. 2013;173(17):1629-37. PubMed
- Abad-Santos F, Novalbos J, Gálvez-Múgica MA, Gallego-Sandín S, Almeida S, Vallée F et al. Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study. Pharmacol Res. 2005;51:445-52. PubMed
- Norvasc (amlodipin). Summary of Procuct Characteristics. Swedish Medical Products Agency [updated 2018-02-12, cited 2019-04-25]
- Kloner RA, Sowers JR, DiBona GF, Gaffney M, Wein M. Sex- and age-related antihypertensive effects of amlodipine The Amlodipine Cardiovascular Community Trial Study Group. Am J Cardiol. 1996;77:713-22. PubMed
- Feldman RD, Flack J, Howes L, Jenssen T, Reeves R, Shi H et al. Impact of age and gender on blood pressure and low-density lipoprotein cholesterol reduction: results of a pooled analysis. Curr Med Res Opin. 2012;28:1421-33. PubMed
- Schmieder RE, Böhm M. Efficacy and safety of olmesartan medoxomil plus amlodipine in age, gender and hypertension severity defined subgroups of hypertensive patients. J Hum Hypertens. 2011;25:354-63. PubMed
- Kario K, Hoshide S. Age- and Sex-Related Differences in Efficacy With an Angiotensin II Receptor Blocker and a Calcium Channel Blocker in Asian Hypertensive Patients. J Clin Hypertens (Greenwich). 2016;18(7):672-8. PubMed
- Leenen FH, Nwachuku CE, Black HR, Cushman WC, Davis BR, Simpson LM et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2006;48:374-84. PubMed
- Lewis CE, Grandits A, Flack J, McDonald R, Elmer PJ. Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension Results of the Treatment of Mild Hypertension Study. Arch Intern Med. 1996;156:377-85. PubMed
- Vukadinović D, Scholz SS, Messerli FH, Weber MA, Williams B, Böhm M, Mahfoud F. Peripheral edema and headache associated with amlodipine treatment: a meta-analysis of randomized, placebo-controlled trials. J Hypertens. 2019;37(10):2093-2103. PubMed
- Seymour RA, Ellis JS, Thomason JM, Monkman S, Idle JR. Amlodipine-induced gingival overgrowth. J Clin Periodontol. 1994;21:281-3. PubMed
- Karnik R, Bhat KM, Bhat GS. Prevalence of gingival overgrowth among elderly patients under amlodipine therapy at a large Indian teaching hospital. Gerodontology. 2012;29:209-13. PubMed
- Bhatnagar V, Garcia EP, O'Connor DT, Brophy VH, Alcaraz J, Richard E et al. CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease. Am J Nephrol. 2010;31:95-103. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk
Reviewed by: Diana Rydberg, Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson