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Amlodipine

Classification: A

Drug products: Amlarrow, Amlobesyl, Amlodipin Accord, Amlodipin Actavis, Amlodipin Aurobindo, Amlodipin Bluefish, Amlodipin BMM Pharma, Amlodipin Hexal, Amlodipin Jubilant, Amlodipin Krka, Amlodipin Medical Valley, Amlodipin Orifarm, Amlodipin ratiopharm, Amlodipin Sandoz, Amlodipin STADA®, Amlodipin/Valsartan 2care4, Amlodipin/Valsartan Ebb, Amlodipin/Valsartan Krka, Amlodipin/Valsartan STADA, Amlodipine, Amlodipine Teva, Amlodipine Vitabalans, Amlodistad, Amloratio, Amlori, Exforge®, Milodimyl, Norvasc, Norvasc®

ATC code: C08CA01, C09DB01

Substances: amlodipine, amlodipine besylate, amlodipine maleate, amlodipine mesilate, amlodipine mesylate monohydrate

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

  1. Michels KB, Rosner BA, Walker AM, Stampfer MJ, Manson JE, Colditz GA, Hennekens CH, Willett WC. Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of US women: the nurses' health study. Cancer. 1998;83(9):2003-7. PubMed
  2. Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?. J Am Coll Cardiol. 1999;34(7):1857-66. PubMed
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Norvasc (amlodipin). Summary of Procuct Characteristics. Swedish Medical Products Agency [updated 2018-02-12, cited 2019-04-25]
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. Seymour RA, Ellis JS, Thomason JM, Monkman S, Idle JR. Amlodipine-induced gingival overgrowth. J Clin Periodontol. 1994;21:281-3. PubMed
  17. 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
  18. 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
  19. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Diana Rydberg, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson