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Verapamil

Classification: A

Drug products: Isoptin Injektionslösung, Isoptin retard, Isoptin Retard, Isoptin®, Isoptin® Retard, Verapamil Mylan, Verapamil-Ratiopharma

ATC code: C08DA01

Substances: verapamil, verapamil hydrochloride

Summary

The effects of verapamil on hypertension and after acute myocardial infarction have shown to be similar in men and women.

One study has shown that oral verapamil induced a faster heart rate in women than in men, while IV administration did not show any sex-difference in heart rate.

Additional information

Pharmacokinetics and dosing

Pharmacokinetic studies have observed sex differences in clearance of verapamil. Half-life of both verapamil and its active metabolite nor-verapamil were shorter in women compared with men [2].

Pharmacokinetics of 240 mg verapamil p.o. and 10 mg verapamil i.v. after morning and evening administration has been compared in healthy volunteers (12 men, 12 women). Women had higher systemic clearance and volume of distribution at steady state during both times of i.v. dosing compared to men [3]. Contrary to these findings, another study (6 men, 6 women) observed lower clearance of 120 mg oral verapamil in women than in men [4]. It has been discussed that the observed sex differences in clearance could be due to differences in intestinal P-glycoprotein (pgp) activity or hormone levels [5, 6]. Bioavailability following 120 mg oral verapamil was found to be 25% higher in women than in men [7].

Despite these pharmacokinetic differences, the clinical studies have shown effect with similar doses in men and women [7-10], and no sex differentiation in dosing have been suggested by the pharmaceutical company [11].

Effects

Hypertension

Sex differences in response of blood pressure (BP) to verapamil (initial dose 240 mg/day) or nifedipine (30 mg/day) were studied in a randomized controlled clinical trial (24 men, 15 women). No difference was seen in ambulatory blood pressure although  women had a greater reduction in systolic BP measured at the clinic after one month of treatment compared to men. [8]. In another randomized clinical trial (42 men, 42 women), changes in BP did not differ between men and women after administration of a 120 mg verapamil oral dose. Verapamil (iv. and p.o.) decreased blood pressure in all subjects, but with greater heart rate increases after p.o. verapamil in women than in men. The authors suggest that this difference is due to greater bioavailability of verapamil in women after oral administration. Another explanation might be sex differences in baroreflex responses [7].

In a post hoc analysis of data from the CHRONO trial (1091 men, 1282 women), hypertensive patients received extended-release formulation of verapamil (initial dose 200 mg/day) for 4-12 weeks. Extended release-verapamil was effective in reducing BP in the African American patients regardless of patient's sex. African Americans achieved systolic BP and diastolic BP response rates and target response rates similar to that of other ethnic groups, with no significant differences in efficacy based on patient's sex. Response rates for the other ethnic groups in the study were not stratified by patient's sex [12].

Several randomized clinical trials have demonstrated that antihypertensive treatment with controlled-onset, extended-release formulation (COER) of verapamil yield greater reductions in systolic and diastolic ambulatory BP in women than in men [9, 10]. Women experienced greater reductions in nighttime BP [9]. COER-verapamil is not manufactured in Sweden.

Acute myocardial infarction

Subgroup analyses of data from the randomized, double-blind, placebo-controlled studies DAVIT I (1150 men, 286 women) and II trials (1416 men, 359 women) showed that long-term treatment with verapamil after an acute myocardial infarction reduce major events and total mortality to a similar extent in men and women [13-15].

Adverse effects

There are conflicting results from studies reporting that calcium channel blockers could be associated with cancer. One study reported suspected increase in breast cancer in women taking calcium channel blockers; however the study was criticised due to methodological problems of the study [1].Data from the randomized, double-blind, placebo-controlled study DAVIT II (1416 men, 359 women), showed that treatment with verapamil 120 mg three times daily was not associated with an increased risk of total cancer [16].

Verapamil has been associated with QT-prolongation. Women have been shown to have a greater risk than men of developing dangerous ventricular tachycardias, “Torsade de Pointes” (TdP), when given drugs prolonging repolarization [17]. A study of drug induced QT-prolongation (11 men, 11 women) showed no difference between men and women in QT prolongation after a single dose verapamil [18].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

A randomized double-blind clinical trial of captopril, atenolol, and slow release verapamil (in all 183 men, 185 women; 53 men, 64 women on verapamil) measured quality of life in African-American hypertensive patients (age 18-70 years) over an 8-week treatment period. Compared to base line,  men receiving slow-release verapamil, improvement in score on the sleep scale, irritability-anger scores, and the sets of cognitive tests were found, while women showed improvement in well-being and cognitive tests and less dry mouth symptoms [19].

Updated: 2019-05-27

Date of litterature search: 2019-05-02

References

  1. Coogan PF. Calcium-channel blockers and breast cancer: a hypothesis revived. JAMA Intern Med. 2013;173:1637-8. PubMed
  2. Dadashzadeh S, Javadian B, Sadeghian S. The effect of gender on the pharmacokinetics of verapamil and norverapamil in human. Biopharm Drug Dispos. 2006;27:329-34. PubMed
  3. Dilger K, Eckhardt K, Hofmann U, Kucher K, Mikus G, Eichelbaum M. Chronopharmacology of intravenous and oral modified release verapamil. Br J Clin Pharmacol. 1999;47:413-9. PubMed
  4. Krecic-Shepard ME, Barnas CR, Slimko J, Schwartz JB. Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil. Clin Pharmacol Ther. 2000;68:286-92. PubMed
  5. Seeland U, Regitz-Zagrosek V. Sex and gender differences in cardiovascular drug therapy. Handb Exp Pharmacol. 2012;214:211-36. PubMed
  6. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics?. Clin Pharmacokinet. 2002;41:329-42. PubMed
  7. Krecic-Shepard ME, Barnas CR, Slimko J, Jones MP, Schwartz JB. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol. 2000;40:219-30. PubMed
  8. Loeb ED, Diamond JA, Krakoff LR, Phillips RA. Sex difference in response of blood pressure to calcium antagonism in the treatment of moderate-to-severe hypertension. Blood Press Monit. 1999;4:209-12. PubMed
  9. White WB, Mehrotra DV, Black HR, Fakouhi TD. Effects of controlled-onset extended-release verapamil on nocturnal blood pressure (dippers versus nondippers) COER-Verapamil Study Group. Am J Cardiol. 1997;80:469-74. PubMed
  10. White WB, Johnson MF, Black HR, Elliott WJ, Sica DA. Gender and age effects on the ambulatory blood pressure and heart rate responses to antihypertensive therapy. Am J Hypertens. 2001;14:1239-47. PubMed
  11. Isoptin retard (verapamil). Summary of Product Characteristics. Medical Products Agency Sweden; 2016.
  12. Prisant LM, Weber M, Black HR. Chronotherapeutic oral drug absorption system verapamil is effective in reducing morning blood pressure in African Americans: a post hoc analysis of the chrono trial. J Natl Med Assoc. 2005;97:377-83. PubMed
  13. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J. 1984;5:516-28. PubMed
  14. The Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II--DAVIT II). Am J Cardiol. 1990;66:779-85. PubMed
  15. Galatius-Jensen S, Launbjerg J, Mortensen LS, Hansen JF. Sex related differences in short and long-term prognosis after acute myocardial infarction: 10 year follow up of 3073 patients in database of first Danish Verapamil Infarction Trial. BMJ. 1996;313(7050):137-40. PubMed
  16. Sajadieh A, Storm HH, Hansen JF. Verapamil and risk of cancer in patients with coronary artery disease DAVIT Study Group Danish Verapamil Infarction Trial. Am J Cardiol. 1999;83:1419-22, A9. PubMed
  17. Vicente J, Johannesen L, Mason JW, Pueyo E, Stockbridge N, Strauss DG. Sex differences in drug-induced changes in ventricular repolarization. J Electrocardiol. 2015;48:1081-7. PubMed
  18. Wolbrette DL. Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues. Am J Cardiol. 2003;91:39D-44D. PubMed
  19. Croog SH, Kong BW, Levine S, Weir MR, Baume RM, Saunders E. Hypertensive black men and women Quality of life and effects of antihypertensive medications Black Hypertension Quality of Life Multicenter Trial Group. Arch Intern Med. 1990;150:1733-41. PubMed
  20. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson