Verapamil

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 [7].

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 [8]. Contrary to these findings, another study (6 men, 6 women) observed lower clearance of 120 mg oral verapamil in women than in men [9]. 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 [10, 11]. Bioavailability following 120 mg oral verapamil was found to be 25% higher in women than in men [12].

Despite these pharmacokinetic differences, the clinical studies have shown effect with similar doses in men and women [12-15], and no sex differentiation in dosing have been suggested by the pharmaceutical company [16].

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. [13]. 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 [12].

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 [17].

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 [14, 15]. Women experienced greater reductions in nighttime BP [14]. 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 [18-20].

Adverse effects

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.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 [21].

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 [22]. 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 [23].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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 [24].