Varenicline

Additional information

Varenicline acts as a partial agonist to the alpha4beta2 sub-type of the nicotinic receptor; it has a weak agonistic effect and prevents nicotine from binding to the nicotinic receptors [15]. 

Pharmacokinetics and dosing

A pooled analysis of nine pharmacokinetic trials of varenicline 0.5, 1 or 2 mg daily in adult smokers (954 men, 924 women) showed similar pharmacokinetics in men and women after adjusting for renal function [16]. The manufacturer recommends the same dose in men and women, with a dose reduction in patients with impaired renal function [15].

Effects

Studies reported in the literature shows conflicting results regarding sex differences in the effect of varenicline.

In a double blind placebo controlled randomized trial (53 men, 35 women), women were more likely to adequately guess that they were receiving varenicline (36% men, 57% women) two weeks after initiation of treatment. Treatment guess, regardless of actual treatment, was a predictor of self-report cigarette craving and smoking reward but did not affect smoking behavior [17].Two randomized controlled trials of supportive counseling combined with varenicline 2 mg/day (in all 228 men, 209 women), bupropion 300 mg/day (in all 252 men, 179 women) or placebo (in all 253 men, 197 women) the smoking cessation frequency was similar in men and women [1, 2].

In contrast to this, in an observational study of a 6-week cognitive behavioral program with opportunity to add nicotine replacement therapy, bupropion or varenicline (552 men, 730 women), predictors for success in smoking cessation were investigated. Follow-up interviews carried out at 12, 26, and 52 weeks showed that women were 1.5 times more likely to continue smoking than men despite similar baseline characteristics and treatments [3].

However in a double-blind parallel-arm adaptive treatment trial excluding responders to one week nicotine patch treatment, smokers were randomized to varenicline 2 mg/day (46 men, 62 women) or a combination of varenicline 2 mg/day and bupropion 300 mg/day (55 men, 58 women). The quit rate with varenicline in monotherapy seemed to be higher in women than in men. However the quit rate with the combination of varenicline and bupropion was higher in men, with odds ratio compared to monotherapy for successful quitting at 8-11 weeks was 4.3 in men and 0.9 in women [4].

Adverse events

In a clinical effectiveness trial where smokers (127 men, 270 women) were prescribed a 12-week treatment with varenicline and randomized to one of three behavioral treatment interventions, women rated the severity of nausea higher than men (1.9 vs 1.1) after 21 days of treatment [18].

A comparative controlled trial investigating side effects of varenicline treatment 28 days after initiation and nicotine withdrawal symptoms 21 days after quit day (339 men, 679 women) found several adverse events to be more common in women; nausea, flatulence, change in appetite, dysguesia, difficulty sleeping, constipation, vomiting, and retching. Changes in dreaming were equally common in men and women. Although the severity of the adverse events was rated higher by women than by men, there was no difference in persistence between men and women. Of the nicotine withdrawal symptoms tension/agitation and anxiety were reported at higher rates by women than men, while craving/desire to smoke, irritability/anger, difficulty concentrating, depression and confusion was equally common in men and women [19].

A study of changes in metabolic syndrome after smoking cessation with cognitive behavioral therapy only (7 men, 9 women) or combined with varenicline (9 men, 7 women) or nicotine replacement therapy (7 men, 9 women), showed that the increase in waist girth, triglycerides, insulin resistance, and decrease in HDL-C was greater in men than in women after 7 weeks. However, the weight gain was lower in men than in women [20].Women who quit smoking without pharmacological treatment have been shown to gain 1 kg more than men [5].In an observational cohort study during 1.5 years of 80 660 smokers (approximately equal sex distribution) who were prescribed nicotine replacement therapy, varenicline or bupropion, the hazard ratio for self-harm was similar in men and women [6].

Reproductive health issues

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

Other information

A cost-utility analysis of reduction of health care costs during 50 years for chronic obstructive pulmonary disease, coronary heart disease, stroke, and lung cancer in Swedish smokers (168 844  men, 208 737 women) was performed. It showed that the increase in the sustained quitting rates at 24 and 52 weeks through adding 12 weeks of varenicline treatment in those who successfully quit smoking after the initial 12 weeks of treatment resulted in slightly lower gained incremental costs per quality-adjusted life-year (QUALY) in men than in women [21]. A Swedish study of smokers treated with varenicline (8639 men, 9287 women) or bupropion (8674 men, 9252 women) showed  that the rate of cardiovascular events per 1000 person years was higher in women than in men six months after treatment with varenicline (4.9 men, 9.1 women) or bupropion (5.8 men, 8.6 women) [7]. No comparison to non-treated smokers was made.

A meta-analysis of observational studies (2,409,955 individuals with 43,995 coronary heart disease events, follow-up varied from 4 to 40 years) showed that, independent of other cardiovascular risk factors, the relative risk of a coronary heart disease event was 25% higher in smoking women than in smoking men, and the risk of a fatal coronary heart disease event was 19% higher in smoking women than in smoking men. When the results were divided by age, the difference was significant only in the age group 60-69 years. For every year of study follow-up, the risk increased by 2% in smoking women compared to smoking men. The beneficial health effects of quitting smoking were inconsistent with regard to sex, in eight studies men would benefit more and in seven studies women would benefit more [8].

A cross sectional survey study that investigated awareness of smoking cessation treatments among parents of pre-adolescent children showed that female smokers had higher awareness of older nicotine replacement therapies, acupuncture and a quit smoking telephone support line than men. There was no sex difference in awareness of varenicline, bupropion, nortriptyline or newer nicotine replacement therapies. Male smokers experienced to a greater degree than female smokers that nicotine gum and lozenge was effective while other treatments were experienced as equally effective among men and women [9].

Several studies have shown that the use of any smoking cessation medication (varenicline, bupropion or nicotine replacement therapies) to quit was less likely in men than in women [6, 10-13] with the exception of one study where prescription of varenicline and bupropion was equally common in men and women [14].