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Mechanism of Action
Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors ( > 500-fold α3β4, > 3500-fold α7, > 20,000-fold α1βγδ), or to non-nicotinic receptors and transporters ( > 2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low ( ≤ 20%) and independent of both age and renal function.
The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.
Pharmacokinetics in Special Patient Populations
There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance > 50 mL/min and ≤ 80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥ 30 mL/min and ≤ 50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance > 80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance < 30 mL/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily. [see DOSAGE AND ADMINISTRATION, and Use In Specific Populations]. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis [see OVERDOSAGE].
A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65-75 yrs) for 7 consecutive days was similar to that of younger subjects.
Because the safety and effectiveness of CHANTIX in pediatric patients have not been established, CHANTIX is not recommended for use in patients under 18 years of age. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight > 55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population.
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.
Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions have been identified.
In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 > 6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.
In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin [see below]) are unlikely to be affected by varenicline.
In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may not necessitate a dose adjustment of CHANTIX as the increase in systemic exposure to CHANTIX is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHANTIX [see CLINICAL PHARMACOLOGY]; therefore, a dose adjustment of CHANTIX would not be required.
When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.
Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.
Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics [see DRUG INTERACTIONS].
Use with Other Drugs for Smoking Cessation
Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers [see DRUG INTERACTIONS].
Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of adverse reactions was greater for the combination than for NRT alone [see DRUG INTERACTIONS].
The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers ( ≥ 10 cigarettes per day) were treated with CHANTIX. In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO ≤ 10 ppm) at weekly visits. Among the CHANTIX-treated patients enrolled in these studies, the completion rate was 65%. Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most patients enrolled in these trials were white (79-96%). All studies enrolled almost equal numbers of men and women. The average age of patients in these studies was 43 years. Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years. Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date.
Three additional studies were conducted in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease [see Clinical Studies], and in patients instructed to select their quit date within days 8 and 35 of treatment [see Clinical Studies].
In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each weekly treatment visit according to Agency for Healthcare Research and Quality guidelines.
Initiation of Abstinence
Study 1: This was a six-week dose-ranging study comparing CHANTIX to placebo. This study provided initial evidence that CHANTIX at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.
Study 2: This study of 627 patients compared CHANTIX 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one week titration) and then were followed for 40 weeks post-treatment. CHANTIX was given in two divided doses daily. Each dose of CHANTIX was given in two different regimens, with and without initial dose titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.
Forty-five percent of patients receiving CHANTIX 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.
Study 3: This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of CHANTIX or placebo. After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.
Of the patients treated with CHANTIX, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.
Study 4 and Study 5: These identical double-blind studies compared CHANTIX 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The CHANTIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.
In Study 4, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.
Similarly in Study 5, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.
Figure 1: Continuous Abstinence, Weeks 9 through 12
Table 4: Continuous Abstinence, Weeks 9 through 12
(95% confidence interval)
|CHANTIX 0.5 mg BID||CHANTIX 1 mg BID||CHANTIX Flexible||Bupropion SR||Placebo|
|BID = twice daily|
Urge to Smoke
Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale “urge to smoke” item, CHANTIX reduced urge to smoke compared to placebo.
Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, CHANTIX-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo (Figure 2, Table 5).
Figure 2: Continuous Abstinence, Weeks 9 through 52
Table 5: Continuous Abstinence, Weeks 9 through 52
(95% confidence interval) across different studies
|CHANTIX 0.5 mg BID||CHANTIX 1 mg BID||CHANTIX Flexible||Bupropion SR||Placebo|
|BID = twice daily|
Study 6: This study assessed the effect of an additional 12 weeks of CHANTIX therapy on the likelihood of long-term abstinence. Patients in this study (n=1927) were treated with open-label CHANTIX 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (n= 1210) were then randomized to double-blind treatment with CHANTIX (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.
The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with CHANTIX (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (CHANTIX 54% versus placebo 39%).
In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of CHANTIX; post-CHANTIX follow-up begins at Week 13 for the placebo group and Week 25 for the CHANTIX group. The y-axis represents the percentage of patients who had been abstinent for the last week of CHANTIX treatment and remained abstinent at the given timepoint.
Figure 3: Continuous Abstinence Rate during
Subjects with Cardiovascular and Chronic Obstructive Pulmonary Disease
CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to CHANTIX 1 mg twice daily (n=353) or placebo (n=350) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).
CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC < 70% and FEV1 ≥ 50% of predicted normal value. Subjects were randomized to CHANTIX 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).
Table 6: Continuous Abstinence (95% confidence
interval), Studies in Patients with Cardiovascular Disease (CVD) and Chronic
Obstructive Pulmonary Disease (COPD)
|Weeks 9 through 12||Weeks 9 through 52|
|CHANTIX 1 mg BID||Placebo||CHANTIX 1 mg BID||Placebo|
|BID = twice daily|
Alternative Instructions for Setting a Quit Date
CHANTIX was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to CHANTIX 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment. Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).
Last reviewed on RxList: 3/12/2013
This monograph has been modified to include the generic and brand name in many instances.
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