Action And Clinical Pharmacology
Mechanism of Action
The efficacy of CHAMPIX in smoking-cessation is believed to be a result of varenicline's partial agonist activity at the α4β2 nicotinic acetylcholine receptor (ie, agonist activity to a lesser degree than nicotine), while simultaneously preventing nicotine binding (ie, antagonist activity).
In vitro, varenicline binds with higher affinity to the α4β2 receptor subtype than to other common nicotinic receptors (>500-fold α3β4; >3,500-fold α7; >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (> 2,000-fold).
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline acts as a partial agonist at α4β2 nicotinic acetylcholine receptors. In the absence of nicotine, varenicline’s agonist activity is at a significantly lower level than nicotine, but sufficient to activate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. In the presence of nicotine, which competes for the same human α4β2 nicotinic acetylcholine receptor (nAChR) binding site, varenicline prevented nicotine from activating the α4β2 receptor, since it has higher affinity for this site and this prevented full stimulation of the central nervous mesolimbic dopamine system.
Varenicline is also a partial agonist at α3β4 receptors, but a full agonist at α7 receptors and a full agonist at 5-HT3 receptors.
Varenicline has moderate affinity for the 5-HT3 serotonergic receptor (Ki=350 nM), at which it acts as a weak, full agonist (EC50=0.96 μM). Varenicline-induced nausea shortly after dosing, when gastrointestinal levels are predicted to be temporarily high, may be due to activation of this peripheral receptor, in addition to a possible role for peripheral α3β4 and/or central α4β2 nAChRs.
Volume of distributionc
1.0 mga BID
aDerived from three multiple-dose studies (N=103); †N=64; ‡N=46
bTmax presented as median [range]
cApparent clearance and central volume of distribution estimated from a population PK analysis conducted on pooled data from 1878 subjects (49.2% females); presented as typical value (interindividual coefficient of variation)
Absorption: Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline to healthy volunteers, steady-state conditions were reached within 4 days. Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated (1 to 3 mg/day) doses. In a mass balance study, absorption of varenicline is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.
Distribution: Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.
Metabolism: Varenicline tartrate undergoes minimal metabolism, with approximately 92% of recovered drug-related entity in urine being unchanged varenicline. Metabolite profiles (for circulation and urine) were similar for smokers and non-smokers, and are from the following minor routes of metabolism: N-carbomyl glucuronidation, N-formylation and conjugation with a hexose sugar.
Elimination: The elimination half-life of varenicline tartrate is approximately 24 hours. Renal elimination of varenicline is the major elimination route, primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.
Special Populations and Conditions
There were no clinically meaningful differences seen in varenicline tartrate pharmacokinetics due to being elderly, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CHAMPIX in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.
Two pharmacokinetic studies have been conducted in adolescent smokers, aged 12-17 inclusive: a single dose study (n= 27), and a multiple dose study (n= 72). Pharmacokinetics were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied.(see INDICATIONS AND CLINICAL USE, Special population: Pediatrics).
Steady-state systemic exposure: In the multiple-dose study, patients were stratified by bodyweight (> 55 kg; ≤ 55 kg), and within each bodyweight group, were randomized into three treatment arms (low dose of varenicline, high dose of varenicline and placebo) using a 2:2:1 randomization scheme. Dosing was as follows:
- >55 kg: 0.5 mg BID (n = 14), 1.0 mg BID (n = 14) and placebo (n = 7);
- ≤ 55 kg 0.5 mg QD (n = 15), 0.5 mg BID (n = 14) and placebo (n= 8).
The dosing period was 14 days, with all arms at target dose by Day 8. Patients were allowed to continue smoking at will throughout the study.
In adolescent patients of bodyweight >55 kg, steady-state systemic exposures, as assessed by AUC (0-24), were consistent with those previously observed in the adult population. In adolescent patients of ≤ 55 kg, steady-state systemic exposure for the 0.5 mg BID was on average approximately 40% higher compared to that previously observed in the adult population.
Individual adverse event terms (MedDRA-coded preferred terms) that were reported in more than one patient taking CHAMPIX and more frequently than for placebo were: nausea (most frequent), headache, vomiting, dizziness, pharyngolaryngeal pain, abdominal pain upper, anorexia, flatulence, abnormal dreams, arthralgia, fatigue, and somnolence. Patients ≤55 kg reported more adverse events than patients > 55 kg.
Mood-related events were reported for three patients of 57 in the CHAMPIX arms (anger, mood swings, irritability; none severe), compared with 0 reports in 15 patients in the placebo arms.
Because the safety and effectiveness of varenicline in pediatric patients have not been established, varenicline is not recommended for use in patients under 18 years of age.
Geriatrics: A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once or twice daily to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days was similar to that of younger subjects.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION, Special Populations: Dosing in Elderly Patients).
Hepatic Insufficiency: Due to the absence of significant hepatic metabolism, varenicline tartrate pharmacokinetics should be unaffected in patients with hepatic insufficiency, except in the case that there is accompanying renal compromise (see DOSAGE AND ADMINISTRATION). The potential for clinically meaningful drug interactions between varenicline and metabolic inhibitors/inducers is low.
Renal Impairment: Varenicline tartrate pharmacokinetics were studied in subjects with normal, mild, moderate, severe renal impairment and end-stage renal disease (n=6 per arm), following 0.5 mg once daily administration for 12 days.
Varenicline pharmacokinetics were essentially unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min).
In patients with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure [AUCτ] 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 [AUCτ] 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 [AUCτ] was increased 2.7-fold; varenicline was efficiently removed by hemodialysis (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function).
Patients with Cardiovascular Disease
CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled smoking cessation study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for >2 months. Subjects were randomized to CHAMPIX 1 mg BID (n=353) or placebo (n=350) for 12 weeks of treatment and then were followed for 40 weeks post-treatment. Quit rates were in the range of those from studies in the general population of smokers. Adverse events in this study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers, other than cardiovascular-related events (see also WARNINGS AND PRECAUTIONS, Cardiovascular Events).
Patients with Chronic Obstructive Pulmonary Disease
CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled smoking cessation study of 499 subjects with mild-to-moderate COPD with post-bronchodilator FEV1/FVC<70% and FEV1 ≥50% of predicted normal value, aged > 35 years. Subjects were randomized and treated with CHAMPIX 1 mg BID (n=248) or placebo (n=251) for 12 weeks and then followed for 40 weeks post-treatment. Quit rates were in the range of those from studies in the general population of smokers. Adverse events in this one-year study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers.
Patients with Stable Schizophrenia or Schizoaffective Disorder (See also below: Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder)
CHAMPIX safety and tolerability was assessed in a double-blind study of 128 smokers with stable schizophrenia or schizoaffective disorder, on antipsychotic medication, randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up.
Assessments including the Positive and Negative Symptom Scale (PANSS), standard questioning regarding adverse events, and the Columbia Suicide Severity Rating Scale (C-SSRS) occurred weekly through week 13 and at weeks 16, 20 and 24.
Based on adverse event rates, including neuropsychiatric, there were no new safety concerns compared to studies in the general population of smokers. The study discontinuation rate due to neuropsychiatric adverse events in the CHAMPIX arm was 4% (3 /84), compared to 0 (0 /43) in the placebo group.
In this study, there was no overall worsening of schizophrenia in either treatment group as measured by PANSS scores nor worsening of extra-pyramidal signs.
Evaluation of suicidal ideation and behavior (including C-SSRS): Reported lifetime history of suicidality was higher in the patients randomized to the CHAMPIX arm compared to placebo [62% (52 /84) and 51% (22/43) respectively]. During the active treatment period, the rate of C-SSRS endorsement was 11% (9/82) in the CHAMPIX arm and 9% (4/43) in the placebo arm. There were two suicide-related actions by two patients treated with CHAMPIX (attempt through overdose, and preparatory act of collecting pills); both patients had a lifetime history of similar behaviours.
During the 12 week post-treatment phase, the rate of C-SSRS endorsement decreased in the placebo arm to 5% (2/39), while the rate in the CHAMPIX arm remained at 11% (8 / 70). For six of the cases, all in the CHAMPIX arm, the C-SSRS endorsements were the first in the study for those individuals and occurred more than 30 days after last treatment dose.
All incidences of suicidal ideation or behavior during the study, except for one patient treated with CHAMPIX, occurred in patients with a prior history of suicidality.
Patients with Major Depressive Disorder (See also below: Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder)
CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of 525 subjects with major depressive disorder without psychotic features (DSM-IV TR), on stable antidepressant treatment and/or who experienced a major depressive episode (which was successfully treated) in the past 2 years. Subjects aged 18 to 75 years were randomized to CHAMPIX 1 mg BID (n=256) or placebo (n=269) for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Quit rates in this study were in the range of those from studies in the general population of smokers.
In general, the adverse events in this one-year study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers.
The following psychiatric AEs were more frequent in the CHAMPIX group vs placebo: agitation (6.6% vs. 4.1%), depression (6.6% vs. 4.8%), tension (3.5% vs. 3.0%), hostility (2.0% vs. 0.4%) and restlessness (2.0% vs. 1.9%). No overall worsening of depression was observed during the study in neither CHAMPIX or placebo treatment groups.
The percentage of subjects with suicidal ideation and/or behavior during treatment were 6.0% and 7.5% respectively for the CHAMPIX and placebo groups and 6.2% vs 5.8% for the non-treatment follow-up period. There was one event of intentional self-injury/possible suicide attempt during treatment (Day 73) in a subject with history of alcohol abuse in the placebo group. A possible suicide could not be ruled out in one subject who died by an overdose of illicit drugs 76 days after last dose of study drug in the CHAMPIX group.
Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder (see also WARNING AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms)
CHAMPIX was evaluated in a randomized, double-blind, active and placebo-controlled study that included subjects with a history of psychiatric disorder (psychiatric cohort, N=4074) and subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3984). Excluded psychiatric disorders included current substance abuse, dementias, impulse control and dissociative disorders. Subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment.
The prospective primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events (which mapped from 261 MedDRA preferred terms): severe events of anxiety, depression, feeling abnormal, or hostility; and moderate or severe events of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior or completed suicide.
The primary diagnoses in the psychiatric cohort of the study were: Affective Disorders ~70%; Anxiety Disorders ~19%; Psychotic Disorders ~ 10%, and Borderline Personality Disorders ~ 1% with all patients judged to be clinically stable.
Table 8 shows the rates of the composite NPS adverse event primary end point by treatment group and the risk differences (RDs) (95% CI) vs placebo in each of the non-psychiatric and psychiatric cohort.
|NRT=Nicotine replacement therapy patch; AE=adverse event; RD = Risk Difference; CI = Confidence Interval.|
|Number of Patients Treated||990||989||1006||999|
|Composite NPS AE Primary|
Endpoint, % (n )
|1.3% (13)||2.2% (22)||2.5% (25)||2.4% (24)|
|RD (95% CI) vs Placebo||-1.28|
|Number of Patients Treated||1026||1017||1016||1015|
|Composite NPS AE Primary|
Endpoint, % (n)
|6.5% (67)||6.7% (68)||5.2% (53)||4.9% (50)|
|RD (95% CI) vs Placebo||1.59|
In the psychiatric cohort, there were more events reported in patients in each treatment group compared with the non-psychiatric cohort, and the incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo.
However, in neither cohort (psychiatric or non-psychiatric) was the use of varenicline or bupropion associated with a significantly increased risk, compared with placebo, of NPS primary endpoint AEs (95% CIs were lower than or included zero).
Various sensitivity analyses were performed, including different expansions of the selected AE definitions. The sensitivity analyses did not reveal significantly increased rates of psychiatric adverse events for CHAMPIX compared to placebo, nor compared to the two other treatments (bupropion, NRT).
The totality of psychiatric adverse events in the study is shown below (Table 9) for reference.
Totality of Psychiatric Adverse Events (All Causality, Any Severity)
High Level Group Terms with Preferred Terms > 2% in any treatment group:
Anxiety disorder & symptoms
Depressed Mood Disorder and disturbances
Mood Disorder and disturbances NEC
Sleep disorders & disturbances
The percentage of subjects with suicidal ideation and/or behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS) was similar between the varenicline and placebo groups for both the non-psychiatric and psychiatric cohort, both during treatment and in the non-treatment follow-up, as shown in Table 10.
There was one completed suicide, which occurred during treatment in a subject treated with placebo, in the non-psychiatric cohort.
|NRT=Nicotine replacement therapy patch|
|7 (0.7)||4 (0.4)||3 (0.3)||7 (0.7)|
|Suicidal behavior||0||0||1 (0.1)||1 (0.1)|
|Suicidal behavior||7 (0.7)||4 (0.4)||3 (0.3)||6 (0.6)|
|During follow up|
|3 (0.4)||2 (0.2)||3 (0.4)||4 (0.5)|
|Suicidal behavior||0||1 (0.1)||0||0|
|Suicidal ideation||3 (0.4)||2 (0.2)||3 (0.4)||4 (0.5)|
|27 ( 2.7)||15 ( 1.5)||20 (2.0)||25 ( 2.5)|
|0||1 (0.1)||0||2 (0.2)|
|27 ( 2.7)||15 ( 1.5)||20 (2.0)||25 ( 2.5)|
|During follow up|
|14 (1.7)||4 (0.5)||9 (1.1)||11 (1.4)|
|1 (0.1)||0||1 (0.1)||1 (0.1)|
|14 (1.7)||4 (0.5)||9 (1.1)||11 (1.4)|
For both the psychiatric and non-psychiatric cohorts, the quit rates for all three treatments (varenicline, bupropion, and NRT patches) were significantly greater than those for placebo. The relative efficacy between treatment arms was evaluated. Quit rates for the non-psychiatric cohort were in the range of those from studies in the general population, as were relative rates between treatments for both cohorts (see CLINICAL TRIALS). Comparing the two cohorts, quit rates for the psychiatric cohort were diminished compared to non-psychiatric cohort for all treatment arms, including placebo. These data are limited to 6 months from the start of treatment.
Flexibility in Setting a Quit Date
CHAMPIX was evaluated in a double-blind, placebo-controlled study where patients were instructed to select a quit date between the start of Week 2 of treatment (Day 8) and the end of Week 5 (Day 35) of treatment. It was not required that the quit date be selected prior to starting treatment. Subjects were randomized 3:1 and treated for 12 weeks with CHAMPIX 1 mg BID (n=486) or placebo (n=165) and followed for another 12 weeks post-treatment. Quit rates were in the range of those from studies with a fixed target quit date.
Setting a Quit Date at 12 Weeks of Treatment with a Gradual Reduction in Smoking
CHAMPIX was evaluated in a 52-week double-blind, placebo-controlled trial of subjects who were willing to gradually reduce their smoking over a 12-week period before quitting. Subjects were randomized to either CHAMPIX 1 mg twice daily (n=760) or placebo (n=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Quit rates were in the range of those from studies with a target quit date either at 1 week of treatment or between days 8 and 35 of treatment.
The CHAMPIX safety profile in this study was consistent with premarketing studies.
Patients Re-treated with CHAMPIX
CHAMPIX was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a previous attempt to quit smoking with CHAMPIX, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to CHAMPIX 1 mg BID (n=249) or placebo (n=245) for 12 weeks of treatment and followed for up to 40 weeks post-treatment. Patients included in this study had taken CHAMPIX for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks. Quit rates in this study were in the range of those from studies in subjects at their first attempt to quit smoking with CHAMPIX.
Adverse events in this one-year study were quantitatively and qualitatively similar to those from studies in subjects at their first attempt to quit with CHAMPIX.
A population-based cohort study compared infants exposed to CHAMPIX in utero (N=335) with infants born to mothers who smoked during pregnancy (N=78,412) and infants born to non-smoking mothers (N=806,438). In this study, infants exposed to CHAMPIX in utero were no more likely to have major congenital malformations (3.6%) than infants born to mothers who smoked during pregnancy (4.3%) or to non-smoking mothers (4.2%). Similarly, infants exposed to CHAMPIX in utero, as compared to infants of smoking and non-smoking mothers, were not at increased risk of stillbirth, (0.3%, 0.5%, 0.3%, respectively), small for gestational age (12.5%, 17.1%, 9.1%), preterm birth (7.5%, 7.9%, 5.8%), or premature rupture of membrane (3.6%, 5.4%, 3.8%).