Pharmacology: Pharmacodynamics: Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.
Electrophysiology studies
in vitro and neurochemical studies
in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki=620 nM, α1βγδ Ki=3,400 nM), or to non-nicotinic receptors and transporters (Ki>1 μM, except to 5-HT3 receptors: Ki=350 nM).
The efficacy of varenicline in smoking cessation is a result of varenicline's partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).
Clinical Efficacy and Safety: The efficacy of varenicline in smoking cessation was demonstrated in 3 pre-marketing clinical trials involving chronic cigarette smokers (≥10 cigarettes per day). 2619 patients received varenicline 1 mg BID (titrated during the first week), 669 patients received bupropion 150 mg BID (also titrated) and 684 patients received placebo.
Comparative Clinical Studies: Two identically designed double-blind clinical trials prospectively compared the efficacy of varenicline (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a 40-week non-treatment phase.
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. Patients set a date to stop smoking (target quit date, TQD) with dosing starting 1 week before this date.
The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-week continuous quit rate (4W-CQR) from Week 9 through Week 12. The primary endpoint for varenicline demonstrated statistical superiority to bupropion and placebo.
After the 40-week non-treatment phase, a key secondary endpoint for both studies was the Continuous Abstinence Rate (CA) at week 52. CA was defined as the proportion of all subjects treated who did not smoke (not even a puff of a cigarette) from Week 9 through Week 52 and did not have an exhaled CO measurement of >10 ppm. The 4W-CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) from studies 1 and 2 are included in the following table: See Table 1.
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Patient Reported Craving, Withdrawal and Reinforcing Effects of Smoking: Across both Studies 1 and 2 during active treatment, Patient Reported Outcomes measures demonstrated that craving and withdrawal were significantly reduced in patients randomized to varenicline in comparison with placebo. Varenicline also significantly reduced reinforcing effects of smoking that can perpetuate smoking behavior in patients who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up phase.
Maintenance of Abstinence Study: The third study assessed the benefit of an additional 12 weeks of varenicline therapy on the maintenance of abstinence. Patients in this study (n=1,927) received open-label varenicline 1 mg twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomized to receive either varenicline (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration of 52 weeks.
The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through week 24 in the double-blind treatment phase. A key secondary endpoint was the continuous abstinence (CA) rate for week 13 through week 52.
This study showed the benefit of an additional 12-week treatment with varenicline 1 mg twice daily for the maintenance of smoking cessation compared to placebo. The odds of maintaining abstinence at week 24, following an additional 12 weeks of treatment with varenicline, were 2.47 times those for placebo (p<0.0001). Superiority to placebo for CA was maintained through week 52 (Odds Ratio=1.35, p=0.0126). The key results are summarized in the following table: See Table 2.
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Flexibility in Setting a Quit Date: The effect of varenicline 1 mg BID in a flexible, patient-selected quit date setting was assessed in a double-blind, placebo-controlled study of 651 subjects. Subjects were randomized 3:1 to varenicline or placebo for a treatment of 12 weeks and a followed up post-treatment for another 12 weeks. In this study, 486 subjects received varenicline and 165 received placebo. Patients were instructed to select a quit date after the initial week of dose titration and before the clinical visit at the end of week 5 of treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (53.94%) compared to patients treated with placebo (19.4%) (odds ratio 6.03; 95% CI 3.80, 9.56; p<0.0001) and from week 9 through 24 (35.2%) compared to subjects treated with placebo (12.73%) (odds ratio 4.45; 95% CI 2.62, 7.55; p<0.0001). Adverse events in this study were quantitatively and qualitatively similar to those observed in pre-marketing studies. The key results are summarized in the following table: See Table 3.
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Study in Subjects Re-treated with Varenicline: Varenicline was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a previous attempt to quit smoking with varenicline, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to varenicline 1 mg twice daily (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 varenicline 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.
Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (45.0%) compared to patients treated with placebo (11.8%) (odds ratio 7.08; 95% CI 4.34, 11.55; p<0.0001) and from weeks 9 through 52 (20.1%) compared to subjects treated with placebo (3.3%) (odds ratio 9.00; 95% CI 3.97, 20.41; p<0.0001).
Adverse events in this study were quantitatively and qualitatively similar to those observed in pre-marketing studies.
The key results are summarized in the following table: See Table 4.
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Gradual Approach to Quitting Smoking: Varenicline was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomized to either varenicline 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% 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. Subjects treated with varenicline had a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32.1% vs. 6.9%; odds ratio 8.74; 95% CI 6.09, 12.53; p<0.0001) and weeks 21 through 52 (27.0% vs. 9.9%; odds ratio 4.02; 95% CI 2.94, 5.50; p<0.0001).
The varenicline safety profile in this study was consistent with the pre-marketing studies.
The key results are summarized in the following table: See Table 5.
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Study in Subjects with Cardiovascular Disease: Varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 703 subjects with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for more than 2 months. Subjects aged 35 to 75 years were randomized to varenicline 1 mg BID or placebo for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47.3%) compared to subjects treated with placebo (14.3%) (odds ratio 6.05; 95% CI 4.13, 8.86; p<0.0001) and from week 9 through 52 (19.8%) compared to subjects treated with placebo (7.4%) (odds ratio 3.19; 95% CI 1.97, 5.18; p<0.0001). Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment-emergent and non-treatment-emergent) were adjudicated by a blinded, independent committee. The following treatment-emergent adjudicated events occurred with a frequency ≥1% in either treatment group: non-fatal myocardial infarction (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalization for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, adjudicated events with a frequency ≥1% included need for coronary revascularization (2.0% vs. 0.6%), hospitalization for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularization underwent the procedure as part of management of non-fatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study (see Precautions).
The key results are summarized in the following table: See Table 6.
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Cardiovascular Safety Assessment Study in Subjects with and without a History of Psychiatric Disorder: The cardiovascular (CV) safety of varenicline was evaluated in the Cardiovascular Safety Assessment Study in subjects with and without a history of psychiatric disorder (parent study) and in a non-treatment extension study. In the parent study (N=8058), 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 non-treatment extension study enrolled 4595 of the 6293 subjects who completed the parent study and followed them through week 52. Of all treated subjects, 1749 (21.7%) had a medium CV risk and 644 (8.0%) had a high CV risk, as defined by Framingham score.
The primary CV endpoint was the time to major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke during treatment. Deaths and cardiovascular events were adjudicated by a blinded, independent committee.
The following table shows the incidence of MACE and Hazard Ratios vs. placebo for all treatment groups during treatment, and cumulative for treatment plus 30 days and through end of study. (See Table 7.)
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Incidence of MACE + (defined as any MACE or a new onset or worsening peripheral vascular disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina) and all cause deaths are shown for all treatment groups during treatment, and cumulative for treatment plus 30 days and through end of study in the following table. (See Table 8.)
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The use of varenicline, bupropion, and NRT was not associated with an increased risk of CV AEs in smokers treated for up to 12 weeks and followed for up to 1 year compared to placebo, although because of the relatively low number of events overall, an association cannot be entirely ruled out. The number of subjects with MACE, MACE + and all cause deaths was similar or lower for the varenicline-treated subjects compared to those treated with placebo. (See Precautions.)
Study in Subjects with Chronic Obstructive Pulmonary Disease: Varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 499 subjects with mild-to-moderate Chronic Obstructive Pulmonary Disease with post-bronchodilator FEV1/FVC <70% and FEV1 ≥50% of predicted normal value. Subjects aged ≥35 years were randomized to varenicline 1 mg BID or placebo for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (42.3%) compared to subjects treated with placebo (8.8%) (odds ratio 8.40; 95% CI 4.99, 14.14; p<0.0001) and from week 9 through 52 (18.6%) compared to subjects treated with placebo (5.6%) (odds ratio 4.04; 95% CI 2.13, 7.67; p<0.0001). Adverse events in this study were quantitatively and qualitatively similar to those observed in pre-marketing studies.
The key results are summarized in the following table: See Table 9.
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Study in Subjects with Major Depressive Disorder: Varenicline 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 in the past 2 years and were successfully treated. Subjects aged 18 to 75 years were randomized to varenicline 1 mg BID or placebo for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (35.9%) compared to subjects treated with placebo (15.6%) (odds ratio 3.35; 95% CI 2.16, 5.21; p<0.0001) and from week 9 through 52 (20.3%) compared to subjects treated with placebo (10.4%) (odds ratio 2.36; 95% CI 1.40, 3.98; p=0.0011).
The most common adverse events (≥10%) in subjects taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%) abnormal dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Additionally, the following psychiatric AEs were reported in ≥2% of patients in either treatment group (varenicline or placebo, respectively): anxiety (7.0% vs. 9.3%), agitation (6.6% vs. 4.1%), depression (6.6% vs. 4.8%), tension (3.5% vs. 3.0%), depressed mood (2.7% vs. 3.7%), sleep disorder (2.7% vs. 1.5%), hostility (2.0% vs. 0.4%) and restlessness (2.0% vs. 1.9%). Psychiatric scales showed no differences between the varenicline and placebo groups and no overall worsening of depression during the study in either treatment group.
The percentage of subjects with suicidal ideation and/or behavior was similar between the varenicline and placebo groups during treatment (6.0% and 7.5%, respectively) and the non-treatment follow-up (6.2% and 5.8%, respectively). 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 varenicline group.
The key efficacy results are summarized in the following table: See Table 10.
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Study in Subjects with Stable Schizophrenia or Schizoaffective Disorder: Varenicline 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.
The most common adverse events in subjects taking varenicline were nausea (23.8% vs. 14.0% on placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment group in ≥5% of subjects at a rate higher in the varenicline group than in placebo (9.5% vs. 4.7%).
Overall, there was no worsening of schizophrenia in either treatment group as measured by psychiatric scales and there were no overall changes in extra-pyramidal signs.
In the varenicline group compared to placebo, a higher proportion of subjects reported suicidal ideation or behavior prior to enrollment (lifetime history) and after the end of active treatment period (on Days 33 to 85 after the last dose of drugs). During the active treatment period, the incidence of suicide-related events was similar between the varenicline-treated and the placebo-treated subjects (11% vs. 9.3%, respectively). The percentage of subjects with suicide-related events in the active treatment phase compared to post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage was lower in the post-treatment phase. There were no completed suicides. There was one suicidal attempt in a varenicline-treated subject whose lifetime history included several similar attempts. The limited data available from this single smoking cessation study is not sufficient to allow definitive conclusions to be drawn. However, these data do not suggest that varenicline treatment causes or worsens suicidality in subjects with stable schizophrenia or schizoaffective disorder.
Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder: Varenicline 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). 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 primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events: 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 (see Precautions).
The following table 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 the non-psychiatric cohort. The individual components of the endpoint are also shown. In addition, the table shows the subset of the endpoint comprised of only events of severe intensity: See Table 11.
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In the non-psychiatric cohort, the rates of events in the composite endpoint were low across all treatment groups and were similar or lower for each of the active treatments compared to placebo: risk differences (RDs (95% Confidence Interval [CI])) vs. placebo were -1.28% (-2.40, -0.15) for varenicline, -0.08% (-1.37, 1.21) for bupropion and -0.21% (-1.54, 1.12) for NRT. The use of varenicline, bupropion and NRT in the non-psychiatric cohort was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs were lower than or included zero). Similarly, the use of varenicline was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with bupropion or NRT in the non-psychiatric cohort (-1.19% (-2.30, -0.09) and -1.07 (-2.21, 0.08), respectively).
In non-psychiatric cohort, 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 during treatment and in the non-treatment follow-up, as shown in the following table: See Table 12.
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There was one completed suicide, which occurred during treatment in a subject treated with placebo in the non-psychiatric cohort.
The following table 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 the psychiatric cohort. The individual components of the endpoint are also shown. In addition, the table shows the subset of the endpoint comprised of only events of severe intensity: See Table 13.
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There were more events reported in patients in the psychiatric cohort in each treatment group compared with the non-psychiatric cohort. In the psychiatric cohort, the incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo: RDs (95% CI) vs. placebo were 1.59% (-0.42, 3.59) for varenicline, 1.78% (-0.24, 3.81) for bupropion and 0.37% (-1.53, 2.26) for NRT. The use of varenicline, bupropion and NRT in the psychiatric cohort was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs included zero). Similarly, the use of varenicline was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with bupropion or NRT in the psychiatric cohort (-0.20% (-2.34, 1.95) and 1.22% (-0.81, 3.25), respectively).
In the psychiatric cohort, 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 during treatment and in the non-treatment follow-up, as shown in the following table: See Table 14.
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There were no completed suicides reported in the psychiatric cohort.
The most commonly reported adverse events in subjects treated with varenicline in this study were similar to those observed in premarketing studies. Adverse events reported in ≥10% of subjects treated with varenicline in the entire study population were nausea (25.3% vs. 6.8% on placebo) and headache (12.2% vs. 9.9% on placebo).
In both cohorts, subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, nicotine patch and placebo.
The key efficacy results are summarized in the following table: See Table 15.
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Neuropsychiatric Safety Meta-analyses and Observational Studies: Analyses of clinical trial data did not show evidence of an increased risk of serious neuropsychiatric events with varenicline compared to placebo. In addition, independent observational studies have not supported an increased risk of serious neuropsychiatric events in patients treated with varenicline compared to patients prescribed nicotine replacement therapy (NRT) or bupropion.
Analyses of Clinical Trials: A meta-analysis of 5 randomized, double blind, placebo controlled trials, including 1907 patients (1130 varenicline, 777 placebo), was conducted to assess suicidal ideation and behavior as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS). This meta-analysis included one trial (N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N=525) in patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behavior in patients treated with varenicline compared to patients treated with placebo, with a Risk Ratio (RR) of 0.79 (95% Confidence Interval [CI]: 0.46, 1.36), as shown in the table as follows. Forty-eight (48) of the 55 patients who reported suicidal ideation or behavior (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression. Few patients reported these events in the other three trials (4 varenicline, 3 placebo).
Number of Patients and Risk Ratio for Suicidal Ideation and/or Behavior Reported on C-SSRS from a Meta-Analysis of 5 Clinical Trials Comparing Varenicline to Placebo: See Table 16.
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A meta-analysis of 18 double-blind, randomized, placebo-controlled clinical trials was conducted to assess the neuropsychiatric safety of varenicline. These trials included the 5 trials described previously that used the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo), some of which had psychiatric conditions. The results showed a similar incidence of combined neuropsychiatric adverse events, other than sleep disorders, in patients treated with varenicline compared to patients treated with placebo, with a risk ratio (RR) of 1.01 (95% CI: 0.88, 1.15). Pooled data from these 18 trials showed a similar incidence rate of individual categories of psychiatric events in patients treated with varenicline compared to patients treated with placebo. The table as follows describes the most frequently (≥1%) reported categories of adverse events related to psychiatric safety other than sleep disorders and disturbances.
Psychiatric Adverse Events Occurring in ≥1% of Patients from Pooled Data from 18 Clinical Trials: See Table 17.
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Observational Studies: Four observational studies, each including 10,000 to 30,000 users of varenicline in the adjusted analyses, compared the risk of serious neuropsychiatric events, including neuropsychiatric hospitalizations and fatal and non-fatal self-harm, in patients treated with varenicline versus patients prescribed NRT or bupropion. All studies were retrospective cohort studies and included patients with and without a psychiatric history. All studies used statistical methods to control for confounding factors, including preferential prescribing of varenicline to healthier patients, although there is the possibility of residual confounding.
Two of the studies found no difference in risk of neuropsychiatric hospitalizations between varenicline users and nicotine patch users (Hazard Ratio [HR] 1.14; 95% Confidence Interval [CI]: 0.56-2.34 in the first study, and 0.76; 95% CI: 0.40-1.46 in the second study). The power to detect differences in these two studies was limited. The third study reported no difference in risk of psychiatric adverse events diagnosed during an emergency department visit or inpatient admission between varenicline users and bupropion users (HR 0.85; 95% CI: 0.55-1.30). Based on post-marketing reports, bupropion may be associated with neuropsychiatric adverse events. The fourth study showed no evidence of a higher risk of fatal and non-fatal self-harm (HR of 0.88; 95% CI: 0.52-1.49) in patients prescribed varenicline compared to patients prescribed NRT. The occurrence of detected suicide was rare during the three months after patients initiated any drug treatment (two cases in 31,260 varenicline users and six cases in 81,545 NRT users).
Other Observational Studies: Pregnancy Cohort Study: A population-based cohort study compared infants exposed to varenicline
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 varenicline
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 varenicline
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%) (see Use in Pregnancy & Lactation).
Pediatric population: The efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, and had a score of at least 4 on the Fagerstrom Test for Nicotine Dependence scale. Patients were stratified by age (12 to 16 years of age and 17 to 19 years of age) and by body weight (≤55 kg and >55 kg). Following two week titration, patients randomized to varenicline with a body weight >55 kg received 1 mg twice daily (high dose group) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤55 kg received 0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study.
The following table from the previously mentioned pediatric study shows a comparison of continuous abstinence rates (CAR) from weeks 9-12, confirmed by urine cotinine test, for the full analysis set overall study population and the 12-16 year old population. (See Table 18.)
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Results from this study showed that neither varenicline dose significantly increased continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 to 19 years of age or in subjects 12 to 16 years of age. The study was not powered to assess efficacy in adolescent smokers 17 to 19 years of age, and in this group conclusions cannot be drawn. The varenicline safety profile in this study was consistent with that shown in adult studies (see Use in pediatric patients under Dosage & Administration and Pharmacokinetics: Use in pediatric patients as follows).
Pharmacokinetics: Absorption: Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses to healthy volunteers, steady-state conditions were reached within 4 days. Absorption 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: Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 415 liters (%CV=50) at steady-state. Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.
Metabolism: Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.
Excretion: The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.
Linearity/Non-linearity: Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated (1 to 3 mg/day) doses.
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.
Patients with hepatic impairment: Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment (see Patients with hepatic impairment under Dosage & Administration).
Patients with renal insufficiency: Varenicline pharmacokinetics were 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 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), varenicline was efficiently removed by hemodialysis (see Patients with renal insufficiency under Dosage & Administration).
Use in elderly patients: The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years) is similar to that of younger adult subjects. In elderly patients with severe renal impairment, dosage adjustment is recommended (see Patients with renal insufficiency under Dosage & Administration).
Use in pediatric patients: 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 (see Use in pediatric patients under Dosage & Administration and Pharmacodynamics: Pediatric population as previously mentioned).
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n=65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats.
Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations
in vivo in rat bone marrow and
in vitro in human lymphocytes.
There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg BID). However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg BID). This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1 mg BID).
Teratogenesis: Varenicline succinate was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36- and 50-times the maximum recommended human daily exposure based on AUC at 1 mg BID, respectively).
Non-teratogenic Effects: Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC at 1 mg BID); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg BID).
Non-clinical data indicate varenicline has reinforcing properties albeit with lower potency than nicotine. Moreover, in clinical studies in humans, varenicline showed low abuse potential.
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