Cimuquit is indicated for smoking cessation in adults.
 

Posology
The recommended dose is 1 mg varenicline twice daily following a 1-week titration as follows:
 

The patient should set a date to stop smoking. CIMUQUIT dosing should usually start at 1-2 weeks before this date (see section 5.1). Patients should be treated with CIMUQUIT for 12 weeks.
For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CIMUQUIT at 1 mg twice daily may be considered for the maintenance of abstinence (see section 5.1).
A gradual approach to quitting smoking with CIMUQUIT should be considered for patients who are not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of treatment and quit by the end of that treatment period. Patients should then continue taking CIMUQUIT for an additional 12 weeks for a total of 24 weeks of treatment (see section 5.1).
Patients who are motivated to quit and who did not succeed in stopping smoking during prior CIMUQUIT therapy, or who relapsed after treatment, may benefit from another quit attempt with CIMUQUIT (see section 5.1).
Patients who cannot tolerate adverse reactions of CIMUQUIT may have the dose lowered temporarily or permanently to 0.5 mg twice daily.
In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediately following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered (see section 4.4).
Elderly
No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.
Renal impairment
No dosage adjustment is necessary for patients with mild (estimated creatinine clearance > 50 ml/min and ≤ 80 ml/min) to moderate (estimated creatinine clearance ≥ 30 ml/min and ≤ 50 ml/min) renal impairment.
For patients with moderate renal impairment who experience adverse reactions that are not tolerable, dosing may be reduced to 1 mg once daily.
For patients with severe renal impairment (estimated creatinine clearance < 30 ml/min), the recommended dose of CIMUQUIT is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Based on insufficient clinical experience with CIMUQUIT in patients with end-stage renal disease, treatment is not recommended in this patient population (see section 5.2).
Hepatic impairment
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).
Paediatric population
CIMUQUIT is not recommended for use in paediatric patients because its efficacy in this population was not demonstrated (see sections 5.1 and 5.2).
Method of administration
CIMUQUIT is for oral use and the tablets should be swallowed whole with water. CIMUQUIT can be taken with or without food
 

Effect of smoking cessation
Physiological changes resulting from smoking cessation, with or without treatment with CIMUQUIT, may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces CYP1A2,
smoking cessation may result in an increase of plasma levels of CYP1A2 substrates.
Neuropsychiatric symptoms
Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal ideation and behaviour and suicide attempts have been reported in patients attempting to quit smoking with CIMUQUIT in the post-marketing experience.
A large randomised, double-blind, active and placebo-controlled study was conducted to compare the risk of serious neuropsychiatric events in patients with and without a history of psychiatric disorder treated for smoking cessation with varenicline, bupropion, nicotine replacement therapy patch (NRT) or placebo.
The primary safety endpoint was a composite of neuropsychiatric adverse events that have been reported in post-marketing experience.
The use of varenicline in patients with or without a history of psychiatric disorder was not associated with an increased risk of serious neuropsychiatric adverse events in the composite primary endpoint
compared with placebo (see section 5.1 Pharmacodynamic properties - Study in Subjects with and without a History of Psychiatric Disorder). Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine withdrawal.
Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in patients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptoms occur whilst on varenicline treatment, patients should discontinue varenicline immediately and contact a healthcare professional for re-evaluation of treatment.
History of psychiatric disorders
Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression).
CIMUQUIT smoking cessation studies have provided data in patients with a history of psychiatric disorders (see section 5.1).
In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently in patients with a history of psychiatric disorders compared to those without a history of psychiatric disorders, regardless of treatment (see section 5.1).
Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.
Seizures
In clinical trials and post-marketing experience there have been reports of seizures in patients with or without a history of seizures, treated with CIMUQUIT. CIMUQUIT should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Treatment discontinuation
At the end of treatment, discontinuation of CIMUQUIT was associated with an increase in irritability,
urge to smoke, depression, and/or insomnia in up to 3% of patients. The prescriber should inform the patient accordingly and discuss or consider the need for dose tapering.
Cardiovascular events
Patients taking CIMUQUIT should be instructed to notify their doctor of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke (see section 5.1).
Hypersensitivity reactions
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), neck (throat and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should discontinue treatment with varenicline and contact a health care provider immediately.
Cutaneous reactions
There have also been post-marketing reports of rare but severe cutaneous reactions, including StevensJohnson Syndrome and Erythema Multiforme in patients using varenicline. As these skin reactions can be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately.
Excipient information
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.
 

Based on varenicline characteristics and clinical experience to date, CIMUQUIT has no clinically meaningful drug interactions. No dosage adjustment of CIMUQUIT or co-administered medicinal
products listed below is recommended.
In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.
Furthermore, since metabolism of varenicline represents less than 10% of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline (see section 5.2) and therefore a dose adjustment of CIMUQUIT would not be required.
In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, active substances that are cleared by renal secretion (e.g., metformin - see below) are unlikely to be affected by varenicline.
Metformin
Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline pharmacokinetics.
Cimetidine
Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided.
Digoxin
Varenicline did not alter the steady-state pharmacokinetics of
digoxin.
Warfarin
Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see section 4.4).
Alcohol
There are limited clinical data on any potential interaction between alcohol and varenicline. There have been post marketing reports of increased intoxicating effects of alcohol in patients treated with varenicline. A causal relationship between these events and varenicline use has not been established.
Use with other therapies for smoking cessation
Bupropion
Varenicline did not alter the steady-state pharmacokinetics of bupropion.
Nicotine replacement therapy (NRT)
When varenicline and transdermal NRT were co-administered to smokers for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia,
and fatigue was greater for the combination than for NRT alone.
Safety and efficacy of CIMUQUIT in combination with other smoking cessation therapies have not been studied.
 

Pregnancy
A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicity of varenicline (see section 5.1).
Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of varenicline during pregnancy (see section 5.1).
Breast-feeding
It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest that varenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with CIMUQUIT should be made taking into account the benefit of breast-feeding to the child and the benefit of CIMUQUIT therapy to the woman.
Fertility
There are no clinical data on the effects of varenicline on fertility.
Non-clinical data revealed no hazard for humans based on standard male and female fertility studies in the rat (see section 5.3).
 

CIMUQUIT may have a minor or moderate influence on the ability to drive and use machines.
CIMUQUIT may cause dizziness, somnolence and transient loss of consciousness, and therefore may influence the ability to drive and use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.
 

Summary of the safety profile
Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the CIMUQUIT studies to distinguish between adverse reactions associated with study drug treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on evaluation
of data from pre-marketing phase 2-3 studies and updated based on pooled data from 18 placebocontrolled pre- and post-marketing studies, including approximately 5,000 patients treated with varenicline.
In patients treated with the recommended dose of 1 mg twice daily following an initial titration period the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea occurred early in the treatment period, was mild to moderate in severity and seldom resulted in discontinuation.
Tabulated summary of adverse reactions
In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

No cases of overdose were reported in pre-marketing clinical trials.
In case of overdose, standard supportive measures should be instituted as required.
Varenicline has been shown to be dialyzed in patients with end stage renal disease (see section 5.2),
however, there is no experience in dialysis following overdose.
 

Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders; Drugs used in
nicotine dependence, ATC code: N07BA03
Mechanism of action
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.
Pharmacovigilance & Medical Device section
- P.O.Box: 1853
- Tel: 80011111
- Email : pv@mohap.gov.ae
- Drug Department Ministry of Health & Prevention, Dubai, UAE
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 > 1µM, except to 5-
HT3 receptors: Ki=350 nM).
Pharmacodynamic effects
The efficacy of CIMUQUIT 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
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop
smoking and who are provided with additional advice and support.
The efficacy of CIMUQUIT in smoking cessation was demonstrated in 3 clinical trials involving
chronic cigarette smokers (≥ 10 cigarettes per day). Two thousand six hundred nineteen (2619)
patients received CIMUQUIT 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 identical double-blind clinical trials prospectively compared the efficacy of CIMUQUIT (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 nontreatment phase.
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
CIMUQUIT 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:

Patient-reported craving, withdrawal and reinforcing effects of smoking
Across both Studies 1 and 2 during active treatment, craving and withdrawal were significantly reduced
in patients randomised to CIMUQUIT in comparison with placebo. CIMUQUIT also significantly
reduced reinforcing effects of smoking that can perpetuate smoking behaviour 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 CIMUQUIT therapy on the maintenance
of abstinence. Patients in this study (n=1,927) received open-label CIMUQUIT 1 mg twice daily for 12
weeks. Patients who stopped smoking by Week 12 were then randomised to receive either CIMUQUIT (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 additional 12-week treatment with CIMUQUIT 1 mg twice daily for the
maintenance of smoking cessation compared to placebo; superiority to placebo for CA was maintained
through week 52. The key results are summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Cimuquit versus Placebo

*CA: Continuous Abstinence Rate
There is currently limited clinical experience with the use of CIMUQUIT among black people to determine
clinical efficacy.
Flexible quit date between weeks 1 and 5
The efficacy and safety of varenicline has been evaluated in smokers who had the flexibility of quitting
between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 12 weeks
followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for varenicline and
placebo was 53.9% and 19.4%, respectively (difference=34.5%, 95% CI: 27.0% - 42.0%) and the CA
week 9-24 was 35.2% (varenicline) vs. 12.7% (placebo) (difference=22.5%, 95% CI: 15.8% - 29.1%).
Patients who are not willing or able to set the target quit date within 1-2 weeks, could be offered to start
treatment and then choose their own quit date within 5 weeks.
Study in subjects re-treated with CIMUQUIT
CIMUQUIT was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a
previous attempt to quit smoking with CIMUQUIT, and either did not succeed in quitting or relapsed
after treatment. Subjects who experienced an adverse event of a concern during previous treatment were
excluded. Subjects were randomised 1:1 to CIMUQUIT 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 CIMUQUIT 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 CIMUQUIT had a superior rate of CO-confirmed abstinence during weeks 9 through
12 and from weeks 9 through 52 compared to subjects treated with placebo. The key results are
summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Cimuquit versus Placebo

*CA: Continuous Abstinence Rate
Gradual approach to quitting smoking
CIMUQUIT 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 randomised to either CIMUQUIT 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. Subjects treated with CIMUQUIT
had a significantly higher Continuous Abstinence Rate compared with placebo; the key results are
summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Cimuquit versus Placebo

The CIMUQUIT safety profile in this study was consistent with that of pre-marketing studies.
Subjects with cardiovascular disease
CIMUQUIT was evaluated in a randomised, double-blind, placebo-controlled study of subjects with
stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for
more than 2 months. Subjects were randomised to CIMUQUIT 1 mg twice daily (n=353) or placebo
(n=350) for 12 weeks and then were followed for 40 weeks post-treatment. The 4 week CQR for
varenicline and placebo was 47.3% and 14.3%, respectively and the CA week 9-52 was 19.8%
(varenicline) vs. 7.4% (placebo).
Deaths and serious cardiovascular events were adjudicated by a blinded, committee. The following
adjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or in the
30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CIMUQUIT and
placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment
follow up to 52 weeks, the adjudicated events included the need for coronary revascularisation (2.0% vs.
0.6%), hospitalisation for angina pectoris (1.7% vs. 1.1%), and a new diagnosis of peripheral vascular
disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring
coronary revascularisation underwent the procedure as part of the management of nonfatal MI and
hospitalisation for angina.
Cardiovascular death occurred in 0.3% of patients in the CIMUQUIT arm and 0.6% of patients in the
placebo arm over the course of the 52-week study.
A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190
CIMUQUIT, 2812 placebo), was conducted to systematically assess the cardiovascular safety of
CIMUQUIT. The study in patients with stable cardiovascular disease described above was included in
the meta-analysis.
The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of
Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, nonfatal MI, and
nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent
committee. Overall, a small number of MACE occurred during treatment in the trials included in the
meta-analysis (CIMUQUIT 7 [0.17%]; placebo 2 [0.07%]).
Additionally, a small number of MACE occurred up to 30 days after treatment (CIMUQUIT 13 [0.31%];
placebo 6 [0.21%]).
The meta-analysis showed that exposure to CIMUQUIT resulted in a hazard ratio for MACE of 2.83
(95% confidence interval from 0.76 to 10.55, p=0.12) for patients during treatment and 1.95 (95%
confidence interval from 0.79 to 4.82, p=0.15) for patients up to 30 days after treatment. These are
equivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events per 1,000 patient-years,
respectively of exposure. The hazard ratio for MACE was higher in patients with cardiovascular risk
factors in addition to smoking compared with that in patients without cardiovascular risk factors other
than smoking. There were similar rates of all-cause mortality (CIMUQUIT 6 [0.14%]; placebo 7
[0.25%]) and cardiovascular mortality (CIMUQUIT 2 [0.05%]; placebo 2 [0.07%]) in the CIMUQUIT
arms compared with the placebo arms in the meta-analysis.
Cardiovascular safety assessment study in subjects with and without a history of psychiatric disorder
The cardiovascular (CV) safety of CIMUQUIT was evaluated in the Study in Subjects with and without a
History of Psychiatric Disorder (parent study; see section 5.1 - Neuropsychiatric safety) and its nontreatment extension, the Cardiovascular Safety Assessment Study, which enrolled 4595 of the 6293
subjects who completed the parent study (N=8058) and followed them through week 52. Of all subjects
treated in the parent study, 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 events (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.

The use of CIMUQUIT, 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.
Subjects with mild-moderate chronic obstructive pulmonary disease (COPD)
The efficacy and safety of CIMUQUIT (1 mg twice daily) for smoking cessation in subjects with mildmoderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical trial. In this
52-week duration study, patients received treatment for 12 weeks, followed by a 40-week non-treatment
follow-up phase. The primary endpoint of the study was the CO-confirmed, 4-week Continuous Quit
Rate (4W CQR) from week 9 through week 12 and a key secondary endpoint was the Continuous
Abstinence (CA) from Week 9 through Week 52. The safety profile of varenicline was comparable to
what was reported in other trials in the general population, including pulmonary safety.
The results for the 4W CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) are shown in the
following table:

Study in subjects with a history of major depressive disorder
The efficacy of varenicline was confirmed in a randomised placebo-controlled trial in 525 subjects with a
history of major depression in the past two years or under current stable treatment. The cessation rates in
this population were similar to those reported in the general population. Continuous abstinence rate
between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in the placebo group
(OR 3.35 (95% CI 2.16-5.21)) and between weeks 9-52 was 20.3% versus 10.4% respectively (OR 2.36
(95% CI 1.40-3.98)). 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%). Psychiatric scales showed no differences
between the varenicline and placebo groups and no overall worsening of depression, or other psychiatric
symptoms, during the study in either treatment group.
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, randomised 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 behaviour prior to enrolment
(lifetime history) and after the end of active treatment period (on Days 33 to 85 after the last dose of
treatment). 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 posttreatment phase was unchanged in the varenicline group; in the placebo group, this percentage was lower
in the post-treatment phase. Although 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 are not sufficient to allow for definitive conclusions to
be drawn about the safety in patients with schizophrenia or schizoaffective disorder.
Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder:
Varenicline was evaluated in a randomised, 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 randomised 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/or moderate or severe events of
agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis,
suicidal ideation, suicidal behaviour or completed suicide.
The following table shows the rates of the composite NPS adverse event primary endpoint by treatment
group and the risk differences (RDs) (95% CI) vs placebo in the non-psychiatric cohort.
In addition, the table shows the subset of the composite NPS AE endpoint of severe intensity:

AE, adverse event; NRT=Nicotine replacement therapy patch
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. The use of varenicline, bupropion and NRT
in the non-psychiatric cohort was not associated with a significantly increased risk of NPS adverse events
in the composite primary endpoint compared with placebo (95% CIs were lower than or included zero).
The percentage of subjects with suicidal ideation and/or behaviour 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:

NRT=Nicotine replacement therapy patch
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 endpoint by treatment
group and the 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 composite NPS AE endpoint of severe intensity:

AE, adverse event; aGrade = severe intensity AE; bGrade = moderate and severe intensity AE;
NRT=Nicotine replacement therapy patch
There were more events reported in patients in the psychiatric cohort 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, the use of varenicline, bupropion and NRT
in the psychiatric cohort was not associated with a significantly increased risk of NPS adverse events in
the composite primary endpoint compared with placebo (95% CIs included zero).
In the psychiatric cohort, the percentage of subjects with suicidal ideation and/or behaviour 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:

NRT=Nicotine replacement therapy patch
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.
In both cohorts, subjects treated with varenicline demonstrated statistical superiority of CO-confirmed
abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion,
nicotine patch and placebo (please see table below).
The key efficacy results are summarised in the following table:

CA = continuous abstinence rate; CI = confidence interval; NRT=Nicotine replacement therapy patch
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.
Treatment discontinuation
The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with
9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in
varenicline treated patients were as follows: nausea (2.7% vs. 0.6% for placebo), headache (0.6% vs.
1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo), and abnormal dreams (0.2% vs. 0.2% for
placebo).
Analyses of Clinical Trials:
A meta-analysis of 5 randomised, double-blind, placebo controlled trials, including 1907 patients (1130
varenicline, 777 placebo), was conducted to assess suicidal ideation and behaviour 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
behaviour in patients treated with varenicline compared to patients treated with placebo, as shown in the
table below. Of the 55 patients who reported suicidal ideation or behaviour, 48 (24 varenicline, 24
placebo) were from the two trials that enrolled patients with a history of schizophrenia/ schizoaffective
disorder, or of 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 Behaviour Reported on C-SSRS
from a Meta- Analysis of 5 Clinical Trials Comparing Varenicline to Placebo:

A meta-analysis of 18 double-blind, randomised, placebo-controlled clinical trials was conducted to
assess the neuropsychiatric safety of varenicline. These trials included the 5 trials described above 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: 0.89-1.15). 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 below 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:

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 hospitalisations 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).
Pregnancy Cohort Study
A population-based cohort study compared infants exposed to CIMUQUIT 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 CIMUQUIT in utero as compared to infants born to
mothers who smoked during pregnancy had lower rates of congenital malformations (3.6% vs 4.3%),
stillbirth (0.3% vs 0.5%), preterm birth (7.5% vs 7.9%), small for gestational age (12.5% vs 17.1%), and
premature rupture of membrane (3.6% vs 5.4%).
Paediatric Population
The efficacy and safety of varenicline was evaluated in a randomised, 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 (12-16 years of age and 17-19 years of age) and by
body weight (≤55 kg and >55 kg). Following two-week titration, patients randomised 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 above paediatric 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 12-17 year old population.

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
litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (≤ 20%) and independent
of both age and renal function. In rodents, varenicline is transferred through the placenta and excreted
in milk.
Biotransformation
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.
In vitro studies demonstrate that varenicline does not inhibit cytochrome P450 enzymes (IC50 > 6,400
ng/ml). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and
3A4/5. Also, in human hepatocytes in vitro, varenicline was shown to not induce the activity of
cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the
pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.
Elimination
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 (see section 4.5).
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 medicinal products, as demonstrated in specific
pharmacokinetic studies and in population pharmacokinetic analyses.
Hepatic impairment
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be
unaffected in patients with hepatic impairment. (see section 4.2).
Renal impairment
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 haemodialysis (see section 4.2).
Elderly
The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years)
is similar to that of younger adult subjects (see section 4.2). For elderly patients with reduced renal
function please refer to section 4.2.
Paediatric population
Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric 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 twice daily
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.
CIMUQUIT is not recommended in paediatric patients because its efficacy in this population was not
demonstrated (see sections 4.2 and 5.1).
 

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male
rats dosed for 2 years with varenicline, there was a dose-related increase in the incidence of hibernoma
(tumour of the brown fat). In the offspring of pregnant rats treated with varenicline there were decreases
in fertility and increases in the auditory startle response (see section 4.6). These effects were observed
only at exposures considered sufficiently in excess of the maximum human exposure indicating little
relevance to clinical use. Nonclinical data indicate varenicline has reinforcing properties albeit with
lower potency than nicotine. In clinical studies in humans, varenicline showed low abuse potential.
 

Tablet Core - Cimuquit 0.5 mg and 1 mg film-coated tablets
- Microcrystalline Cellulose
- Dicalcium Phosphate Anhydrous
- Croscarmellose Sodium (see section 2 “Cimuquit contains sodium”
- Colloidal Silica Anhydrous
- Magnesium Stearate
Tablet film coating - Cimuquit 0.5 mg film-coated tablets
- Opadry White (03A18480)
- Purified water
Tablet film coating - Cimuquit 1 mg film-coated tablets
- Opadry Blue (03A505009)
- Hypromellose (HPMC-E3)
- Purified water
 

Not applicable.
 

Do not Store above 30°C
Keep out of the reach and sight of children
 

Cimuquit comes in two tablet strengths:
Cimuquit Tablets are provided in Blister packs (PVC blisters with aluminium foil backing). Blisters are
packed in a carton along with a patient information leaflet
Cimuquit film-coated tablets are provided in pack sizes of 25 tablets and 56 tablets
CIMUQUIT is available in the following pack presentations:
- A treatment initiation pack containing 2 blisters; 1 clear blister of 11 x CIMUQUIT 0.5 mg film coated
tablets and 1 clear blister of 14 x CIMUQUIT 1 mg film-coated tablets in a carton box packaging.
- A follow-on (maintenance) pack containing 4 clear blisters of 14 x CIMUQUIT 0.5 mg film-coated tablets
in in a carton box packaging.
- A follow-on (maintenance) pack containing 4 clear blisters of 14 x CIMUQUIT 1mg film coated tablets in in
a carton box packaging.
 

No special requirements
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.