Included as part of the PRECAUTIONS section.
Neuropsychiatric Adverse Events Including Suicidality
Serious neuropsychiatric adverse events have been
reported in patients being treated with CHANTIX [see ADVERSE REACTIONS].
These postmarketing reports have included changes in mood (including depression
and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, hostility, agitation, anxiety, and panic, as well as suicidal
ideation, suicide attempt, and completed suicide. Some patients who stopped
smoking may have been experiencing symptoms of nicotine withdrawal, including
depressed mood. Depression, rarely including suicidal ideation, has been reported
in smokers undergoing a smoking cessation attempt without medication. However,
some of these adverse events occurred in patients taking CHANTIX who continued
Neuropsychiatric adverse events occurred in patients
without and with pre-existing psychiatric disease; some patients experienced
worsening of their psychiatric illnesses. Some neuropsychiatric adverse events,
including unusual and sometimes aggressive behavior directed to oneself or
others, may have been worsened by concomitant use of alcohol [see Interaction with Alcohol, ADVERSE REACTIONS]. Observe patients for the
occurrence of neuropsychiatric adverse events. Advise patients and caregivers
that the patient should stop taking CHANTIX and contact a healthcare provider
immediately if agitation, depressed mood, or changes in behavior or thinking
that are not typical for the patient are observed, or if the patient develops
suicidal ideation or suicidal behavior. The healthcare provider should evaluate
the severity of the symptoms and the extent to which the patient is benefiting
from treatment, and consider options including dose reduction, continued
treatment under closer monitoring, or discontinuing treatment. In many
postmarketing cases, resolution of symptoms after discontinuation of CHANTIX
was reported. However, the symptoms persisted in some cases; therefore, ongoing
monitoring and supportive care should be provided until symptoms resolve.
The neuropsychiatric safety of CHANTIX was evaluated in a
randomized, double-blind, active and placebo-controlled study that included
patients without a history of psychiatric disorder (nonpsychiatric cohort,
N=3912) and patients with a history of psychiatric disorder (psychiatric
cohort, N=4003). In the non-psychiatric cohort, CHANTIX was not associated with
an increased incidence of clinically significant neuropsychiatric adverse
events in a composite endpoint comprising anxiety, depression, feeling
abnormal, hostility, agitation, aggression, delusions, hallucinations,
homicidal ideation, mania, panic, and irritability. In the psychiatric cohort,
there were more events reported in each treatment group compared to the
non-psychiatric cohort, and the incidence of events in the composite endpoint
was higher for each of the active treatments compared to placebo: Risk
Differences (RDs) (95%CI) vs. placebo were 2.7% (-0.05, 5.4) for CHANTIX, 2.2%
(-0.5, 4.9) for bupropion, and 0.4% (-2.2, 3.0) for transdermal nicotine. In
the non-psychiatric cohort, neuropsychiatric adverse events of a serious nature
were reported in 0.1% of CHANTIX-treated patients and 0.4% of placebo-treated patients.
In the psychiatric cohort, neuropsychiatric events of a serious nature were
reported in 0.6% of CHANTIX-treated patients, with 0.5% involving psychiatric
hospitalization. In placebo-treated patients, serious neuropsychiatric events
occurred in 0.6%, with 0.2% requiring psychiatric hospitalization [see Clinical
During clinical trials and the post marketing experience,
there have been reports of seizures in patients treated with CHANTIX. Some
patients had no history of seizures, whereas others had a history of seizure
disorder that was remote or well-controlled. In most cases, the seizure
occurred within the first month of therapy. Weigh this potential risk against
the potential benefits before prescribing CHANTIX in patients with a history of
seizures or other factors that can lower the seizure threshold. Advise patients
to discontinue CHANTIX and contact a healthcare provider immediately if they
experience a seizure while on treatment [see ADVERSE REACTIONS].
Interaction With Alcohol
There have been postmarketing reports of patients
experiencing increased intoxicating effects of alcohol while taking CHANTIX.
Some cases described unusual and sometimes aggressive behavior, and were often
accompanied by amnesia for the events. Advise patients to reduce the amount of
alcohol they consume while taking CHANTIX until they know whether CHANTIX
affects their tolerance for alcohol [see ADVERSE REACTIONS].
There have been postmarketing reports of traffic
accidents, near-miss incidents in traffic, or other accidental injuries in
patients taking CHANTIX. In some cases, the patients reported somnolence, dizziness,
loss of consciousness or difficulty concentrating that resulted in impairment,
or concern about potential impairment, in driving or operating machinery.
Advise patients to use caution driving or operating machinery or engaging in
other potentially hazardous activities until they know how CHANTIX may affect
In a placebo-controlled clinical trial of CHANTIX
administered to patients with stable cardiovascular disease, with approximately
350 patients per treatment arm, all-cause and cardiovascular mortality was lower
in patients treated with CHANTIX, but certain nonfatal cardiovascular events
occurred more frequently in patients treated with CHANTIX than in patients
treated with placebo [see ADVERSE REACTIONS]. Table 1 below shows the
incidence of deaths and of selected nonfatal serious cardiovascular events
occurring more frequently in the CHANTIX arm compared to the placebo arm. These
events were adjudicated by an independent blinded committee. Nonfatal serious
cardiovascular events not listed occurred at the same incidence or more commonly
in the placebo arm. Patients with more than one cardiovascular event of the
same type are counted only once per row. Some of the patients requiring coronary
revascularization underwent the procedure as part of management of nonfatal MI
and hospitalization for angina.
Table 1: Mortality and Adjudicated Nonfatal Serious
Cardiovascular Events in the Placebo-Controlled CHANTIX Trial in Patients with
Stable Cardiovascular Disease
|Mortality and Cardiovascular Events
|Mortality (Cardiovascular & All-cause up to 52 wks)
|Nonfatal Cardiovascular Events (rate on CHANTIX > Placebo)
|Up to 30 days after treatment
|Nonfatal myocardial infarction
|Beyond 30 days after treatment & up to 52 weeks
|Nonfatal myocardial infarction
|Need for coronary revascularization
|Hospitalization for angina pectoris
|Transient ischemia attack
|New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure
A meta-analysis of 15 clinical trials of ≥ 12 weeks
treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was
conducted to systematically assess the cardiovascular safety of CHANTIX. The
study in patients with stable cardiovascular disease described above was
included in the meta-analysis. There were lower rates of all-cause mortality
(CHANTIX 6 [0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHANTIX 2
[0.05%]; placebo 2 [0.07%]) in the CHANTIX arms compared with the placebo arms
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 in the trials
included in the meta-analysis, as described in Table 2. These events occurred
primarily in patients with known cardiovascular disease.
Table 2: Number of MACE cases, Hazard Ratio and Rate
Difference in a Meta-Analysis of 15 Clinical Trials Comparing CHANTIX to
|MACE cases, n (%)
|Patient-years of exposure
|Hazard Ratio (95% CI)
|Rate Difference per 1,000 patient-years (95% CI)
|*Includes MACE occurring up to 30 days post-treatment.
The meta-analysis showed that exposure to CHANTIX
resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79
to 4.82) for patients up to 30 days after treatment; this is equivalent to an
estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The
meta-analysis showed higher rates of CV endpoints in patients on CHANTIX
relative to placebo across different time frames and pre-specified sensitivity
analyses, including various study groupings and CV outcomes. Although these
findings were not statistically significant they were consistent. Because the
number of events was small overall, the power for finding a statistically
significant difference in a signal of this magnitude is low.
CHANTIX was not studied in patients with unstable
cardiovascular disease or cardiovascular events occurring within two months
before screening. Patients should be advised to notify a healthcare provider of
new or worsening symptoms of cardiovascular disease. The risks of CHANTIX
should be weighed against the benefits of its use in smokers with
cardiovascular disease. Smoking is an independent and major risk factor for
cardiovascular disease. CHANTIX has been demonstrated to increase the
likelihood of abstinence from smoking for as long as one year compared to
treatment with placebo.
Cases of somnambulism have been reported in patients
taking CHANTIX. Some cases described harmful behavior to self, others, or
property. Instruct patients to discontinue CHANTIX and notify their healthcare
provider if they experience somnambulism [see ADVERSE REACTIONS].
Angioedema And Hypersensitivity Reactions
There have been postmarketing reports of hypersensitivity
reactions including angioedema in patients treated with CHANTIX [see ADVERSE
REACTIONS, PATIENT INFORMATION]. Clinical signs included
swelling of the face, mouth (tongue, lips, and gums), extremities, and neck
(throat and larynx). There were infrequent reports of life-threatening
angioedema requiring emergent medical attention due to respiratory compromise.
Instruct patients to discontinue CHANTIX and immediately seek medical care if
they experience these symptoms.
Serious Skin Reactions
There have been postmarketing reports of rare but serious
skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in
patients using CHANTIX [see ADVERSE REACTIONS]. As these skin reactions
can be life-threatening, instruct patients to stop taking CHANTIX and contact a
healthcare provider immediately at the first appearance of a skin rash with
mucosal lesions or any other signs of hypersensitivity.
Nausea was the most common adverse reaction reported with
CHANTIX treatment. Nausea was generally described as mild or moderate and often
transient; however, for some patients, it was persistent over several months.
The incidence of nausea was dose-dependent. Initial dose-titration was beneficial
in reducing the occurrence of nausea. For patients treated to the maximum
recommended dose of 1 mg twice daily following initial dosage titration, the
incidence of nausea was 30% compared with 10% in patients taking a comparable
placebo regimen. In patients taking CHANTIX 0.5 mg twice daily following
initial titration, the incidence was 16% compared with 11% for placebo.
Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies
involving 12 weeks of treatment discontinued treatment prematurely because of
nausea. For patients with intolerable nausea, a dose reduction should be
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Initiate Treatment And Continue To Attempt To Quit If Lapse
Instruct patients to set a date to quit smoking and to
initiate CHANTIX treatment one week before the quit date. Alternatively, the
patient can begin CHANTIX dosing and then set a date to quit smoking between
days 8 and 35 of treatment. Encourage patients to continue to attempt to quit
if they have early lapses after quit day [see DOSAGE AND ADMINISTRATION].
For patients who are sure that they are not able or
willing to quit abruptly, a gradual approach to quitting smoking with CHANTIX
may be considered. Patients should begin CHANTIX dosing and reduce smoking
during the first 12 weeks of treatment, then quit by the end of that period and
continue treatment for an additional 12 weeks for a total of 24 weeks [see DOSAGE
Encourage patients who are motivated to quit and who did
not succeed in stopping smoking during prior CHANTIX therapy for reasons other
than intolerability due to adverse events, or who relapsed after treatment to
make another attempt with CHANTIX once factors contributing to the failed
attempt have been identified and addressed [see DOSAGE AND ADMINISTRATION,
How To Take
Advise patients that CHANTIX should be taken orally after
eating, and with a full glass of water [see DOSAGE AND ADMINISTRATION].
Starting Week Dosage
Instruct patients on how to titrate CHANTIX, beginning at
a dose of 0.5 mg/day. Explain that one 0.5 mg tablet should be taken daily for
the first three days, and that for the next four days, one 0.5 mg tablet should
be taken in the morning and one 0.5 mg tablet should be taken in the evening [see
DOSAGE AND ADMINISTRATION].
Continuing Weeks Dosage
Advise patients that, after the first seven days, the
dose should be increased to one 1 mg tablet in the morning and one 1 mg tablet
in the evening [see DOSAGE AND ADMINISTRATION].
Dosage Adjustment For CHANTIX Or Other Drugs
Inform patients that nausea and insomnia are side effects
of CHANTIX and are usually transient; however, advise patients that if they are
persistently troubled by these symptoms, they should notify the prescribing
physician so that a dose reduction can be considered.
Inform patients that some drugs may require dose
adjustment after quitting smoking [see DOSAGE AND ADMINISTRATION].
Counseling And Support
Provide patients with educational materials and necessary
counseling to support an attempt at quitting smoking [see DOSAGE AND
Neuropsychiatric Adverse Events
Inform patients that some patients have experienced
changes in mood (including depression and mania), psychosis, hallucinations,
paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety,
and panic, as well as suicidal ideation and suicide when attempting to quit
smoking while taking CHANTIX. Instruct patients to discontinue CHANTIX and
contact a healthcare professional if they experience such symptoms [see WARNINGS
AND PRECAUTIONS, ADVERSE REACTIONS].
History Of Psychiatric Illness
Encourage patients to reveal any history of psychiatric
illness prior to initiating treatment.
Inform patients that quitting smoking, with or without
CHANTIX, may be associated with nicotine withdrawal symptoms (including
depression or agitation) or exacerbation of pre-existing psychiatric illness.
Encourage patients to report any history of seizures or
other factors that can lower seizure threshold. Instruct patients to
discontinue CHANTIX and contact a healthcare provider immediately if they experience
a seizure while on treatment [see WARNINGS AND PRECAUTIONS].
Interaction With Alcohol
Advise patients to reduce the amount of alcohol they
consume while taking CHANTIX until they know whether CHANTIX affects their
tolerance for alcohol [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Driving Or Operating Machinery
Advise patients to use caution driving or operating
machinery until they know how quitting smoking and/or varenicline may affect
them [see WARNINGS AND PRECAUTIONS].
Patients should be instructed to notify their healthcare
providers of symptoms of new or worsening cardiovascular events and to seek
immediate medical attention if they experience signs and symptoms of myocardial
infarction or stroke [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Patients should be instructed to discontinue CHANTIX and
notify their healthcare providers if they experience somnambulism [see WARNINGS
Inform patients that there have been reports of
angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck
(larynx and pharynx) that can lead to life-threatening respiratory compromise.
Instruct patients to discontinue CHANTIX and immediately seek medical care if
they experience these symptoms [see WARNINGS AND PRECAUTIONS, ADVERSE
Serious Skin Reactions
Inform patients that serious skin reactions, such as
Stevens-Johnson Syndrome and erythema multiforme, were reported by some
patients taking CHANTIX. Advise patients to stop taking CHANTIX at the first sign
of rash with mucosal lesions or skin reaction and contact a healthcare provider
immediately [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Vivid, Unusual, Or Strange Dreams
Inform patients that they may experience vivid, unusual
or strange dreams during treatment with CHANTIX.
Pregnancy And Lactation
Patients who are pregnant or breastfeeding or planning to
become pregnant should be advised of: the risks of smoking to a pregnant mother
and her developing baby, the potential risks of CHANTIX use during pregnancy
and breastfeeding, and the benefits of smoking cessation with and without
CHANTIX. Advise breastfeeding women to monitor the infant for seizures and
vomiting [see Use In Specific Populations].
This product's label may have been updated. For full
prescribing information, please visit www.pfizer.com
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 (MRHD) 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 MRHD exposure based on AUC) and maximum dose (2 tumors,
15 mg/kg/day, 67 times the MRHD 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.
Impairment Of Fertility
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 MRHD exposure based on AUC at 1 mg twice
daily). Maternal toxicity, characterized by a decrease in body weight gain, was
observed at 15 mg/kg/day. 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. 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
MRHD exposure based on AUC at 1 mg twice daily).
Use In Specific Populations
Available human data on the use of CHANTIX in pregnant
women are not sufficient to inform a drug associated risk. Smoking during
pregnancy is associated with maternal, fetal, and neonatal risks [see Clinical
Considerations]. In animal studies, varenicline did not result in major
malformations but caused decreased fetal weights in rabbits when dosed during
organogenesis at exposures equivalent to 50 times the exposure at the maximum
recommended human dose (MRHD). Additionally, administration of varenicline to
pregnant rats during organogenesis through lactation produced developmental
toxicity in offspring at maternal exposures equivalent to 36 times human
exposure at the MRHD [see Data].
The estimated background risk of oral clefts is increased
by approximately 30% in infants of women who smoke during pregnancy, compared
to pregnant women who do not smoke. The background risk of other major birth
defects and miscarriage for the indicated population are unknown. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Smoking during pregnancy causes increased risks of
orofacial clefts, premature rupture of membranes, placenta previa, placental
abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth,
preterm delivery and shortened gestation, neonatal death, sudden infant death
syndrome and reduction of lung function in infants. It is not known whether
quitting smoking with CHANTIX during pregnancy reduces these risks.
Pregnant rats and rabbits received varenicline succinate
during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively.
While no fetal structural abnormalities occurred in either species, maternal toxicity,
characterized by reduced body weight gain, and reduced fetal weights occurred
in rabbits at the highest dose (exposures 50 times the human exposure at the
MRHD of 1 mg twice daily based on AUC). Fetal weight reduction did not occur in
rabbits at exposures 23 times the human exposure at the MRHD based on AUC.
In a pre- and postnatal development study, pregnant rats
received up to 15 mg/kg/day of oral varenicline succinate from organogenesis
through lactation. Maternal toxicity, characterized by a decrease in body weight
gain was observed at 15 mg/kg/day (36 times the human exposure at the MRHD
based on AUC). However, decreased fertility and increased auditory startle
response occurred in offspring at the highest maternal dose of 15 mg/kg/day.
There are no data on the presence of varenicline in human
milk, the effects on the breastfed infant, or the effects on milk production.
In animal studies varenicline was present in milk of lactating rats [see Data].
However, due to species-specific differences in lactation physiology, animal
data may not reliably predict drug levels in human milk. The lack of clinical
data during lactation precludes a clear determination of the risk of CHANTIX to
an infant during lactation; however the developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for CHANTIX
and any potential adverse effects on the breastfed child from CHANTIX or from
the underlying maternal condition.
Because there are no data on the presence of varenicline
in human milk and the effects on the breastfed infant, breastfeeding women
should monitor their infant for seizures and excessive vomiting, which are adverse
reactions that have occurred in adults that may be clinically relevant in
In a pre- and postnatal development study, pregnant rats
received up to 15 mg/kg/day of oral varenicline succinate through gestation and
lactation Mean serum concentrations of varenicline in the nursing pups were
5–22% of maternal serum concentrations.
Safety and effectiveness of CHANTIX in pediatric patients
have not been established.
A combined single- and multiple-dose pharmacokinetic
study demonstrated that the pharmacokinetics of 1 mg varenicline given once
daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75
years) for 7 consecutive days was similar to that of younger subjects. No
overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
Varenicline is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients
with impaired renal function. 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].
No dosage adjustment is recommended for elderly patients.
Varenicline is substantially eliminated by renal
glomerular filtration along with active tubular secretion. Dose reduction is
not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment (estimated creatinine clearance <30 mL/min),
and for patients with end-stage renal disease undergoing hemodialysis, dosage
adjustment is needed [see DOSAGE AND ADMINISTRATION, CLINICAL