CHANTIX 0.5 MG Oral Tablet
DRUG INTERACTIONS
7 Based on varenicline characteristics and clinical experience to date, CHANTIX has no clinically meaningful pharmacokinetic drug interactions [see Clinical Pharmacology (12.3) ].
Other smoking cessation therapies: Safety and efficacy in combination with other smoking cessation therapies has not been established.
Coadministration of varenicline and transdermal nicotine resulted in a high rate of discontinuation due to adverse events.
( 7.1 ) Effect of smoking cessation: Pharmacokinetics or pharmacodynamics of certain drugs may be altered due to smoking cessation with CHANTIX, necessitating dose adjustment.
( 7.2 ) 7.1 Use With Other Drugs for Smoking Cessation Safety and efficacy of CHANTIX in combination with other smoking cessation therapies have not been studied.
Bupropion : Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers.
The safety of the combination of bupropion and varenicline has not been established.
Nicotine replacement therapy (NRT ) : Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone.
In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.
7.2 Effect of Smoking Cessation on Other Drugs Physiological changes resulting from smoking cessation, with or without treatment with CHANTIX, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
OVERDOSAGE
10 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 Clinical Pharmacology (12.3) ], however, there is no experience in dialysis following overdose.
DESCRIPTION
11 CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α 4 β 2 nicotinic acetylcholine receptor subtypes.
Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6 H -pyrazino[2,3- h][3]benzazepine, (2 R ,3 R )-2,3-dihydroxybutanedioate (1:1).
It is highly soluble in water.
Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C 13 H 13 N 3 • C 4 H 6 O 6 .
The chemical structure is: CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with ” Pfizer ” on one side and “CHX 0.5″ on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with ” Pfizer ” on one side and “CHX 1.0” on the other side.
Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base.
The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
Chemical Structure
CLINICAL STUDIES
14 The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (≥10 cigarettes per day) were treated with CHANTIX.
In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO≤10 ppm) at weekly visits.
Among the CHANTIX-treated patients enrolled in these studies, the completion rate was 65%.
Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment.
Most patients enrolled in these trials were white (79–96%).
All studies enrolled almost equal numbers of men and women.
The average age of patients in these studies was 43 years.
Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years.
Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date.
Three additional studies were conducted in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease [see Clinical Studies (14.4) ], and in patients instructed to select their quit date within days 8 and 35 of treatment [see Clinical Studies (14.5) ] .
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.
14.1 Initiation of Abstinence Study 1 : This was a six-week dose-ranging study comparing CHANTIX to placebo.
This study provided initial evidence that CHANTIX at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.
Study 2 : This study of 627 patients compared CHANTIX 1 mg per day and 2 mg per day with placebo.
Patients were treated for 12 weeks (including one week titration) and then were followed for 40 weeks post-treatment.
CHANTIX was given in two divided doses daily.
Each dose of CHANTIX was given in two different regimens, with and without initial dose titration, to explore the effect of different dosing regimens on tolerability.
For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing.
The titrated and nontitrated groups were pooled for efficacy analysis.
Forty-five percent of patients receiving CHANTIX 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1).
In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.
Study 3 : This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of CHANTIX or placebo.
After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day.
Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study.
For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.
Of the patients treated with CHANTIX, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group.
In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.
Study 4 and Study 5 : These identical double-blind studies compared CHANTIX 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo.
Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment.
The CHANTIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days.
The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily.
Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients.
Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.
In Study 4, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%).
The bupropion SR quit rate was also superior to placebo.
In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.
Similarly in Study 5, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%).
The bupropion SR quit rate was also superior to placebo.
In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.
Figure 1: Continuous Abstinence, Weeks 9 through 12 Table 2: Continuous Abstinence, Weeks 9 through 12 (95% confidence interval) CHANTIX 0.5 mg BID CHANTIX 1 mg BID CHANTIX Flexible Bupropion SR Placebo BID = twice daily Study 2 45% (39%, 51%) 51% (44%, 57%) 12% (6%, 18%) Study 3 40% (32%, 48%) 12% (7%, 17%) Study 4 44% (38%, 49%) 30% (25%, 35%) 17% (13%, 22%) Study 5 44% (38%, 49%) 30% (25%, 35%) 18% (14%, 22%) Figure 1 14.2 Urge to Smoke Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale “urge to smoke” item, CHANTIX reduced urge to smoke compared to placebo.
14.3 Long-Term Abstinence Studies 1 through 5 included 40 weeks of post-treatment follow-up.
In each study, CHANTIX-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo ( Figure 2 , Table 3 ).
Figure 2: Continuous Abstinence, Weeks 9 through 52 Table 3: Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) across different studies CHANTIX 0.5 mg BID CHANTIX 1 mg BID CHANTIX Flexible Bupropion SR Placebo BID = twice daily Study 2 19% (14%, 24%) 23% (18%, 28%) 4% (1%, 8%) Study 3 22% (16%, 29%) 8% (3%, 12%) Study 4 21% (17%, 26%) 16% (12%, 20%) 8% (5%, 11%) Study 5 22% (17%, 26%) 14% (11%, 18%) 10% (7%, 13%) Figure 2 Study 6 : This study assessed the effect of an additional 12 weeks of CHANTIX therapy on the likelihood of long-term abstinence.
Patients in this study (n=1927) were treated with open-label CHANTIX 1 mg twice daily for 12 weeks.
Patients who had stopped smoking for at least a week by Week 12 (n=1210) were then randomized to double-blind treatment with CHANTIX (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.
The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with CHANTIX (70%) than for patients switching to placebo (50%).
Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (CHANTIX 54% versus placebo 39%).
In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of CHANTIX; post-CHANTIX follow-up begins at Week 13 for the placebo group and Week 25 for the CHANTIX group.
The y-axis represents the percentage of patients who had been abstinent for the last week of CHANTIX treatment and remained abstinent at the given timepoint.
Figure 3: Continuous Abstinence Rate during Nontreatment Follow-Up Figure 3 14.4 Subjects with Cardiovascular and Chronic Obstructive Pulmonary Disease CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months.
Subjects were randomized to CHANTIX 1 mg twice daily (n=353) or placebo (n=350) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment.
Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).
CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV 1 /FVC <70% and FEV 1 ≥ 50% of predicted normal value.
Subjects were randomized to CHANTIX 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment.
Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).
Table 4: Continuous Abstinence (95% confidence interval), Studies in Patients with Cardiovascular Disease (CVD) and Chronic Obstructive Pulmonary Disease (COPD) Weeks 9 through 12 Weeks 9 through 52 CHANTIX 1 mg BID Placebo CHANTIX 1 mg BID Placebo BID = twice daily CVD Study 47% (42%, 53%) 14% (11%, 18%) 20% (16%, 24%) 7% (5%, 10%) COPD Study 41% (34%, 47%) 9% (6%, 13%) 19% (14%, 24%) 6% (3%, 9%) 14.5 Alternative Instructions for Setting a Quit Date CHANTIX was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment.
Subjects were randomized 3:1 to CHANTIX 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment.
Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).
HOW SUPPLIED
16 /STORAGE AND HANDLING CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with ” Pfizer ” on one side and “CHX 0.5″ on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with ” Pfizer ” on one side and “CHX 1.0” on the other side.
CHANTIX is supplied in the following package configurations: Description NDC Packs Starting Month PAK (First month of therapy): Pack includes 1 card of 0.5 mg x 11 tablets and 3 cards of 1 mg x 14 tablets NDC 0069-0471-97 Continuing Month PAK (Continuing months of therapy): Pack includes 4 cards of 1 mg x 14 tablets NDC 0069-0469-97 Starting Month Box: 0.5 mg x 11 tablets and 1 mg x 42 tablets NDC 0069-0471-02 Continuing Month Box : 1 mg x 56 tablets NDC 0069-0469-12 Bottles 0.5 mg – bottle of 56 NDC 0069-0468-56 1 mg – bottle of 56 NDC 0069-0469-56 Store at 25ºC (77ºF); excursions permitted to 15–30ºC (59–86ºF) (see USP Controlled Room Temperature).
RECENT MAJOR CHANGES
Dosage and Administration Alternative Instructions for Setting a Quit Date ( 2.1 ) 7/2011 Warnings and Precautions Cardiovascular Events ( 5.4 ) 7/2011
GERIATRIC USE
8.5 Geriatric Use A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects.
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 (2.2) ].
No dosage adjustment is recommended for elderly patients.
DOSAGE FORMS AND STRENGTHS
3 Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with ” Pfizer ” on one side and “CHX 0.5″ on the other side) and 1 mg (light blue, debossed with ” Pfizer ” on one side and “CHX 1.0” on the other side) Tablets: 0.5 mg and 1 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors.
The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline’s activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine.
Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking.
Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2000-fold).
Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.
INDICATIONS AND USAGE
1 CHANTIX is indicated for use as an aid to smoking cessation treatment.
CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to smoking cessation treatment.
( 1 and 2.1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of CHANTIX in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
There are no adequate and well-controlled studies of CHANTIX use in pregnant women.
In animal studies, CHANTIX caused decreased fetal weights, increased auditory startle response, and decreased fertility in offspring.
CHANTIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive and developmental toxicity studies, pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively.
These exposures were 36 (rats) and 50 (rabbits) times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 1 mg twice daily.
While no fetal structural abnormalities occurred in either species, reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD based on AUC).
Fetal weight reduction did not occur at animal 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.
These resulted in exposures up to 36 times the human exposure (based on AUC) at the MRHD of 1 mg twice daily.
Decreased fertility and increased auditory startle response occurred in offspring.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether CHANTIX is excreted in human milk.
In animal studies varenicline was excreted in milk of lactating animals.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CHANTIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking CHANTIX.
Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal.
Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke.
All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide.
These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking CHANTIX in the postmarketing experience.
When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.
These events have occurred in patients with and without pre-existing psychiatric disease.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established.
Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, 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.
In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of CHANTIX should be weighed against the benefits of its use.
CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
The health benefits of quitting smoking are immediate and substantial.
[see Warnings and Precautions (5.1) and Adverse Reactions 6.2) ] WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS See full prescribing information for complete boxed warning.
Serious neuropsychiatric events have been reported in patients taking CHANTIX.
( 5.1 and 6.2 ) Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, 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 while taking CHANTIX or shortly after discontinuing CHANTIX.
( 5.1 and 6.2 ) Weigh the risks of CHANTIX against benefits of its use.
CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
The health benefits of quitting smoking are immediate and substantial.
( 5.1 and 6.2 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Angioedema and hypersensitivity reactions: Such reactions, including angioedema, infrequently life threatening, have been reported.
Instruct patients to discontinue CHANTIX and immediately seek medical care if symptoms occur.
( 5.2 and 6.2 ) Serious skin reactions: Rare, potentially life-threatening skin reactions have been reported.
Instruct patients to discontinue CHANTIX and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions.
( 5.3 and 6.2 ) Cardiovascular events: In a trial of patients with stable cardiovascular disease (CVD) certain cardiovascular events were reported more frequently in patients treated with CHANTIX.
Patients with CVD should be instructed to notify their health care providers of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction.
( 5.4 and 6.1 ) Accidental injury: Accidental injuries (e.g., traffic accidents) have been reported.
Instruct patients to use caution driving or operating machinery until they know how CHANTIX may affect them.
( 5.5 ) Nausea: Nausea is the most common adverse reaction (up to 30% incidence rate).
Dose reduction may be helpful.
( 5.6 ) 5.1 Neuropsychiatric Symptoms and Suicidality Serious neuropsychiatric symptoms have been reported in patients being treated with CHANTIX [see Boxed Warning and Adverse Reactions (6.2) ] .
These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.
Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal.
Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke.
When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.
These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses.
All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established.
Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.
In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of CHANTIX should be weighed against the benefits of its use.
CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
The health benefits of quitting smoking are immediate and substantial.
5.2 Angioedema and Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2) , and Patient Counseling Information (17.10) ] .
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.
5.3 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 (6.2) ].
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.
5.4 Cardiovascular Events In a controlled clinical trial of CHANTIX administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, certain cardiovascular events were reported more frequently in patients treated with CHANTIX than in patients treated with placebo [see Clinical Trials Experience (6.1) ] .
These included treatment-emergent events (on-treatment or 30 days after treatment) of angina pectoris (13 patients in the varenicline arm vs.
7 in the placebo arm), and the serious cardiovascular events of nonfatal MI (4 vs.
1) and nonfatal stroke (2 vs.
0).
During non-treatment follow up to 52 weeks, serious cardiovascular events included nonfatal myocardial infarction (3 vs.
2), need for coronary revascularization (7 vs.
2), hospitalization for angina pectoris (6 vs.
4), transient ischemic attack (1 vs.
0), new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (5 vs.
2).
Serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by an independent blinded committee.
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 health care 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.
5.5 Accidental Injury 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 them .
5.6 Nausea 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 considered.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See Medication Guide 17.1 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 (2.1) ].
17.2 How To Take Advise patients that CHANTIX should be taken after eating, and with a full glass of water [see Dosage and Administration (2.1) ].
17.3 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 (2.1) ].
17.4 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 (2.1) ].
17.5 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 (2.1) ].
17.6 Counseling and Support Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking [see Dosage and Administration (2.1) ].
17.7 Neuropsychiatric Symptoms Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking CHANTIX.
If patients develop agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to discontinue CHANTIX and report these symptoms to their healthcare provider immediately [see Boxed Warning , Warnings and Precautions (5.1) , Adverse Reactions (6.2) ].
17.8 History of Psychiatric Illness Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.
17.9 Nicotine Withdrawal 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.
17.10 Angioedema 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 (5.2) , and Adverse Reactions (6.2) ].
17.11 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 (5.3) , and Adverse Reactions (6.2) ].
17.12 Patients with Cardiovascular Disease Patients with cardiovascular disease should be instructed to notify their health care providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction.
[see Warnings and Precautions (5.4) , and Adverse Reactions (6.1) ].
17.13 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 (5.5) ].
17.14 Vivid, Unusual, or Strange Dreams Inform patients that they may experience vivid, unusual or strange dreams during treatment with CHANTIX.
17.15 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 [see Use in Specific Populations (8.1 and 8.3) ].
DOSAGE AND ADMINISTRATION
2 Begin CHANTIX dosing one week before the date set by the patient to stop smoking.
Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
( 2.1 ) Starting week: 0.5 mg once daily on days 1–3 and 0.5 mg twice daily on days 4–7.
( 2.1 ) Continuing weeks: 1 mg twice daily for a total of 12 weeks.
( 2.1 ) An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence.
( 2.1 ) Renal impairment: Reduce the dose in patients with severe renal impairment (estimated creatinine clearance <30 mL/min).
( 2.2 ) Consider dose reduction for patients who cannot tolerate adverse effects.
( 2.1 ) Another attempt at treatment is recommended for those who fail to stop smoking or relapse when factors contributing to the failed attempt have been addressed.
( 2.1 ) Provide patients with appropriate educational materials and counseling to support the quit attempt.
( 2.1 ) 2.1 Usual Dosage for Adults Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support.
Provide patients with appropriate educational materials and counseling to support the quit attempt.
The patient should set a date to stop smoking.
Begin CHANTIX dosing one week before this date.
Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
CHANTIX should be taken after eating and with a full glass of water.
The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows: Days 1 – 3: 0.5 mg once daily Days 4 – 7: 0.5 mg twice daily Day 8 – end of treatment: 1 mg twice daily Patients should be treated with CHANTIX for 12 weeks.
For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks’ treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.
Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
2.2 Dosage in Special Populations Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment.
For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily.
The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day.
For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .
Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment.
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 Use in Specific Populations (8.5) ] .