WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Seizures: New or worsening seizures have been observed in patients taking CHANTIX.

CHANTIX should be used cautiously in patients with a history of seizures or other factors that can lower the seizure threshold.

(5.2) • Interaction with alcohol: Increased effects of alcohol have been reported.

Instruct patients to reduce the amount of alcohol they consume until they know whether CHANTIX affects them.

(5.3) • 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.

(5.4) • Cardiovascular events: A meta-analysis of 15 clinical trials, including a trial in patients with stable cardiovascular disease, demonstrated that while cardiovascular events were infrequent overall, some were reported more frequently in patients treated with CHANTIX.

These events occurred primarily in patients with known cardiovascular disease.

In both the clinical trial and meta-analysis, all-cause and cardiovascular mortality was lower in patients treated with CHANTIX.

Instruct patients 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 or stroke.

(5.5 and 6.1) • 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.

(5.6 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.

(5.7 and 6.2) • Nausea: Nausea is the most common adverse reaction (up to 30% incidence rate).

Dose reduction may be helpful.

(5.8) 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.

Limited safety data are available from post-marketing smoking cessation studies in two patient groups: 1) patients with major depressive disorder, and 2) patients with stable schizophrenia or schizoaffective disorder [see Adverse Reactions (6.1) , Clinical Studies (14.5) ] .

Some reported neuropsychiatric 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 (5.3) , Adverse Reactions (6.2) ] .

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.

Since the initial signal of neuropsychiatric symptoms and suicidality emerged, additional analyses and studies have been conducted to further evaluate this association.

Analyses of clinical trials A meta-analysis of 5 randomized, double blind, placebo controlled trials, including 1907 patients (1130 CHANTIX, 777 placebo) was conducted to assess suicidal ideation and behavior as reported on the Columbia-Suicide Severity Rating Scale (C SSRS).

This meta-analysis included one trial (N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N=525) in patients with a history of depression.

The results showed no increase in the incidence of suicidal ideation and/or behavior in patients treated with CHANTIX compared to patients treated with placebo, with a Risk Ratio (RR) of 0.79 (95% Confidence Interval [CI]: 0.46, 1.36), as shown in Table 1.

Forty-eight (48) of the 55 patients who reported suicidal ideation or behavior (24 CHANTIX, 24 placebo) were observed in the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression.

Few events were observed in the other three trials (4 CHANTIX, 3 placebo).

Table 1.

Number of Patients and Risk Ratio for Suicidal Ideation and/or Behavior Reported on C-SSRS from a Meta-Analysis of 5 Clinical Trials Comparing CHANTIX to Placebo CHANTIX (N=1130) Placebo (N=777) Patients with Suicidal ideation and/or behaviorOf the events, one patient in each treatment arm reported suicidal behavior [n (%)]Patients with events up to 30 days after treatment; % are not weighted by study 28 (2.5) 27 (3.5) Patient-years of exposure 325 217 Risk Ratio # RR of incidence rates per 100 patient years (RR; 95% CI) 0.79 (0.46, 1.36) A pooled analysis of 18 double-blind, randomized, placebo-controlled clinical trials, which includes the 5 trials that collected C-SSRS described in Table 1, was conducted to assess the psychiatric safety of CHANTIX.

This pooled analysis included 8521 patients (5072 CHANTIX, 3449 placebo), some of whom had psychiatric conditions at baseline.

Table 2 describes the most frequently (≥ 1%) reported adverse events related to psychiatric safety.

The results showed a similar incidence of common psychiatric events in patients treated with CHANTIX compared to patients treated with placebo.

Table 2.

Psychiatric Adverse Events Occurring in ≥ 1% of Patients from Pooled Analysis of 18 Clinical Trials CHANTIX (N=5072) Placebo (N=3449) Anxiety disorders and symptoms 253 (5.0) 206 (6.0) Depressed mood disorders and disturbances 179 (3.5) 108 (3.1) Mood disorders and disturbances NECNEC = Not Elsewhere Classified Counts (percentages) corresponds to the number of patients reporting the event 116 (2.3) 53 (1.5) Observational Studies Four observational studies, each including 10,000 to 30,000 users of CHANTIX in the adjusted analyses, compared the risk of selected serious neuropsychiatric events (neuropsychiatric hospitalizations, fatal and non-fatal self-harm), between CHANTIX users and prescription NRT or bupropion users.

All studies were retrospective cohort studies and included patients with and without a psychiatric history.

Two of the studies found no difference in risk of neuropsychiatric hospitalizations between CHANTIX 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).

However, neither study validated the diagnostic codes used to identify outcomes against medical records.

A third study reported no difference in risk of psychiatric adverse events diagnosed during an emergency department visit or inpatient admission between CHANTIX users and bupropion users (HR 0.85; 95% CI: 0.55–1.30).

Bupropion has also been associated with neuropsychiatric adverse events.

A fourth study examined risk of fatal and non-fatal self-harm in users of CHANTIX compared to users of NRT.

Although the occurrence of detected suicide was rare during the three months after patients initiated any drug treatment (two cases in 31,260 CHANTIX users and six cases in 81,545 NRT users), this study has important limitations.

Most importantly, these data were captured following public awareness of reports of neuropsychiatric adverse events in CHANTIX users.

CHANTIX users had fewer comorbid conditions that could put them at risk for neuropsychiatric adverse events, suggesting that patients with a history of neuropsychiatric illness were preferentially prescribed NRT, and healthier patients were preferentially prescribed CHANTIX.

Outcomes examined in these studies did not include the full range of neuropsychiatric adverse events that have been reported.

5.2 Seizures 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 (6.2) ].

5.3 Interaction with Alcohol There have been post-marketing 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 (6.2) ] .

5.4 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.

5.5 Cardiovascular Events 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 Clinical Trials Experience (6.1)].

Table 3 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 3.

Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-Controlled CHANTIX Trial in Patients with Stable Cardiovascular Disease Mortality and Cardiovascular Events CHANTIX (N=353) n (%) Placebo (N=350) n (%) Mortality (Cardiovascular & All-cause up to 52 wks) Cardiovascular death 1 (0.3) 2 (0.6) All-cause mortality 2 (0.6) 5 (1.4) Nonfatal Cardiovascular Events (rate on CHANTIX > Placebo) Up to 30 days after treatment Nonfatal myocardial infarction 4 (1.1) 1 (0.3) Nonfatal Stroke 2 (0.6) 0 (0) Beyond 30 days after treatment & up to 52 weeks Nonfatal myocardial infarction 3 (0.8) 2 (0.6) Need for coronary revascularization 7 (2.0) 2 (0.6) Hospitalization for angina pectoris 6 (1.7) 4 (1.1) Transient ischemia attack 1 (0.3) 0 (0) New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure 5 (1.4) 2 (0.6) 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 4.

These events occurred primarily in patients with known cardiovascular disease.

Table 4.

Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15 Clinical Trials Comparing CHANTIX to PlaceboIncludes MACE occurring up to 30 days post treatment.

CHANTIX N=4190 Placebo N=2812 MACE cases, n (%) 13 (0.31%) 6 (0.21%) Patient-years of exposure 1316 839 Hazard Ratio (95% CI) 1.95 (0.79, 4.82) Rate Difference per 1,000 patient-years (95% CI) 6.30 (-2.40, 15.10) 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 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.

5.6 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)].

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.

5.7 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.

5.8 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.