Prescription Drug Information: CHANTIX

CHANTIX- varenicline tartrate
Proficient Rx LP

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.

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)]

1 INDICATIONS AND USAGE

CHANTIX is indicated for use as an aid to smoking cessation treatment.

2 DOSAGE AND ADMINISTRATION

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 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, should be encouraged to make another attempt with CHANTIX 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)].

3 DOSAGE FORMS AND STRENGTHS

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).

4 CONTRAINDICATIONS

CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.

5 WARNINGS AND PRECAUTIONS

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)
*
Of the events, one patient in each treatment arm reported suicidal behavior
Patients with events up to 30 days after treatment; % are not weighted by study
# RR of incidence rates per 100 patient years

Patients with Suicidal ideation and/or behavior * [n (%)]

28 (2.5)

27 (3.5)

Patient-years of exposure

325

217

Risk Ratio (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)
*
NEC = Not Elsewhere ClassifiedCounts (percentages) corresponds to the number of patients reporting the event

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 NEC *

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.

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