CHAMPIX 0.5 MG

מ"עב לארשי הקיטבצמרפ רזייפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

מ"עב לארשי הקיטבצמרפ רזייפ

רבמטפס

2018

,ה/דבכנ ת/חקור ,ה/אפור

ןוכדע לע ךעידוהל וננוצרב אפורל ןולעב

ןכרצל ןולעבו

לש

Champix 0.5 mg, Champix 1.0 mg

:

:ליעפה ביכרמה

Varenicline (as tartrate) 0.5 mg, Varenicline (as tartrate) 1 mg

Indicated for:

CHAMPIX is indicated as an aid to smoking cessation treatment for adults over 18 years of age.

ןולעב םיירקיעה םינוכדעה ןלהל אפורל

:

WARNINGS AND PRECAUTIONS

5.5 Cardiovascular Events

A comprehensive evaluation of cardiovascular (CV) risk with CHAMPIX suggests that patients with

underlying CV disease may be at increased risk; however, these concerns must be balanced with the health

benefits of smoking cessation. CV risk has been assessed for CHAMPIX in randomized controlled trials

(RCT) and meta-analyses of RCTs. In a smoking cessation trial in patients with stable CV disease, CV

events were infrequent overall; however, nonfatal myocardial infarction (MI) and nonfatal stroke occurred

more frequently in patients treated with CHAMPIX compared to placebo. All-cause and CV mortality was

lower in patients treated with CHAMPIX [see Clinical Studies (14.8)]. This study was included in a meta-

analysis of 15 CHAMPIX efficacy trials in various clinical populations that showed an increased hazard

ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the finding was not statistically

significant (95% CI: 0.79, 4.82). In the large postmarketing neuropsychiatric safety outcome trial, an analysis

of adjudicated MACE events was conducted for patients while in the trial and during a 28-week non-

treatment extension period. Few MACE events occurred during the trial; therefore, the findings did not

contribute substantively to the understanding of CV risk with CHAMPIX . Instruct patients to notify their

healthcare providers of new or worsening CV symptoms and to seek immediate medical attention if they

experience signs and symptoms of MI or stroke [see Clinical Studies (14.10)].

םישגדומה םייונישה .הרמחה םיווהמ בוהצ עקרב עדימ תטמשה ,עדימ תפסות םיללוכה םיפסונ םייוניש ועצוב ,ןכ ומכ .הרמחה םיווהמ םניאש חסונ ינוכדעו

.תואירבה דרשמ רתאב םינימז םינכדועמה םינולעה

ןכרצל ןולעב ועצובש םייונישה עדימ תפסות םיללוכ

עדימ תטמשה

הווהמ וניא הרמחה

rufot/index.asp?safa=h

https://www.old.health.gov.il/units/pharmacy/t

רקנש ,מ"עב לארשי הקיטבצמרפ רזייפ תרבחל תונפל ןתינ ספדומ אלמ ןולע תלבקל ,ןיפוליחל

.ד.ת ,

12133

,חותיפ הילצרה

46725

,הכרבב

קו'צשילופ הטירגרמ

הנוממ תחקור

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

FULL PRESCRIBING INFORMATION

NAME OF THE MEDICINAL PRODUCT

CHAMPIX 0.5 mg

CHAMPIX 1.0 mg

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 0.5 mg CHAMPIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of

varenicline free base.

Each 1mg CHAMPIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline

free base

For the full list of excipients, see section 11.

PHARMACEUTICAL FORM

Film coated tablets

1

INDICATIONS AND USAGE

CHAMPIX is indicated as an aid to smoking cessation treatment for adults over 18 years of age.

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 CHAMPIX dosing one week before this date.

Alternatively, the patient can begin CHAMPIX dosing and then quit smoking between days 8 and 35 of

treatment.

CHAMPIX should be taken orally after eating and with a full glass of water.

The recommended dose of CHAMPIX 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

treatment:

1 mg twice daily

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

Patients should be treated with CHAMPIX for 12 weeks. For patients who have successfully stopped

smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX is

recommended to further increase the likelihood of long-term abstinence.

For patients who are sure that they are not able or willing to quit abruptly, consider a gradual approach to

quitting smoking with CHAMPIX. Patients should begin CHAMPIX dosing and reduce smoking by 50%

from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue

reducing with the goal of reaching complete abstinence by 12 weeks. Continue CHAMPIX treatment for

an additional 12 weeks, for a total of 24 weeks of treatment. Encourage patients to attempt quitting sooner

if they feel ready [see Clinical Studies (14.5)].

Patients who are motivated to quit, and who did not succeed in stopping smoking during prior

CHAMPIX therapy for reasons other than intolerability due to adverse events or who relapsed after

treatment, should be encouraged to make another attempt with CHAMPIX 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

CHAMPIX.

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 less than 30 mL per min), the recommended

starting dose of CHAMPIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum

dose of 0.5 mg twice daily. 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), 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

CHAMPIX is contraindicated in patients with a known history of serious hypersensitivity reactions or

skin reactions to CHAMPIX.

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2016-0021417, 2016-0021421

5

WARNINGS AND PRECAUTIONS

5.1

Neuropsychiatric Adverse Events including Suicidality

Serious neuropsychiatric adverse events have been reported in patients being treated with CHAMPIX

[see Adverse Reactions (6.2)]. 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 CHAMPIX who continued to smoke.

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 Warnings and Precautions (5.3), Adverse Reactions (6.2)].

Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers

that the patient should stop taking CHAMPIX 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 CHAMPIX 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 CHAMPIX was evaluated in a randomized, double-blind, active and

placebo-controlled study that included patients without a history of psychiatric disorder (non-psychiatric

cohort, N=3912) and patients with a history of psychiatric disorder (psychiatric cohort, N=4003). In the

non-psychiatric cohort, CHAMPIX 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 CHAMPIX, 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 CHAMPIX -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 CHAMPIX -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 Studies (14.10)].

5.2 Seizures

During clinical trials and the postmarketing experience, there have been reports of seizures in patients

treated with CHAMPIX. Some patients had no history of seizures, whereas others had a history of seizure

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

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 CHAMPIX in patients

with a history of seizures or other factors that can lower the seizure threshold. Advise patients to

discontinue CHAMPIX 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 postmarketing reports of patients experiencing increased intoxicating effects of alcohol

while taking CHAMPIX. 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 CHAMPIX until they know whether CHAMPIX 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 CHAMPIX. 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

CHAMPIX may affect them.

5.5 Cardiovascular Events

A comprehensive evaluation of cardiovascular (CV) risk with CHAMPIX suggests that patients with

underlying CV disease may be at increased risk; however, these concerns must be balanced with the

health benefits of smoking cessation. CV risk has been assessed for CHAMPIX in randomized controlled

trials (RCT) and meta-analyses of RCTs. In a smoking cessation trial in patients with stable CV disease,

CV events were infrequent overall; however, nonfatal myocardial infarction (MI) and nonfatal stroke

occurred more frequently in patients treated with CHAMPIX compared to placebo. All-cause and CV

mortality was lower in patients treated with CHAMPIX [see Clinical Studies (14.8)]. This study was

included in a meta-analysis of 15 CHAMPIX efficacy trials in various clinical populations that showed

an increased hazard ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the

finding was not statistically significant (95% CI: 0.79, 4.82). In the large postmarketing neuropsychiatric

safety outcome trial, an analysis of adjudicated MACE events was conducted for patients while in the trial

and during a 28-week non-treatment extension period. Few MACE events occurred during the trial;

therefore, the findings did not contribute substantively to the understanding of CV risk with CHAMPIX .

Instruct patients to notify their healthcare providers of new or worsening CV symptoms and to seek

immediate medical attention if they experience signs and symptoms of MI or stroke [see Clinical Studies

(14.10)].

5.6 Somnambulism

Cases of somnambulism have been reported in patients taking CHAMPIX. Some cases described harmful

behavior to self, others, or property. Instruct patients to discontinue CHAMPIX and notify their

healthcare provider if they experience somnambulism [see Adverse Reactions (6.2)].

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

5.7 Angioedema and Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions including angioedema in patients

treated with CHAMPIX [see Adverse Reactions (6.2),]. 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 CHAMPIX and immediately seek medical care if they experience these

symptoms.

5.8 Serious Skin Reactions

There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson

Syndrome and erythema multiforme, in patients using CHAMPIX [see Adverse Reactions (6.2)]. As

these skin reactions can be life-threatening, instruct patients to stop taking CHAMPIX and contact a

healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other

signs of hypersensitivity.

5.9 Nausea

Nausea was the most common adverse reaction reported with CHAMPIX 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 CHAMPIX 0.5 mg twice daily following initial

titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated

with CHAMPIX 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.

6

ADVERSE REACTIONS

The following serious adverse reactions were reported in postmarketing experience and are discussed in

greater detail in other sections of the labeling:

Neuropsychiatric Adverse Events including Suicidality [see Warnings and Precautions (5.1)]

Seizures [see Warnings and Precautions (5.2)]

Interaction with Alcohol [see Warnings and Precautions (5.3)]

Accidental Injury [see Warnings and Precautions (5.4)]

Cardiovascular Events [see Warnings and Precautions (5.5)]

Somnambulism [see Warnings and Precautions (5.6)]

Angioedema and Hypersensitivity Reactions [see Warnings and Precautions (5.7)]

Serious Skin Reactions [see Warnings and Precautions (5.8)]

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2016-0021417, 2016-0021421

In the placebo-controlled premarketing studies, the most common adverse events associated with

CHAMPIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid,

unusual, or strange) dreams, constipation, flatulence, and vomiting.

The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12%

for CHAMPIX, compared to 10% for placebo in studies of three months’ treatment. In this group, the

discontinuation rates that are higher than placebo for the most common adverse events in CHAMPIX-

treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo),

and abnormal dreams (0.3% vs. 0.2% for placebo).

Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has

also been associated with the exacerbation of underlying psychiatric illness.

6.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reactions rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in clinical practice.

During the premarketing development of CHAMPIX, over 4500 subjects were exposed to CHAMPIX,

with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants

were treated for 12 weeks or less.

The most common adverse event associated with CHAMPIX treatment is nausea, occurring in 30% of

patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo

regimen [see Warnings and Precautions (5.9)].

Table 1 shows the adverse events for CHAMPIX and placebo in the 12- week fixed dose premarketing

studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were

categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).

MedDRA High Level Group Terms (HLGT) reported in ≥5% of patients in the CHAMPIX 1 mg twice

daily dose group, and more commonly than in the placebo group, are listed, along with subordinate

Preferred Terms (PT) reported in ≥1% of CHAMPIX patients (and at least 0.5% more frequent than

placebo). Closely related Preferred Terms such as ‘Insomnia’, ‘Initial insomnia’, ‘Middle insomnia’,

‘Early morning awakening’ were grouped, but individual patients reporting two or more grouped events

are only counted once.

Table 1. Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies

(HLGTs >5% of Patients in the 1 mg BIDCHAMPIX Group and More Commonly than Placebo

and PT ≥1% in the 1 mg BID CHAMPIX Group, and 1 mg BID CHAMPIX at Least 0.5% More

than Placebo)

SYSTEM ORGAN

CLASS

High Level Group Term

Preferred Term

CHAMPIX 0.5

mg BID

N=129

CHAMPIX

1 mg BID

N=821

Placebo

N=805

GASTROINTESTINAL

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

(GI)

GI Signs and Symptoms

Nausea

Abdominal Pain *

Flatulence

Dyspepsia

Vomiting

GI Motility/Defecation

Conditions

Constipation

Gastroesophageal

reflux

disease

Salivary Gland

Conditions

Dry mouth

PSYCHIATRIC

DISORDERS

Sleep

Disorder/Disturbances

Insomnia **

Abnormal dreams

Sleep disorder

Nightmare

NERVOUS SYSTEM

Headaches

Headache

Neurological Disorders

Dysgeusia

Somnolence

Lethargy

GENERAL DISORDERS

General Disorders NEC

Fatigue/Malaise/Asthenia

RESPIR/THORACIC/M

EDIAST

Respiratory Disorders

Rhinorrhea

Dyspnea

Upper Respiratory

Tract

Disorder

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SKIN/SUBCUTANEOU

S TISSUE

Epidermal and Dermal

Conditions

Rash

Pruritis

METABOLISM and

NUTRITION

Appetite/General

Nutrition

Disorders

Increased appetite

Decreased appetite/

Anorexia

* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness,

distension) and Stomach discomfort

** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening

The overall pattern and frequency of adverse events during the longer-term premarketing trials was

similar to those described in Table 1, though several of the most common events were reported by a

greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated

with CHAMPIX 1 mg twice daily in a one year study, compared to 8% of placebo-treated patients).

Following is a list of treatment-emergent adverse events reported by patients treated with CHAMPIX

during all premarketing clinical trials and updated based on pooled data from 18 placebo-controlled pre-

and postmarketing studies, including approximately 5,000 patients treated with varenicline. Adverse

events were categorized using MedDRA, Version 16.0. The listing does not include those events already

listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote,

those events which were so general as to be uninformative, and those events reported only once which did

not have a substantial probability of being acutely life-threatening.

Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis,

splenomegaly, thrombocytopenia.

Cardiac Disorders. Infrequent: angina pectoris, myocardial infarction, palpitations, tachycardia. Rare:

acute coronary syndrome, arrhythmia, atrial fibrillation, bradycardia, cardiac flutter, cor pulmonale,

coronary artery disease, ventricular extrasystoles.

Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere’s disease.

Endocrine Disorders. Infrequent: thyroid gland disorders.

Eye Disorders. Infrequent: conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment. Rare:

blindness transient, cataract subcapsular, dry eye, night blindness, ocular vascular disorder, photophobia,

vitreous floaters.

Gastrointestinal Disorders. Frequent: diarrhea, toothache. Infrequent: dysphagia, eructation, gastritis,

gastrointestinal hemorrhage, mouth ulceration. Rare: enterocolitis, esophagitis, gastric ulcer, intestinal

obstruction, pancreatitis acute.

General Disorders and Administration Site Conditions. Frequent: chest pain. Infrequent: chest

discomfort, chills, edema, influenza-like illness, pyrexia.

Hepatobiliary Disorders. Rare: gall bladder disorder.

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Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram

abnormal. Rare: muscle enzyme increased, urine analysis abnormal.

Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hypoglycemia. Rare: hyperlipidemia,

hypokalemia.

Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, myalgia. Infrequent:

arthritis, muscle cramp, musculoskeletal pain. Rare: myositis, osteoporosis.

Nervous System Disorders. Frequent: disturbance in attention, dizziness. Infrequent: amnesia,

convulsion, migraine, parosmia, syncope, tremor. Rare: balance disorder, cerebrovascular accident,

dysarthria, mental impairment, multiple sclerosis, VII

nerve paralysis, nystagmus, psychomotor

hyperactivity, psychomotor skills impaired, restless legs syndrome, sensory disturbance, transient

ischemic attack, visual field defect.

Psychiatric Disorders. Infrequent: dissociation, libido decreased, mood swings, thinking abnormal. Rare:

bradyphrenia, disorientation, euphoric mood.

Renal and Urinary Disorders. Infrequent: nocturia, pollakiuria, urine abnormality. Rare: nephrolithiasis,

polyuria, renal failure acute, urethral syndrome, urinary retention.

Reproductive System and Breast Disorders. Frequent: menstrual disorder. Infrequent: erectile

dysfunction. Rare: sexual dysfunction.

Respiratory, Thoracic and Mediastinal Disorders. Frequent: respiratory disorders. Infrequent: asthma,

epistaxis, rhinitis allergic, upper respiratory tract inflammation. Rare: pleurisy, pulmonary embolism.

Skin and Subcutaneous Tissue Disorders. Infrequent: acne, dry skin, eczema, erythema, hyperhidrosis,

urticaria. Rare: photosensitivity reaction, psoriasis.

Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.

CHAMPIX has also been studied in postmarketing trials including (1) a trial conducted in patients with

chronic obstructive pulmonary disease (COPD), (2) a trial conducted in generally healthy patients (similar

to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and

35 of treatment (“alternative quit date instruction trial”), (3) a trial conducted in patients who did not

succeed in stopping smoking during prior CHAMPIX therapy, or who relapsed after treatment (“re-

treatment trial”), (4) a trial conducted in patients with stable cardiovascular disease, (5) a trial conducted

in patients with stable schizophrenia or schizoaffective disorder, (6) a trial conducted in patients with

major depressive disorder, (7) a postmarketing neuropsychiatric safety outcome trial in patients without or

with a history of psychiatric disorder, (8) a non-treatment extension of the postmarketing neuropsychiatric

safety outcome trial that assessed CV safety, (9) a trial in patients who were not able or willing to quit

abruptly and who were instructed to quit gradually (“gradual approach to quitting smoking trial”).

Adverse events in the trial of patients with COPD (1), in the alternative quit date instruction trial (2), and

in the gradual approach to quitting smoking trial (9) were similar to those observed in premarketing

studies. In the re-treatment trial (3), the profile of common adverse events was similar to that previously

reported, but, in addition, varenicline-treated patients also commonly reported diarrhea (6% vs. 4% in

placebo-treated patients), depressed mood disorders and disturbances (6% vs. 1%), and other mood

disorders and disturbances (5% vs. 2%).

In the trial of patients with stable cardiovascular disease (4), more types and a greater number of

cardiovascular events were reported compared to premarketing studies, as shown in Table 1 and in Table

2 below.

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2016-0021417, 2016-0021421

Table 2. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency >1%

in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease

CHAMPIX

1 mg BID

N=353

Placebo

N=350

Adverse Events ≥1% in either treatment

group

Up to 30 days after treatment

Angina pectoris

Chest pain

Peripheral edema

Hypertension

Palpitations

Adjudicated Cardiovascular Mortality (up

to 52 weeks)

Adjudicated Nonfatal Serious

Cardiovascular Events ≥1% in either

treatment group

Up to 30 days after treatment

Nonfatal MI

Hospitalization for angina pectoris

Beyond 30 days after treatment and up to

52 weeks

Need for coronary revascularization*

Hospitalization for angina pectoris

New diagnosis of peripheral vascular

disease (PVD) or admission for a PVD

procedure

*some procedures were part of management of nonfatal MI and hospitalization for

angina

In the trial of patients with stable schizophrenia or schizoaffective disorder (5), 128 smokers on

antipsychotic medication were randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks

with 12-week non-drug follow-up. The most common treatment emergent adverse events reported in this

trial are shown in Table 3 below.

Table 3. Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia

or Schizoaffective Disorder

CHAMPIX

1 mg BID

N=84

Placebo

N=43

Adverse Events ≥10% in the varenicline

group

Nausea

Headache

Vomiting

Champix 0.5 mg and 1.0 mg, LPD, Israel, 03 September 2018

2016-0021417, 2016-0021421

Psychiatric Adverse Events ≥5% and at a

higher rate than in the placebo group

Insomnia

For the trial of patients with major depressive disorder (6), the most common treatment emergent adverse

events reported are shown in Table 4 below. Additionally, in this trial, patients treated with varenicline

were more likely than patients treated with placebo to report one of events related to hostility and

aggression (3% vs. 1%).

Table 4. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive

Disorder

CHAMPIX

1 mg BID

N=256

Placebo

N=269

Adverse Events ≥10% in either treatment

group

Nausea

Headache

Abnormal dreams

Insomnia

Irritability

Psychiatric Adverse Events ≥2% in any

treatment group and not included above

Depressed mood disorders and

disturbances

Anxiety

Agitation

Tension

Hostility

Restlessness

In the trial of patients without or with a history of psychiatric disorder (7), the most common adverse

events in subjects treated with varenicline were similar to those observed in premarketing studies. Most

common treatment-emergent adverse events reported in this trial are shown in Table 5 below.

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Table 5. Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History

of Psychiatric Disorder

CHAMPIX

1 mg BID

Placebo

Adverse Events ≥10% in the varenicline

group

Entire study population, N

1982

1979

Nausea

Headache

Psychiatric Adverse Events ≥2% in any

treatment group

Non-psychiatric cohort, N

Abnormal dreams

Agitation

Anxiety

Depressed mood

Insomnia

Irritability

Sleep disorder

Psychiatric cohort, N

1007

Abnormal dreams

Agitation

Anxiety

Depressed mood

Depression

Insomnia

Irritability

Nervousness

Sleep disorder

In the non-treatment extension of the postmarketing neuropsychiatric safety outcomes trial that assessed

CV safety (8), the most common adverse events in subjects treated with varenicline and occurring up to

30 days after last dose of treatment were similar to those observed in premarketing studies.

6.2

Postmarketing Experience

The following adverse events have been reported during post-approval use of CHAMPIX. Because these

events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate

their frequency or establish a causal relationship to drug exposure.

There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal

ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, and

completed suicide in patients attempting to quit smoking while taking CHAMPIX [see Warnings and

Precautions (5.1)].

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There have been postmarketing reports of new or worsening seizures in patients treated with CHAMPIX

[see Warnings and Precautions (5.2)].

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol

while taking CHAMPIX. Some reported neuropsychiatric events, including unusual and sometimes

aggressive behavior [see Warnings and Precautions (5.1) and (5.3)].

There have been reports of hypersensitivity reactions, including angioedema [see Warnings and

Precautions (5.7)].

There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and

erythema multiforme, in patients taking CHAMPIX [see Warnings and Precautions (5.8)].

There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including

ischemic and hemorrhagic events in patients taking CHAMPIX. In the majority of the reported cases,

patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk

factor for MI and CVA, based on temporal relationship between medication use and events, a

contributory role of varenicline cannot be ruled out [see Warnings and Precautions (5.5)].

There have been reports of hyperglycemia in patients following initiation of CHAMPIX.

There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property

in patients treated with CHAMPIX [see Warnings and Precautions (5.6)].

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse event

should be reported to the Ministry of Health according to the National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.healt

h.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

7

DRUG INTERACTIONS

Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically

meaningful pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

7.1

Use with Other Drugs for Smoking Cessation

Safety and efficacy of CHAMPIX 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.

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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 CHAMPIX, may

alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin)

for which dosage adjustment may be necessary.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary

Available data have not suggested an increased risk for major birth defects following exposure to

varenicline in pregnancy, compared with women who smoke [see Data]. 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 US general

population, the estimated background risk of major birth defects and miscarriage in clinically recognized

pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

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 CHAMPIX during

pregnancy reduces these risks.

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Data

Human Data

A population-based observational cohort study using the national registers of Denmark and Sweden

compared pregnancy and birth outcomes among women exposed to varenicline (N=335, includes 317 first

trimester exposed) with women who smoked during pregnancy (N=78,412) and with non-smoking

pregnant women (N=806,438). The prevalence of major malformations, the primary outcome, was similar

in all groups, including between smoking and non-smoking groups. The prevalence of adverse perinatal

outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked,

and differed somewhat between the three cohorts. The prevalences of the primary and secondary

outcomes are shown in Table 6.

Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts

Outcome

Varenicline

Cohort

(n=335)

Smoking

Cohort

(n=78,412)

Non-Smoking

Cohort

(n=806,438)

Major congenital

malformation

12 / 334 (3.6%)

3,382 / 78,028

(4.3%)

33,950 /804,020

(4.2%)

Stillbirth

1 (0.3%)

384 (0.5%)

2,418 (0.3%)

Small for gestational age

42 (12.5%)

13,433 (17.1%)

73,135 (9.1%)

Preterm birth

25 (7.5%)

6,173 (7.9%)

46,732 (5.8%)

Premature rupture of

membranes

12 (3.6%)

4,246 (5.4%)

30,641 (3.8%)

Sudden infant death

syndrome

0/307 (0.0%)

51/71,720

(0.1%)

58/755,939

(<0.1%)

Included only live births in the cohorts. Prevalence among first trimester varenicline-

exposed pregnancies (11/317 [3.5%]).

There was a lag in death data in Denmark, so the cohorts were smaller.

The study limitations include the inability to capture malformations in pregnancies that do not result in a

live birth, and possible misclassification of outcome and of exposure to varenicline or to smoking.

Other small epidemiological studies of pregnant women exposed to varenicline did not identify an

association with major malformations, consistent with the Danish and Swedish observational cohort

study. Methodological limitations of these studies include small samples and lack of adequate controls.

Overall, available studies cannot definitely establish or exclude any varenicline-associated risk during

pregnancy.

Animal Data

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.

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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.

8.2

Lactation

Risk Summary

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 CHAMPIX to an infant during lactation; however the developmental and health benefits of

breastfeeding should be considered along with the mother’s clinical need for CHAMPIX and any

potential adverse effects on the breastfed child from CHAMPIX or from the underlying maternal

condition.

Clinical Considerations

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 breastfeeding infants.

Data

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.

8.4

Pediatric Use

Safety and effectiveness of CHAMPIX in pediatric patients have not been established.

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 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

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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.

8.6 Renal Impairment

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

(2.2), Clinical Pharmacology (12.3)].

9

DRUG ABUSE AND DEPENDENCE

9.1

Controlled Substance

Varenicline is not a controlled substance.

9.3 Dependence

Humans

Fewer than 1 out of 1,000 patients reported euphoria in clinical trials with CHAMPIX. At higher doses

(greater than 2 mg), CHAMPIX produced more frequent reports of gastrointestinal disturbances such as

nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical

studies, which suggests that tolerance does not develop. Abrupt discontinuation of CHAMPIX was

associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests

that, in some patients, varenicline may produce mild physical dependence which is not associated with

addiction.

In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any

significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline

produced an increase in some positive subjective effects, but this was accompanied by an increase in

negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced

unpleasant subjective responses in both smokers and non-smokers.

Animals

Studies in rodents have shown that varenicline produces behavioral responses similar to those produced

by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to

the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is

dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions

continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more

demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline

pretreatment also reduced nicotine self-administration.

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10

OVERDOSAGE

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.

11 DESCRIPTION

CHAMPIX tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective

for α

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-6H-pyrazino[2,3- h][3]benzazepine,

(2R,3R)-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

C

. The chemical

structure is:

CHAMPIX

CHAMPIX 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 CHAMPIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of

varenicline free base; each 1mg CHAMPIX 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

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dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry®

Clear.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors.

The efficacy of CHAMPIX 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, >3,500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters

(>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

12.3 Pharmacokinetics

Absorption

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration.

Following administration of multiple oral doses of varenicline, steady-state conditions were reached

within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after

single or repeated doses.

In a mass balance study, absorption of varenicline was virtually complete after oral administration and

systemic availability was ~90%.

Food Effect

Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

Distribution

Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.

Elimination

The elimination half-life of varenicline is approximately 24 hours.

Metabolism

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.

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Excretion

Renal elimination of varenicline is primarily through glomerular filtration along with active tubular

secretion possibly via the organic cation transporter, OCT2.

Specific Populations

There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender,

smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies

and in population pharmacokinetic analyses.

Age: Geriatric Patients

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.

Age: Pediatric Patients

Because the safety and effectiveness of CHAMPIX in pediatric patients have not been established,

CHAMPIX is not recommended for use in patients under 18 years of age. Single and multiple-dose

pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old

(inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied.

Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0-24),

was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given,

steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent

patients with bodyweight ≤ 55 kg compared to that noted in the adult population.

Renal Impairment

Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated

creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment

(estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure increased 1.5-fold

compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In

subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure

was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session

of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once

daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were

similar to those of healthy subjects receiving 1 mg twice daily [see Dosage and Administration (2.2), Use

in Specific Populations (8.6)]. Additionally, in subjects with ESRD, varenicline was efficiently removed

by hemodialysis [see Overdosage (10)].

Hepatic Impairment

Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected

in patients with hepatic impairment.

Drug-Drug Interactions

In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes

(IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human

hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.

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In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at

therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin [see

below]) are unlikely to be affected by varenicline.

In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic

cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may

not necessitate a dose adjustment of CHAMPIX as the increase in systemic exposure to CHAMPIX is

not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less

than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the

pharmacokinetics of CHAMPIX [see Clinical Pharmacology (12.3)]; therefore, a dose adjustment of

CHAMPIX would not be required.

Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine,

bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions

have been identified.

Metformin

When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state

pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no

effect on varenicline steady-state pharmacokinetics.

Cimetidine

Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg

single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%,

36.9%) due to a reduction in varenicline renal clearance.

Digoxin

Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as

a 0.25 mg daily dose in 18 smokers.

Warfarin

Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-

warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself

may result in changes to warfarin pharmacokinetics [see Drug Interactions (7.2)].

Use with Other Drugs for Smoking Cessation

Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion

(150 mg twice daily) in 46 smokers [see Drug Interactions (7.1)].

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 adverse reactions was greater

for the combination than for NRT alone [see Drug Interactions (7.1)].

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13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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.

Mutagenesis

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).

14

CLINICAL STUDIES

The efficacy of CHAMPIX 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 CHAMPIX. 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 CHAMPIX -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.

Seven additional studies evaluated the efficacy of CHAMPIXin patients with cardiovascular disease, in

patients with chronic obstructive pulmonary disease [see Clinical Studies (14.7)], in patients instructed to

select their quit date within days 8 and 35 of treatment [see Clinical Studies (14.4)], patients with major

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depressive disorder [see Clinical Studies (14.9)], patients who had made a previous attempt to quit

smoking with CHAMPIX, and either did not succeed in quitting or relapsed after treatment [see Clinical

Studies (14.6)], in patients without or with a history of psychiatric disorder enrolled in a postmarketing

neuropsychiatric safety outcome trial [see Warnings and Precautions (5.1), Clinical Studies (14.10)], and

in patients who were not able or willing to quit abruptly and were instructed to quit gradually [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 CHAMPIX to placebo. This study provided initial

evidence that CHAMPIX 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 CHAMPIX 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. CHAMPIX was given in two divided doses daily. Each dose of CHAMPIX 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 CHAMPIX 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

CHAMPIX 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 CHAMPIX, 40% had CO-confirmed continuous abstinence during weeks 9

through 12 compared to 12% in the placebo group. In addition, 29% of the CHAMPIX group were

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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 CHAMPIX 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX

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.

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Figure 1: Continuous Abstinence, Weeks 9 through 12

Table 7. Continuous Abstinence, Weeks 9 through 12 (95% confidence interval)

CHAMPIX

CHAMPIX

CHAMPIX

Bupropion

Placebo

CHANTIX 0.5 mg

CHANTIX 1.0 mg

Placebo

CHANTIX Flexible

Placebo

CHANTIX 1.0 mg

Bupropion SR

150 mg BID

Placebo

CHANTIX 1.0 mg

Bupropion SR

150 mg BID

Placebo

STUDY 2

STUDY 3

STUDY 4

STUDY 5

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0.5 mg BID

1 mg BID

Flexible

SR

Study

(39%, 51%)

(44%, 57%)

(6%, 18%)

Study

(32%, 48%)

(7%, 17%)

Study

(38%, 49%)

(25%, 35%)

(13%, 22%)

Study

(38%, 49%)

(25%, 35%)

(14%, 22%)

BID = twice daily

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, CHAMPIX 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, CHAMPIX-treated

patients were more likely to maintain abstinence throughout the follow-up period than were patients

treated with placebo (Figure 2, Table 8).

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Figure 2: Continuous Abstinence, Weeks 9 through 52

Table 8. Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) Across Different

Studies

CHAMPIX

0.5 mg BID

CHAMPIX

1 mg BID

CHAMPIX

Flexible

Bupropion

SR

Placebo

Study 2

(14%, 24%)

(18%, 28%)

(1%, 8%)

Study 3

(16%, 29%)

(3%, 12%)

Study 4

(17%, 26%)

(12%, 20%)

(5%, 11%)

Study 5

(17%, 26%)

(11%, 18%)

(7%, 13%)

BID = twice daily

Study 6

This study assessed the effect of an additional 12 weeks of CHAMPIX therapy on the likelihood of long-

term abstinence. Patients in this study (N=1927) were treated with open-label CHAMPIX 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 CHAMPIX (1 mg twice daily) or placebo for an

additional 12 weeks and then followed for 28 weeks post-treatment.

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The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing

treatment with CHAMPIX (70%) than for patients switching to placebo (50%). Superiority to placebo

was also maintained during 28 weeks post-treatment follow-up (CHAMPIX 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 CHAMPIX; postCHAMPIX follow-up begins at Week

13 for the placebo group and Week 25 for the CHAMPIX group. The y-axis represents the percentage of

patients who had been abstinent for the last week of CHAMPIX treatment and remained abstinent at the

given timepoint.

Figure 3: Continuous Abstinence Rate during Nontreatment Follow-Up

14.4

Alternative Instructions for Setting a Quit Date

CHAMPIX 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

CHAMPIX 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 CHAMPIX 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%).

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14.5

Gradual Approach to Quitting Smoking

CHAMPIX was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who

were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their

smoking over a 12 week period before quitting. Subjects were randomized to either CHAMPIX 1 mg

twice daily (N=760) or placebo (N=750) for 24 weeks and followed up post-treatment through week 52.

Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of

the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight

of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week

reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with CHAMPIX had

a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32%

vs. 7%) and weeks 15 through 52 (24% vs. 6%).

14.6

Re-Treatment Study

CHAMPIX was evaluated in a double-blind, placebo-controlled trial of patients who had made a previous

attempt to quit smoking with CHAMPIX, and either did not succeed in quitting or relapsed after

treatment. Subjects were randomized 1:1 to CHAMPIX 1 mg twice daily (N=249) or placebo (N=245) for

12 weeks of treatment and followed for 40 weeks post-treatment. Patients included in this study had taken

CHAMPIX for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of

two weeks), at least three months prior to study entry, and had been smoking for at least four weeks.

Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks 9 through

12 (45%) compared to patients treated with placebo (12%) and from weeks 9 through 52 (20%) compared

to subjects treated with placebo (3%).

Table 9. Continuous Abstinence (95% confidence interval), Re-Treatment Study

Weeks 9 through 12

Weeks 9 through 52

CHAMPIX

1 mg BID

Placebo

CHAMPIX

1 mg BID

Placebo

Retreatme

Study

(39%, 51%)

(8%, 16%)

(15%, 25%)

(1%, 5%)

BID = twice daily

14.7

Subjects with Chronic Obstructive Pulmonary Disease

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged

years with mild-to-moderate COPD with post-bronchodilator FEV

/FVC <70% and FEV

50% of

predicted normal value. Subjects were randomized to CHAMPIX 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 CHAMPIX 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%).

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Table 10. Continuous Abstinence (95% confidence interval), Studies in Patients with Chronic

Obstructive Pulmonary Disease (COPD)

Weeks 9 through 12

Weeks 9 through 52

CHAMPIX

1 mg BID

Placebo

CHAMPIX

1 mg BID

Placebo

COPD

Study

(34%, 47%)

(6%, 13%)

(14%, 24%)

(3%, 9%)

BID = twice daily

14.8

Subjects with Cardiovascular Disease and Other Cardiovascular Analyses

CHAMPIX 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 CHAMPIX

1 mg twice daily (N=353) or placebo (N=350) for a treatment period of 12 weeks and then were followed

for 40 weeks post-treatment. Subjects treated with CHAMPIX 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%).

Table 11. Continuous Abstinence (95% confidence interval), Studies in Patients with

Cardiovascular Disease (CVD)

Weeks 9 through 12

Weeks 9 through 52

CHAMPIX

1 mg BID

Placebo

CHAMPIX

1 mg BID

Placebo

Study

(42%, 53%)

(11%, 18%)

(16%, 24%)

(5%, 10%)

BID = twice daily

In this study, all-cause and CV mortality was lower in patients treated with CHAMPIX , but certain

nonfatal CV events occurred more frequently in patients treated with CHAMPIX than in patients treated

with placebo [see Warnings and Precautions (5.5), Adverse Reactions (6.1)]. Table 12 below shows

mortality and the incidence of selected nonfatal serious CV events occurring more frequently in the

CHAMPIX arm compared to the placebo arm. These events were adjudicated by an independent blinded

committee. Nonfatal serious CV events not listed occurred at the same incidence or more commonly in

the placebo arm. Patients with more than one CV 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 12. Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-

Controlled CHAMPIX Trial in Patients with Stable Cardiovascular Disease

Mortality and Cardiovascular

Events

CHAMPIX

(N=353)

n (%)

Placebo

(N=350)

n (%)

Mortality (Cardiovascular and All-cause up to 52 weeks)

Cardiovascular

1 (0.3)

2 (0.6)

All-cause

2 (0.6)

5 (1.4)

Nonfatal Cardiovascular Events (rate on CHAMPIX > Placebo)

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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 and 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)

Following the CVD study, a meta-analysis of 15 clinical trials of ≥12 weeks treatment duration, including

7002 patients (4190 CHAMPIX , 2812 placebo), was conducted to systematically assess the CV safety of

CHAMPIX . The study in patients with stable CV disease described above was included in the meta-

analysis. There were lower rates of all-cause mortality (CHAMPIX 6 [0.14%]; placebo 7 [0.25%]) and

CV mortality (CHAMPIX 2 [0.05%]; placebo 2 [0.07%]) in the CHAMPIX arms compared with the

placebo arms in the meta-analysis.

The key CV safety analysis included occurrence and timing of a composite endpoint of Major Adverse

Cardiovascular Events (MACE), defined as CV 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 13. These events

occurred primarily in patients with known CV disease.

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Table 13. Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15

Clinical Trials Comparing CHAMPIX to Placebo*

CHAMPIX

N=4190

Placebo

N=2812

MACE cases, n (%)

13 (0.31%)

6 (0.21%)

Patient-years of

exposure

1316

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)

*Includes MACE occurring up to 30 days post-treatment.

The meta-analysis showed that exposure to CHAMPIX 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 CHAMPIX 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.

Additionally, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety

outcome study along with a non-treatment extension, [see Warnings and Precautions (5.5), Adverse

Reactions (6.1), Clinical Studies (14.10)].

14.9

Subjects with Major Depressive Disorder

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 18 to

75 years with major depressive disorder without psychotic features (DSM-IV TR). If on medication,

subjects were to be on a stable antidepressant regimen for at least two months. If not on medication,

subjects were to have experienced a major depressive episode in the past 2 years, which was successfully

treated. Subjects were randomized to CHAMPIX 1 mg twice daily (N=256) or placebo (N=269) for a

treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with CHAMPIX

had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (36%) compared to subjects

treated with placebo (16%) and from week 9 through 52 (20%) compared to subjects treated with placebo

(10%).

Table 14. Continuous Abstinence (95% confidence interval), Study in Patients with Major

Depressive Disorder (MDD)

Weeks 9 through 12

Weeks 9 through 52

CHAMPIX

1 mg BID

Placebo

CHAMPIX

1 mg BID

Placebo

Study

(30%, 42%)

(11%, 20%)

(15%, 25%)

(7%, 14%)

BID = twice daily

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14.10

Postmarketing Neuropsychiatric Safety Outcome Trial

CHAMPIX was evaluated in a randomized, double-blind, active and placebo-controlled trial that included

subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3912) and with a history of

psychiatric disorder (psychiatric cohort, N=4003). Subjects aged 18-75 years, smoking 10 or more

cigarettes per day were randomized 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID, NRT

patch 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for

another 12 weeks post-treatment. [See Warnings and Precautions (5.1)]

A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse

events included the following NPS adverse events: anxiety, depression, feeling abnormal, hostility,

agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis,

irritability, suicidal ideation, suicidal behavior or completed suicide.

As shown in Table 15, the use of CHAMPIX, bupropion, and NRT in the non-psychiatric cohort was not

associated with an increased risk of clinically significant NPS adverse events compared with placebo.

Similarly, in the non-psychiatric cohort, the use of CHAMPIX was not associated with an increased risk

of clinically significant NPS adverse events in the composite safety endpoint compared with bupropion or

NRT.

Table 15. Number of Patients with Clinically Significant or Serious NPS Adverse Events by

Treatment Group Among Patients without a History of Psychiatric Disorder

CHAMPIX

(N=975)

n (%)

Bupropion

(N=968)

n (%)

NRT

(N=987)

n (%)

Placebo

(N=982)

n (%)

Clinically Significant

30 (3.1)

34 (3.5)

33 (3.3)

40 (4.1)

Serious NPS

1 (0.1)

5 (0.5)

1 (0.1)

4 (0.4)

Psychiatric

Hospitalizations

1 (0.1)

2 (0.2)

0 (0.0)

1 (0.1)

As shown in Table 16, there were more clinically significant NPS adverse events reported in patients in

the psychiatric cohort in each treatment group compared with the non-psychiatric cohort. 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 CHAMPIX, 2.2% (-0.5, 4.9) for

bupropion, and 0.4% (-2.2, 3.0) for NRT transdermal nicotine.

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Table 16. Number of Patients with Clinically Significant or Serious NPS Adverse Events by

Treatment Group Among Patients with a History of Psychiatric Disorder

CHAMPIX

(N=1007)

n (%)

Bupropion

(N=1004)

n (%)

NRT

(N=995)

n (%)

Placebo

(N=997)

n (%)

Clinically Significant

123 (12.2)

118 (11.8)

98 (9.8)

95 (9.5)

Serious NPS

6 (0.6)

8 (0.8)

4 (0.4)

6 (0.6)

Psychiatric

hospitalizations

5 (0.5)

8 (0.8)

4 (0.4)

2 (0.2)

There was one completed suicide, which occurred during treatment in a patient treated with placebo in the

non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort.

In both cohorts, subjects treated with CHAMPIX had a superior rate of CO-confirmed abstinence during

weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, nicotine patch and

placebo.

Table 17 Continuous Abstinence (95% confidence interval), Study in Patients with or without a

History of Psychiatric Disorder

CHAMPIX

1 mg BID

Bupropion SR

150 mg BID

NRT

21 mg/day with

taper

Placebo

Weeks 9 through 12

Non-

Psychiatri

c Cohort

(35%, 41%)

(23%, 29%)

(24%, 29%)

(12%, 16%)

Psychiatri

c Cohort

(26%, 32%)

(17%, 22%)

(18%, 23%)

(10%, 14%)

Weeks 9 through 24

Non-

Psychiatri

c Cohort

(23%, 28%)

(16%, 21%)

(16%, 21%)

(9%, 13%)

Psychiatri

c Cohort

(16%, 21%)

(12%, 16%)

(11%, 15%)

(7%, 10%)

BID = twice daily

Cardiovascular Outcome Analysis

To obtain another source of data regarding the CV risk of CHAMPIX , a cardiovascular endpoint

analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-

treatment extension. In the parent study (N=8027), subjects aged 18-75 years, smoking 10 or more

cigarettes per day were randomized 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID,

nicotine replacement therapy (NRT) patch 21 mg/day or placebo for a treatment period of 12 weeks; they

were then followed for another 12 weeks post-treatment. The extension study enrolled 4590 (57.2%) of

the 8027 subjects who were randomized and treated in the parent study and followed them for additional

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28 weeks. Of all treated subjects, 1743 (21.7%) had a medium CV risk and 640 (8.0%) had a high CV

risk, as defined by Framingham score. Note that one site from the parent study was excluded in the

assessment of CV safety and two sites were excluded in the assessment of neuropsychiatric safety.

The primary CV endpoint was the time to major adverse CV event (MACE), defined as CV death,

nonfatal myocardial infarction or nonfatal stroke during treatment. Deaths and CV events were

adjudicated by a blinded, independent committee. Table 18 below shows the incidence of MACE and

Hazard Ratios compared to placebo for all randomized subjects exposed to at least 1 partial dose of study

treatment in the parent study.

Table 18. The Incidence of MACE and Hazard Ratios in the Cardiovascular Safety Assessment

Trial in Subjects without or with a History of Psychiatric Disorder

CHAMPIX

N=2006

Bupropion

N=1997

NRT

N=2017

Placebo

N=2007

During treatment*

MACE, n [IR]

1 [2.4]

2 [4.9]

1 [2.4]

4 [9.8]

Hazard

Ratio (95% CI)

vs. placebo

0.24

(0.03, 2.18)

0.49

(0.09,

2.69)

0.24

(0.03,

2.18)

Through end of study**

MACE, n [IR]

3 [2.1]

9 [6.3]

6 [4.3]

8 [5.7]

Hazard

Ratio (95% CI)

vs. placebo

0.36

(0.10, 1.36)

1.09

(0.42,

2.83)

0.74

(0.26,

2.13)

[IR] indicates incidence rate per 1000 person-years

*during treatment in the parent neuropsychiatric safety study

**either the end of the extension study or the end of parent

neuropsychiatric safety study

for those subjects not enrolled into the extension study

For this study, MACE+ was defined as any MACE or a new onset or worsening peripheral vascular

disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for

unstable angina. Incidence rates of MACE+ and all-cause mortality for all randomized subjects exposed

to at least 1 partial dose of study treatment in the parent study are shown for all treatment groups during

treatment, and through end of study in the Table 19 below.

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Table 19. The Incidence of MACE+ and All-Cause Death in the Cardiovascular Safety Assessment

Trial in Subjects without or with a History of Psychiatric Disorder

CHAMPIX

N=2006

Bupropion

N=1997

NRT

N=2017

Placebo

N=2007

During treatment*

MACE+, n [IR]

5 [12.1]

4 [9.9]

2 [4.8]

5 [12.2]

All-cause deaths,

n [IR]

2 [4.9]

2 [4.9]

Through end of study**

MACE+, n [IR]

10 [6.9]

15 [10.5]

10 [7.1]

12 [8.6]

All-cause deaths,

n [IR]

2 [1.4]

4 [2.8]

3 [2.1]

4 [2.9]

[IR] indicates incidence rate per 1000 person-years

*during treatment in the parent neuropsychiatric safety study

**either the end of the extension study or the end of the parent

neuropsychiatric safety study

for those subjects not enrolled into the extension study

The number of subjects who experienced MACE, MACE+ and all-cause death was similar or lower

among patients treated with CHAMPIX than patients treated with placebo. The number of events

observed overall was too low to distinguish meaningful differences between the treatment arms.

16

HOW SUPPLIED

CHAMPIX 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. CHAMPIX is supplied in the following package configurations:

Description

Packs

Full treatment: 0.5 mg × 11 tablets and 1 mg ×154 tabs

Starting 4-week wallet: 0.5 mg × 11 tablets and 1 mg × 42

tablets

Continuing 4-week wallet: 1 mg × 56 tablets

For special population : 0.5mg × 55 tablets

17. PHARMACEUTICAL PARTICULARS

List of Excipients :

Microcrystalline cellulose

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Dibasic calcium phosphate anhydrous

Croscarmellose sodium

Colloidal silicon dioxide

Magnesium stearate

Opadray Blue (in Champix 1.0mg tablets)

Opadry white (in Champix 0.5mg tablets)

Opadry clear (in both Champix 0.5 & 1.0mg tablets)

Special Precautions for Storage:

Store below 25°C.

Rx only

Shelf Life:

The expiry date of the product is indicated on the packaging materials

Manufacturer:

R-Pharm Germany GmbH, Illertissen Germany

License holder:

Pfizer Pharmaceuticals Israel Ltd.

9 Shenkar St., Herzliya Pituach 46725

License number:

Champix 0.5 mg: 137-66-31510

Champix 1.0 mg: 137-67-31511

The content of this leaflet was approved by the Ministry of Health in October 2017 and updated

according to the guidelines of the Ministry of Health in September 2018.