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CHAMPIX (varenicline tartrate) Warnings And Precautions

Warnings And Precautions

Psychiatric Symptoms (in Patients with and without Pre-existing Psychiatric Disorder or Symptoms) (see also ADVERSE REACTIONS, Post-Marketing Experience).

There have been post-marketing reports of serious neuropsychiatric symptoms in patients being treated with CHAMPIX, including anxiety, psychosis, mood swings, depressed mood, agitation, aggression, hostility, changes in behavior or thinking, suicidal ideation, suicidal behavior and suicide, as well as worsening of pre-existing psychiatric disorder (previously diagnosed or not). Not all patients had stopped smoking at the time of onset of symptoms, and not all patients had known pre-existing psychiatric illness, or were using concomitant CNS drugs.

Randomized Study Data: A large randomized, double-blind, active and placebo-controlled study (“EAGLES” study) was conducted to compare the risk of serious neuropsychiatric events in patients with and without a history of psychiatric disorder treated for smoking cessation with varenicline, bupropion, nicotine replacement therapy patch (NRT) or placebo. The primary safety endpoint was a composite of neuropsychiatric adverse events that have been reported in post-marketing experience. The findings were that the use of CHAMPIX, in patients with or without a history of psychiatric disorder, was not associated with an increased risk of serious neuropsychiatric adverse events in the composite primary endpoint compared with placebo (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder).

Recommendations: Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in patients attempting to quit smoking, with or without treatment.

Alcohol intake: There have been post-marketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHAMPIX. Some cases described unusual and sometimes aggressive behaviour, and were often accompanied by amnesia for the events.

Pre-existing Psychiatric Disorder or Symptoms: Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression, anxiety). Patients with a history of psychiatric symptoms should be monitored for worsening or new symptoms when attempting to quit smoking, regardless of how well controlled symptoms may be when starting smoking cessation treatment. Patients should be instructed to report strongly atypical and concerning symptoms to their healthcare provider, so that dose adjustments of psychiatric medications or CHAMPIX may be considered.

General: Patients should be informed that if they experience thoughts, moods or behaviours that are strongly atypical and concerning while on smoking-cessation medication, including CHAMPIX, the medication should be discontinued immediately, with urgent medical help sought as needed, and the symptoms reported to their healthcare provider.

Angioedema and Hypersensitivity reactions

There have been post-marketing reports of hypersensitivity reactions, including angioedema, in patients treated with CHAMPIX (see ADVERSE REACTIONS, Post-Marketing Experience). Clinical signs included swelling of the face, mouth (tongue, lips and gums), neck (pharynx and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should be instructed to discontinue treatment with CHAMPIX and contact a healthcare provider immediately.

Serious Skin Reactions

There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme, in patients using CHAMPIX (see ADVERSE REACTIONS, Post-Marketing Experience). As these skin reactions can be life-threatening, patients should be instructed to discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately.

Seizures

In clinical trials and post-marketing 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 disorder that was remote or well-controlled. CHAMPIX should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Advise patients to discontinue CHAMPIX and immediately contact a healthcare provider if they experience a seizure while on treatment (see Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

Somnambulism

Cases of somnambulism have been reported post-marketing 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.

Cardiovascular Events

In a placebo-controlled smoking cessation clinical trial in patients with stable cardiovascular disease (CVD), patients were treated with CHAMPIX 1 mg BID or placebo for 12 weeks, and then followed for another 40 weeks. There were approximately 350 patients per arm.

Serious cardiovascular (CV) events that were reported more frequently in CHAMPIX compared to placebo (difference > 2 subjects) were: non-fatal myocardial infarctions (4 vs. 1, on-treatment phase) and need for coronary revascularization (7 vs. 2, post-treatment phase). The total number of patients that experienced serious CV events in CHAMPIX compared to placebo was: 10 vs. 9 on treatment phase, 16 vs. 11 post-treatment phase, for a total of 25 vs. 20 over the 52 week duration. The serious CV events occurring during the treatment and post-treatment phases were adjudicated by an independent blinded committee.

The study was powered for assessing efficacy (ie quit rates) but not for assessing differences in the occurrence of serious CV events between CHAMPIX and placebo. Therefore, the study was not large enough to allow conclusions regarding the difference in the incidence of CV events reported in the two arms (See also ADVERSE EVENTS, Clinical Trial in Special Populations; and ACTION AND CLINICAL PHARMACOLOGY, Special Population). Physicians are to inform patients of the symptoms of a heart attack and stroke, and instruct them to get emergency medical help right away if they experience any of these symptoms (see also Patient Counselling Information).

The CV safety of CHAMPIX was also evaluated in the Cardiovascular Safety Assessment Study in subjects with and without a history of psychiatric disorder that randomized subjects 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks.  Subjects were then followed post-treatment through a period of up to a total of 52 weeks (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Cardiovascular Safety Assessment Study in Subjects with and without a History of Psychiatric Disease).  Major CV events (CV death, non-fatal MI, non-fatal stroke) were infrequent overall (1/2016 and 4/2014, for patients treated with CHAMPIX and placebo, respectively) during the treatment period. However, because of the relatively low number of events overall and the lack of power for assessing differences between CHAMPIX and placebo, an association between the use of CHAMPIX and an increased risk of CV adverse events cannot be entirely ruled out.

CHAMPIX has not been studied in patients with unstable cardiovascular disease or those with cardiovascular events occurring within two months before study screening. Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease. The risks of CHAMPIX should be weighed against the benefits of its use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. CHAMPIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo

Accidental Injury, including while Driving, Operating Machinery

There have been post-marketing reports of traffic accidents, near-miss incidents in traffic, and other accidental injuries in patients taking CHAMPIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness (blackouts), seizures or difficulty concentrating.

Therefore, patients should be advised not to engage in potentially hazardous activities, such as driving a car or operating dangerous machines, until they know how CHAMPIX may affect them.

Concomitant Illness The full consequences of using this product in patients with concomitant illness have not been studied, and caution should be exercised (see Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

Nicotine replacement therapy (NRT)

The concomitant use of NRT with CHAMPIX (varenicline tartrate) may result in an increase in adverse reactions. In a clinical drug interaction study (N=24), the incidences of nausea, headache, vomiting, dizziness, dyspepsia and fatigue were greater for the combination of NRT and varenicline than for NRT alone (see DRUG INTERACTIONS). The safety and efficacy of the combination treatment with CHAMPIX and NRT have not been studied. Due to the proposed mechanism of action of varenicline, it is not anticipated that co-administration with NRT would confer additional benefit compared with CHAMPIX alone.

Effect of smoking-cessation

Physiological changes resulting from smoking-cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some drugs for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces cytochrome P450 (CYP) isoenzyme 1A2, smoking-cessation may result in an increase of plasma levels of CYP1A2 substrates.

Nausea

Nausea was the most common adverse event associated with CHAMPIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. Nausea was reported by approximately 30% of patients treated with CHAMPIX 1.0 mg BID after an initial week of dose titration. In patients taking CHAMPIX 0.5 mg BID, the incidence of nausea was 16% following initial titration. Approximately 3% of subjects treated with CHAMPIX 1.0 mg BID in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, dose reduction should be considered (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY section.

Dependence/Tolerance

Animal Studies
The subjective nicotine-like effects of varenicline were investigated in drug discrimination studies. At 1.0 mg/kg, there was complete substitution of varenicline for nicotine in a paradigm of nicotine-associated lever pressing for food reward. In an efficacy model, varenicline pretreatment dose-dependently reduced nicotine self-administration under a fixed-ratio schedule. Under a progressive ratio schedule rats worked harder for nicotine than for varenicline.

Human Studies
The rewarding potential of varenicline (1 mg and 3 mg doses) was compared with that of amphetamines in subjects experienced with psychomotor stimulants. The pattern for both smokers and non-smokers was consistent with a profile of a drug that, while having some pharmacological activity, did not produce amphetamine-like subjective effects.

Patient Counselling Information

Consumer Information is included in the package of CHAMPIX dispensed to the patient.

Prior to prescribing CHAMPIX, physicians should:

  • Discuss with the patient the expected benefits and risks of CHAMPIX, as well as those of all smoking-cessation options.
  • Inform the patients that quitting smoking, with or without treatment, may be associated with nicotine withdrawal symptoms (including depression, irritation or agitation) or exacerbation of pre-existing psychiatric disorder.
  • Encourage the patient to reveal any history of psychiatric disorder prior to initiating treatment. Patients with such history who are trying to stop smoking should be monitored by their physician for new or worsened psychiatric events.
  • Advise patients:
    - not to engage in potentially hazardous tasks, such as driving a car or operating dangerous machines, until they know how CHAMPIX may affect them. In some cases, patients have reported somnolence, dizziness, loss of consciousness, seizures or difficulty concentrating while driving.
    - that some people have reported seizures while taking CHAMPIX and encourage them to report any history of seizures or other factors that can lower seizure threshold. Instruct patients to discontinue CHAMPIX and immediately contact a healthcare provider if they experience a seizure while on treatment.
    - that there have been post-marketing reports of serious neuropsychiatric symptoms in patients being treated with CHAMPIX, including anxiety, psychosis, mood swings, aggression, depressed mood, agitation, hallucinations, hostility, changes in behavior or thinking, suicidal ideation, suicidal behavior and suicide, as well as worsening of pre-existing psychiatric disorder. 
    - that i) new or worse cardiovascular events (heart and stroke) have been reported, primarily in those who already have cardiovascular problems and ii) based on available data, it is not possible to determine whether CHAMPIX increases the risk of cardiovascular events.

For those patients receiving CHAMPIX:

  • Patients should be instructed to read the patient information leaflet supplied with every CHAMPIX prescription before starting their CHAMPIX pills. This leaflet is approved by Health Canada and is Part III of the CHAMPIX Product Monograph.
  • Patients should also be provided with educational materials and necessary counselling to support an attempt at quitting smoking, including a review of the overall smoking cessation plan with the physician.
  • Patients should call 1-800-CHAMPIX for a list of provincial Smoking Cessation resources (toll-free quit line) which can be used to support a quit attempt.
  • Patients should be informed that there are three choices in setting a quit date when using CHAMPIX, and discuss with their physician which one is best for them.
  • Patients should be instructed on how to titrate CHAMPIX:
    - Beginning at a dose of 0.5 mg per day. Prescribers should explain that one 0.5 mg tablet should be taken daily for the first three days, and then for the next four days, two 0.5 mg tablets should be taken daily: one in the morning and one in the evening.
    - Following this one week of titration, there are two dosing options:
    the dose can remain at 0.5 mg twice daily or can go up to 1.0 mg twice daily, depending on the physician judgment and patient preference. Based on the limited data available, the two-doses do not appear different in terms of either quit rates, or rates of serious psychiatric side effects (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
    -If needed, the dose can be changed depending on how well the patient tolerates CHAMPIX and how effective the doctor and patient consider it is in helping the patient quit smoking.
    - Patients should be informed that the maximum dose of CHAMPIX is 1.0 mg twice a day.
  • Patients should be encouraged to continue in their quit attempt if they have early lapses after their quit date.
  • Patients should be encouraged to inform friends and family members of their quit attempt which includes treatment with CHAMPIX and ask for their support and help in monitoring for any changes in behavior or thinking that are not typical for the patient.
  • Patients should be advised that drinking alcohol may increase the risk of experiencing psychiatric adverse events during treatment with CHAMPIX.
  • Patients with pre-existing psychiatric disorder should be instructed that if they develop worsened or new symptoms, to report these to their healthcare provider; dose adjustments of psychiatric medications or CHAMPIX may be considered.
  • Patients should be informed that if they experience thoughts, moods or behaviours that are strongly atypical and concerning while on smoking-cessation medication, including CHAMPIX, the medication should be discontinued immediately, urgent medical help sought as needed, and the symptoms reported to their healthcare provider.
  • Patients should be informed that:
    - they may experience vivid, unusual or strange dreams during treatment with CHAMPIX.
    - nausea is the most common adverse event associated with CHAMPIX and is usually transient. CHAMPIX should be taken after eating and with a full glass of water. Patients should be advised that if they are persistently troubled by this symptom, a dose reduction may be considered.
    - if they experience sleepwalking, they should discontinue CHAMPIX and notify their healthcare provider.
    - there have been reports of angioedema, with swelling of the face, mouth (tongue, lips and gums) and neck (pharynx and larynx) that can lead to life-threatening respiratory compromise. Patients should be instructed to discontinue CHAMPIX and seek immediate emergency medical attention if they experience these symptoms.
    - serious skin reactions, such as Stevens-Johnson syndrome and erythema multiforme, were reported by some patients taking CHAMPIX. Patients should be advised to stop taking CHAMPIX at the first sign of rash with mucosal lesions or skin reaction and seek immediate emergency medical attention.
  • Patients should be instructed to notify their healthcare providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.

Special Populations

Use of CHAMPIX in Patients with Concomitant Conditions:

Psychiatric Patients

Smoking-cessation with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness Patients with a history of psychiatric symptoms who are attempting to quit smoking should be monitored by a healthcare professional for new or worsened psychiatric events (see DOSAGE AND ADMINISTRATION, Special Populations, Psychiatric Patients; as well as WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms).

In a large randomized, double-blind, active and placebo-controlled smoking cessation study, use of CHAMPIX was not associated with an increased risk of serious neuropsychiatric adverse events in the composite endpoint compared with placebo, in patients with or without a history of psychiatric disorder (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder). Major depressive disorder, bipolar disorder I and II, anxiety, and schizophrenia were the primary baseline psychiatric conditions reported in the study; only patients judged to be clinically stable were included. Current substance abuse was among the conditions that were excluded.

Patients with Epilepsy
The use of CHAMPIX has not been studied in patients with epilepsy. There have been post-marketing reports of seizures in patients using varenicline. It is not known for how many of these there is a prior history or risk of a seizure disorder (see WARNINGS AND PRECAUTIONS, Seizures).

Patients with Diabetes
Smoking cessation, with or without treatment, may be associated with altered glycemic control. There have been post-marketing reports of diabetic patients experiencing loss of glycemic control while taking CHAMPIX. Therefore, increased glycemic monitoring is recommended in diabetic patients, with resultant adjustment of diabetic medications as necessary.

Patients with Irritable Bowel or Other Gastrointestinal (GI) Problems
The use of CHAMPIX has not been studied in patients with irritable bowel syndrome or other GI problems. Post marketing reports of irritable bowel syndrome, abdominal pain, faecal incontinence and other GI issues have been reported in patients taking CHAMPIX.

Patients Exposed to Chemotherapy
The use of CHAMPIX has not been studied in patients exposed to emetogenic chemotherapy.

Pregnant Women

Studies in animals have shown reproductive toxicity (see TOXICOLOGY). The potential risk for humans is not fully known (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations: Pregnant Women). CHAMPIX should not be used during pregnancy. 

Nonteratogenic Effects
Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC at 1.0 mg BID); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1.0 mg BID).

Nursing Women
Animal studies have shown that varenicline can be transferred to nursing pups. It is not known whether varenicline is excreted in human milk. Because many drugs are excreted in human milk and because the potential for adverse reactions in nursing infants from CHAMPIX is unknown, a decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatrics (<18 years of age)
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CHAMPIX in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Special Populations:Pediatrics).

Geriatrics (>65 years of age)
A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1.0 mg varenicline given once daily (QD) or BID to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days was similar to that of younger subjects. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION, Special Populations: Geriatrics).

Renal Impairment
A multiple dose pharmacokinetic study was conducted in patients with normal renal function, with mild, moderate, or severe renal impairment (estimated creatinine clearance: >80 mL/min, >50 and ≤80 mL/min, ≥ 30 and ≤50 mL/min, and <30 mL/min, respectively) or end-stage renal disease (ESRD). Varenicline pharmacokinetics was unchanged in subjects with mild renal impairment. Relative to subjects with normal renal function, varenicline exposure increased 1.5-fold in patients with moderate renal impairment and 2.1-fold in patients with severe renal impairment. In subjects with ESRD, varenicline was efficiently removed by hemodialysis. The recommended dose of CHAMPIX is reduced in patients with severe renal impairment. CHAMPIX is not recommended in patients with ESRD (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions: Renal Impairment, and DOSAGE AND ADMINISTRATION, Special Populations: Patients with Impaired Renal Function).

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