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What is Chantix (varenicline)?
Chantix (varenicline) is a partial agonist selective for a4ß2 nicotinic acetylcholine receptor subtypes used to promote cessation of smoking. It competes with nicotine from cigarettes for binding to nicotine receptors in the brain.
Common side effects of Chantix include:
- sleep disturbance,
- gas (flatulence),
- abnormal dreams, and
- taste disturbance.
Chantix is not addictive; however, some patients may experience irritability and sleep disturbance if it is abruptly discontinued.
Serious side effects of Chantix include:
- worsening symptoms of underlying heart disease,
- psychiatric symptoms (such as behavioral changes, agitation, depressed mood, and suicidal behavior), and
- rare life-threatening skin reactions and hypersensitivity reactions.
There are no adequate studies of Chantix in pregnant women. It is unknown if Chantix is excreted in breast milk. Nursing mothers should consider discontinuing Chantix or breastfeeding because of the potential for adverse effects in the infant.
What are the important side effects of Chantix (varenicline)?
The most common adverse effects of varenicline are:
Headaches, abnormal dreams and taste disturbance also are frequent side effects of varenicline.
Varenicline is not addictive and is not a controlled substance; however, some patients may experience irritability and sleep disturbance if varenicline is abruptly discontinued.
Varenicline may worsen symptoms of underlying heart disease.
Patients may experience psychiatric symptoms such as behavioral changes, agitation, depressed mood, and suicidal behavior during varenicline treatment.
Patients should stop taking varenicline if psychiatric symptoms occur.
Rare life-threatening skin reactions and hypersensitivity reactions have been reported.
Chantix (varenicline) side effects list for healthcare professionals
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
- Interaction with alcohol
- Accidental injury
- Cardiovascular events
- Angioedema and hypersensitivity reactions
- Serious skin reactions
In the placebo-controlled premarketing studies, the most common adverse events associated with Chantix (>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 Chantix, 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 Chantix-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.
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 Chantix, over 4500 subjects were exposed to Chantix, 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 Chantix treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen.
Table 3 shows the adverse events for Chantix 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 Chantix 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 Chantix 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 3: Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo- Controlled Studies (HLGTs ≥ 5% of patients in the 1 mg BID Chantix Group and more commonly than Placebo and PT ≥ 1% in the 1 mg BID Chantix Group, and 1 mg BID Chantix at least 0.5% more than Placebo)
|SYSTEM ORGAN CLASS High Level Group Term Preferred Term||Chantix 0.5 mg BID|
|Chantix 1 mg BID|
|GI Signs and Symptoms|
|Abdominal Pain *||5||7||5|
|GI Motility/Defecation Conditions|
|Gastroesophageal reflux disease||1||1||0|
|Salivary Gland Conditions|
|Neurological Disorders NEC|
|General Disorders NEC|
|Respiratory Disorders NEC|
|Upper Respiratory Tract Disorder||7||5||4|
|Epidermal and Dermal Conditions|
|METABOLISM & NUTRITION|
|Appetite/General mNutrition Disorders|
|*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 3, 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 Chantix 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 Chantix during all premarketing clinical trials and updated based on pooled data from 18 placebo-controlled preand post-marketing 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.
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.
Endocrine Disorders. Infrequent: thyroid gland disorders.
Gastrointestinal Disorders. Frequent: diarrhea, toothache. Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute.
Hepatobiliary Disorders. Rare: gall bladder disorder.
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 th 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.
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.
Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.
Chantix 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 Chantix 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, and
- (8) 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, in the alternative quit date instruction trial, and in the gradual approach to quitting smoking trial were similar to those observed in premarketing studies. In the re-treatment trial, 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, more types and a greater number of cardiovascular events were reported compared to premarketing studies. Treatment-emergent (ontreatment or 30 days after treatment) cardiovascular events reported with a frequency ≥ 1% in either treatment group in this study were:
- angina pectoris (3.7% and 2.0% for varenicline and placebo, respectively),
- chest pain (2.5% vs. 2.3%),
- peripheral edema (2.0% vs. 1.1%),
- hypertension (1.4% vs. 2.6%), and
- palpitations (0.6 % vs. 1.1%).
Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by a blinded, independent committee. The following treatment-emergent adjudicated events occurred with a frequency ≥ 1% in either treatment group:
- nonfatal MI (1.1% vs. 0.3% for varenicline and placebo, respectively), and
- hospitalization for angina pectoris (0.6% vs. 1.1%).
During non-treatment follow-up to 52 weeks, the adjudicated events included:
- the need for coronary revascularization (2.0% vs. 0.6%),
- hospitalization for angina pectoris (1.7% vs. 1.1%), and
- new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%).
Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study.
In the trial of patients with stable schizophrenia or schizoaffective disorder, 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 adverse events in patients taking varenicline were:
- nausea (24% vs. 14.0% on placebo),
- headache (11% vs. 19% on placebo) and
- vomiting (11% vs. 9% on placebo).
Among reported neuropsychiatric adverse events, insomnia was the only event that occurred in either treatment group in ≥5% of subjects at a rate higher in the varenicline group than in placebo (10% vs. 5%). These common and neuropsychiatric adverse events occurred on treatment or within 30 days after the last dose of study drug. There was no consistent worsening of schizophrenia in either treatment group as measured by the Positive and Negative Syndrome Scale. There were no overall changes in extra-pyramidal signs, as measured by the Simpson-Angus Rating Scale. The Columbia-Suicide Severity Rating Scale was administered at baseline and at clinic visits during the treatment and non-treatment follow-up phases.
Over half of the patients had a lifetime history of suicidal behavior and/or ideation (62% on varenicline vs. 51% on placebo), but at baseline, no patients in the varenicline group reported suicidal behavior and/or ideation vs. one patient in the placebo group (2%). Suicidal behavior and/or ideation were reported in 11% of the varenicline-treated and 9% of the placebo-treated patients during the treatment phase.
During the post-treatment phase, suicidal behavior and/or ideation were reported in 11% of patients in the varenicline group and 5% of patients in the placebo group. Many of the patients reporting suicidal behavior and ideation in the follow-up phase had not reported such experiences in the treatment phase.
However, no new suicidal ideation or behavior emerged in either treatment group shortly (within one week) after treatment discontinuation (a phenomenon noted in postmarketing reporting). There were no completed suicides. There was one suicide attempt in a varenicline-treated patient. The limited data available from this single smoking cessation study are not sufficient to allow conclusions to be drawn.
In the trial of patients with major depressive disorder, the most common adverse events (≥ 10%) in subjects taking varenicline were:
- nausea (27% vs. 10% on placebo),
- headache (17 vs. 11%),
- abnormal dreams (11% vs. 8%),
- insomnia (11% vs. 5%) and
- irritability (11% vs. 8%).
Additionally, the following psychiatric AEs were reported in ≥ 2% of patients in either treatment group (varenicline or placebo, respectively):
- anxiety (7% vs. 9%),
- agitation (7% vs. 4%),
- depressed mood disorders and disturbances (11% vs. 9%),
- tension (4% vs. 3%),
- hostility (2% vs. 0.4%) and
- restlessness (2% vs. 2%).
Patients treated with varenicline were more likely than patients treated with placebo to report one of various events related to hostility and aggression (3% vs. 1%). Psychiatric scales showed no differences between the varenicline and placebo groups and no overall worsening of depression during the study in either treatment group. The percentage of subjects with suicidal ideation and/or behavior was similar between the varenicline and placebo groups during treatment (6% and 8%, respectively) and the nontreatment follow-up (6% and 6%, respectively). There was one event of intentional self-injury/possible suicide attempt during treatment (Day 73) in a subject in the placebo group. Suicide could not be ruled out in one subject who died by an overdose of illicit drugs 76 days after last dose of study drug in the varenicline group.
In the trial of patients without or with a history of psychiatric disorder, the most common adverse events in subjects treated with varenicline were similar to those observed in premarketing studies. Adverse events reported in ≥ 10% of subjects treated with varenicline in the entire study population were nausea (25% vs. 7% on placebo) and headache (12% vs. 10% on placebo).
Additionally, the following psychiatric adverse events were reported in ≥ 2% of patients in either treatment group (varenicline vs. placebo) by cohort. For the non-psychiatric cohort, these adverse events were
- abnormal dreams (8% vs. 4%),
- agitation (3% vs. 3%),
- anxiety (5% vs. 6%),
- depressed mood (3% vs. 3%),
- insomnia (10% vs. 7%),
- irritability (3% vs. 4%),
- sleep disorder (3% vs. 2%).
For the psychiatric cohort, these adverse events were:
- abnormal dreams (12% vs. 5%),
- agitation (5% vs. 4%),
- anxiety (8% vs. 6%),
- depressed mood (5% vs. 5%),
- depression (5% vs. 5%),
- insomnia (9% vs. 7%),
- irritability (5% vs. 7%),
- nervousness (2% vs. 3%),
- sleep disorder (3% vs. 2%).
The following adverse events have been reported during post-approval use of Chantix. 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.
In patients attempting to quit smoking while taking Chantix, there have been reports of:
- homicidal ideation,
- anxiety, and panic, as well as
- suicidal ideation, suicide attempt, and completed suicide.
There have been postmarketing reports of new or worsening seizures in patients treated with Chantix.
There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking Chantix. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior.
There have been reports of hypersensitivity reactions, including angioedema.
There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking Chantix. There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Chantix. 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.
There have been reports of hyperglycemia in patients following initiation of Chantix. There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with Chantix.
What drugs interact with Chantix (varenicline)?
Based on varenicline characteristics and clinical experience to date, Chantix has no clinically meaningful pharmacokinetic drug interactions.
Use With Other Drugs For Smoking Cessation
Safety and efficacy of Chantix in combination with other smoking cessation therapies have not been studied.
Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established.
Nicotine Replacement Therapy (NRT)
Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.
Effect Of Smoking Cessation On Other Drugs
Physiological changes resulting from smoking cessation, with or without treatment with Chantix, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
Drug Abuse And Dependence
Varenicline is not a controlled substance.
Fewer than 1 out of 1,000 patients reported euphoria in clinical trials with Chantix. At higher doses (greater than 2 mg), Chantix 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 Chantix 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.
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.
Chantix (varenicline) is a partial agonist selective for a4ß2 nicotinic acetylcholine receptor subtypes used to promote cessation of smoking. It competes with nicotine from cigarettes for binding to nicotine receptors in the brain. Common side effects of Chantix include nausea, sleep disturbance, constipation, gas (flatulence), vomiting, headaches, abnormal dreams, and taste disturbance. Chantix is not addictive; however, some patients may experience irritability and sleep disturbance if it is abruptly discontinued. Drug interactions of Chantix include the nicotine patch, which may lead to additional adverse effects. There are no adequate studies of Chantix in pregnant women. It is unknown if Chantix is excreted in breast milk. Nursing mothers should consider discontinuing Chantix or breastfeeding because of the potential for adverse effects in the infant.
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