What are the black box warnings associated with Varenicline (Chantix)?

Varenicline Black Box Warnings

As of 2016, the FDA removed the black box warning for neuropsychiatric adverse events from varenicline, though serious warnings remain in the prescribing information. 1

Current FDA Warnings (Not Black Box)

The FDA label contains several serious warnings and precautions, but these are no longer designated as black box warnings:

Neuropsychiatric Adverse Events

• Serious neuropsychiatric adverse events have been reported postmarketing, including changes in mood (depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide 1
• Patients should be observed for neuropsychiatric symptoms and instructed to discontinue varenicline immediately if agitation, depressed mood, or atypical behavioral changes occur 1
• The large EAGLES trial (N=8,144) found no significant increase in neuropsychiatric events with varenicline compared to nicotine patch or placebo in both psychiatric and non-psychiatric cohorts, which led to the removal of the black box warning 2, 1

Seizures

• New or worsening seizures have been observed in patients taking varenicline 1
• Varenicline should be avoided in patients with brain metastases who have a history or elevated risk of seizures 2, 3
• Use cautiously in patients with seizure history or factors that lower seizure threshold 1

Other Serious Warnings

Cardiovascular Events:

• Patients with underlying cardiovascular disease may be at increased risk, though these concerns must be balanced against smoking cessation benefits 1
• Patients should seek immediate medical attention for signs of myocardial infarction or stroke 1
• Recent systematic reviews have not identified a significant link between varenicline and increased cardiovascular adverse events 2, 3

Somnambulism (Sleepwalking):

• Cases of somnambulism, including harmful behavior to self, others, or property, have been reported 1
• Patients should discontinue varenicline if somnambulism occurs 1

Angioedema and Hypersensitivity:

• Life-threatening angioedema and hypersensitivity reactions have been reported 1
• Immediate discontinuation and medical care required if symptoms occur 1

Serious Skin Reactions:

• Rare, potentially life-threatening skin reactions (Stevens-Johnson syndrome, erythema multiforme) have been reported 1
• Discontinue immediately at first appearance of skin rash with mucosal lesions 1

Alcohol Interaction:

• Increased effects of alcohol have been reported 1
• Patients should reduce alcohol consumption until they know how varenicline affects them 1

Accidental Injury:

• Traffic accidents and other accidental injuries have been reported 1
• Use caution when driving or operating machinery 1

Clinical Context

The removal of the black box warning reflects accumulating evidence that varenicline does not significantly increase neuropsychiatric risks 2, 4. Multiple large studies, including reanalysis of 17 randomized controlled trials (N=8,027), found no evidence that varenicline increases risk of suicidal events, depression, or aggression compared to placebo 4. The National Comprehensive Cancer Network considers varenicline to have a favorable risk/benefit ratio and recommends it as the most effective single pharmacotherapy for smoking cessation 2, 5.