Varenicline Tartrate

Varenicline tablets are indicated for use as an aid to smoking cessation treatment.

•   Begin varenicline tablets dosing one week before the date set by the patient to stop smoking. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Starting Week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on days 4-7. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Consider a gradual approach to quitting smoking with varenicline tablets for patients who are sure that they are not able or willing to quit abruptly. Patients should begin varenicline tablets 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 treatment for an additional 12 weeks, for a total of 24 weeks. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Severe Renal Impairment (estimated creatinine clearance less than 30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum of 0.5 mg daily may be given if tolerated. (
  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 varenicline tablets 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)].
  )
•   Consider dose reduction for patients who cannot tolerate adverse effects. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Another attempt at treatment is recommended for those who fail to stop smoking or relapse when factors contributing to the failed attempt have been addressed. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )
•   Provide patients with appropriate educational materials and counseling to support the quit attempt. (
  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 varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

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

  The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

  Days 1 – 3:	0.5 mg once daily
  Days 4 – 7:	0.5 mg twice daily
  Day 8 – end of treatment:	1 mg twice daily

  Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets 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 varenicline tablets. Patients should begin varenicline tablets 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 varenicline tablets 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 varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets 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 varenicline tablets.
  )

Modified capsule shaped tablets: 0.5 mg (white to off-white, film coated tablets debossed with 'L' on one side and '11' on other side) and 1 mg (light pink to pink color, film coated tablets debossed with 'L' on one side and '12' on other side).

Available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke

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.

• Neuropsychiatric Adverse Events
  : Postmarketing reports of serious or clinically significant neuropsychiatric adverse events 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. Observe patients attempting to quit smoking with varenicline tablets for the occurrence of such symptoms and instruct them to discontinue varenicline tablets and contact a healthcare provider if they experience such adverse events. (
  5.1 Neuropsychiatric Adverse Events including Suicidality

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

  [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 varenicline tablets 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 varenicline tablets 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 varenicline tablets 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 varenicline tablets 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, varenicline tablets 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 varenicline tablets, 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 varenicline tablets-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 varenicline tablets-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)]

  .
  )
• Seizures
  : New or worsening seizures have been observed in patients taking varenicline tablets. Varenicline tablets should be used cautiously in patients with a history of seizures or other factors that can lower the seizure threshold. (
  5.2 Seizures

  During clinical trials and the postmarketing experience, there have been reports of seizures in patients treated with varenicline tablets. Some patients had no history of seizures, whereas others had a history of seizure 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 varenicline tablets in patients with a history of seizures or other factors that can lower the seizure threshold. Advise patients to discontinue varenicline tablets and contact a healthcare provider immediately if they experience a seizure while on treatment

  [see Adverse Reactions (6.2)]

  .
  )
• Interaction with Alcohol
  : Increased effects of alcohol have been reported. Instruct patients to reduce the amount of alcohol they consume until they know whether varenicline tablets affects them. (
  5.3 Interaction with Alcohol

  There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. 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 varenicline tablets until they know whether varenicline tablets affects their tolerance for alcohol

  [see Adverse Reactions (6.2)]

  .
  )
• Accidental Injury
  : Accidental injuries (e.g., traffic accidents) have been reported. Instruct patients to use caution driving or operating machinery until they know how varenicline tablets may affect them. (
  5.4 Accidental Injury

  There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking varenicline tablets. 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 varenicline tablets may affect them.
  )
• Cardiovascular Events
  : Patients with underlying cardiovascular (CV) disease may be at increased risk of CV events; however, these concerns must be balanced with the health benefits of smoking cessation. 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 myocardial infarction (MI) or stroke. (
  5.5 Cardiovascular Events

  A comprehensive evaluation of cardiovascular (CV) risk with varenicline tablets 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 varenicline tablets 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 varenicline tablets compared to placebo. All-cause and CV mortality was lower in patients treated with varenicline tablets

  [see Clinical Studies (14.8)].

  This study was included in a meta-analysis of 15 varenicline tablets 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 varenicline tablets. 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)].
  and
  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 varenicline tablets, over 4500 subjects were exposed to varenicline tablets, 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 varenicline tablets 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 varenicline tablets 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 varenicline tablets 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 varenicline tablets 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 BID Varenicline Tablets Group and More Commonly than Placebo and PT ≥1% in the 1 mg BID Varenicline Tablets Group, and 1 mg BID Varenicline Tablets at Least 0.5% More than Placebo)

  SYSTEM ORGAN CLASS High Level Group Term Preferred Term	Varenicline Tablets 0.5 mg BID N=129	Varenicline Tablets 1 mg BID N=821	Placebo N=805
  GASTROINTESTINAL (GI)
  GI Signs and Symptoms
  Nausea	16	30	10
  Abdominal Pain *	5	7	5
  Flatulence	9	6	3
  Dyspepsia	5	5	3
  Vomiting	1	5	2
  GI Motility/Defecation Conditions
  Constipation	5	8	3
  Gastroesophageal reflux disease	1	1	0
  Salivary Gland Conditions
  Dry mouth	4	6	4
  PSYCHIATRIC DISORDERS
  Sleep Disorder/Disturbances
  Insomnia **	19	18	13
  Abnormal dreams	9	13	5
  Sleep disorder	2	5	3
  Nightmare	2	1	0
  NERVOUS SYSTEM
  Headaches
  Headache	19	15	13
  Neurological Disorders
  NEC
  Dysgeusia	8	5	4
  Somnolence	3	3	2
  Lethargy	2	1	0
  GENERAL DISORDERS
  General Disorders NEC
  Fatigue/Malaise/Asthenia	4	7	6
  RESPIR/THORACIC/MEDIAST
  Respiratory Disorders NEC
  Rhinorrhea	0	1	0
  Dyspnea	2	1	1
  Upper Respiratory Tract Disorder	7	5	4
  SKIN/SUBCUTANEOUS TISSUE
  Epidermal and Dermal Conditions
  Rash	1	3	2
  Pruritis	0	1	1
  METABOLISM and NUTRITION
  Appetite/General Nutrition Disorders
  Increased appetite	4	3	2
  Decreased appetite/ Anorexia	1	2	1

  * 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 varenicline tablets 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 varenicline tablets 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.

  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^thnerve 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.

  Varenicline tablets 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 varenicline tablets 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.

  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

  	Varenicline tablets 1 mg BID N=353	Placebo N=350
  Adverse Events ≥1% in either treatment group
  Up to 30 days after treatment
  Angina pectoris	3.7	2.0
  Chest pain	2.5	2.3
  Peripheral edema	2.0	1.1
  Hypertension	1.4	2.6
  Palpitations	0.6	1.1
  Adjudicated Cardiovascular Mortality (up to 52 weeks)	0.3	0.6
  Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in either treatment group
  Up to 30 days after treatment
  Nonfatal MI	1.1	0.3
  Hospitalization for angina pectoris	0.6	1.1
  Beyond 30 days after treatment and up to 52 weeks
  Need for coronary revascularization*	2.0	0.6
  Hospitalization for angina pectoris	1.7	1.1
  New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure	1.4	0.6

  *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

  	Varenicline tablets 1 mg BID N=84	Placebo N=43
  Adverse Events ≥10% in the varenicline group
  Nausea	24	14
  Headache	11	19
  Vomiting	11	9
  Psychiatric Adverse Events ≥5% and at a higher rate than in the placebo group
  Insomnia	10	5

  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

  	Varenicline tablets 1 mg BID N=256	Placebo N=269
  Adverse Events ≥10% in either treatment group
  Nausea	27	10
  Headache	17	11
  Abnormal dreams	11	8
  Insomnia	11	5
  Irritability	11	8
  Psychiatric Adverse Events ≥2% in any treatment group and not included above
  Depressed mood disorders and disturbances	11	9
  Anxiety	7	9
  Agitation	7	4
  Tension	4	3
  Hostility	2	0.4
  Restlessness	2	2

  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.

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

  	Varenicline tablets 1 mg BID	Placebo
  Adverse Events ≥10% in the varenicline group
  Entire study population, N	1982	1979
  Nausea	25	7
  Headache	12	10
  Psychiatric Adverse Events ≥2% in any treatment group
  Non-psychiatric cohort, N	975	982
  Abnormal dreams	8	4
  Agitation	3	3
  Anxiety	5	6
  Depressed mood	3	3
  Insomnia	10	7
  Irritability	3	4
  Sleep disorder	3	2
  Psychiatric cohort, N	1007	997
  Abnormal dreams	12	5
  Agitation	5	4
  Anxiety	8	6
  Depressed mood	5	5
  Depression	5	5
  Insomnia	9	7
  Irritability	5	7
  Nervousness	2	3
  Sleep disorder	3	2

  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.
  )
• Somnambulism
  : Cases of somnambulism have been reported in patients taking varenicline tablets. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue varenicline tablets and notify their healthcare provider if they experience somnambulism. (
  5.6 Somnambulism

  Cases of somnambulism have been reported in patients taking varenicline tablets. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue varenicline tablets and notify their healthcare provider if they experience somnambulism

  [see Adverse Reactions (6.2)].
  and
  6.2 Postmarketing Experience

  The following adverse events have been reported during post-approval use of varenicline tablets. 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 varenicline tablets

  [see Warnings and Precautions (5.1)].

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

  [see Warnings and Precautions (5.2)].

  There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior

  [see Warnings and Precautions (5.1)and ].

  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 varenicline tablets

  [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 varenicline tablets. 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 varenicline tablets.

  There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with varenicline tablets

  [see Warnings and Precautions (5.6)].
  )
• Angioedema and Hypersensitivity Reactions
  : Such reactions, including angioedema, infrequently life-threatening, have been reported. Instruct patients to discontinue varenicline tablets and immediately seek medical care if symptoms occur. (
  5.7 Angioedema and Hypersensitivity Reactions

  There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline tablets

  [see Adverse Reactions (6.2), Patient Counseling Information (17)].

  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 varenicline tablets and immediately seek medical care if they experience these symptoms.
  and
  6.2 Postmarketing Experience

  The following adverse events have been reported during post-approval use of varenicline tablets. 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 varenicline tablets

  [see Warnings and Precautions (5.1)].

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

  [see Warnings and Precautions (5.2)].

  There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior

  [see Warnings and Precautions (5.1)and ].

  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 varenicline tablets

  [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 varenicline tablets. 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 varenicline tablets.

  There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with varenicline tablets

  [see Warnings and Precautions (5.6)].
  )
• Serious Skin Reactions
  : Rare, potentially life-threatening skin reactions have been reported. Instruct patients to discontinue varenicline tablets and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions. (
  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 varenicline tablets

  [see Adverse Reactions (6.2)]

  . As these skin reactions can be life-threatening, instruct patients to stop taking varenicline tablets and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.
  and
  6.2 Postmarketing Experience

  The following adverse events have been reported during post-approval use of varenicline tablets. 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 varenicline tablets

  [see Warnings and Precautions (5.1)].

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

  [see Warnings and Precautions (5.2)].

  There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior

  [see Warnings and Precautions (5.1)and ].

  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 varenicline tablets

  [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 varenicline tablets. 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 varenicline tablets.

  There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with varenicline tablets

  [see Warnings and Precautions (5.6)].
  )
• Nausea
  : Nausea is the most common adverse reaction (up to 30% incidence rate). Dose reduction may be helpful. (
  5.9 Nausea

  Nausea was the most common adverse reaction reported with varenicline tablets 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 varenicline tablets 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with varenicline tablets 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.
  )