VARENICLINE- varenicline tartrate_tablet, film coated

Varenicline binds with high affinity and selectivity at alpha4beta2 neuronal nicotinic acetylcholine receptors. The efficacy of varenicline in smoking cessation is believed to be the result of varenicline’s activity at alpha4beta2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors. Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to alpha4beta2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate alpha4beta2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to alpha4beta2 receptors than to other common nicotinic receptors (>500-fold alpha3beta4, >3,500-fold alpha7, >20,000-fold alpha1betagammadelta), or to non-nicotinic receptors and transporters (>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor. Absorption Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption ofvarenicline was virtually complete after oral administration and systemic availability was ~90%. Food Effect Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Distribution Plasma protein binding of varenicline is low (<=20%) and independent ofboth age and renal function. Elimination The elimination half-life of varenicline is approximately 24 hours. Metabolism Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Excretion Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2. Specific Populations There are noclinically meaningful differences in varenicline pharmacokinetics due toage, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses. Age: Geriatric Patients A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 to 75 years) for 7 consecutive days was similar to that of younger subjects. Age: Pediatric Patients Varenicline is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated [see Use in Specific Populations (8. Renal Impairment Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and <=80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance >=30 mL/min and <=50 mL/min), varenicline exposure increased 1. 5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2. In subjects with end-stage-renal disease (ESRD) undergoing a three- hour session of hemodialysis for three days a week, varenicline exposure was increased 2. 7-fold following 0. 5 mg once daily administration for 12 days. The plasma C max Hepatic Impairment Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment. Drug-Drug Interactions In vitro in vitro In vitro [see below] In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e. , cimeditine [see below]) may not necessitate a dose adjustment of varenicline as the increase in systemic exposure to varenicline is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline [see Clinical Pharmacology (12. 3)]; therefore, a dose adjustment of varenicline would not be required. Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. Noclinically meaningful pharmacokinetic drug-drug interactions have been identified. Metformin When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics. Cimetidine Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21. 9%) due to a reduction in varenicline renal clearance. Digoxin Varenicline (1 mg twice daily) did not alterthe steady-state pharmacokinetics of digoxin administered as a 0. 25 mg daily dose in 18 smokers. Warfarin Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics [see Drug Interactions (7. Use with Other Drugs forSmoking Cessation Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers [see Drug Interactions (7. NRT: Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of adverse reactions was greater forthe combination than for NRT alone [see Drug Interactions (7.

Varenicline tablets are indicated for use as an aid to smoking cessation treatment. Varenicline is a nicotinic receptor partial agonist 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. 1) Starting Week: 0. 5 mg once daily on days 1 to 3 and 0. 5 mg twice daily on days 4 to 7. 1) Continuing Weeks: 1 mg twice daily for a total of 12 weeks. 1) An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence. 1) 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. 1) 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) Consider dose reduction for patients who cannot tolerate adverse effects. 1) 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. 1) Provide patients with appropriate educational materials and counseling to support the quit attempt. 1) 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 tosupport the quit attempt. Days 1 to 3: 0. 5 mg once Days 4 to 7: 0. 5 mg twice Day 8 to end of 1 mg twice daily Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of12 weeks, an additional course of 12 weeks treatment with varenicline tablets is recommended to further increase the likelihood of long-term abstinence. [see Clinical Studies (14. 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. 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. 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.

The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling: Neuropsychiatric Adverse Events including Suicidality [see Warnings and Precautions (5. 1)] Seizures [ see Warnings and Precautions (5. 2)] Interaction with Alcohol [ see Warning and Precautions (5. 3 Accidental Injury [ see Warnings and Precautions (5. 4)] [see Warnings and Precautions (5. 5)] [see Warnings and Precautions (5. 6)] Angioedema and Hypersensitivity Reactions [see Warnings and Precautions (5. 7)] Serious Skin Reactions [see Warnings and Precautions (5. 8)] In the placebo-controlled premarketing studies, the most common adverse events associated with varenicline (>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 varenicline, 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 varenicline-treated patients were as follows: nausea (3% vs. 5% for placebo), insomnia (1. 1% for placebo), and abnormal dreams (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. Most common adverse reactions (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (e. , vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Avalanche Pharmaceutical LLC. at 1-800- 569-8990 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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, over 4500 subjects were exposed to varenicline, 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 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. Table 1 shows the adverse events for varenicline 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. MedDRA High Level Group Terms (HLGT) reported in >=5% of patients in the varenicline 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 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. Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies (HLGTs >= 5% of Patients in the 1 mg BID Varenicline Group and More Commonly than Placebo and PT >= 1% in the 1 mg BID Varenicline Group, and 1 mg BID Varenicline at Least 0. 5% More than Placebo) SYSTEM ORGAN CLASS High Level Group Term Preferred Term Varenicline 0. 5 mg BID N=129 Varenicline 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 Following is a list of treatment-emergent adverse events reported by patients treated with varenicline during all Blood and Lymphatic System Disorders. Infrequent Rare Cardiac Disorders Infrequent Rare Ear and Labyrinth Disorders Infrequent Rare Endocrine Disorders Infrequent Eye Disorders Gastrointestinal Disorders Frequent Infrequent Rare: General Disorders and Administration Site Conditions Frequent Infrequent Hepatobiliary Disorders Rare Investigations Frequent Infrequent Rare Metabolism and Nutrition Disorders Infrequent Rare Musculoskeletal and Connective Tissue Disorders Nervous System Disorders Psychiatric Disorders Infrequent Rare Renal and Urinary Disorders Infrequent Rare Reproductive System and Breast Disorders Frequent Infrequent Rare Respiratory, Thoracic and Mediastinal Disorders Skin and Subcutaneous Tissue Disorders Infrequent Rare Vascular Disorders Infrequent Rare Varenicline 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 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 dateinstruction trial (2), and in the gradual approach toquitting 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. 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. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency >1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease Varenicline 1 mg BID N=353 Placebo N=350 Adverse Events >=1% in either treatment group Up to 30 days after treatment Angina pectoris 3. 0 Chest pain 2. 3 Peripheral edema 2. 1 Hypertension 1. 6 Palpitations 0. 1 Adjudicated Cardiovascular Mortality (up to 52 weeks) 0. 6 Adjudicated Nonfatal Serious Cardiovascular Events >=1% in either treatment group Up to 30 days after treatment Nonfatal MI 1. 3 Hospitalization for angina pectoris 0. 1 Beyond 30 days after treatment and up to 52 weeks Need for coronary revascularization* 2. 6 Hospitalization for angina pectoris 1. 1 New diagnosis of peripheral vascular disease (PVD) or 1. 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. Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia or Schizoaffective Disorder Varenicline 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. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder Varenicline 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. Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History of Psychiatric Disorder Varenicline 1 mg BID Placebo Adverse Events >=10% in the varenicline group Entire study population, 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 ofthe 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 The following adverse events have been reported during post-approval use of varenicline. 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 [see Warnings and Precautions (5. There have been postmarketing reports of new or worsening seizures in patients treated with varenicline [see Warnings and Precautions (5. There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior [see Warnings and Precautions (5. There have been reports ofhypersensitivity reactions, including angioedema [see Warnings and Precautions (5. There havealso been reports of serious skinreactions, including Stevens-Johnson syndrome and erythema multiforme, in patients taking varenicline [see Warnings and Precautions (5. There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking varenicline. 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. There have been reports of hyperglycemia in patients following initiation of varenicline. There have been reports ofsomnambulism, some resulting in harmful behaviorto self, others, or property in patients treated with varenicline [see Warnings and Precautions (5.

Varenicline tablets are contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to varenicline tablets. History of serious hypersensitivity or skin reactions to varenicline tablets.

Risk Summary Available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke [see Data]. Smoking during pregnancy is associated with maternal, fetal, and neonatal risks (see Clinical Considerations). In animal studies, varenicline did not result in major malformations but caused decreased fetal weights in rabbits when dosed during organogenesis at exposures equivalent to 50 times the exposure at the maximum recommended human dose (MRHD). Additionally, administration of varenicline to pregnant rats during organogenesis through lactation produced developmental toxicity in offspring at maternal exposures equivalent to 36 times human exposure at the MRHD [see Data]. The estimated background risk of oral clefts is increased by approximately 30% in infants of women who smoke during pregnancy, compared to pregnant women whodo not smoke. The background risk of other major birth defects and miscarriage for the indicated population are unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. It is not known whether quitting smoking with varenicline during pregnancy reduces these risks. Data Human Data A population-based observational cohort study using the national registers of Denmark and Sweden compared pregnancy and birth outcomes among women exposed to varenicline (N=335, includes 317 first trimester exposed) with women who smoked during pregnancy (N=78,412) and with non-smoking pregnant women (N=806,438). The prevalence of major malformations, the primary outcome, was similar in all groups, including between smoking and non-smoking groups. The prevalence of adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked, and differed somewhat between the three cohorts. The prevalences of the primary and secondary outcomes are shown in Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts Outcome Varenicline Cohort (n=335) Smoking Cohort (n=78,412) Non-Smoking Cohort (n=806,438) Major congenital 12 / 334 (3. 6%) 3,382 / 78,028 33,950 /804,020 malformation* (4. 2%) Stillbirth 1 (0. 5%) 2,418 (0. 3%) Small 42 (12. 5%) 13,433 (17. 1%) 73,135 (9. 1%) Preterm birth 25 (7. 5%) 6,173 (7. 9%) 46,732 (5. 8%) Premature rupture of 12 (3. 6%) 4,246 (5. 4%) 30,641 (3. 8%) Sudden infant death 0/307 (0. 0%) 51/71,720 (0. 1%) 58/755,939 (<0. 1%) *Included only live births in the cohorts. Prevalence among first trimester varenicline- exposed pregnancies (11/317 [3. **There was a lag in death data in Denmark, so the cohorts were smaller. The study limitations include the inability to capture malformations in pregnancies that do not result in a live birth, and possible misclassification of outcome and of exposure to varenicline or to smoking. Other small Overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy. Animal Data Pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. While no fetal structural abnormalities occurred in either species, maternal toxicity, characterized by reduced body weight gain, and reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD of 1 mg twice daily based on AUC). Fetal weight reduction did not occur in rabbits at exposures 23 times the human exposure at the MRHD based on AUC. In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. Maternal toxicity, characterized by a decrease in body weight gain was observed at 15 mg/kg/day (36 times the human exposure at the MRHD based on AUC). However, decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day. Risk Summary There are no data on the presence of varenicline in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies varenicline was present in milk of lactating rats [see Data]. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of varenicline to an infant during lactation; however the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for varenicline and any potential adverse effects on the breastfed child from varenicline or from the underlying maternal condition. Clinical Considerations Because there are no data on the presence of varenicline in human milk and the effects on the breastfed infant, breastfeeding women should monitor their infant for seizures and excessive vomiting, which are adverse reactions that have occurred in adults that may be clinically relevant in breastfeeding infants. Data In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate through gestation and lactation Mean serum concentrations of varenicline in the nursing pups were 5-22% of maternal serum concentrations. Varenicline is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose- proportional over the 0. 5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. 5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with body weight <= 55 kg compared to that noted in the adult population. The efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, had a score of at least 4 on the Fagerstrom Test for Nicotine Dependence scale, and at least one previous failed quit attempt. Patients were stratified by age (12 to 16 years of age, n=216 and 17 to 19 years of age, n=96) and by body weight (<=55 kg and >55 kg). Patients were randomized to one of two doses of varenicline, adjusted by weight to provide plasma levels in the efficacious range (based on adult studies) and placebo. Patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study. Results from this study showed that varenicline, at either dose studied, did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 to 19 years of age. The varenicline safety profile in this study was consistent with that observed in adult studies. A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 to 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 (2. No dosage adjustment is recommended for elderly patients. Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see Dosage and Administration (2. 2), Clinical Pharmacology (12.

Based on varenicline characteristics and clinical experience to date, varenicline has no clinically meaningful pharmacokinetic drug interactions [see Clinical Pharmacology (12. Other Smoking Cessation Therapies Effect of Smoking Cessation on Other Drugs Safety and efficacy of varenicline in combination with other smoking cessation therapies have not been studied. Bupropion Varenicline (1 mg twice daily) did not alterthe 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 ofvarenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo. Physiological changes resulting from smoking cessation, with or without treatment with varenicline, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e. , theophylline, warfarin, insulin) for which dosage adjustment may be necessary.

These highlights do not include all the information needed to use VARENICLINE TABLETS safely and effectively. See full prescribing information for VARENICLINE TABLETS.
These highlights do not include all the information needed to use VARENICLINE TABLETS safely and effectively. See full prescribing information for VARENICLINE TABLETS. VARENICLINE tablets, for oral use Warnings and Precautions, Cardiovascular Events (5.5) 6/2018
OVERDOSAGE
In case ofoverdose, standard supportive measures should be instituted as required. Varenicline has been shown to be dialyzed in patients with end-stage renal disease [see Clinical Pharmacology (12.3)]
NONCLINICAL TOXICOLOGY
Carcinogenesis Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily (MRHD) exposure based on AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the MRHD exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the MRHD exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats. Mutagenesis Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes. Impairment of Fertility There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the MRHD exposure based on AUC at 1 mg twice daily). Maternal toxicity, characterized by a decrease in body weight gain, was observed at 15 mg/kg/day. However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day. This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the MRHD exposure based on AUC at 1 mg twice daily).
CLINICAL STUDIES
The efficacy of varenicline in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (>=10 cigarettes per day) were treated with varenicline. In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO<=10 ppm) at weekly visits. Among the varenicline-treated patients enrolled in these studies, the completion rate was 65%. Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most patients enrolled in these trials were white (79-96%). All studies enrolled almost equal numbers of men and women. The average age of patients in these studies was 43 years. Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years. Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date. Seven additional studies evaluated the efficacy of varenicline in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease [see Clinical Studies (14. 7)], in patients instructed to select their quit date within days 8 and 35 of treatment [see Clinical Studies (14. 4)], patients with major depressive disorder [see Clinical Studies (14. 9)], patients who had made a previous attempt to quit smoking with varenicline, and either did not succeed in quitting or relapsed after treatment [see Clinical Studies (14. 6)], in patients without or with a history of psychiatric disorder enrolled in a postmarketing neuropsychiatric safety outcome trial [see Warnings and Precautions (5. 1), Clinical Studies (14. 10)], and in patients who were not able or willing to quit abruptly and were instructed to quit gradually [see Clinical studies (14. In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each weekly treatment visit according to Agency for Healthcare Research and Quality guidelines. Study 1 This was a six-week dose-ranging study comparing varenicline to placebo. This study provided initial evidence that varenicline at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation. Study 2 This study of 627 patients compared varenicline 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one-week titration) and then were followed for 40 weeks post-treatment. Varenicline was given in two divided doses daily. Each dose of varenicline was given in two different regimens, with and without initial dose-titration, to explorethe effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis. Forty-five percent of patients receiving varenicline 1 mg per day (0. 5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group. Study 3 This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of varenicline or placebo. After an initial one-week titration to a dose of 0. 5 mg twice daily, patients could adjust their dosage as often as they wished between 0. 5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less. Of the patients treated with varenicline, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the varenicline group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group. Study 4 and Study 5 These identical double-blind studies compared varenicline 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The varenicline dosage of 1 mg twice daily was achieved using a titration of 0. 5 mg once daily for the initial 3 days followed by 0. 5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded. In Study 4, patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the varenicline group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group. Similarly in Study 5, patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). In addition, 29% of the varenicline group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group. Figure 1: Continuous Abstinence, Weeks 9 through 12 Table 7. Continuous Abstinence, Weeks 9 through 12 (95% confidence interval Varenicline 0. 5 mg BID Varenicline 1 mg BID Varenicline Flexible Bupropion SR Placebo Study 2 45% 51% 12% Study 3 40% 12% Study 4 44% 30% 17% Study 5 44% 30% 18% BID = twice daily vareniclinetablets-figure1 Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale “urge to smoke” item, varenicline reduced urge to smoke compared to placebo. Varenicline was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to varenicline 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%). Varenicline was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomized to either varenicline 1 mg twice daily (N=760) or placebo (N=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with varenicline had a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32% vs. 7%) and weeks 15 through 52 (24% vs. Varenicline was evaluated in a double-blind, placebo-controlled trial of patients who had made a previous attempt to quit smoking with varenicline, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to varenicline 1 mg twice daily (N=249) or placebo (N=245) for 12 weeks of treatment and followed for 40 weeks post-treatment. Patients included in this study had taken varenicline for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (45%) compared to patients treated with placebo (12%) and from weeks 9 through 52 (20%) compared to subjects treated with placebo (3%). Continuous Abstinence (95% confidence interval), Re-Treatment Study Weeks 9 through 12 Weeks 9 through 52 Varenicline Placebo Varenicline Placebo Retreatment 45% 12% 20% 3% BID = twice daily Varenicline was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged >= 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 >= 50% of predicted normal value. Subjects were randomized to varenicline 1 mg twice daily (N=223) or placebo (N=237) fora treatment of12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with vareniclinehad a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%). Continuous Abstinence (95% confidence interval), Studies in Patients with Chronic Obstructive Pulmonary Disease (COPD) Weeks 9 through 12 Weeks 9 through 52 Varenicline Placebo Varenicline Placebo COPD Study 41% 9% 19% 6% BID = twice daily Varenicline was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to varenicline 1 mg twice daily (N=353) or placebo (N=350) for a treatment period of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO- confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%). Continuous Abstinence (95% confidence interval), Studies in Patients with Cardiovascular Disease (CVD) Weeks 9 through 12 Weeks 9 through 52 Varenicline Placebo Varenicline Placebo CVD Study 47% 14% 20% 7% BID = twice daily In this study, all-cause and CV mortality was lower in patients treated with varenicline, but certain nonfatal CV events occurred more frequently in patients treated with varenicline than in patients treated with placebo [see Warnings and Precautions (5. 5), Adverse Reactions (6. Table 12 below shows mortality and the incidence of selected nonfatal serious CV events occurring more frequently in the varenicline arm compared to the placebo arm. These events were adjudicated by an independent blinded committee. Nonfatal serious CV events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one CV event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-Controlled Varenicline Trial in Patients with Stable Cardiovascular Disease Mortality and Cardiovascular Events Varenicline (N=353) n (%) Placebo (N=350) n (%) Mortality (Cardiovascular and All-cause up to 52 weeks) Cardiovascular 1 (0. 6) All-cause 2 (0. 4) Nonfatal Cardiovascular Events (rate on varenicline > Placebo) Up to 30 days after treatment Nonfatal myocardial infarction 4 (1. 3) Nonfatal Stroke 2 (0. 6) 0 (0) Beyond 30 days after treatment and upto 52 weeks Nonfatal myocardial infarction 3 (0. 6) Need for coronary revascularization 7 (2. 6) Hospitalization for angina pectoris 6 (1. 1) Transient ischemia attack 1 (0. 3) 0 (0) New diagnosis of peripheral vascular disease (PVD) or 5 (1. 6) Following the CVD study, a meta-analysis of 15 clinical trials of >=12 weeks treatment duration, including 7002 patients (4190 varenicline, 2812 placebo), was conducted to systematically assess the CV safety of varenicline. The study in patients with stable CV disease described above was included in the meta-analysis. There were lower rates all-cause mortality (varenicline 6 [0. 14%]; placebo 7 [0. 25%]) and CV mortality (varenicline 2 [0. 05%]; placebo 2 [0. 07%]) in the varenicline arms compared with the placebo arms in the meta-analysis. The key CV safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as CV death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred in the trials included in the meta-analysis, as described in Table 13. These events occurred primarily in patients with known CV disease. Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15 Clinical Trials Comparing Varenicline to Placebo* Varenicline N=4190 Placebo N=2812 MACE cases, n (%) 13 (0. 21%) Patient-years of exposure 1316 839 Hazard Ratio (95% CI) 1. 82) Rate Difference per 1,000 patient-years (95% CI) 6. 10) *Includes MACE occurring up to 30 days post-treatment. The meta-analysis showed that exposure to varenicline resulted in a hazard ratio for MACE of 1. 95 (95% confidence interval from 0. 82) for patients up to 30 days after treatment; this is equivalent to an estimated increase of 6. 3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV endpoints in patients on varenicline relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small Additionally, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension, [see Warnings and Precautions (5. 10)] Varenicline was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 18 to 75 years with major depressive disorder without psychotic features (DSM-IV TR). If on medication, subjects were to be on a stable antidepressant regimen for at least two months. If not on medication, subjects were to have experienced a major depressive episode in the past 2 years, which was successfully treated. Subjects were randomized to varenicline 1 mg twice daily (N=256) or placebo (N=269) for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (36%) compared to subjects treated with placebo (16%) and from week 9 through 52 (20%) compared to subjects treated with placebo (10%). Continuous Abstinence (95% confidence interval), Study in Patients with Major Depressive Disorder (MDD) Weeks 9 through 12 Weeks 9 through 52 Varenicline Placebo Varenicline Placebo MDD Study 36% 16% 20% 10% BID = twice daily Varenicline was evaluated in a randomized, double-blind, active and placebo-controlled trial that included subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3912) and with a history of psychiatric disorder (psychiatric cohort, N=4003). Subjects aged 18-75 years, smoking 10 or more cigarettes per day wererandomized 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, NRT patch 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. [See Warnings and Precautions (5. 1)] A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse events included the following NPS adverse events: anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, irritability, suicidal ideation, suicidal behavior or completed suicide. As shown in Table 15, the use of varenicline, bupropion, and NRT in the non-psychiatric cohort was not associated with an increased risk of clinically significant NPS adverse events compared with placebo. Similarly, in the non-psychiatric cohort, the use of varenicline was not associated with an increased risk of clinically significant NPS adverse events in the composite safety endpoint compared with bupropion or NRT. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients without a History of Psychiatric Disorder Varenicline (N=975) n (%) Bupropion (N=968) n (%) NRT (N=987) n (%) Placebo (N=982) n (%) Clinically Significant 30 (3. 1) Serious NPS 1 (0. 4) Psychiatric 1 (0. 1) As shown in Table 16, there were more clinically significant NPS adverse events reported in patients in the psychiatric cohort in each treatment group compared with the non- psychiatric cohort. The incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo: Risk Differences (RDs) (95%CI) vs placebo were 2. 4) forvarenicline, 2. 9) for bupropion, and 0. 0) for NRT transdermal nicotine. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients with a History of Psychiatric Disorder Varenicline (N=1007) n(%) Bupropion (N=1004) n (%) NRT (N=995) n (%) Placebo (N=997) n (%) Clinically Significant NPS 123 (12. 5) Serious NPS 6 (0. 6) Psychiatric hospitalizations 5 (0. 2) There was one completed suicide, which occurred during treatment in a patient treated with placebo in the non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort. In both cohorts, subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, nicotine patch and placebo. Continuous Abstinence (95% confidence interval), Study in Patients with or without a History of Psychiatric Disorder Varenicline 1 mg BID Bupropion SR 150 mg BID NRT 21 mg/day with taper Placebo Weeks 9 through 12 Non- 38% 26% 26% 14% Psychiatric (35%, 41%) (23%, 29%) (24%, 29%) (12%, 16%) Cohort Psychiatric 29% 19% 20% 11% Cohort (26%, 32%) (17%, 22%) (18%, 23%) (10%, 14%) Weeks 9 through 24 Non- 25% 19% 18% 11% Psychiatric (23%, 28%) (16%, 21%) (16%, 21%) (9%, 13%) Cohort Psychiatric 18% 14% 13% 8% Cohort (16%, 21%) (12%, 16%) (11%, 15%) (7%, 10%) BID = twice daily Cardiovascular Outcome Analysis To obtain another source of data regarding the CV risk of varenicline, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension. In the parent study (N=8027), subjects aged 18 to 75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy (NRT) patch 21 mg/day or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. The extension study enrolled 4590 (57. 2%) of the 8027 subjects who were randomized and treated in the parent study and followed them for additional 28 weeks. Of all treated subjects, 1743 (21. 7%) had a medium CV risk and 640 (8. 0%) had a high CV risk, as defined by Framingham score. Note that one site from the parent study was excluded in the assessment of CV safety and two sites were excluded in the assessment of neuropsychiatric safety. The primary CV endpoint was the time to major adverse CV event (MACE), defined as CV death, nonfatal myocardial infarction or nonfatal stroke during treatment. Deaths and CV events were adjudicated by a blinded, independent committee. Table 18 below shows the incidence of MACE and Hazard Ratios compared to placebo for all randomized subjects exposed to at least 1 partial dose of study treatment in the parent study. The Incidence of MACE and Hazard Ratios in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder Varenicline Bupropion NRT Placebo N=2006 N=1997 N=2017 N=2007 During treatment* MACE, n [IR] 1 [2. 8] Hazard Ratio (95% CI) vs. 24 Through end of study** MACE, n [IR] 3 [2. 7] Hazard Ratio (95% CI) vs. 74 [IR] indicates incidence rate per 1000 person-years *during treatment in the parent neuropsychiatric safety study **either the end of the extension study or the end of parent neuropsychiatric safety study for those subjects not enrolled into the extension study For this study, MACE+ was defined as any MACE or a new onset or worsening peripheral vascular disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina. Incidence rates of MACE+ and all-cause mortality for all Table 19. The Incidence of MACE+ and All-Cause Death in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder Varenicline N=2006 Bupropion N=1997 NRT N=2017 Placebo N=2007 During treatment* MACE+, n [IR] 5 [12. 2] All-cause deaths, n [IR] 0 2 [4. 9] Through end of study** MACE+, n [IR] 10 [6. 6] All-cause deaths, n [IR] 2 [1. 9] [IR] indicates incidence rate per 1000 person-years *during treatment in the parent neuropsychiatric safety study **either the end of the extension study or the end of the parent neuropsychiatric safety study for those subjects not enrolled into the extension study The number of subjects who experienced MACE, MACE+ and all-cause death was similar or lower among patients treated with varenicline than patients treated with placebo. The number of events observed overall Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, varenicline-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo(Figure 2, Table 8). Continuous Abstinence, Weeks 9 through 52 Table 8. Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) Across Different Studies Varenicline 0. 5 mg BID Varenicline 1 mg BID Varenicline Flexible Bupropion SR Placebo Study 2 19% 23% 4% Study 3 22% 8% Study 4 21% 16% 8% Study 5 22% 14% 10% BID = twice daily Study 6 This study assessed the effect of an additional 12 weeks of varenicline therapy on the likelihood of long-term abstinence. Patients in this study (N=1927) were treated with open-label varenicline 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (N= 1210) were then randomized to double-blind treatment with varenicline (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment. The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with varenicline (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (varenicline 54% versus placebo 39%). In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of varenicline; post- varenicline follow-up begins at Week 13 for the placebo group and Week 25 for the varenicline group. The y-axis represents the percentage of patients who had been abstinent for the last week of varenicline treatment and remained abstinent at the given time point. Continuous Abstinence Rate during Nontreatment Follow-Up vareniclinetablets-figure3 vareniclinetablets-figure2.
SPL MEDGUIDE SECTION
MEDICATION GUIDE Varenicline Tablets (var EN i kleen) What is the most important information I should know about varenicline tablets? urge to smoke frustration restlessness depressed mood anger decreased heart rate trouble sleeping feeling anxious increased appetite irritability difficulty concentrating weight gain New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depressed mood, or suicidal thoughts or actions. Stop taking varenicline tablets and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms. Before taking varenicline tablets What are varenicline tablets? Who should not take varenicline tablets? What should I tell my healthcare provider before taking varenicline tablets? See “What is the most important information I should know about varenicline tablets?” Before you take varenicline tablets, tell your healthcare provider if you: How should I take varenicline tablets? quit date quit date OR quit date. OR Weeks 1 through 4 Weeks 5 through 8 Weeks 9 through 12 Aim to quit by the end of the 12th week of treatment, or sooner if you feel ready. Continue to take varenicline tablets for another 12 weeks, for a total of 24 weeks of treatment. quit date Day 1 to Day 3 - White tablet (0.5 mg) Day 4 to Day 7 - White tablet (0.5 mg) Day 8 to end of treatment - Blue tablet (1 mg) What should I avoid while taking varenicline tablets? What are the possible side effects of varenicline tablets? Serious side effects of varenicline tablets may include: See “What is the most important information I should know about varenicline tablets?” Seizures New or worse heart or blood vessel (cardiovascular) problems Get emergency medical help right away if you have any of the following symptoms of a heart attack, including chest discomfort (uncomfortable pressure, squeezing, fullness or pain) that lasts more than a few minutes, or that goes away and comes back pain or discomfort in one or both arms, back, neck, jaw or stomach shortness of breath, sweating, nausea, vomiting, or feeling lightheaded associated with chest discomfort Sleepwalking Allergic reactions Serious skin reactions Stop taking varenicline tablets and get medical help right away if you have any of the following symptoms: swelling of the face, mouth (tongue, lips, and gums), throat or neck trouble breathing rash with peeling skin blisters in your mouth nausea sleep problems (trouble sleeping or vivid, unusual, or strange dreams) constipation gas vomiting How should I store varenicline tablets? Keep varenicline tablets and all medicines out of the reach of children. General information about the safe and effective use of varenicline tablets What are the ingredients in varenicline tablets? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U.S. Food and Administration Revised 3/2023

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