VARENICLINE

Warnings and Precautions, Cardiovascular Events ( 5.5 ) 6/2018

1 INDICATIONS AND USAGE Varenicline tablets are indicated for use as an aid to smoking cessation treatment. Varenicline tablets are a nicotinic receptor partial agonist indicated for use as an aid to smoking cessation treatment. ( 1 and 2.1 )

2 DOSAGE AND ADMINISTRATION • 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 ) • Starting Week: 0.5 mg once daily on days 1 to 3 and 0.5 mg twice daily on days 4 to 7. ( 2.1 ) • Continuing Weeks: 1 mg twice daily for a total of 12 weeks. ( 2.1 ) • An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence. ( 2.1 ) • 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. ( 2.1 ) • 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. ( 2.2 ) • Consider dose reduction for patients who cannot tolerate adverse effects. ( 2.1 ) • 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. ( 2.1 ) • Provide patients with appropriate educational materials and counseling to support the quit attempt. ( 2.1 ) 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 to 3: 0.5 mg once daily Days 4 to 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 are 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. 2.2 Dosage in Special Populations Patients with Impaired Renal Function No dosage adjustment is necessary for patients with mild to moderate renal …

3 DOSAGE FORMS AND STRENGTHS Varenicline tablets, 0.5 mg are white to off-white, capsule shaped, biconvex, film-coated tablets, debossed with "ZV1" on one side and plain on other side. Varenicline tablets, 1 mg are light blue to blue, capsule shaped, biconvex, film-coated tablets, debossed with "ZV2" on one side and plain on other side. Tablets: 0.5 mg and 1 mg ( 3 )

4 CONTRAINDICATIONS 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. ( 4 )

6 ADVERSE REACTIONS 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 Warnings and Precautions (5.3) ] • Accidental Injury [see Warnings and Precautions (5.4) ] • Cardiovascular Events [see Warnings and Precautions (5.5) ] • Somnambulism [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 tablets (>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 tablets, 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 tablets-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo). Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. Most common adverse reactions (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals , Inc. at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Vareniclin …

7 DRUG INTERACTIONS Based on varenicline characteristics and clinical experience to date, varenicline tablets have no clinically meaningful pharmacokinetic drug interactions [see Clinical Pharmacology ( 12.3 )]. • Other Smoking Cessation Therapies: Safety and efficacy in combination with other smoking cessation therapies has not been established. Coadministration of varenicline and transdermal nicotine resulted in a high rate of discontinuation due to adverse events. ( 7.1 ) • Effect of Smoking Cessation on Other Drugs: Pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) may be altered, necessitating dose adjustment. ( 7.2 ) 7.1 Use with Other Drugs for Smoking Cessation Safety and efficacy of varenicline tablets in combination with other smoking cessation therapies have not been studied. Bupropion Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established. Nicotine replacement therapy (NRT) Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo. 7.2 Effect of Smoking Cessation on Other Drugs Physiological changes resulting from smoking cessation, with or without treatment with varenicline tablets, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 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% to 4% and 15% to 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. Table 6 Summary of Primary and Secondary Outcomes for Three Birth Cohorts * Included only live births in the cohorts. Prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]). ** There was a lag in death data in Denmark, so the cohorts were smaller. Outcome Varenicline Cohort (n=335) Smoking Cohort (n=78,412) Non-Smoking Cohort (n=806,438) Major congenital malformation * 12/334 (3.6%) 3,382/78,028 (4.3%) 33,950/804,020 (4.2%) Stillbirth 1 (0.3%) 384 (0.5%) 2,418 (0.3%) Small for gestational age 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 membranes 12 (3.6%) 4,246 (5.4%) 30,641 (3.8%) Sudden infant death syndrome ** 0/307 (0%) 51/71,720 (0.1%) 58/755,939 ( 55 kg, as assessed by AUC (0 to 24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 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 years 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 yea …

12.1 Mechanism of Action Varenicline binds with high affinity and selectivity at α 4 β 2 neuronal nicotinic acetylcholine receptors. The efficacy of varenicline in smoking cessation is believed to be the result of varenicline’s activity at α 4 β 2 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 α 4 β 2 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 α 4 β 2 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 α 4 β 2 receptors than to other common nicotinic receptors (>500-fold α 3 β 4 , >3,500-fold α 7 , >20,000-fold α 1 βγδ), or to non-nicotinic receptors and transporters (>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT 3 receptor.

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 Initial U.S. Approval: 2006

11 DESCRIPTION Varenicline tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α 4 β 2 nicotinic acetylcholine receptor subtypes. Varenicline, as the tartrate salt, is a powder which is an off-white to white color powder with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6Hpyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C 13 H 13 N 3 ∙C 4 H 6 O 6 . The chemical structure is: Varenicline tablets are supplied for oral administration in two strengths: a 0.5 mg capsular, biconvex, white to off-white film-coated tablets, debossed with “0.5” on one side and plain on the other side and a 1 mg capsular, biconvex, light blue film-coated tablets, debossed with “1.0” on one side and plain on the other side. Each 0.5 mg varenicline tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1 mg varenicline tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, purified water, magnesium stearate, The tablets are film-coated with a coating material containing hypromellose, triacetin, titanium dioxide. In addition to these, the 1 mg tablet film coating includes FD&C blue #2/ indigo carmine aluminum lake. Varenicline Structure

10 OVERDOSAGE In case of overdose, 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 )] , however, there is no experience in dialysis following overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Varenicline tablets are supplied for oral administration in two strengths: a 0.5 mg White to off white, round shaped, biconvex, film-coated tablets debossed with 'M 33' on one side and plain on the other side and a 1 mg White to off white colored, capsule shaped, biconvex, film-coated tablets debossed with 'M 34' on one side and plain on the other side. Varenicline tablets are supplied in the following package configurations: Description NDC Packs Starting Month Box: 0.5 mg x 11 tablets and 1 mg x 42 tablets NDC 33342-577-49 Starting 4-week card: 0.5 mg x 11 tablets and 1 mg x 42 tablets NDC 33342-577-49 Continuing Month Box: 1 mg x 56 tablets NDC 33342-490-27 Continuing 4-week card: 1 mg x 56 tablets NDC 33342-490-27 Bottles 0.5 mg – bottle of 56 NDC 33342-489-19 1 mg – bottle of 56 NDC 33342-490-19 Store at 20°c to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59° to 86 °F) [see USP Controlled Room Temperature].