CHANTIX

Dosage and Administration Usual Dosage for Adults ( 2.1 ) 10/2014 Warnings and Precautions Neuropsychiatric Symptoms and Suicidality ( 5.1 ) 09/2014 Seizures ( 5.2 ) 09/2014 Interaction with Alcohol ( 5.3 ) 09/2014

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

2 DOSAGE AND ADMINISTRATION • Begin CHANTIX dosing one week before the date set by the patient to stop smoking. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment. ( 2.1 ) • Starting week: 0.5 mg once daily on days 1–3 and 0.5 mg twice daily on days 4–7. ( 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 ) • Renal impairment: Reduce the dose in patients with severe renal impairment (estimated creatinine clearance <30 mL/min). ( 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 CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment. CHANTIX should be taken after eating and with a full glass of water. The recommended dose of CHANTIX 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 CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence. Patients who are motivated to quit, and who did not succeed in stopping smoking during prior CHANTIX therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with CHANTIX 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 CHANTIX. 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 <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. 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) and 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) ] .

3 DOSAGE FORMS AND STRENGTHS Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with " Pfizer " on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with " Pfizer " on one side and "CHX 1.0" on the other side). Tablets: 0.5 mg and 1 mg ( 3 )

4 CONTRAINDICATIONS CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX. History of serious hypersensitivity or skin reactions to CHANTIX. ( 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 symptoms and suicidality [see Boxed Warning and 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) ] • Angioedema and hypersensitivity reactions [see Warnings and Precautions (5.6) ] • Serious skin reactions [see Warnings and Precautions (5.7) ] In the placebo-controlled premarketing studies, the most common adverse events associated with CHANTIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting. The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of three months' treatment. In this group, the discontinuation rates that are higher than placebo for the most common adverse events in CHANTIX-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo). Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 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 CHANTIX, over 4500 subjects were exposed to CHANTIX, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less. The most common adverse event associated with CHANTIX treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen [see Warnings and Precautions (5.6) ] . Table 5 shows the adverse events for CHANTIX and placebo in the 12- week fixed dose premarketing studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1). MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the CHANTIX 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥ 1% of CHANTIX patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once. Table 5: Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies (HLGTs ≥ 5% of patients in the 1 mg BID CHANTIX Group and more commonly than placebo and PT ≥ 1% in the 1 mg BID CHANTIX Group, and 1 mg BID CHANTIX at least 0.5% more than Placebo) SYSTEM ORGAN CLASS High Level Group Term CHANTIX 0.5 mg BID CHANTIX 1 mg BID Placebo Preferred Term N=129 N=821 N=805 GASTROINTESTINAL (GI) GI Signs and Symptoms Nausea 16 30 10 Abdominal Pain Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, …

7 DRUG INTERACTIONS Based on varenicline characteristics and clinical experience to date, CHANTIX has 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: Pharmacokinetics or pharmacodynamics of certain drugs may be altered due to smoking cessation with CHANTIX, necessitating dose adjustment. ( 7.2 ) 7.1 Use With Other Drugs for Smoking Cessation Safety and efficacy of CHANTIX 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 CHANTIX, 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 • Pregnancy: CHANTIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ( 8.1 ) • Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother. ( 8.3 ) • Pediatric Use: Safety and effectiveness not established. ( 8.4 ) • Renal Impairment: Dosage adjustment is required for severe renal impairment. ( 2.2 , 8.6 ) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies of CHANTIX use in pregnant women. In animal studies, CHANTIX caused decreased fetal weights, increased auditory startle response, and decreased fertility in offspring. CHANTIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive and developmental toxicity studies, pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. These exposures were 36 (rats) and 50 (rabbits) times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 1 mg twice daily. While no fetal structural abnormalities occurred in either species, reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD based on AUC). Fetal weight reduction did not occur at animal 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. These resulted in exposures up to 36 times the human exposure (based on AUC) at the MRHD of 1 mg twice daily. Decreased fertility and increased auditory startle response occurred in offspring. 8.3 Nursing Mothers It is not known whether CHANTIX is excreted in human milk. In animal studies varenicline was excreted in milk of lactating animals. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CHANTIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of CHANTIX in pediatric patients have not been established. 8.5 Geriatric Use 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 65–75 yrs) 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 (2.2) ]. No dosage adjustment is recommended for elderly patients. 8.6 Renal Impairment 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) and Clinical Pharmacology (12.3) ].

12.1 Mechanism of Action Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at α4β2 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 α4β2 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 α4β2 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 α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

11 DESCRIPTION CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α 4 β 2 nicotinic acetylcholine receptor subtypes. Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6 H -pyrazino[2,3- h][3]benzazepine, (2 R ,3 R )-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: CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with " Pfizer " on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with " Pfizer " on one side and "CHX 1.0" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1mg CHANTIX 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, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear. Chemical 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 CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with " Pfizer " on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with " Pfizer " on one side and "CHX 1.0" on the other side. CHANTIX is supplied in the following package configurations: Description NDC Starting 4-week card: 0.5 mg × 11 tablets and 1 mg × 42 tablets NDC 63187-618-53 Starting Month Box: 0.5 mg × 11 tablets and 1 mg × 42 tablets NDC 63187-618-53 Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (see USP Controlled Room Temperature).