Varenicline

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 )

12.1 Mechanism of Action Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of varenicline 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, >3,500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

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 are 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 to 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 impairment. For p

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 (>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. 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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, 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 (5.9) ] . 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 7.1). 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. Table 1. 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 * Includes PTs Abdominal (pain, pain upper, pain lower

5 WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Events: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients attempting to quit smoking with varenicline for the occurrence of such symptoms and instruct them to discontinue varenicline and contact a healthcare provider if they experience such adverse events. ( 5.1 ) Seizures: New or worsening seizures have been observed in patients taking varenicline. Varenicline should be used cautiously in patients with a history of seizures or other factors that can lower the seizure threshold. ( 5.2 ) Interaction with Alcohol: Increased effects of alcohol have been reported. Instruct patients to reduce the amount of alcohol they consume until they know whether varenicline affects them. ( 5.3 ) Accidental Injury: Accidental injuries (e.g., traffic accidents) have been reported. Instruct patients to use caution driving or operating machinery until they know how varenicline may affect them. ( 5.4 ) Cardiovascular Events: Patients with underlying cardiovascular (CV) disease may be at increased risk of CV events; however, these concerns must be balanced with the health benefits of smoking cessation. Instruct patients to notify their healthcare providers of new or worsening CV symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction (MI) or stroke. ( 5.5 and 6.1 ) Somnambulism: Cases of somnambulism have been reported in patients taking varenicline. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue varenicline and notify their healthcare provider if they experience somnambulism. ( 5.6 and 6.2 ) Angioedema and Hypersensitivity Reactions: Such reactions, including angioedema, infrequently life-threatening, have been reported. Instruct patients to discontinue varenicline and immediately seek medical care if symptoms occur. ( 5.7 and 6.2 ) Serious Skin Reactions: Rare, potentially life-threatening skin reactions have been reported. Instruct patients to discontinue varenicline and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions. ( 5.8 and 6.2 ) Nausea: Nausea is the most common adverse reaction (up to 30% incidence rate). Dose reduction may be helpful. ( 5.9 ) 5.1 Neuropsychiatric Adverse Events including Suicidality Serious neuropsychiatric adverse events have been reported in patients being treated with varenicline [see Adverse Reactions (6.2) ] . These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking varenicline who continued to smoke. Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Some neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) ]. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking varenicline and contact

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 )

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.