Chantix Drug Information

CHANTIX is indicated for use as an aid to smoking cessation treatment.

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: 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.

• 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.
• 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.

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. 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.

Table 5 shows the adverse events for CHANTIX and placebo in the 12- week fixed dose premarketing studies with titration in the first week. 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 1 2 1 The overall pattern and frequency of adverse events during the longer-term premarketing trials was similar to those described in Table 5, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg twice daily in a one-year study, compared to 8% of placebo-treated patients). Following is a list of treatment-emergent adverse events reported by patients treated with CHANTIX during all premarketing clinical trials and updated based on pooled data from 18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated with varenicline.

Adverse events were categorized using MedDRA, Version 16.0. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Blood and Lymphatic System Disorders.

Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia. Cardiac Disorders.

Infrequent: angina pectoris, myocardial infarction, palpitations, tachycardia. Rare: acute coronary syndrome, arrhythmia, atrial fibrillation, bradycardia, cardiac flutter, cor pulmonale, coronary artery disease, ventricular extrasystoles. Ear and Labyrinth Disorders.

Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease. Endocrine Disorders.

Infrequent: thyroid gland disorders. Eye Disorders. Infrequent: conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment.

Rare: blindness transient, cataract subcapsular, dry eye, night blindness, ocular vascular disorder, photophobia, vitreous floaters. Gastrointestinal Disorders. Frequent: diarrhea, toothache.

Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute. General Disorders and Administration Site Conditions.

Frequent: chest pain. Infrequent: chest discomfort, chills, edema, influenza-like illness, pyrexia. Hepatobiliary Disorders.

Rare: gall bladder disorder. Investigations. Frequent: liver function test abnormal, weight increased.

Infrequent: electrocardiogram abnormal. Rare: muscle enzyme increased, urine analysis abnormal. Metabolism and Nutrition Disorders.

Infrequent: diabetes mellitus, hypoglycemia. Rare: hyperlipidemia, hypokalemia. Musculoskeletal and Connective Tissue Disorders.

Frequent: arthralgia, back pain, myalgia. Infrequent: arthritis, muscle cramp, musculoskeletal pain. Rare: myositis, osteoporosis.

Nervous System Disorders. Frequent: disturbance in attention, dizziness. Infrequent: amnesia, convulsion, migraine, parosmia, syncope, tremor.

Rare: balance disorder, cerebrovascular accident, dysarthria, mental impairment, multiple sclerosis, VII th nerve paralysis, nystagmus, psychomotor hyperactivity, psychomotor skills impaired, restless legs syndrome, sensory disturbance, transient ischemic attack, visual field defect. Psychiatric Disorders. Infrequent: dissociation, libido decreased, mood swings, thinking abnormal.

Rare: bradyphrenia, disorientation, euphoric mood. Renal and Urinary Disorders. Infrequent: nocturia, pollakiuria, urine abnormality.

Rare: nephrolithiasis, polyuria, renal failure acute, urethral syndrome, urinary retention. Reproductive System and Breast Disorders. Frequent: menstrual disorder.

Infrequent: erectile dysfunction. Rare: sexual dysfunction. Respiratory, Thoracic and Mediastinal Disorders.

Frequent: respiratory disorders. Infrequent: asthma, epistaxis, rhinitis allergic, upper respiratory tract inflammation. Rare: pleurisy, pulmonary embolism.

Skin and Subcutaneous Tissue Disorders. Infrequent: acne, dry skin, eczema, erythema, hyperhidrosis, urticaria. Rare: photosensitivity reaction, psoriasis.

Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.

CHANTIX has also been studied in postmarketing trials including a trial conducted in patients with chronic obstructive pulmonary disease (COPD), 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"), a trial conducted in patients who did not succeed in stopping smoking during prior CHANTIX therapy, or who relapsed after treatment ("re-treatment trial"), a trial conducted in patients with stable cardiovascular disease, a trial conducted in patients with stable schizophrenia or schizoaffective disorder and a trial conducted in patients with major depressive disorder. Adverse events in the trial of patients with COPD, in the alternative quit date instruction trial, were quantitatively and qualitatively similar to those observed in premarketing studies. In the trial of patients with stable cardiovascular disease, more types and a greater number of cardiovascular events were reported compared to premarketing studies.

Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by a blinded, independent committee. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study.

In the trial of patients with stable schizophrenia or schizoaffective disorder, 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. Among reported neuropsychiatric adverse events, insomnia was the only event that occurred in either treatment group in ≥5% of subjects at a rate higher in the varenicline group than in placebo (10% vs. 5%). These common and neuropsychiatric adverse events occurred on treatment or within 30 days after the last dose of study drug.

There was no consistent worsening of schizophrenia in either treatment group as measured by the Positive and Negative Syndrome Scale. There were no overall changes in extra-pyramidal signs, as measured by the Simpson-Angus Rating Scale. The Columbia-Suicide Severity Rating Scale was administered at baseline and at clinic visits during the treatment and non-treatment follow-up phases.

Over half of the patients had a lifetime history of suicidal behavior and/or ideation (62% on varenicline vs. 51% on placebo), but at baseline, no patients in the varenicline group reported suicidal behavior and/or ideation vs. one patient in the placebo group (2%). Suicidal behavior and/or ideation were reported in 11% of the varenicline-treated and 9% of the placebo-treated patients during the treatment phase. During the post-treatment phase, suicidal behavior and/or ideation were reported in 11% of patients in the varenicline group and 5% of patients in the placebo group.

Many of the patients reporting suicidal behavior and ideation in the follow-up phase had not reported such experiences in the treatment phase. However, no new suicidal ideation or behavior emerged in either treatment group shortly (within one week) after treatment discontinuation (a phenomenon noted in post-marketing reporting). There were no completed suicides.

There was one suicide attempt in a varenicline-treated patient. The limited data available from this single smoking cessation study are not sufficient to allow conclusions to be drawn. Patients treated with varenicline were more likely than patients treated with placebo to report one of various events related to hostility and aggression (3% vs 1%).

Psychiatric scales showed no differences between the varenicline and placebo groups and no overall worsening of depression during the study in either treatment group. There was one event of intentional self-injury/possible suicide attempt during treatment (Day 73) in a subject in the placebo group. Suicide could not be ruled out in one subject who died by an overdose of illicit drugs 76 days after last dose of study drug in the varenicline group.

Postmarketing Experience

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

Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had discontinued smoking. There have been post-marketing reports of new or worsening seizures in patients treated with CHANTIX.

There have been post-marketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHANTIX. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior. There have been reports of hypersensitivity reactions, including angioedema.

There have also been reports of serious skin reactions, including Stevens- Johnson Syndrome and erythema multiforme, in patients taking CHANTIX. There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking CHANTIX. 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.

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.

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.

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.

Pediatric Use Safety and effectiveness of CHANTIX in pediatric patients have not been established.

CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.

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, however, there is no experience in dialysis following overdose.