CHANTIX (Page 2 of 11)

5.4 Accidental Injury

There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how CHANTIX may affect them.

5.5 Cardiovascular Events

A comprehensive evaluation of cardiovascular (CV) risk with CHANTIX suggests that patients with underlying CV disease may be at increased risk; however, these concerns must be balanced with the health benefits of smoking cessation. CV risk has been assessed for CHANTIX in randomized controlled trials (RCT) and meta-analyses of RCTs. In a smoking cessation trial in patients with stable CV disease, CV events were infrequent overall; however, nonfatal myocardial infarction (MI) and nonfatal stroke occurred more frequently in patients treated with CHANTIX compared to placebo. All-cause and CV mortality was lower in patients treated with CHANTIX [see Clinical Studies (14.8)]. This study was included in a meta-analysis of 15 CHANTIX efficacy trials in various clinical populations that showed an increased hazard ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the finding was not statistically significant (95% CI: 0.79, 4.82). In the large postmarketing neuropsychiatric safety outcome trial, an analysis of adjudicated MACE events was conducted for patients while in the trial and during a 28-week non-treatment extension period. Few MACE events occurred during the trial; therefore, the findings did not contribute substantively to the understanding of CV risk with CHANTIX. 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 MI or stroke [see Clinical Studies (14.10)].

5.6 Somnambulism

Cases of somnambulism have been reported in patients taking CHANTIX. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue CHANTIX and notify their healthcare provider if they experience somnambulism [see Adverse Reactions (6.2)].

5.7 Angioedema and Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2), Patient Counseling Information (17)]. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.

5.8 Serious Skin Reactions

There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX [see Adverse Reactions (6.2)]. As these skin reactions can be life-threatening, instruct patients to stop taking CHANTIX and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.

5.9 Nausea

Nausea was the most common adverse reaction reported with CHANTIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking CHANTIX 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.

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:

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.

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 (5.9)].

Table 1 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 1. 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 CLASSHigh Level Group Term CHANTIX0.5 mg BID CHANTIX1 mg BID Placebo
Preferred Term N=129 N=821 N=805
*
Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort
Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening
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

The overall pattern and frequency of adverse events during the longer-term premarketing trials was similar to those described in Table 1, 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 postmarketing 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, VIIth 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 (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 CHANTIX 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 date instruction trial (2), and in the gradual approach to quitting 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. 2%).

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.

Table 2. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency >1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease
CHANTIX1 mg BID Placebo
N=353 N=350
*
some procedures were part of management of nonfatal MI and hospitalization for angina
Adverse Events ≥1% in either treatment group
Up to 30 days after treatment
Angina pectoris 3.7 2.0
Chest pain 2.5 2.3
Peripheral edema 2.0 1.1
Hypertension 1.4 2.6
Palpitations 0.6 1.1
Adjudicated Cardiovascular Mortality (up to 52 weeks) 0.3 0.6
Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in either treatment group
Up to 30 days after treatment
Nonfatal MI 1.1 0.3
Hospitalization for angina pectoris 0.6 1.1
Beyond 30 days after treatment and up to 52 weeks
Need for coronary revascularization * 2.0 0.6
Hospitalization for angina pectoris 1.7 1.1
New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure 1.4 0.6

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.

Table 3. Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia or Schizoaffective Disorder
CHANTIX1 mg BID Placebo
N=84 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. 1%).

Table 4. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder
CHANTIX1 mg BID Placebo
N=256 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.

Table 5. Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History of Psychiatric Disorder
CHANTIX1 mg BID Placebo
Adverse Events ≥10% in the varenicline group
Entire study population, N 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 of the 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.

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