CHAMPIX (varenicline) Adverse Reactions

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

Smoking-cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain have been reported in patients attempting to stop smoking.

Overview

Pre-marketing clinical trials included approximately 2300 patients treated for at least 12 weeks, approximately 700 for 6 months, and approximately 100 for one year. In general, onset of adverse events was in the first few weeks of therapy and severity was generally mild to moderate. No differences were observed by age, race or gender with regard to the incidence of adverse reactions, although patient numbers in elderly, and in non-caucasian races were too limited to allow conclusions.

Commonly Observed Adverse Events

The most commonly observed adverse events associated with CHAMPIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal dreams, constipation, flatulence, and vomiting.

For patients exposed to the maximum recommended dose of 1.0 mg BID following initial dosage titration, the incidence of nausea was 30%, compared with 16% in 0.5 mg BID and approximately 10% in placebo-treated patients. Nausea was generally described as mild to moderate and often transient; however, for some subjects, it was persistent throughout the treatment period.

Adverse Events Leading to Discontinuation

In Phase 2 and 3 placebo-controlled studies, the treatment discontinuation rate due to adverse events in patients randomized to 12 weeks treatment with the recommended maximum dose of 1.0 mg BID was 12% for CHAMPIX compared to 10% for placebo. In this group, the adverse events most frequently resulting in treatment discontinuation in CHAMPIX treated patients were as follows: nausea (2.7% vs 0.6% for placebo), insomnia (1.3% vs 1.2% for placebo), fatigue/malaise/asthenia (1.0% vs 0.5% for placebo), and dizziness (0.7% vs 0.4% for placebo).

Table 1 shows the adverse events for CHAMPIX and placebo in the 12-week fixed dose studies with titration in the first week (Studies 1 (titrated arm only), 3, and 4). MedDRA High Level Group Terms (HLGT) reported in ≥5% of patients in the CHAMPIX 1.0 mg BID dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥1% of CHAMPIX patients (and at least 0.5% more frequently 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 were only counted once.

* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort
** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening
NEC: Not Elsewhere Classified

Initial dose titration was beneficial in reducing the occurrence of nausea.

An additional 12 weeks of CHAMPIX 1.0 mg BID was well-tolerated in patients who had completed 12 weeks of treatment and had stopped smoking. Adverse events resulted in treatment discontinuation in 1.7% of patients who received CHAMPIX compared with 1.3% of placebo patients.

Safety Study: One-Year, Double-Blind Drug-Treatment
The overall pattern and the frequency of adverse events during a 52-week trial with CHAMPIX 1.0 mg BID (n=251 subjects randomized to CHAMPIX arm, and n=126 to placebo arm) were similar to those described in Table 1, except for the following events which were seen to be increased relative to placebo, as compared to the profile for 12 week drug exposure: nausea (40% vs 8% placebo); and the pooled terms of: abdominal pain (17% vs 3% placebo), and increased blood pressure (11% vs 6% placebo). Few of these events were recorded as severe.

Neuropsychiatric Adverse Events in Randomized, Double-Blind, Placebo-Controlled Clinical Studies of Varenicline

Meta-Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS)

A meta-analysis of 5 randomized, double blind, placebo controlled trials, including 1907 patients (1130 CHAMPIX, 777 placebo), was conducted to assess suicidal ideation and behavior as reported on the C-SSRS. This meta-analysis included one trial (N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N=525) in patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behavior in patients treated with CHAMPIX compared to patients treated with placebo, with a Risk Ratio (RR) of 0.79 (95% Confidence Interval [CI]: 0.46, 1.36), as shown in Table 2. Forty-eight (48) of the 55 patients who reported suicidal ideation or behavior (24 CHAMPIX, 24 placebo) were from the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Few patients reported these events in the other three trials (4 CHAMPIX, 3 placebo).

* Of these, one patient in each treatment arm reported suicidal behavior
** Patients with events up to 30 days after treatment; % are not weighted by study
# RR of incidence rates per 100 patient years

Pooled Data including Ten Smoking Cessation Trials

Table 3 below provides the incidence of all causality, treatment-emergent neuropsychiatric adverse events with varenicline as compared to placebo (≥ 0.2% more than placebo) in adult smokers, adverse event summarized from all randomized, placebo-controlled, double-blind varenicline studies (10 studies) completed by 31 December 2008, regardless of Study Dose or Duration. Four of these are described in the CLINICAL TRIALS section. There were no suicidal and self-injurious behaviors reported (suicide ideation and suicide attempt) in the varenicline group versus 2 events (0.1%) in the placebo group.

MedDRA version 11; included data up to 30 days after last dose of drug
NEC: Not Elsewhere Classified
Number (%) of Subjects with Adverse Events by:
* Psychiatric Disorders System Organ Class: All High Level Group Terms (HLGT)
and Preferred Terms (PTs) reported in each HLGT that are ≥ 0.2 % greater than placebo.
** Nervous System Disorder System Organ Class Selected HLGTs and PTs reported in each HLGT that are ≥ 0.2 % greater than placebo.

Data from One Phase 2 Trial with Two Varenicline Doses

Data are shown from the Phase 2 trial (12 weeks duration) that included both efficacious doses, 0.5 mg BID and 1.0 mg BID (see CLINICAL TRIALS, Study 1).

MedDRA version 11; included data up to 30 days after last dose of drug
NEC: Not Elsewhere Classified
Number (%) of Subjects with Adverse Events by:
* Psychiatric Disorder System Organ Class: High Level Group Terms (HLGT) and Preferred Terms (PT) reported in each HLGT ≥ 1% greater than placebo.
** Nervous System Disorders System Organ Class: Selected HLGTs and PTs reported in each HLGT ≥ 1% greater than placebo.

Additional Clinical Trial Adverse Drug Reactions

The adverse drug reactions listed below are based on evaluation of data from pre-marketing phase 2-3 studies and updated based on a pooled database of a total of 18 placebo-controlled, pre- and post-marketing smoking cessation studies, with approximately 5,000 patients treated with CHAMPIX. All reported events are included except those already listed in Table 1, those too general to be informative, and those not reasonably possibly associated with the use of the drug. In some cases, separate event terms have been consolidated to facilitate meaningful presentation. It is important to emphasize that although the events reported occurred during treatment with CHAMPIX, they were not necessarily caused by it.

The ADRs listed below are presented by the Medical Dictionary for Regulatory Activities (MedDRA, Version 16) System Organ Class (SOC). The variability associated with adverse event reporting and the terminology used to describe adverse events limit the value of the quantitative frequency estimates provided. Events are further classified within system organ class categories and enumerated in order of decreasing frequency using the following definitions: very frequent (occurring in at least 1/10 patients), frequent (occurring in at least 1/100 patients), infrequent (occurring in <1/100 to 1/1000 patients) and rare (occurring in fewer than 1/1000 patients).

Blood and Lymphatic System Disorders: Infrequent: Anemia, Lymphadenopathy. Rare: Leukocytosis, Platelet count decreased, Thrombocytopenia, Splenomegaly.

Cardiac Disorders: Infrequent: Angina pectoris, Electrocardiogram abnormal, Heart rate increased, Myocardial infarction, Palpitations, Tachycardia. Rare: Arrhythmia, Atrial fibrillation, Bradycardia, Cardiac flutter, Coronary artery disease, Cor pulmonale, Acute coronary syndrome, Electrocardiogram ST segment depression, Electrocardiogram T wave amplitude decreased, 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, Vision blurred, Visual impairment, Eye pain. Rare: Acquired night blindness, Blindness transient, Cataract subcapsular, Dry eye, Mydriasis, Myopia, Lacrimation increased, Ocular vascular disorder, Photophobia, Scleral discolouration, Scotoma, Vitreous floaters.

Gastrointestinal Disorders: Frequent: Diarrhea, Toothache. Infrequent: Change of bowel habit, Aphthous stomatitis, Gingival pain, Dysphagia, Eructation, Gastritis, Gastrointestinal hemorrhage, Hematochezia, Mouth ulceration. Rare: Abnormal feces, Enterocolitis, Esophagitis, Gastric ulcer, Hematemesis, Intestinal obstruction, Pancreatitis acute, Tongue coated.

General Disorders and Administration Site Conditions: Frequent: Chest pain, Irritability. Infrequent: Chest discomfort, Chills, Edema, Influenza like illness, Pyrexia, Thirst. Rare: Cyst, Feeling cold.

Hepatobiliary Disorders: Rare: Gall bladder disorder, Worsening of existing autoimmune hepatitis.

Immune System Disorders: Infrequent: Hypersensitivity. Rare: Drug hypersensitivity.

Infections and Infestations: Very frequent: Nasopharyngitis. Frequent: Bronchitis, Sinusitis. Infrequent: Fungal infection, Gingivitis, Viral infection, Tooth abscess, Urinary Tract Infection.

Investigations: Frequent: Liver function test abnormal, alanine aminotransferase increased, Rare: Muscle enzyme increased, Semen abnormal, C-reactive protein increased, Blood calcium decreased, Urine analysis abnormal.

Metabolism and Nutrition Disorders: Frequent: Weight increased. Infrequent: Diabetes mellitus, Hypoglycemia. Rare: Hyperkalemia, Hyperlipidemia, Hypokalemia, Polydipsia.

Musculoskeletal and Connective Tissue Disorders: Frequent: Arthralgia, Back pain, Myalgia. Infrequent: Arthritis, Musculoskeletal chest pain, Muscle cramp, Musculoskeletal pain, Muscle spasms. Rare: Costochondritis, Joint stiffness, Myositis, Osteoporosis.

Nervous System Disorders: Frequent: Disturbance in attention, Dizziness, Somnolence. Infrequent: Amnesia, Convulsion, Hypoesthesia, Migraine, Parosmia, Syncope, Tremor. Rare: Balance disorder, Cerebrovascular accident, Circadian rhythm sleep disorder, Coordination abnormal, Dysarthria, Hypertonia, Hypogeusia, 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: Frequent: Agitation, Anxiety, Depression. Infrequent: Aggression, Dissociation, Libido decreased, Libido increased, Mood swings, Panic reaction, Restlessness, Suicidal ideation, Thinking abnormal. Rare: Bradyphrenia, Disorientation, Dysphoria, Emotional disorder, Euphoric mood, Hallucination, Psychotic disorder, Suicide attempt.

Renal and Urinary Disorders: Infrequent: Nocturia, Pollakiuria, Urine abnormality. Rare: Glycosuria, Nephrolithiasis, Polyuria, Renal failure acute, Urethral syndrome, Urinary retention.

Reproductive System and Breast Disorders: Frequent: Menstrual disorder. Infrequent: Erectile dysfunction, Menorrhagia. Rare: Sexual dysfunction, Vaginal discharge.

Respiratory, Thoracic and Mediastinal Disorders: Frequent:Cough, Respiratory disorders. Infrequent: Asthma, Dysphonia, Epistaxis, Rhinitis allergic, Throat irritation, Respiratory tract congestion, Sinus congestion, Rhinorrhea, Upper-airway cough syndrome, Upper respiratory tract inflammation. Rare: Laryngeal pain, Pleurisy, Pulmonary embolism, Snoring.

Skin and Subcutaneous Tissue Disorders: Frequent: Rash. Infrequent: Acne, Dry skin, Eczema, Erythema, Hyperhidrosis, Night sweats, Urticaria. Rare: Dermatitis, Photosensitivity reaction, Psoriasis.

Vascular Disorders: Frequent: Hypertension. Infrequent: Blood pressure increased, Hot flush, Hypotension. Rare: Peripheral ischemia, Thrombosis.
Clinical Trials in Special Populations

Adverse Events in Adolescents: (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics).

Cardiovascular Adverse Events in Pooled Clinical Studies of Varenicline

In pooled data of 14 completed randomized double-blind placebo controlled smoking cessation trials (not including the study in patients with stable cardiovascular disease), the rate of reported treatment-emergent myocardial infarction (MI) or cerebrovascular accident (CVA) related adverse events was: 8 of 3317 (0.24%) patients on CHAMPIX (>1 mg), compared to 4 of 2542 (0.16%) patients on placebo.

Study in patients with Cardiovascular Disease

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of 703 subjects aged 35 to 75 years with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for more than 2 months. Patients were treated with CHAMPIX 1 mg BID or placebo for 12 weeks, and then followed for another 40 weeks post-treatment (See WARNINGS AND PRECAUTIONS, Cardiovascular Events).

There are two partially overlapping data sets of cardiovascular events from the study:

1. Treatment-emergent CV AEs captured via standard clinical trial AE reporting, while on drug treatment, (including, 30 days post-dose); and
2. Pre-specified serious CV events that were adjudicated by an independent blinded committee captured throughout the 52 week duration (ie both “on-treatment” [including 30 days post-dose], and “post-treatment”).

The study was powered for assessing efficacy (ie quit rates) but not for assessing differences in the occurrence of serious CV events between CHAMPIX and placebo.

More cardiovascular events were reported in both arms compared to other studies, as expected due to underlying conditions.

Treatment-emergent cardiovascular events which occurred within 30 days after the last dose, and in at least 3 subjects in either arm, are shown in Table 5.

The adjudicated serious cardiovascular events are shown below in Table 6.

Patients are counted only once within each row per study phase.

As shown in Table 6, the individual serious cardiovascular (CV) events that were reported more frequently in CHAMPIX compared to placebo (difference > 2 subjects) were: non-fatal myocardial infarctions (4 vs. 1, on-treatment phase) and need for coronary revascularization (7 vs. 2, post-treatment phase). Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.

^a one of the events occurred while the subject was taking during the post treatment phase "off-protocol" CHAMPIX or ^b CHAMPIX and other smoking cessation medication.

CHAMPIX was not studied in patients with unstable cardiovascular disease or those with cardiovascular events occurring within two months before screening. (See also: WARNINGS AND PRECAUTIONS, Cardiovascular Events, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions)

Cardiovascular Safety Assessment Study in Patients with and without a History of Psychiatric Disorder

The cardiovascular (CV) safety of CHAMPIX was evaluated in the Cardiovascular Safety Assessment Study in subjects with and without a history of psychiatric disorder. Subjects aged 18-75 years, smoking 10 or more cigarettes per day (N=8058) were randomized 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed another 12 weeks post-treatment through a period of up to a total of 52 weeks. Of all treated subjects, 1749 (21.7%) had a medium CV risk and 644 (8.0%) had a high CV risk, as defined by Framingham score.

Major adverse cardiovascular event (MACE), were defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke during treatment.

Deaths and cardiovascular events were adjudicated by a blinded, independent committee. The study was not powered for assessing differences between CHAMPIX and placebo in the time to MACE

The following table shows the incidence of MACE for all treatment groups during treatment, and cumulative for treatment plus 30 days and through end of study.

Because of the relatively low number of events overall and the lack of power for assessing differences between CHAMPIX and placebo, an association between the use of CHAMPIX and an increased risk of CV adverse events cannot be entirely ruled out.

Post-Marketing Experience

The following adverse events have been reported during post-approval use of CHAMPIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric Symptoms
There have been reports of depressed mood, agitation, aggression, hostility, anxiety, changes in behavior or thinking, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, mood swings, suicidal ideation and completed suicide in patients attempting to quit smoking while taking CHAMPIX (see WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms). Of the cases with information provided, the majority reported possible contributing factors, including primarily prior psychiatric history and/or concurrent psychiatric medications. Smoking status at the time of event onset was not reported in most cases. Patients should be advised that alcohol intake may increase the risk of experiencing psychiatric adverse events. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. The role of CHAMPIX in these reports is not known (see also WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms).

Hypersensitivity and Serious Skin Reactions
There have also been reports of hypersensitivity reactions, including angioedema and of rare but severe cutaneous reactions including Stevens-Johnson syndrome and erythema multiforme in patients taking CHAMPIX (see WARNINGS AND PRECAUTIONS, Angioedema and Hypersensitivity Reactions and Serious Skin Reactions).

Myocardial Infarction and Cerebrovascular Accident
There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Champix. In the majority of the reported cases, patients had preexisting cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, a contributory role of varenicline cannot be ruled out, based on temporal relationship between medication use and events.

Hyperglycemia and Diabetes Mellitus
Smoking cessation, with or without treatment, may be associated with altered glycemic control. There have been reports of hyperglycemia in patients taking CHAMPIX. While the majority of these cases involved diabetic patients experiencing loss of glycemic control (see Special Populations, Patients with Diabetes), there have also been reports of new onset diabetes in patients with no pre-existing diabetes or pre-diabetes.