* During the premarketing development of Varenicline, over 4500 individuals 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.

* In Phase 2 and 3 placebo-controlled studies, the treatment discontinuation rate due to adverse events in patients dosed with 1 mg BID was 12% for Varenicline compared to 10% for placebo in studies of three months' treatment.
In this group, the discontinuation rates for the most common adverse events in Varenicline treated patients were as follows: nausea (3% vs. 0.5% for placebo), headache (0.6% vs. 0.9% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).
Adverse Events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).

* The most common adverse events associated with Varenicline (>5% and twice the rate seen in placebo-treated patients) were nausea, sleep disturbance, constipation, flatulence, and vomiting.

* Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness.

* The most common adverse event associated with Varenicline treatment is nausea.
For patients treated to the maximum recommended dose of 1 mg BID following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen.

In patients taking Varenicline 0.5 mg BID following initial titration, the incidence was 16% compared with 11% for placebo.
Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent throughout the treatment period.

* Table 3 shows the adverse events for Varenicline and placebo in the 12 week fixed dose studies with titration in the first week (Studies 2 (titrated arm only), 4, and 5).
MedDRA High Level Group Terms (HLGT) reported in >/= 5% of patients in the Varenicline 1 mg BID 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 a wakening' were grouped, but individual patients reporting two or more grouped events are only counted once.

Table: Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies
(>/= 1% in the 1 mg BID Varenicline Group, and 1 mg BID Varenicline at least 0.5% more than Placebo)

* The overall pattern, and the frequency of adverse events during the longer-term trials was very similar to that described in Table 3, though several of the most common events were reported by a greater proportion of patients.
Nausea, for instance, was reported in 40% of patients treated with Varenicline 1 mg BID 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 Varenicline during all clinical trials.
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, Thrombocytopenia, Splenomegaly.

CARDIAC DISORDERS.
Infrequent: Angina pectoris, Arrhythmia, Bradycardia, Ventricular extrasystoles, Myocardial infarction, Palpitations, Tachycardia.
Rare: Atrial fibrillation, Cardiac flutter, Coronary artery disease, Cor pulmonale, Acute coronary syndrome.

EAR AND LABYRINTH DISORDERS.
Infrequent: Tinnitus, Vertigo.
Rare: Deafness, Meniere's disease.

ENDOCRINE DISORDERS.
Infrequent: Thyroid gland disorders.

EYE DISORDERS.
Infrequent: Conjunctivitis, Dry eye, Eye irritation, Vision blurred, Visual disturbance, Eye pain.
Rare: Acquired night blindness, Blindness transient, Cataract subcapsular, Ocular vascular disorder, Photophobia, Vitreous floaters.

GASTROINTESTINAL DISORDERS.
Frequent: Diarrhea, Gingivitis.
Infrequent: Dysphagia, Enterocolitis, Eructation, Gastritis, Gastrointestinal hemorrhage, Mouth ulceration, Esophagitis.
Rare: Gastric ulcer, Intestinal obstruction, Pancreatitis acute.

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS.
Frequent: Chest pain, Influenza like illness, Edema, Thirst.
Infrequent: Chest discomfort, Chills, Pyrexia.

HEPATOBILIARY DISORDERS.
Infrequent: Gall bladder disorder.

IMMUNE SYSTEM DISORDERS.
Infrequent: Hypersensitivity.
Rare: Drug hypersensitivity.

INVESTIGATIONS.
Frequent: Liver function test abnormal, Weight increased.
Infrequent: Electrocardiogram abnormal, Muscle enzyme increased, Urine analysis abnormal.

METABOLISM AND NUTRITION DISORDERS.
Infrequent: Diabetes mellitus, Hyperlipidemia, Hypokalemia.
Rare: Hyperkalemia, Hypoglycemia.

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS.
Frequent: Arthralgia, Back pain, Muscle cramp, Musculoskeletal pain, Myalgia. Infrequent: Arthritis, Osteoporosis.
Rare: Myositis.

NERVOUS SYSTEM DISORDERS.
Frequent: Disturbance in attention, Dizziness, Sensory disturbance.
Infrequent: Amnesia, Migraine, Parosmia, Psychomotor hyperactivity, Restless legs syndrome, Syncope, Tremor.
Rare: Balance disorder, Cerebrovascular accident, Convulsion, Dysarthria, Facial palsy, Mental impairment, Multiple sclerosis, Nystagmus, Psychomotor skills impaired, Transient ischemic attack, Visual field defect.

PSYCHIATRIC DISORDERS.
Frequent: Anxiety, Depression, Emotional disorder, Irritability, Restlessness. Infrequent: Aggression, Agitation, Disorientation, Dissociation, Libido decreased, Mood swings, Thinking abnormal.
Rare: Bradyphrenia, Euphoric mood, Hallucination, Psychotic disorder, Suicidal ideation.

RENAL AND URINARY DISORDERS.
Frequent: Polyuria.
Infrequent: Nephrolithiasis, Nocturia, Urine abnormality, Urethral syndrome.
Rare: Renal failure acute, Urinary retention.

REPRODUCTIVE SYSTEM AND BREAST DISORDERS.
Frequent: Menstrual disorder.
Infrequent: Erectile dysfunction.
Rare: Sexual dysfunction.

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS.
Frequent: Epistaxis, Respiratory disorders.
Infrequent: Asthma.
Rare: Pleurisy, Pulmonary embolism.

SKIN AND SUBCUTANEOUS TISSUE DISORDERS.
Frequent: Hyperhidrosis.
Infrequent: Acne, Dermatitis, Dry skin, Eczema, Erythema, Psoriasis, Urticaria.
Rare: Photosensitivity reaction.

VASCULAR DISORDERS.
Frequent: Hot flush, Hypertension.
Infrequent: Hypotension, Peripheral ischemia, Thrombosis.