Adverse reactions : תופעות לוואי

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 CHAMPIX (>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 CHAMPIX, 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 CHAMPIX- 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 CHAMPIX, over 4500 subjects were exposed to CHAMPIX, 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX 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 CHAMPIX Group and More Commonly than Placebo and PT ≥1% in the 1 mg BID CHAMPIX Group, and 1 mg BID CHAMPIX at Least 0.5% More than Placebo)


           SYSTEM ORGAN                 CHAMPIX 0.5        CHAMPIX     Placebo
CLASS                          mg BID            1 mg BID
High Level Group Term          N=129              N=821     N=805
Preferred Term
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               1               1         0 reflux disease
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
4               7         6
Fatigue/Malaise/Asthenia
RESPIR/THORACIC/M
EDIAST
Respiratory Disorders
NEC
Rhinorrhea                     0               1         0
                Dyspnea                       2                  1                 1
Upper Respiratory             7                  5                 4
Tract
Disorder
SKIN/SUBCUTANEOU
S 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/           1                  2                 1
Anorexia
* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort
** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening 
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 CHAMPIX 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 CHAMPIX 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.

CHAMPIX 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 CHAMPIX 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 CHAMPIX              Placebo
1 mg BID
N=353             N=350
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             0.3               0.6 to 52 weeks)
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         1.4               0.6 disease (PVD) or admission for a PVD procedure
*some procedures were part of management of nonfatal MI and hospitalization for angina

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



                                                               CHAMPIX              Placebo
1 mg BID
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
CHAMPIX             Placebo
1 mg BID
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                 11                 9 disturbances
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
CHAMPIX       Placebo
1 mg BID
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.

6.2 Postmarketing 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 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 CHAMPIX [see Warnings and Precautions (5.1)].


There have been postmarketing reports of new or worsening seizures in patients treated with CHAMPIX [see Warnings and Precautions (5.2)].

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHAMPIX. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior [see Warnings and Precautions (5.1) and (5.3)].

There have been reports of hypersensitivity reactions, including angioedema [see Warnings and Precautions (5.7)].

There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking CHAMPIX [see Warnings and Precautions (5.8)].

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 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 [see Warnings and Precautions (5.5)].

There have been reports of hyperglycemia in patients following initiation of CHAMPIX.

There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with CHAMPIX [see Warnings and Precautions (5.6)].

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.