ADVERSE REACTIONS
Dementia of the Alzheimer’s
T
ype
Adverse Events Leading to
Discontinuation
The rate of discontinuation due to adverse events in controlled
clinical trials of Exelon® (rivastigmine tartrate) was
15% for patients receiving 6-12 mg/day compared to 5% for patients on placebo
during forced weekly dose titration. While on a maintenance dose, the rates were
6% for patients on Exelon compared to 4% for those on placebo.
The most common adverse events leading to discontinuation, defined as
those occurring in at least 2% of patients and at twice the incidence seen in
placebo patients, are shown in Table 1.
Table 1. Most Frequent Adverse Events Leading to Withdrawal from
Clinical Trials during Titration and Maintenance in Patients Receiving 6-12
mg/day Exelon® Using a Forced-Dose Titration
Study Phase
|
Titration
|
Maintenance
|
Overall
|
|
Placebo
|
Exelon
®
greater than or equal to 6-12
mg/day
|
Placebo
|
Exelon
®
greater than or equal to 6-12
mg/day
|
Placebo
|
Exelon
®
greater than or equal to 6-12 mg/day
|
|
(n=868)
|
(n=1,189)
|
(n=788)
|
(n=987)
|
(n=868)
|
(n=1,189)
|
Event/%
Discontinuing
|
|
|
|
|
|
|
Nausea |
less than 1 |
8 |
less than 1 |
1 |
1 |
8 |
Vomiting |
less than 1 |
4 |
less than 1 |
1 |
less than 1 |
5 |
Anorexia |
0 |
2 |
less than 1 |
1 |
less than 1 |
3 |
Dizziness |
less than 1 |
2 |
less than 1 |
1 |
less than 1 |
2 |
Most Frequent Adverse
Clinical Events Seen in Association with the Use of Exelon
The most common adverse events, defined as those occurring at a
frequency of at least 5% and twice the placebo rate, are largely predicted by
Exelon's cholinergic effects. These include nausea, vomiting, anorexia,
dyspepsia, and asthenia.
Gastrointestinal Adverse
Reactions
Exelon use is associated with significant nausea, vomiting, and
weight loss (see WARNINGS).
Adverse Events Reported in
Controlled Trials
Table 2 lists treatment-emergent signs and symptoms that were
reported in at least 2% of patients in placebo-controlled trials and for which
the rate of occurrence was greater for patients treated with Exelon doses of
6-12 mg/day than for those treated with placebo. The prescriber should be aware
that these figures cannot be used to predict the frequency of adverse events in
the course of usual medical practice when patient characteristics and other
factors may differ from those prevailing during clinical studies. Similarly, the
cited frequencies cannot be directly compared with figures obtained from other
clinical investigations involving different treatments, uses, or investigators.
An inspection of these frequencies, however, does provide the prescriber with
one basis by which to estimate the relative contribution of drug and non-drug
factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of
treatment.
No systematic effect of race or age could be determined from the
incidence of adverse events in the controlled studies. Nausea, vomiting and
weight loss were more frequent in women than men.
Table 2. Adverse Events Reported in Controlled Clinical Trials in
at Least 2% of Patients Receiving Exelon® (6-12 mg/day)
and at a Higher Frequency than Placebo-treated Patients
Body System/Adverse Event
|
Placebo
(n=868)
|
Exelon
®
(6-12
mg/day)
(n=1,189)
|
Percent of Patients with any Adverse
Event
|
79 |
92 |
|
Autonomic Nervous System
|
Sweating Increased |
1 |
4 |
Syncope |
2 |
3 |
Body as a Whole
|
Accidental Trauma |
9 |
10 |
Fatigue |
5 |
9 |
Asthenia |
2 |
6 |
Malaise |
2 |
5 |
Influenza-like Symptoms |
2 |
3 |
Weight Decrease |
less than 1 |
3 |
Cardiovascular Disorders,
General
|
Hypertension |
2 |
3 |
Central and Peripheral Nervous
System
|
Dizziness |
11 |
21 |
Headache |
12 |
17 |
Somnolence |
3 |
5 |
Tremor |
1 |
4 |
Gastrointestinal System
|
Nausea |
12 |
47 |
Vomiting |
6 |
31 |
Diarrhea |
11 |
19 |
Anorexia |
3 |
17 |
Abdominal Pain |
6 |
13 |
Dyspepsia |
4 |
9 |
Constipation |
4 |
5 |
Flatulence |
2 |
4 |
Eructation |
1 |
2 |
Psychiatric Disorders
|
Insomnia |
7 |
9 |
Confusion |
7 |
8 |
Depression |
4 |
6 |
Anxiety |
3 |
5 |
Hallucination |
3 |
4 |
Aggressive Reaction |
2 |
3 |
Resistance Mechanism Disorders
|
Urinary Tract Infection |
6 |
7 |
Respiratory System
|
Rhinitis |
3 |
4 |
Other adverse events observed at a rate of 2% or more on Exelon 6-12
mg/day but at a greater or equal rate on placebo were chest pain, peripheral
edema, vertigo, back pain, arthralgia, pain, bone fracture, agitation,
nervousness, delusion, paranoid reaction, upper respiratory tract infection,
infection (general), coughing, pharyngitis, bronchitis, rash (general), urinary
incontinence.
Dementia Associated with Parkinson’s
D
isease
Adverse Events
L
eading to
D
iscontinuation
The rate of discontinuation due to adverse events in the single
controlled trial of Exelon (rivastigmine tartrate) was 18.2% for patients
receiving 3-12 mg/day compared to 11.2% for patients on placebo during the
24-week study.
The most frequent adverse events that led to discontinuation from this
study, defined as those occurring in at least 1% of patients receiving Exelon
and more frequent than those receiving placebo, were nausea (3.6% Exelon vs.
0.6% placebo), vomiting (1.9% Exelon vs. 0.6% placebo), and tremor (1.7% Exelon
vs. 0.0% placebo).
Most Frequent Adverse
Clinical Events Seen in Association with the Use of Exelon
The most common adverse events, defined as those occurring at a
frequency of at least 5% and twice the placebo rate, are largely predicted by
Exelon's cholinergic effects. These include nausea, vomiting, tremor, anorexia,
and dizziness.
Adverse Events Reported in
Controlled Trials
Table 3 lists treatment-emergent signs and symptoms that were
reported in at least 2% of patients in placebo-controlled trials and for which
the rate of occurrence was greater for patients treated with Exelon doses of
3-12 mg/day than for those treated with placebo. The prescriber should be aware
that these figures cannot be used to predict the frequency of adverse events in
the course of usual medical practice when patient characteristics and other
factors may differ from those prevailing during clinical studies. Similarly, the
cited frequencies cannot be directly compared with figures obtained from other
clinical investigations involving different treatments, uses, or investigators.
An inspection of these frequencies, however, does provide the prescriber with
one basis by which to estimate the relative contribution of drug and non-drug
factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of
treatment.
Table 3. Adverse Events Reported in the Single Controlled
Clinical Trial in at Least 2% of Patients Receiving Exelon® (3-12 mg/day) and at a Higher Frequency than Placebo-treated
Patients
Body System/Adverse Event
|
Placebo
(n=179)
|
Exelon
®
(3-12
mg/day)
(n=362)
|
Percent of Patients with any Adverse
Event
|
71 |
84 |
|
Gastrointestinal
D
isorders
|
Nausea |
11 |
29 |
Vomiting |
2 |
17 |
Diarrhea |
4 |
7 |
Upper Abdominal Pain |
1 |
4 |
General Disorders and
A
dministrative
S
ite
C
onditions
|
Fatigue |
3 |
4 |
Asthenia |
1 |
2 |
Metabolism and
N
utritional
D
isorders
|
Anorexia |
3 |
6 |
Dehydration |
1 |
2 |
Nervous
S
ystem
D
isorders
|
Tremor |
4 |
10 |
Dizziness |
1 |
6 |
Headache |
3 |
4 |
Somnolence |
3 |
4 |
Parkinson’s Disease (worsening) |
1 |
3 |
Parkinsonism |
1 |
2 |
Psychiatric Disorders
|
Anxiety |
1 |
4 |
Insomnia |
2 |
3 |
Other Adverse Events Observed During
Clinical Trials
Dementia of the Alzheimer’s
T
ype
Exelon has been administered to over 5,297 individuals during
clinical trials worldwide. Of these, 4,326 patients have been treated for at
least 3 months, 3,407 patients have been treated for at least 6 months, 2,150
patients have been treated for 1 year, 1,250 patients have been treated for 2
years, and 168 patients have been treated for over 3 years. With regard to
exposure to the highest dose, 2,809 patients were exposed to doses of 10-12 mg,
2,615 patients treated for 3 months, 2,328 patients treated for 6 months, 1,378
patients treated for 1 year, 917 patients treated for 2 years, and 129 patients
treated for over 3 years.
Treatment-emergent signs and symptoms that occurred during 8 controlled
clinical trials and 9 open-label trials in North America, Western Europe,
Australia, South Africa, and Japan were recorded as adverse events by the
clinical investigators using terminology of their own choosing. To provide an
overall estimate of the proportion of individuals having similar types of
events, the events were grouped into a smaller number of standardized categories
using a modified WHO dictionary, and event frequencies were calculated across
all studies. These categories are used in the listing below. The frequencies
represent the proportion of 5,297 patients from these trials who experienced
that event while receiving Exelon. All adverse events occurring in at least 6
patients (approximately 0.1%) are included, except for those already listed
elsewhere in labeling, WHO terms too general to be informative, relatively minor
events, or events unlikely to be drug-caused. Events are classified by body
system and listed using the following definitions: frequent adverse events –
those occurring in at least 1/100 patients; infrequent adverse events – those
occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily
related to Exelon treatment and in most cases were observed at a similar
frequency in placebo-treated patients in the controlled studies.
Autonomic Nervous System: Infrequent: Cold clammy skin, dry mouth, flushing,
increased saliva.
Body as a Whole:
Frequent: Accidental trauma, fever, edema, allergy, hot flushes, rigors.
Infrequent: Edema periorbital or facial, hypothermia,
edema, feeling cold, halitosis.
Cardiovascular System: Frequent: Hypotension, postural hypotension, cardiac
failure.
Central and Peripheral Nervous System:
Frequent: Abnormal gait, ataxia, paresthesia, convulsions.
Infrequent: Paresis, apraxia, aphasia, dysphonia,
hyperkinesia, hyperreflexia, hypertonia, hypoesthesia, hypokinesia, migraine,
neuralgia, nystagmus, peripheral neuropathy.
Endocrine System:
Infrequent: Goiter, hypothyroidism.
Gastrointestinal System:
Frequent: Fecal incontinence, gastritis. Infrequent: Dysphagia, esophagitis, gastric ulcer,
gastroesophageal reflux, GI hemorrhage, hernia, intestinal obstruction, melena,
rectal hemorrhage, gastroenteritis, ulcerative stomatitis, duodenal ulcer,
hematemesis, gingivitis, tenesmus, pancreatitis, colitis, glossitis.
Hearing and Vestibular Disorders:
Frequent: Tinnitus.
Heart Rate and Rhythm Disorders:
Frequent: Atrial fibrillation, bradycardia, palpitation.
Infrequent: AV block, bundle branch block, sick sinus
syndrome, cardiac arrest, supraventricular tachycardia, extrasystoles,
tachycardia.
Liver and Biliary System Disorders:
Infrequent: Abnormal hepatic function, cholecystitis.
Metabolic and Nutritional Disorders:
Frequent: Dehydration, hypokalemia. Infrequent: Diabetes mellitus, gout, hypercholesterolemia,
hyperlipemia, hypoglycemia, cachexia, thirst, hyperglycemia, hyponatremia.
Musculoskeletal Disorders:
Frequent: Arthritis, leg cramps, myalgia. Infrequent: Cramps, hernia, muscle weakness.
Myo-, Endo-, Pericardial and Valve
Disorders:
Frequent: Angina pectoris,
myocardial infarction.
Platelet, Bleeding, and Clotting
Disorders:
Frequent: Epistaxis. I
nfrequent: Hematoma,
thrombocytopenia, purpura.
Psychiatric Disorders:
Frequent: Paranoid reaction, confusion. Infrequent: Abnormal dreaming, amnesia, apathy, delirium,
dementia, depersonalization, emotional lability, impaired concentration,
decreased libido, personality disorder, suicide attempt, increased libido,
neurosis, suicidal ideation, psychosis.
Red Blood Cell Disorders:
Frequent: Anemia. Infrequent: Hypochromic
anemia.
Reproductive Disorders (Female and
Male):
Infrequent: Breast pain, impotence,
atrophic vaginitis.
Resistance Mechanism Disorders:
Infrequent: Cellulitis, cystitis, herpes simplex, otitis
media.
Respiratory System:
Infrequent: Bronchospasm, laryngitis, apnea.
Skin and Appendages:
Frequent: Rashes of various kinds (maculopapular, eczema, bullous,
exfoliative, psoriaform, erythematous). Infrequent:
Alopecia, skin ulceration, urticaria, contact dermatitis.
Special Senses:
Infrequent: Perversion of taste, loss of taste.
Urinary System Disorders:
Frequent: Hematuria. Infrequent: Albuminuria,
oliguria, acute renal failure, dysuria, micturition urgency, nocturia, polyuria,
renal calculus, urinary retention.
Vascular (extracardiac) Disorders:
Infrequent: Hemorrhoids, peripheral ischemia, pulmonary
embolism, thrombosis, deep thrombophlebitis, aneurysm,
intracranial hemorrhage.
Vision Disorders:
Frequent: Cataract. Infrequent: Conjunctival
hemorrhage, blepharitis, diplopia, eye pain, glaucoma.
White Cell and Resistance Disorders:
Infrequent: Lymphadenopathy, leukocytosis.
Dementia Associated with
Parkinson’s
D
isease
Exelon has been administered to 485 individuals during clinical
trials worldwide. Of these, 413 patients have been treated for at least 3
months, 253 patients have been treated for at least 6 months, and 113 patients
have been treated for 1 year.
Additional treatment-emergent adverse events in patients with
Parkinson’s disease dementia occurring in at least 1 patient (approximately
0.3%) are listed below, excluding events that are already listed above for the
dementia of the Alzheimer’s type or elsewhere in labeling, WHO terms too general
to be informative, relatively minor events, or events unlikely to be
drug-caused. Events are classified by body system and listed using the following
definitions: frequent adverse events – those occurring in at least 1/100
patients; infrequent adverse events – those occurring in 1/100 to 1/1,000
patients. These adverse events are not necessarily related to Exelon treatment
and in most cases were observed at a similar frequency in placebo-treated
patients in the controlled studies.
Cardiovascular System: Frequent: Chest pain. Infrequent:
Sudden cardiac death.
Central and Peripheral Nervous System:
Frequent: Dyskinesia, bradykinesia, restlessness,
transient ischemic attack. Infrequent: Dystonia,
hemiparesis, epilepsy, restless leg syndrome.
Endocrine System:
Infrequent: Elevated prolactin level.
Gastrointestinal System:
Frequent: Dyspepsia. Infrequent: Fecaloma,
dysphagia, diverticulitis, peritonitis.
Hearing and Vestibular Disorders:
Frequent: Vertigo. Infrequent:
Meniere’s disease.
Heart Rate and Rhythm Disorders:
Infrequent: Adam-Stokes syndrome.
Liver and Biliary System Disorders:
Infrequent: Elevated alkaline phosphatase level, elevated
gamma-glutamyltransferase level.
Musculoskeletal Disorders:
Frequent:
Back pain. Infrequent: Muscle
stiffness, myoclonus, freezing phenomenon.
Psychiatric Disorders:
Frequent: Agitation, depression. Infrequent:
Delusion, insomnia.
Reproductive Disorders (Female and
Male):
Infrequent: endometrial hypertrophy,
mastitis, prostatic adenoma.
Respiratory System:
Frequent: Dyspnea. Infrequent:
Cough.
Urinary System Disorders:
Infrequent: Urinary incontinence, neurogenic bladder.
Vascular (extracardiac) Disorders:
Infrequent: Vasovagal syncope, vasculitis.
Vision Disorders:
Infrequent: Blurred vision, blepharospasm,
conjunctivitis, retinopathy.
Post-Introduction Reports
Voluntary reports of adverse events temporally associated with
Exelon that have been received since market introduction that are not listed
above, and that may or may not be causally related to the drug include the
following:
Skin and Appendages: Stevens-Johnson syndrome.
|