SIDE EFFECTS
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 ExelonŽ
Using a Forced Dose Titration
| Study Phase |
Titration
|
Maintenance
|
Overall
|
| |
Placebo
(n=868) |
Exelon
≥6-12 mg/day
(n=1189) |
Placebo
(n=788) |
Exelon
≥6-12 mg/day
(n=987) |
Placebo
(n=868) |
Exelon
≥6-12 mg/day
(n=1189) |
| Event/%
Discontinuing |
| Nausea |
<1
|
8
|
<1
|
1
|
1
|
8
|
| Vomiting
|
<1
|
4
|
<1
|
1
|
<1
|
5
|
| Anorexia
|
0
|
2
|
<1
|
1
|
<1
|
3
|
| Dizziness
|
<1
|
2
|
<1
|
1
|
<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
on 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 ExelonŽ (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=1189) |
|
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
|
<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 infections, infection
(general), coughing, pharyngitis, bronchitis, rash (general),
urinary incontinence.
Other Adverse Events Observed During Clinical
Trials
Exelon has been administered to over 5297 individuals
during clinical trials worldwide. Of these, 4326 patients
have been treated for at least 3 months, 3407 patients
have been treated for at least 6 months, 2150 patients
have been treated for 1 year, 1250 have been treated for
2 years, and 168 have been treated for over 3 years. With
regard to exposure to the highest dose, 2809 patients
were exposed to doses of 10-12 mg, 2615 patients treated
for 3 months, 2328 patients treated for 6 months, 1378
patients treated for 1 year, 917 patients treated for
2 years, and 129 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 5297 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 1/1000 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, paraesthesia, convulsions.
Infrequent: Paresis, apraxia, aphasia, dysphonia, hyperkinesia,
hyperreflexia, hypertonia, hypoesthesia, hypokinesia,
migraine, neuralgia, nystagmus, peripheral neuropathy.
Endocrine System: Infrequent: Goitre,
hypothyroidism.
Gastrointestinal System: Frequent: Fecal
incontinence, gastritis. Infrequent: Dysphagia, esophagitis,
gastric ulcer, gastritis, 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. Infrequent : 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 & 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, dermatitis contact.
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, thrombophlebitis deep, aneurysm, hemorrhage
intracranial.
Vision Disorders: Frequent: Cataract.
Infrequent: Conjunctival hemorrhage, blepharitis, diplopia,
eye pain, glaucoma.
White Cell and Resistance Disorders:
Infrequent: Lymphadenopathy, leukocytosis.
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.
DRUG INTERACTIONS
Effect of Exelon on the Metabolism of OtherDrugs:
Rivastigmine is primarily metabolized through hydrolysis
by esterases. Minimal metabolism occurs via the major
cytochrome P450 isoenzymes. Based on in vitro studies,
no pharmacokinetic drug interactions with drugs metabolized
by the following isoenzyme systems are expected: CYP1A2,
CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19.
No pharmacokinetic interaction was observed between rivastigmine
and digoxin, warfarin, diazepam, or fluoxetine in studies
in healthy volunteers. The elevation ofprothrombin time
induced by warfarin is not affected by administration
of Exelon.
Effect of Other Drugs on the Metabolism of Exelon:
Drugs that induce or inhibit CYP450 metabolism
are not expected to alter the metabolism of rivastigmine.
Single dose pharmacokinetic studies demonstrated that
the metabolism of rivastigmine is not significantly affected
by concur-rent administration of digoxin, warfarin, diazepam,
or fluoxetine.
Population PK analysis with a database of 625 patients
showed that the pharmacokinetics of rivastigmine were
not influenced by commonly prescribed medications such
as antacids (n=77), antihypertensives (n=72), (beta)-blockers
(n=42), calcium channel blockers (n=75), antidiabetics
(n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens
(n=70), salicylate analgesics (n=177), antianginals (n=35),
and antihistamines (n=15). In addition, in clinical trials,
no increased risk of clinically relevant untoward effects
was observed in patients treated concomitantly with Exelon
and these agents.
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