A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Exelon Side Effects, and Drug Interactions - Rivastigmine Tartrate
Exelon Side Effects, and Drug Interactions - Rivastigmine Tartrate
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 Exelon® Using a Forced Dose Titration
|
|
Study Phase
|
Titration
|
Maintenance
|
Overall
|
|
Placebo (n=868)
|
Exelon >6-12 mg/day (n=1,189)
|
Placebo (n=788)
|
Exelon >6-12 mg/day (n=987)
|
Placebo (n=868)
|
Exelon >6-12 mg/day (n=1,189)
|
|
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 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
|
<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 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 have been treated for 2 years,
and 168 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 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, 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 Appendages: Stevens-Johnson syndrome.
DRUG INTERACTIONS
Drug-Drug Interactions
Effect of Exelon® (rivastigmine tartrate)
on the Metabolism of Other Drugs: 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 of prothrombin 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 concurrent
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), β-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).
Use with Anticholinergics: Because of their mechanism
of action, cholinesterase inhibitors have the potential to interfere with the
activity of anticholinergic medications.
Use with Cholinomimetics and Other Cholinesterase Inhibitors:
A synergistic effect may be expected when cholinesterase inhibitors are given
concurrently with succinylcholine, similar neuromuscular blocking agents or
cholinergic agonists such as bethanechol.
top
