(rivastigmine tartrate) use is
associated with significant gastrointestinal adverse reactions, including nausea
and vomiting, anorexia, and weight loss. For this reason, patients should always
be started at a dose of 1.5 mg BID and titrated to their maintenance dose. If
treatment is interrupted for longer than several days, treatment should be
reinitiated with the lowest daily dose (see DOSAGE AND ADMINISTRATION) to reduce
the possibility of severe vomiting and its potentially serious sequelae (e.g.,
there has been one postmarketing report of severe vomiting with esophageal
rupture following inappropriate reinitiation of treatment with a 4.5-mg dose
after 8 weeks of treatment interruption).
Nausea and Vomiting:
controlled clinical trials, 47% of the patients treated with an Exelon dose in
the therapeutic range of 6-12 mg/day (n=1189) developed nausea (compared with
12% in placebo). A total of 31% of Exelon-treated patients developed at least
one episode of vomiting
(compared with 6% for placebo).
The rate of vomiting was higher during the titration phase (24% vs. 3% for
placebo) than in the maintenance phase (14% vs. 3% for placebo). The rates were
higher in women than men. Five percent of patients discontinued for vomiting,
compared to less than 1% for patients on placebo. Vomiting was severe in 2% of
Exelon-treated patients and was rated as mild or moderate each in 14% of
patients. The rate of nausea was higher during the titration phase (43% vs. 9%
for placebo) than in the maintenance phase (17% vs. 4% for placebo).
controlled trials, approximately 26% of women on high doses of Exelon (greater
than 9 mg/day) had weight loss equal to or greater than 7% of their baseline
weight compared to 6% in the placebo-treated patients. About 18% of the males in
the high-dose group experienced a similar degree of weight loss compared to 4%
in placebo-treated patients. It is not clear how much of the weight loss was
associated with anorexia, nausea, vomiting, and the diarrhea associated with the
controlled clinical trials, of the patients treated with an Exelon dose of 6-12
mg/day, 17% developed anorexia compared to 3% of the placebo patients. Neither
the time course nor the severity of the anorexia is known.
Peptic Ulcers/Gastrointestinal Bleeding:
Because of their pharmacological action, cholinesterase inhibitors may be
expected to increase gastric acid secretion due to increased cholinergic
activity. Therefore, patients should be monitored closely for symptoms of active
or occult gastrointestinal bleeding, especially those at increased risk for
developing ulcers, e.g., those with a history of ulcer disease or those
receiving concurrent nonsteroidal antiinflammatory drugs (NSAIDs). Clinical
studies of Exelon have shown no significant increase, relative to placebo, in
the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Exelon as a cholinesterase inhibitor, is likely to exaggerate
succinylcholine-type muscle relaxation during anesthesia.
Drugs that increase cholinergic activity may have vagotonic
effects on heart rate (e.g., bradycardia). The potential for this action may be
particularly important to patients with "sick sinus syndrome" or other
supraventricular cardiac conduction conditions. In clinical trials, Exelon was
not associated with any increased incidence of cardiovascular adverse events,
heart rate or blood pressure changes, or ECG abnormalities. Syncopal episodes
have been reported in 3% of patients receiving 6-12 mg/day of Exelon, compared
to 2% of placebo patients.
Although this was not observed in clinical trials of Exelon,
drugs that increase cholinergic activity may cause urinary obstruction.
Seizures: Drugs that increase
cholinergic activity are believed to have some potential for causing seizures.
However, seizure activity also may be a manifestation of Alzheimer's
Like other drugs that increase cholinergic activity, Exelon
should be used with care in patients with a history of asthma or obstructive
Information for Patients and
Caregivers should be advised of the high incidence of nausea and
vomiting associated with the use of the drug along with the possibility of
anorexia and weight loss. Caregivers should be encouraged to monitor for these
adverse events and inform the physician if they occur. It is critical to inform
caregivers that if therapy has been interrupted for more than several days, the
next dose should not be administered until they have discussed this with the
Caregivers should be instructed in the correct procedure for
(rivastigmine tartrate) Oral Solution. In addition, they
should be informed of the existence of an Instruction Sheet (included with the
product) describing how the solution is to be administered. They should be urged
to read this sheet prior to administering Exelon Oral Solution. Caregivers
should direct questions about the administration of the solution to either their
physician or pharmacist.
Caregivers and patients should be advised that like other
cholinomimetics, Exelon® may exacerbate or induce
extrapyramidal symptoms. Worsening in patients with Parkinson’s disease,
including an increased incidence or intensity of tremor, has been
Effect of Exelon 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), ß-blockers
(n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal
antiinflammatory 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.
Impairment of Fertility
In carcinogenicity studies conducted at dose levels up to 1.1
mg-base/kg/day in rats and 1.6 mg-base/kg/day in mice, rivastigmine was not
carcinogenic. These dose levels are approximately 0.9 times and 0.7 times the
maximum recommended human daily dose of 12 mg/day on a mg/m2 basis.
Rivastigmine was clastogenic in two in vitro assays in the presence,
but not the absence, of metabolic activation. It caused structural chromosomal
aberrations in V79 Chinese hamster lung cells and both structural and numerical
(polyploidy) chromosomal aberrations in human peripheral blood lymphocytes.
Rivastigmine was not genotoxic in three in vitro assays: the Ames test, the
unscheduled DNA synthesis (UDS) test in rat hepatocytes (a test for induction of
DNA repair synthesis), and the HGPRT test in V79 Chinese hamster cells.
Rivastigmine was not clastogenic in the in vivo mouse micronucleus test.
Rivastigmine had no effect on fertility or reproductive performance in
the rat at dose levels up to 1.1 mg-base/kg/day. This dose is approximately 0.9
times the maximum recommended human daily dose of 12 mg/day on a mg/m2 basis.
Pregnancy Category B: Reproduction
studies conducted in pregnant rats at doses up to 2.3 mg-base/kg/day
(approximately 2 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 2.3
mg-base/kg/day (approximately 4 times the maximum recommended human dose on a
mg/m2 basis) revealed no evidence of teratogenicity.
Studies in rats showed slightly decreased fetal/pup weights, usually at doses
causing some maternal toxicity; decreased weights were seen at doses which were
several fold lower than the maximum recommended human dose on a mg/m2 basis. There are no adequate or well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive of
human response, Exelon should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
It is not known whether rivastigmine is excreted in human breast
milk. Exelon has no indication for use in nursing mothers.
There are no adequate and well-controlled trials documenting the
safety and efficacy of Exelon in any illness occurring in children.