CONTRAINDICATIONS
Rivastigmine tartrate is contraindicated in patients with known hypersensitivity to rivastigmine, other
carbamate derivatives or other components of the formulation (see DESCRIPTION).
WARNINGS
Gastrointestinal Adverse Reactions
Rivastigmine tartrate use is associated with significant gastrointestinal adverse reactions,
including nausea and vomiting, anorexia, and weight loss.
Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an
rivastigmine tartrate dose in the therapeutic range of 6-12 mg/day (n=1189) developed
nausea (compared with 12% in placebo). A total of 31% of rivastigmine tartrate-treated
patients developed at least 1 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 rivastigmine tartrate-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).
Weight Loss: In the controlled trials, approximately 26% of women on high doses of
rivastigmine tartrate (greater than 9 mg/day) had weight loss of 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 drug.
Anorexia: In the controlled clinical trials, of the patients treated with an rivastigmine tartrate dose
of 6-12 mg/day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time
course or 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 anti-inflammatory drugs (NSAIDS). Clinical
studies of rivastigmine tartrate have shown no significant increase, relative to placebo, in the
incidence of either peptic ulcer disease or gastrointestinal bleeding.
Anesthesia: Rivastigmine tartrate as a cholinesterase inhibitor, is likely to exaggerate
succinylcholine-type muscle relaxation during anesthesia.
Cardiovascular Conditions: 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, rivastigmine tartrate 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 rivastigmine
tartrate, compared to 2% of placebo patients.
Genitourinary: Although this was not observed in clinical trials of rivastigmine tartrate , drugs that
increase cholinergic activity may cause urinary obstruction.
Neurological Conditions: 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 Disease.
Pulmonary Conditions: Like other drugs that increase cholinergic activity, rivastigmine tartrate
should be used with care in patients with a history of asthma or obstructive pulmonary disease.
PRECAUTIONS
Information for the Patient and Caregivers
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.
Oral Solution: Caregivers should be instructed in the correct procedure for administering
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 rivastigmine tartrate oral solution.
Caregivers should direct questions about the administration of the solution to either their physician or
pharmacist.
Carcinogenesis, Mutagenesis, and 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 2 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 3 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, 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, rivastigmine tartrate should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether rivastigmine is excreted in human breast milk. Rivastigmine tartrate has no
indication for use in nursing mothers.
Pediatric Use
There are no adequate and well controlled trials documenting the safety and efficacy of
rivastigmine tartrate in any illness occurring in children.