Oral Exelon (rivastigmine) Drug Warnings & Precautions

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WARNINGS

Gastrointestinal Adverse Reactions

Exelon® (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 post-marketing 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: In the 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).

Weight Loss: In the 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 drug.

Anorexia: In 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 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 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.

Anesthesia

Exelon 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, 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.

Genitourinary

Although this was not observed in clinical trials of Exelon, 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, Exelon should be used with care in patients with a history of asthma or obstructive pulmonary disease.


PRECAUTIONS

Carcinogenesis, Mutagenesis, 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

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.

Nursing Mothers

It is not known whether rivastigmine is excreted in human breast milk. Exelon has no indication for use in nursing mothers.

Pediatric Use

There are no adequate and well-controlled trials documenting the safety and efficacy of Exelon in any illness occurring in children.