"Today, the U.S. Food and Drug Administration issued a proposal designed to assist companies developing new treatments for patients in the early stages of Alzheimer's disease, before the onset of noticeable (overt) dementia.
Gastrointestinal Adverse Reactions
EXELON can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. The incidence and severity of these reactions are dose-related [see ADVERSE REACTIONS]. For this reason, patients should always be started at a dose of 1.5 mg twice a day and titrated to their maintenance dose.
If treatment is interrupted for longer than 3 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).
Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.
There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). Treatment should be discontinued if disseminated allergic dermatitis occurs [see CONTRAINDICATIONS]. Patients and caregivers should be instructed accordingly [see PATIENT INFORMATION].
In patients who develop application site reactions suggestive of allergic contact dermatitis to EXELON PATCH and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.
Other Adverse Reactions From Increased Cholinergic Activity
Cholinomimetics, including rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson's disease who were treated with EXELON Capsules.
Peptic Ulcers/Gastrointestinal Bleeding
Cholinesterase inhibitors, including rivastigmine, may be expected to increase gastric acid secretion due to increased cholinergic activity. Monitor patients using EXELON 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 have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Use with Anesthesia
Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Cardiac Conduction Effects
Because rivastigmine increases cholinergic activity, use of rivastigmine may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, rivastigmine 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 mg to 12 mg per day of EXELON, compared to 2% of placebo patients.
Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.
Drugs that increase cholinergic activity, including rivastigmine, should be used with care in patients with a history of asthma or obstructive pulmonary disease.
Impairment In Driving Or Use Of Machinery
Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions. During treatment with the EXELON, routinely evaluate the patient's ability to continue driving or operating machinery.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Gastrointestinal Adverse Reactions
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 physician [see WARNINGS AND PRECAUTIONS].
Caregivers and patients should be advised that allergic skin reactions have been reported in association with EXELON regardless of formulation (capsules, oral solution or transdermal patch). In case of skin reaction while taking EXELON, patients should consult with their physician immediately [see WARNINGS AND PRECAUTIONS].
Importance of Correct Usage
Caregivers should be instructed in the correct procedure for administering EXELON 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. See EXELON Oral Solution Instructions for Use.
Concomitant Use of Drugs with Cholinergic Action
Caregivers and patients should be advised that cholinomimetics, including rivastigmine, may exacerbate or induce extrapyramidal symptoms. Worsening in patients with Parkinson's disease, including an increased incidence or intensity of tremor, has been observed [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In oral carcinogenicity studies conducted at doses up to 1.1 mg-base/kg/day in rats and 1.6 mg-base/kg/day in mice, rivastigmine was not carcinogenic. These doses are less than the maximum recommended human dose (MRHD) of 12 mg per day on a mg/m² basis.
Rivastigmine was clastogenic in in vitro chromosomal aberration assays in mammalian cells in the presence, but not the absence, of metabolic activation. Rivastigmine was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro HGPRT assay, and in an in vivo mouse micronucleus test.
Impairment of Fertility
Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg-base/kg/day, a dose less than the MRHD on a mg/m² basis.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Reproduction studies conducted in pregnant rats and rabbits at oral doses up to 2.3 mg-base/kg/day, or 2 (rat) and 4 (rabbit) times the maximum recommended human dose (MRHD) of 12 mg per day on a mg/m² basis, revealed no evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Rivastigmine and its metabolites are excreted in rat milk following oral administration of rivastigmine; levels of rivastigmine plus metabolites in rat milk are approximately 2 times that in maternal plasma. It is not known whether rivastigmine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from EXELON, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established. The use of EXELON in pediatric patients (below 18 years of age) is not recommended.
Of the total number of patients in clinical studies of EXELON, 86 percent were 65 years and older while 46 percent were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients with mild or moderate hepatic impairment may be able to only tolerate lower doses [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. No data are available on the use of EXELON in patients with severe hepatic impairment.
Low Or High Body Weight
Because rivastigmine blood levels vary with weight, careful titration and monitoring should be performed in patients with low or high body weights [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/13/2015
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