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Significant gastrointestinal adverse reactions including nausea, vomiting, anorexia, and weight loss have been reported with the Exelon Patch (rivastigmine transdermal system) at higher than recommended doses [see WARNINGS AND PRECAUTIONS].

Incidence in Controlled Clinical Trial in Alzheimer's Disease

Associated with Discontinuation of Treatment

In the single controlled clinical trial of Exelon Patch [see Clinical Studies], which randomized a total of 1195 patients, the proportions of patients in the Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups who discontinued treatment due to adverse events were 9.6%, 8.6%, 8.1%, and 5.0%, respectively.

The most common adverse events in the Exelon Patch (rivastigmine transdermal system) -treated groups that led to treatment discontinuation in this study were nausea and vomiting. The proportions of patients who discontinued treatment due to nausea were 0.7%, 1.7%, 1.7%, and 1.3% in the Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 1.7%, 2.0%, and 0.3% in the Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively.

Most Commonly Observed Adverse Events

The most commonly observed adverse events seen in patients administered Exelon Patch in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours group and at a frequency at least as high as in the placebo group are largely predicted by the cholinergic effects of Exelon. These are nausea, vomiting, and diarrhea. All these events were more common at the higher Exelon Patch (rivastigmine transdermal system) dose of 17.4 mg/24 hours than at a dose of 9.5 mg/24 hours.

Adverse Events Observed at an Incidence of ≥ 2%

The following table lists treatment-emergent adverse events that were seen at an incidence of ≥ 2% in either Exelon Patch (rivastigmine transdermal system) -treated group in the controlled clinical trial and for which the rate of occurrence was greater for patients treated with that dose of Exelon Patch (rivastigmine transdermal system) than for those treated with placebo. The prescriber should be aware that these frequencies 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 frequencies 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.

Table 2: Adverse Events Observed with a Frequency of ≥ 2% and Occurring with a Rate Greater Than Placebo

Incidence of Application Site Reactions

The vast majority of patients participating in the controlled clinical trial had either no observed skin irritation or mild to moderate skin reactions. Among the skin reactions reported were the following: application site reactions, application site dermatitis, application site irritation and application site eczema. The incidence of severe reactions was very low regardless of administered dosage.

Other Adverse Events Observed During Clinical Trials

Exelon Patch (rivastigmine transdermal system) has been administered to 1071 patients with Alzheimer's disease during clinical trials worldwide. Of these, 869 patients have been treated for at least 3 months, 706 patients have been treated for at least 6 months, and 212 patients have been treated for 1 year.

Treatment-emergent signs and symptoms that occurred during 1 controlled and 4 open-label trials in North America, Europe, Latin America, Asia 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 the MedDRA dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 1071 patients from these trials who experienced that event while receiving Exelon Patch (rivastigmine transdermal system) . All patch doses are pooled.

All adverse events occurring in at least 1 patient (approximately 0.1%) are included, except for those already listed elsewhere in labeling, too general to be informative, or relatively minor events.

Events are classified by system organ class and listed using the following definitions: Frequent – those occurring in at least 1/100 patients; Infrequent – those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Exelon Patch (rivastigmine transdermal system) treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Blood and Lymphatic System Disorders: Frequent: Anemia.

Cardiac Disorders: Infrequent: Angina pectoris, cardiac failure, bradycardia, atrial fibrillation, supraventricular extrasystoles, myocardial infarction, tachycardia, arrhythmia, atrioventricular block.

Ear and Labyrinth Disorders: Infrequent: Tinnitus.

Eye Disorders: Infrequent: Cataract, glaucoma, vision blurred.

Gastrointestinal System: Frequent: Constipation, gastritis. Infrequent: Gastroesophageal reflux disease, hematochezia, peptic ulcer, hematemesis, pancreatitis, salivary hypersecretion.

General Disorders and Administration Site Conditions: Infrequent: Application site dermatitis, application site irritation, peripheral edema, chest pain, application site eczema, hyperpyrexia.

Hepatobiliary Disorders: Infrequent: Cholecystitis.

Infections and Infestations: Frequent: Nasopharyngitis, pneumonia. Infrequent: Diverticulitis.

Injury, Poisoning and Procedural Complications: Frequent: Fall. Infrequent: Hip fracture, subdural hematoma.

Investigations: Infrequent: Blood creatine phosphokinase increased, lipase increased, blood amylase increased, electrocardiogram QT prolonged.

Metabolic and Nutritional Disorders: Frequent: Dehydration. Infrequent: Hyperlipidemia, hypokalemia, hyponatremia.

Musculoskeletal and Connective Tissue Disorders: Infrequent: Arthralgia, muscle spasms, myalgia.

Nervous System Disorders: Frequent: Tremor. Infrequent: Migraine, parkinsonism, epilepsy.

Psychiatric Disorders: Infrequent: Delusion.

Renal and Urinary Disorders: Frequent: Urinary incontinence. Infrequent: Pollakiuria, hematuria, nocturia, renal failure.

Reproductive System and Breast Disorders: Infrequent: Benign prostatic hyperplasia.

Respiratory, Thoracic, and Mediastinal Disorders: Infrequent: Dyspnea, bronchospasm, chronic obstructive pulmonary disease.

Skin and Subcutaneous Tissue Disorders: Frequent: Pruritus. Infrequent: Erythema, eczema, dermatitis, rash erythematous, skin ulcer.

Vascular Disorders: Infrequent: Hypotension.

Post-Introduction Reports

The following additional adverse reactions have been identified based on post-marketing spontaneous reports and are not listed above. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypertension, application site hypersensitivity, urticaria, blister, dermatitis allergic, seizure, worsening of Parkinson's disease in patients with Parkinson's disease who were treated with Exelon patch (rivastigmine transdermal system) es.

Additional Adverse Reactions Reported

The following additional adverse reactions have been observed with Exelon capsules/oral solution. Confusion, abnormal liver function tests, duodenal ulcers.

No specific interaction studies have been conducted with Exelon Patch (rivastigmine transdermal system).

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 taken orally and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine.

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.

Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally 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 anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15).

Use with Anticholinergics, Cholinomimetics and Other Cholinesterase Inhibitors

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and might interfere with the activity of anticholinergic medications. A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

Last reviewed on RxList: 9/17/2010
This monograph has been modified to include the generic and brand name in many instances.