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Included as part of the PRECAUTIONS section.

Medication Errors Resulting in Overdose

Medication errors with Exelon patch (rivastigmine transdermal system) es have resulted in serious adverse events; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time. Patients and caregivers must be given proper instruction on the dosage and administration of Exelon patches.

Gastrointestinal Adverse Reactions

At higher than recommended doses, Exelon Patch (rivastigmine transdermal system) use is associated with significant gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, anorexia/decreased appetite and weight loss. For this reason, patients administered Exelon Patch (rivastigmine transdermal system) should always be started at a dose of 4.6 mg/24 hours and titrated to the maintenance dose of 9.5 mg/24 hours. If treatment is interrupted for longer than three 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 of an oral formulation after 8 weeks of treatment interruption).

At higher than recommended doses, caregivers should be advised of the high incidence of nausea and vomiting associated with the use of Exelon Patch (rivastigmine transdermal system) 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 three days, the next dose should not be administered until they have discussed this with the physician.

Nausea and Vomiting

In the controlled clinical trial, 7% of patients treated with Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours developed nausea, as compared to 23% of patients who received the Exelon capsule at doses up to 6 mg BID and 5% of those who received placebo. In the same clinical trial, 6% of patients treated with Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours developed vomiting, as compared with 17% of patients who received the Exelon capsule at doses up to 6 mg BID and 3% of those who received placebo. The proportion of patients who discontinued treatment on account of vomiting was 0% of the patients who received Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours as well as 2% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo. Vomiting was severe in 0% of patients who received Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours and 1% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo.

In the same clinical trial, 21% of patients treated with the higher dose of Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours developed nausea, 19% developed vomiting, and the proportion of these patients who discontinued treatment on account of vomiting was 2%. Vomiting was severe in 1% of patients treated with Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours.

Weight Loss

In the controlled clinical trial, the proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, 11% of patients who received the Exelon capsule at doses up to 6 mg BID and 6% of those who received placebo.

In the same clinical trial, 12% of those treated with 17.4 mg/24 hours had weight loss equal to or greater than 7% of their baseline weight. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.

Diarrhea

In the controlled clinical trial, 6% of patients treated with Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours developed diarrhea, as compared with 5% of patients who received the Exelon capsule at doses up to 6 mg BID, 10% of those treated with 17.4 mg/24 hours and 3% of those who received placebo.

Anorexia/Decreased Appetite

In the controlled clinical trial, 3% of patients treated with Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours were recorded as developing decreased appetite or anorexia, as compared with 9% of patients who received the Exelon capsule at doses up to 6 mg BID, 9% of those treated with Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours and 2% of those who received placebo.

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 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.

Genitourinary Conditions

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.

Extrapyramidal Symptoms

Like other cholinomimetics, 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.

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.

Effects on Ability to Drive and Use Machines

Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse events that are detrimental to these functions. Thus, the ability to continue driving or operating machinery should be routinely evaluated by the treating physician.

Special Populations

Low Body Weight

Patients with body weight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse events. Particular caution should be exercised in titrating these patients above the recommended maintenance dose of the Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours.

Patient Counseling Information

General

Patient information is printed in section 17.8. To assure safe and effective use of Exelon Patch (rivastigmine transdermal system) , this information and instructions provided in the patient information section should be discussed with patients.

Importance of Correct Usage

Patients or caregivers should be informed of the importance of applying the correct dose on the correct part of their body. They should be instructed to rotate the application site in order to minimize skin irritation. The same site should not be used within 14 days. The previous day's patch must be removed before applying a new patch to a different skin location. Exelon Patch (rivastigmine transdermal system) should be replaced every 24 hours and the time of day should be consistent. It may be helpful for this to be part of a daily routine, such as the daily bath or shower.

Patients or caregivers should be told to avoid exposure of the patch to external heat sources (excessive sunlight, saunas, solariums) for long periods of time.

Discarding Used Patches

Patients or caregivers should be instructed to fold the patch in half after use. Return the used patch to its original pouch and discard it out of the reach and sight of children and pets. They should also be informed that drug still remains in the patch after 24-hour usage. They should be instructed to avoid eye contact and to wash their hands after handling the patch.

Concomitant Use of Drugs with Cholinergic Action

Patients or caregivers should be told that while wearing Exelon Patch (rivastigmine transdermal system) they should not be taking Exelon capsules or Exelon oral solution or other drugs with cholinergic effects.

Gastrointestinal Adverse Events

Patients or caregivers should be informed of the potential gastrointestinal adverse events such as nausea, vomiting and diarrhea. Patients and caregivers should be instructed to observe for these adverse reactions at all times, in particular when treatment is initiated or the dose is increased. Patients and caregivers should be instructed to inform their physician if these adverse events persist as a dose adjustment/ reduction may be required.

Monitoring the Patient's Weight

Patients or caregivers should be informed that Exelon Patch (rivastigmine transdermal system) may affect the patient's appetite and/or the patient's weight. Any loss of appetite or weight reduction needs to be monitored.

Missed Doses

If the patient has missed a dose, he/she should be instructed to apply a new patch immediately. They may apply the next patch at the usual time the next day. Patients should not apply two patches to make up for one missed.

If treatment has been missed for three or more days, the patient or caregiver should be informed to restart treatment with the starting patch dose of 4.6 mg/24 hours. Titration to the next patch dose should proceed after 4 weeks [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

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.

In a dermal carcinogenicity study conducted at doses up to 0.75 mg base/kg/day in mice, rivastigmine was not carcinogenic. The mean rivastigmine plasma exposure (AUC) at this dose was 0.3-0.4 times that observed in Alzheimer's disease patients at the recommended clinical dose (one Exelon Patch 9.5 mg/24 hours).

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.

No fertility or reproduction studies have been conducted in animals treated with dermal rivastigmine. Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg base/kg/day.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Exelon Patch should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. No dermal reproduction studies in animals have been conducted. Oral reproduction studies conducted in pregnant rats at doses up to 2.3 mg base/kg/day and in pregnant rabbits at doses up to 2.3 mg base/kg/day revealed no evidence of teratogenicity. Studies in rats showed slightly decreased fetal/pup weights, usually at doses causing some maternal toxicity.

Nursing Mothers

Milk transfer studies in animals have not been conducted with dermal rivastigmine. In rats given rivastigmine orally, concentrations of rivastigmine plus metabolites were approximately two times higher in milk than in plasma. It is not known whether rivastigmine is excreted in human breast milk. Exelon Patch (rivastigmine transdermal system) 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.

Geriatric Use

Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with Exelon Patch (rivastigmine transdermal system) .

Hepatic Disease

No pharmacokinetic study was conducted with Exelon Patch (rivastigmine transdermal system) in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg BID oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5-6) and moderate (n=3, Child-Pugh score 7-9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10). Dosage adjustment is not necessary in hepatically impaired patients as the dose of drug is individually titrated to tolerability.

Renal Disease

No study was conducted with Exelon Patch (rivastigmine transdermal system) in subjects with renal impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine is 64% lower in moderately impaired renal patients (n=8, GFR=1050 mL/min) than in healthy subjects (n=10, GFR ≥ 60 mL/min); Cl/F=1.7 L/min (cv=45%) and 4.8 L/min (cv=80%), respectively. In severely impaired renal patients (n=8, GFR < 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR ≥ 60 mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively. For unexplained reasons, the severely impaired renal patients had a higher clearance of rivastigmine than moderately impaired patients. However, dosage adjustment may not be necessary in renally impaired patients as the dose of the drug is individually titrated to tolerability.

Low Body Weight

Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved. This suggests special attention should be given to patients with very low body weight during up-titration [see DOSAGE AND ADMINISTRATION].

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Exelon, but a population pharmacokinetic analysis indicates that gender (n=277 males and 348 females) and race (n=575 White, 34 Black, 4 Asian, and 12 Other) did not affect the clearance of Exelon administered orally. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Exelon Patch (rivastigmine transdermal system) .

Nicotine Use

Population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% (n=75 Smokers and 549 Nonsmokers). No dose adjustment is necessary as the dose of the drug is individually titrated to tolerability.

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