WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
The dosage of Exelon shown to be effective in controlled clinical trials in Alzheimer’s disease is 6 mg to 12 mg per day, administered twice a day (daily doses of 3 mg to 6 mg twice a day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial.
Initial Dose
Initiate treatment with the 1.5 mg twice a day with Exelon.
Dose Titration
After a minimum of 2 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).
Parkinson’s Disease Dementia
The dosage of Exelon shown to be effective in the single controlled clinical trial conducted in dementia associated with Parkinson’s disease is 3 mg to 12 mg per day, administered twice a day (daily doses of 1.5 mg to 6 mg twice a day).
Initial Dose
Initiate treatment with the 1.5 mg twice a day with Exelon.
Dose Titration
After a minimum of 4 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).
Interruption of Treatment
If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level.
If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower dose of Exelon. If dosing is interrupted for more than 3 days, treatment should be restarted with 1.5 mg twice a day and titrated as described above [see Warnings and Precautions (5.1)].
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Rivastigmine (oral) in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rivastigmine (oral) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Rivastigmine (oral) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Rivastigmine (oral) in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rivastigmine (oral) in pediatric patients.
Contraindications
Exelon is contraindicated in patients with:
known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation.
a previous history of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing.
Isolated cases of generalized skin reactions have been described in postmarketing experience.
Warnings
Precautions
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 (6.1)]. 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 (2.1)] 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.
Hypersensitivity Reactions of the Skin
There have been isolated postmarketing reports of patients experiencing disseminated hypersensitivity reactions of the skin when administered rivastigmine irrespective of the route of administration (oral or transdermal). Treatment should be discontinued if disseminated hypersensitivity reaction of the skin occurs [see Contraindications (4)]. Patients and caregivers should be instructed accordingly [see Patient Counseling Information (17)].
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
Neurologic Effects
Extrapyramidal Symptoms: 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.
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.
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.
Genitourinary Effects
Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.
Pulmonary Effects
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.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Exelon has been administered to over 5,297 individuals during clinical trials worldwide. Of these, 4,326 patients have been treated for at least 3 months, 3,407 patients have been treated for at least 6 months, 2,150 patients have been treated for 1 year, 1,250 patients have been treated for 2 years, and 168 patients have been treated for over 3 years. With regard to exposure to the highest dose, 2,809 patients were exposed to doses of 10 mg to 12 mg, 2,615 patients treated for 3 months, 2,328 patients treated for 6 months, 1,378 patients treated for 1 year, 917 patients treated for 2 years, and 129 patients treated for over 3 years.
Mild to Moderate Alzheimer’s Disease
Most Commonly Observed Adverse Reactions
The most common adverse reactions, defined as those occurring at a frequency of at least 5% and twice the placebo rate, are largely predicted by Exelon's cholinergic effects. These include nausea, vomiting, anorexia, dyspepsia, and asthenia.
Gastrointestinal Adverse Reactions
Exelon use is associated with significant nausea, vomiting, and weight loss [see Warnings and Precautions (5.1)].
Discontinuation Rates
The rate of discontinuation due to adverse events in controlled clinical trials of Exelon (rivastigmine tartrate) was 15% for patients receiving 6 mg to 12 mg per day compared to 5% for patients on placebo during forced weekly dose titration. While on a maintenance dose, the rates were 6% for patients on Exelon compared to 4% for those on placebo.
The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1.
t1
Adverse Reactions Observed at an Incidence of at Least 2%
Table 2 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials and for which the rate of occurrence was greater for patients treated with Exelon doses of 6 mg to 12 mg per day than for those treated with placebo. The prescriber should be aware that these figures 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 figures 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 nondrug factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of treatment.
No systematic effect of race or age could be determined from the incidence of adverse events in the controlled studies. Nausea, vomiting and weight loss were more frequent in women than men.
T2
Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an Exelon dose in the therapeutic range of 6 mg to 12 mg per day (n=1189) developed nausea (compared with 12% in placebo). A total of 31% of Exelon-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% versus 3% for placebo) than in the maintenance phase (14% versus 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% versus 9% for placebo) than in the maintenance phase (17% versus 4% for placebo).
Weight Decreased: In the controlled trials, approximately 26% of women on high doses of Exelon (greater than 9 mg per 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 mg to 12 mg per day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time course nor the severity of the anorexia is known.
Mild to Moderate Parkinson’s Disease Dementia
Exelon has been administered to 779 individuals during clinical trials worldwide. Of these, 663 patients have been treated for at least 3 months, 476 patients have been treated for at least 6 months, and 313 patients have been treated for 1 year.
Most Commonly Observed Adverse Reactions
The most common adverse events, defined as those occurring at a frequency of at least 5% and twice the placebo rate, are largely predicted by Exelon's cholinergic effects. These include nausea, vomiting, tremor, anorexia, and dizziness.
Discontinuation Rates
The rate of discontinuation due to adverse events in the single placebo-controlled trial of Exelon was 18.2% for patients receiving 3 mg to 12 mg per day compared to 11.2% for patients on placebo during the 24-week study.
The most frequent adverse events that led to discontinuation from this study, defined as those occurring in at least 1% of patients receiving Exelon and more frequent than those receiving placebo, were nausea (3.6% Exelon versus 0.6% placebo), vomiting (1.9% Exelon versus 0.6% placebo), and tremor (1.7% Exelon versus 0.0% placebo).
Adverse Reactions Observed at an Incidence of at Least 2%
Table 3 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in a single placebo-controlled trial and during the first 24 weeks of a 76-week open-label active-controlled trial for which the rate of occurrence was greater for patients treated with Exelon doses of 3 mg to 12 mg per day than for those treated with placebo in the placebo-controlled trial. The prescriber should be aware that these figures 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 figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with 1 basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of treatment.
T3
Other Adverse Events Observed During Clinical Trials
Mild to Moderate Alzheimer’s Disease
Treatment-emergent signs and symptoms that occurred during 8 controlled clinical trials and 9 open-label trials in North America, Western Europe, Australia, South Africa, 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 a modified WHO dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 5,297 patients from these trials who experienced that event while receiving Exelon. All adverse events occurring in at least 6 patients (approximately 0.1%) are included, except for those already listed elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused.
Events are classified by body system and listed using the following definitions: frequent adverse events-those occurring in at least 1/100 patients; infrequent adverse events-those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to Exelon treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Additional treatment-emergent adverse events in patients with Parkinson’s disease dementia occurring in at least 1 patient (approximately 0.3%) are listed below, excluding events that are already listed above for the dementia of the Alzheimer’s type or elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused. Events are classified by body system and listed using the following definitions: frequent adverse events– those occurring in at least 1/100 patients; infrequent adverse events–those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to Exelon treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
01.png){kind=link}