Rivastigmine transdermal system is an acetylcholinesterase inhibitor indicated for treatment of:
Mild, moderate, and severe dementia of the Alzheimer’s type (AD). ( 1.1 )
Mild-to-moderate dementia associated with Parkinson’s disease (PD). ( 1.2 )
1.1Alzheimer’s Disease
Rivastigmine transdermal system is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.
1.2Parkinson’s Disease Dementia
Rivastigmine transdermal system is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).
Contraindications
Rivastigmine transdermal system is contraindicated in patients with:
known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation [see Description (11) ]
previous history of application-site reactions with rivastigmine transdermal system suggestive of allergic contact dermatitis [see Warnings and Precautions (5.3) ] . Isolated cases of generalized skin reactions have been described in postmarketing experience [see Adverse Reactions (6.2) ] .
Known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation. ( 4 )
History of application-site reactions with rivastigmine transdermal system suggestive of allergic contact dermatitis. ( 4 , 6.2 )
Warnings and precautions
Hospitalization and, rarely, death have been reported due to application of multiple transdermal systems at same time. Ensure patients or caregivers receive instruction on proper dosing and administration. ( 5.1 )
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
Gastrointestinal Adverse Reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. ( 5.2 )
Application-site reactions may occur with the transdermal system form of rivastigmine. Discontinue treatment if application-site reactions spread beyond the transdermal system size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after transdermal system removal. ( 5.3 )
5.1Medication Errors Resulting in Overdose
Medication errors with rivastigmine transdermal system have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old transdermal system when putting on a new one and the use of multiple transdermal systems at one time. Instruct patients and their caregivers on important administration instructions for rivastigmine transdermal system [see Dosage and Administration (2.4) ] .
5.2Gastrointestinal Adverse Reactions
Rivastigmine transdermal system 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, initiate treatment with rivastigmine transdermal system at a dose of 4.6 mg/24 hours and titrate to a dose of 9.5 mg/24 hours, and then to a dose of 13.3 mg/24 hours, if appropriate [see Dosage and Administration (2.1) ] .
If treatment is interrupted for more than 3 days because of intolerance, reinitiate rivastigmine transdermal system with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae. A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration 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.
5.3Skin Reactions
Skin application-site reactions may occur with rivastigmine transdermal system. These reactions are not in themselves an indication of sensitization. However, use of rivastigmine transdermal system may lead to allergic contact dermatitis. Allergic contact dermatitis should be suspected if application-site reactions spread beyond the transdermal system size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after transdermal system removal.
In these cases, treatment should be discontinued [see Contraindications (4) ] . In patients who develop application-site reactions to rivastigmine transdermal system, suggestive of allergic contact dermatitis 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 transdermal system may not be able to take rivastigmine in any form.
There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). In these cases, treatment should be discontinued [see Contraindications (4) ] . Patients and caregivers should be instructed accordingly.
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 rivastigmine 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 increase gastric acid secretion due to increased cholinergic activity. Monitor patients using rivastigmine transdermal system 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 the rivastigmine transdermal system 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. 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 transdermal system, should be used with care in patients with a history of asthma or obstructive pulmonary disease.
5.5Impairment 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 rivastigmine transdermal system, routinely evaluate the patient’s ability to continue driving or operating machinery.
Interactions
Concomitant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended. ( 7.1 , 7.2 , 7.3 )
7.1 Metoclopramide Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and rivastigmine transdermal system is not recommended.
7.2Cholinomimetic and Anticholinergic Medications
Rivastigmine transdermal system may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine). Concomitant use of rivastigmine transdermal system with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see Warnings and Precautions (5.5) ] .
7.3Beta-Blockers
Additive bradycardic effects resulting in syncope may occur when rivastigmine transdermal system is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use is not recommended when signs of bradycardia, including syncope are present.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no adequate data on the developmental risks associated with the use of rivastigmine transdermal system in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 times the maximum recommended human dose (MRHD) (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data Animal Data Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis.
Adverse reactions
The following adverse reactions are described below and elsewhere in the labeling:
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ]
Skin Reactions [see Warnings and Precautions (5.3) ]
Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions (5.4) ] Most common adverse reactions (less than 5% and higher than with placebo): Nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. Rivastigmine transdermal system has been administered to 4516 patients with Alzheimer’s disease during clinical trials worldwide. Of these, 3005 patients have been treated for at least 26 weeks, 1771 patients have been treated for at least 52 weeks, 974 patients have been treated for at least 78 weeks, and 24 patients have been treated for at least 104 weeks.
Mild-to-Moderate Alzheimer’s Disease 24-Week International Placebo-Controlled Trial (Study 1) Most Common Adverse Reactions The most common adverse reactions in patients administered rivastigmine transdermal system in Study 1 [see Clinical Studies (14) ] , defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours rivastigmine transdermal system arm and at a frequency at higher than in the placebo group, were nausea, vomiting, and diarrhea.
These reactions were dose-related, with each being more common in patients using the unapproved 17.4 mg/24 hours rivastigmine transdermal system than in those using the 9.5 mg/24 hours rivastigmine transdermal system. Discontinuation Rates In Study 1, which randomized a total of 1195 patients, the proportions of patients in the rivastigmine transdermal system 9.5 mg/24 hours, rivastigmine capsules 6 mg twice daily, and placebo groups who discontinued treatment due to adverse events were 10%, 8%, and 5%, respectively.
The most common adverse reactions in the 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%, and 1.3% in the rivastigmine transdermal system 9.5 mg/24 hours, rivastigmine capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2.0%, and 0.3% in the rivastigmine transdermal system 9.5 mg/24 hours, rivastigmine capsules 6 mg twice daily, and placebo groups, respectively.
Adverse Reactions Observed at an Incidence of Greater than or Equal to 2% Table 1 lists adverse reactions seen at an incidence of greater than or equal to 2% in either rivastigmine transdermal system-treated group in Study 1, and for which the rate of occurrence was greater for patients treated with that dose of rivastigmine transdermal system than for those treated with placebo. The unapproved 17.4 mg/24 hours rivastigmine transdermal system arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours rivastigmine transdermal system.
Table 1: Proportion of Adverse Reactions Observed With a Frequency of Greater Than or Equal to 2% and Occurring at a Rate Greater Than Placebo in Study 1 Abbreviation: ARs, adverse reactions. Adverse reaction Rivastigmine Transdermal System 9.5 mg/24 hours Rivastigmine Transdermal System 17.4 mg/24 hours Rivastigmine Capsule 6 mg twice daily Placebo Total patients studied 291 303 294 302 Total percentage of patients with ARs (%) 51 66 63 46 Nausea 7 21 23 5 Vomiting Vomiting was severe in 0% of patients who received rivastigmine transdermal system 9.5 mg/24 hours, 1% of patients who received rivastigmine transdermal system 17.4 mg/24 hours, 1% of patients who received the rivastigmine capsule at doses up to 6 mg twice daily, and 0% of those who received placebo. 6 19 17 3 Diarrhea 6 10 5 3 Depression 4 4 4 1 Headache 3 4 6 2 Anxiety 3 3 2 1 Anorexia/Decreased appetite 3 9 9 2 Weight decreased Weight Decreased as presented in Table 1 is based upon clinical observations and/or adverse events reported by patients or caregivers.
Body weight was also monitored at prespecified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with rivastigmine transdermal system 9.5 mg/24 hours, 12% of those treated with rivastigmine transdermal system 17.4 mg/24 hours, 11% of patients who received the rivastigmine capsule at doses up to 6 mg twice daily and 6% of those who received placebo.
It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug. 3 8 5 1 Dizziness 2 7 7 2 Abdominal pain 2 4 1 1 Urinary tract infection 2 2 1 1 Asthenia 2 3 6 1 Fatigue 2 2 1 1 Insomnia 1 4 2 2 Abdominal pain upper 1 3 2 2 Vertigo 0 2 1 1 48-Week International Active Comparator-Controlled Trial (Study 2) Most Common Adverse Reactions In Study 2 [see Clinical Studies (14) ] of the commonly observed adverse reactions (greater than or equal to 3% in any treatment group), the most frequent event in the rivastigmine transdermal system 13.3 mg/24 hours group was nausea, followed by vomiting, fall, weight decreased, application-site erythema, decreased appetite, diarrhea and urinary tract infection (Table 3).
The percentage of patients with these events was higher in the rivastigmine transdermal system 13.3 mg/24 hours group than in the rivastigmine transdermal system 9.5 mg/24 hours group. Patients with nausea, vomiting, diarrhea and decreased appetite experienced these reactions more often during the first 4 weeks of the double-blind treatment phase. These reactions decreased over time in each treatment group. Weight decreased was reported to have increased over time in each treatment group.
Discontinuation Rates Table 2 displays the most common adverse reactions leading to discontinuation during the 48-week, double-blind treatment phase in Study 2. Table 2: Proportion of Most Common Adverse Reactions (Greater Than 1% at any Dose) Leading to Discontinuation During 48-week Double-Blind Treatment Phase in Study 2 Abbreviation: ARs, adverse reactions. Adverse reaction Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 9.5 mg/24 hours Total Total patients studied 280 283 563 Total percentage of patients with ARs leading to discontinuation (%) 9.6 12.7
11.2 Vomiting 1.4 0.4
0.9 Application-site pruritus 1.1 1.1
1.1 Aggression 0.4 1.1
0.7Most Common Adverse Reactions Greater than or Equal to 3%
Other adverse reactions of interest which occurred less frequently, but which were observed in a markedly higher percentage of patients in the rivastigmine transdermal system 13.3 mg/24 hours group than in the rivastigmine transdermal system 9.5 mg/24 hours group in Study 2, included dizziness and upper abdominal pain. The percentage of patients with these reactions decreased over time in each treatment group (Table 3).
The adverse reaction severity profile was generally similar for both the rivastigmine transdermal system 13.3 mg/24 hours and 9.5 mg/24 hours groups. Table 3: Proportion of Adverse Reactions Over Time in the 48-week Double-Blind Treatment Phase (at least 3% in any Treatment Group) in Study 2 Abbreviations: DB, double blind; ARs, adverse reactions. Cumulative week 0 to 48 (DB Phase) Week 0 to 24 (DB Phase) Week > 24 to 48 (DB Phase) Adverse reaction Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 9.5 mg/24 hours Rivastigmine Transdermal
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Composition
Active ingredients
RIVASTIGMINE 13.3MG/24HR
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
