DailyMed Label: Rivastigmine Transdermal System

DailyMed Label: Rivastigmine Transdermal System

2024

DailyMed Prescription

Rivastigmine Transdermal System

Rivastigmine Transdermal System

Alvogen Inc.

NDC: 47781-304

NDC: 47781-304

NDC: 47781-305

NDC: 47781-305

NDC: 47781-405

NDC: 47781-405

Rivastigmine Transdermal System contains rivastigmine, a reversible cholinesterase inhibitor known chemically as (S)- 3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate. It has an empirical formula of C 14 H 22 N 2 O 2 as the base and a molecular weight of 250.34 g/mol (as the base). Rivastigmine is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate. The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27.   Rivastigmine Transdermal System is for transdermal administration. The patch comprises a multi-layer laminate containing the coversheet,  backing film, reservoir layer, adhesive layer, and release liner as described below. The release liner is removed and discarded prior to use. See Figure 1 for a detailed illustration. a cover sheet: siliconised polyethylene terephthalate film a backing film: Polyethylene / thermoplastic resin / aluminum coated polyester film an active reservoir layer containing the active pharmaceutical ingredient an adhesive matrix layer a release liner: fluoropolymer coated polyester film Figure 1 : Schematic drawing of Rivastigmine Transdermal System Excipients within the formulation include colloidal silicon dioxide, light mineral oil, polyisobutylene adhesive, acrylate-vinylacetate pressure sensitive adhesive, aluminum coated polyester backing.

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 ) 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. Rivastigmine Transdermal System is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).

Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours. ( 2.1 , 2.4 ) Initial Dose: Initiate treatment with 4.6 mg/24 hours Rivastigmine Transdermal System ( 2.1 ) Dose Titration: After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours. (2.1) Mild-to-Moderate Alzheimer’s Disease and Parkinson’s Disease Dementia: Rivastigmine Transdermal System 9.5 mg/24 hours or 13.3 mg/24 hours once daily. ( 2.1 ) Severe Alzheimer’s Disease: Rivastigmine Transdermal System 13.3 mg/24 hours once daily. (2.1) For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours. ( 2.1 ) Consider dose adjustments in patients with ( 2.2 ): Mild-to-moderate hepatic impairment ( 8.6 ) Low (less than 50 kg) body weight ( 8.7 ) Initial Dose Initiate treatment with one 4.6 mg/24 hours Rivastigmine Transdermal System applied to the skin once daily [see Dosage and Administration ( 2.4 )] . Dose Titration  Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been tolerated. For mild-to-moderate AD and PDD patients, continue the effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists. Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose. For patients with severe AD, 13.3 mg/24 hours is the effective dose. Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 )]. Mild-to-Moderate Alzheimer’s Disease and Mild-to-Moderate Parkinson’s Disease Dementia The effective dosage of Rivastigmine Transdermal System is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours. Severe Alzheimer’s Disease   The effective dosage of Rivastigmine Transdermal System in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours. Interruption of Treatment If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength Rivastigmine Transdermal System. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours Rivastigmine Transdermal System and titrate as described above. Dosing Modifications in Patients with Hepatic Impairment Consider using the 4.6 mg/24 hours Rivastigmine Transdermal System as both the initial and maintenance dose in patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3 )] .  Dosing Modifications in Patients with Low Body Weigh t Carefully titrate and monitor patients with low body weight (less than 50 kg) for toxicities (e.g., excessive nausea, vomiting), and consider reducing the maintenance dose to the 4.6 mg/24 hours Rivastigmine Transdermal System if such toxicities develop. Patients treated with rivastigmine capsules or oral solution may be switched to Rivastigmine Transdermal System as follows: A patient who is on a total daily dose of less than 6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours Rivastigmine Transdermal System. A patient who is on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 hours Rivastigmine Transdermal System. Instruct patients or caregivers to apply the first patch on the day following the last oral dose. Rivastigmine Transdermal System is for transdermal use on intact skin. (a) Do not use the patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. (b) Apply the Rivastigmine Transdermal System once a day. Press down firmly for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing. Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient. If sites on the back are not accessible, apply the patch to the upper arm or chest. Do not apply to a skin area where cream, lotion, or powder has recently been applied. (c) Do not apply to skin that is red, irritated, or cut. (d) Replace the Rivastigmine Transdermal System with a new patch every 24 hours. Instruct patients to only wear 1 patch at a time (remove the previous day's patch before applying a new patch) [see Warnings and Precautions ( 5.1), Overdosage ( 10 )] . If a patch falls off or if a dose is missed, apply a new patch immediately, and then replace this patch the following day at the usual application time. (e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days. Do not apply a new patch to the same location for at least 14 days. (f) May wear the patch during bathing and in hot weather. Avoid long exposure to external heat sources (excessive sunlight, saunas, solariums). (g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children. (h) Wash hands with soap and water after removing the patch. In case of contact with eyes or if the eyes become red after handling the patch, rinse immediately with plenty of water, and seek medical advice if symptoms do not resolve.

Rivastigmine Transdermal System is available in 3 strengths. Each patch has a tan backing layer labeled as either: Rivastigmine Transdermal System 4.6 mg/24 hours, “RIVASTIGMINE 4.6 mg/24 hr” Rivastigmine Transdermal System 9.5 mg/24 hours, “RIVASTIGMINE 9.5 mg/24 hr” Rivastigmine Transdermal System 13.3 mg/24 hours, “RIVASTIGMINE 13.3 mg/24 hr” Patch: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours ( 3 )

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 patch 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 patch suggestive of allergic contact dermatitis. ( 4 , 6.2 )

Hospitalization and, rarely, death have been reported due to application of multiple patches at same time. Ensure patients or caregivers receive instruction on proper dosing and administration. ( 5.1 ) 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 patch form of rivastigmine. Discontinue treatment if application-site reactions spread beyond the patch 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 patch removal. ( 5.3 ) 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 patch when putting on a new one and the use of multiple patches at one time. Instruct patients and their caregivers on important administration instructions for Rivastigmine Transdermal System [see Dosage and Administration ( 2.4 )] . 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. Skin application-site reactions may occur with Rivastigmine Transdermal System. These reactions are not in themselves an indication of sensitization.  However, use of rivastigmine patch may lead to allergic contact dermatitis. Allergic contact dermatitis should be suspected if application-site reactions spread beyond the patch 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 patch 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 patch 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. 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 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. 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.

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

Concominant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended. ( 7.1 , 7.2 , 7.3 ) Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and Rivastigmine Transdermal System is not recommended. 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 )]. Additive bradycardic effects resulting in syncope may occur when rivastigmine 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.

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 to 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% to 4% and 15% to 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. Risk Summary There are no data on the presence of rivastigmine in human milk, the effects on the breastfed infant, or the effects of rivastigmine on milk production. 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.   The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rivastigmine Transdermal System and any potential adverse effects on the breastfed infant from Rivastigmine Transdermal System or from the underlying maternal condition. Safety and effectiveness in pediatric patients have not been established. The use of Rivastigmine Transdermal System in pediatric patients (below 18 years of age) is not recommended. Of the total number of patients in clinical studies of Rivastigmine Transdermal System, 88% were 65 years and over, while 55% were 75 years. 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. Increased exposure to rivastigmine was observed in patients with mild or moderate hepatic impairment with oral rivastigmine. Patients with mild or moderate hepatic impairment may be able to only tolerate lower doses [see Dosage and Administration ( 2.2), Clinical Pharmacology ( 12.3 )] . No data are available on the use of rivastigmine in patients with severe hepatic impairment. 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 ( 2.2), Clinical Pharmacology ( 12.3 )] .

Rivastigmine Transdermal System: 4.6 mg/24 hours Each patch of 4.6 cm 2 contains 6.9 mg rivastigmine with in vivo release rate of 4.6 mg/24 hours. Carton of 30………………………NDC 47781-304-03 Rivastigmine Transdermal System: 9.5 mg/24 hours Each patch of 9.2 cm 2 contains 13.8 mg rivastigmine with in vivo release rate of 9.5 mg/24 hours. Carton of 30………………………NDC 47781-305-03 Rivastigmine Transdermal System: 13.3 mg/24 hours Each patch of 13.8 cm 2 contains 20.7 mg rivastigmine with in vivo release rate of 13.3 mg/24 hours. Carton of 30………………………NDC 47781-405-03 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep Rivastigmine Transdermal System in the individual sealed pouch until use. Each pouch contains 1 patch. Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.

Although the precise mechanism of action of rivastigmine is unknown, it is thought to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. The effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process. After a 6-mg oral dose of rivastigmine in humans, anticholinesterase activity is present in cerebrospinal fluid for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing. In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist. Absorption After the initial application of Rivastigmine Transdermal System, there is a lag time of 0.5 to 1 hour in the absorption of rivastigmine. Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (C max ) can also occur later (at 10 to 16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady state, trough levels are approximately 60% to 80% of peak levels. Rivastigmine Transdermal System 9.5 mg/24 hours gave exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day). Inter-subject variability in exposure was lower (43% to 49%) for the Rivastigmine Transdermal System formulation as compared with the oral formulations (73% to 103%). Fluctuation (between C max and C min ) is less for Rivastigmine Transdermal System than for the oral formulation of rivastigmine. Figure 2 displays rivastigmine plasma concentrations over 24 hours for the 3 available patch strengths. Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system. Exposure area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) to rivastigmine (and metabolite NAP226-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the 3 other sites is available, but the practitioner should be aware that the rivastigmine plasma exposure associated with these sites was approximately 20% to 30% lower. There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease with daily dosing. The pharmacokinetic profile of rivastigmine transdermal patches was comparable in patients with Alzheimer’s disease and in patients with dementia associated with Parkinson’s disease. Distribution   Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 L/kg to 2.7 L/kg. Metabolism   Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro , this metabolite shows minimal inhibition of acetylcholinesterase (less than 10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. The metabolite-to-parent AUC ∞ ratio was about 0.7 after Rivastigmine Transdermal System application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin. Elimination Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine.  Following administration of 14 C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1 L/hr to 2.8 L/hr. Age Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with Rivastigmine Transdermal System. Gender and Race No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Rivastigmine Transdermal System. A population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 black, 4 Asian, and 12 Other) affected clearance of the drug. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Rivastigmine Transdermal System. Body Weight   A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. 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 [see Dosage and Administration ( 2.2 )] . Renal Impairment   No study was conducted with Rivastigmine Transdermal System in subjects with renal impairment. Based on population analysis, creatinine clearance did not show any clear effect on steady-state concentrations of rivastigmine or its metabolite. Hepatic Impairment    No pharmacokinetic study was conducted with 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 twice a day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10) [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 )] . Smoking   Following oral rivastigmine administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers). Drug Interaction Studies   No specific interaction studies have been conducted with Rivastigmine Transdermal System. Information presented below is from studies with oral rivastigmine. Effect of Rivastigmine 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, CYP2C19, or CYP2B6. 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 Rivastigmine Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Population pharmacokinetic 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), beta-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).

Carcinogenesis In oral carcinogenicity studies conducted at doses up to 1.1 mg/kg/day in rats and 1.6 mg/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 less than that in humans at the maximum recommended human dose (13.3 mg/24 hours). Mutagenesis 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 No fertility or reproduction studies of dermal rivastigmine have been conducted in animals. Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg/kg/day.

The effectiveness of the Rivastigmine Transdermal System in dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease was based on the results of controlled trials of Rivastigmine Transdermal System in patients with Alzheimer’s disease (Studies 1, 2 and 3) (see below); 3 controlled trials of oral rivastigmine in patients with dementia of the Alzheimer’s type; and 1 controlled trial of oral rivastigmine in patients with dementia associated with Parkinson’s disease. See the prescribing information for oral rivastigmine for details of the four studies of oral rivastigmine. Mild-to-Moderate Alzheimer’s Disease International 24-Week Study of Rivastigmine Transdermal System in Dementia of the Alzheimer’s Type (Study 1) This study was a randomized double-blind, double-dummy clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score greater than or equal to 10 and less than or equal to 20] (Study 1). The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years. Approximately 67% of patients were women, and 33% were men. The racial distribution was Caucasian 75%, black 1%, Asian 9%, and other races 15%. The effectiveness of the Rivastigmine Transdermal System was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect. The ability of the Rivastigmine Transdermal System to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients. The ADAS-Cog examines selected aspects of cognitive performance, including elements of memory, orientation, attention, reasoning, language, and praxis. The ADAS-Cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher. The ability of the Rivastigmine Transdermal System to produce an overall clinical effect was assessed using the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of the Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus) and is also scored as a 7-point categorical rating; scores range from 1, indicating “markedly improved,” to 4, indicating “no change,” to 7, indicating “marked worsening.” In Study 1, 1195 patients were randomized to 1 of the following 4 treatments: Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine Transdermal System 17.4 mg/24 hours, rivastigmine capsules in a dose of 6 mg twice daily, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability. Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the rivastigmine-treated patients compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine Transdermal System 17.4 mg/24 hours, and rivastigmine capsule 6 mg twice daily groups, respectively. The difference between each of these groups and placebo was statistically significant. Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation (see Figure 4). Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 1   Figure 4 presents the distribution of patients’ scores on the ADCS-CGIC for all 4 treatment groups. At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the rivastigmine-treated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant. Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing Study 1   International 48-Week Study of Rivastigmine Transdermal System in Dementia of the Alzheimer’s Type (Study 2) This study was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 10 and less than or equal to 24] (Study 2). The mean age of patients participating in this trial was 76 years with a range of 50 to 85 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 97%, black 2%, Asian 0.5%, and other races 1%. Approximately 27% of the patients were taking memantine throughout the entire duration of the study. Alzheimer’s disease patients who received 24 to 48 weeks open-label treatment with Rivastigmine Transdermal System 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either Rivastigmine Transdermal System 9.5 mg/24 hours or Rivastigmine Transdermal System 13.3 mg/24 hours in a 48-week, double-blind treatment phase. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of greater than or equal to 2 points from the previous visit or a decrease of greater than or equal to 3 points from baseline. Study 2 was designed to compare the efficacy of Rivastigmine Transdermal System 13.3 mg/24 hours versus that of Rivastigmine Transdermal System 9.5 mg/24 hours during the 48-week, double-blind treatment phase. The ability of the Rivastigmine Transdermal System 13.3 mg/24 hours to improve cognitive performance over that provided by the Rivastigmine Transdermal System 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) [see Clinical Studies ( 14 )] . The ability of the Rivastigmine Transdermal System 13.3 mg/24 hours to improve overall function versus that provided by Rivastigmine Transdermal System 9.5 mg/24 hours was assessed by the instrumental subscale of the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-IADL). The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale. The ADCS-IADL assesses activities, such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests. A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment. Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study. Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours Rivastigmine Transdermal System treatment group and 280 patients entered the 13.3 mg/24 hours Rivastigmine Transdermal System treatment group. Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study. Decline in the mean ADCS-IADL score from the double-blind baseline for the Intent to Treat–Last Observation Carried Forward (ITT-LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours Rivastigmine Transdermal System treatment group than in the 9.5 mg/24 hours Rivastigmine Transdermal System treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5 mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint). Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase. The between-treatment group difference for Rivastigmine Transdermal System 13.3 mg/24 hours versus Rivastigmine Transdermal System 9.5 mg/24 hours was nominally statistically significant at week 24 (p=0.027), but not at week 48 (p=0.227), which was the primary endpoint. Figure 5: Time Course of the Change From Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6: Time Course of the Change From Double-Blind Baseline in ADAS - Cog Score for Patients Observed at Each Time Point in Study 2 Severe Alzheimer’s Disease 24-Week United States Study With Rivastigmine Transdermal System  in Severe Alzheimer’s Disease (Study 3 ) This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 3 and less than or equal to 12]. The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged greater than 75 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 87%, black 7%, Asian 1%, and other races 5%. Patients on a stable dose of memantine were permitted to enter the study. Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study. The study was designed to compare the efficacy of Rivastigmine Transdermal System  13.3 mg/24 hours versus that of Rivastigmine Transdermal System  4.6 mg/24 hours during the 24-week double-blind treatment phase.   The ability of the 13.3 mg/24 hours Rivastigmine Transdermal System  to improve cognitive performance versus that provided by the 4.6 mg/24 hours Rivastigmine Transdermal System  was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.   The ability of the 13.3 mg/24 hours Rivastigmine Transdermal System  to improve overall function versus that provided by the 4.6 mg/24 hours Rivastigmine Transdermal System  was assessed with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living–Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia. It is designed to assess the patient's performance of both basic and instrumental activities of daily living, such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment. In this study, 716 patients were randomized into one of the following treatments: Rivastigmine Transdermal System  13.3 mg/24 hours or Rivastigmine Transdermal System 4.6 mg/24 hours in a 1:1 ratio. This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase. In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.   Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours Rivastigmine Transdermal System  treatment group than in the 4.6 mg/24 hours Rivastigmine Transdermal System  treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).   Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean ADCS-ADL-SIV score from baseline for the MFAS-LOCF analysis was less at each timepoint in the 13.3 mg/24 hours Rivastigmine Transdermal System  treatment group than in the 4.6 mg/24 hours Rivastigmine Transdermal System treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).   Figure 7: Time Course of the Change From Baseline in SIB Score for Patients Observed at Each Time Point (Modified Full Analysis Set-LOCF) Figure 8: Time Course of the Change From Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified Full Analysis Set–LOCF)

Patient Information Rivastigmine (riv” a stig’ meen) Transdermal System What is the most important information I should know about Rivastigmine Transdermal System? Rivastigmine Transdermal System is for skin use only. What is Rivastigmine Transdermal System?  Rivastigmine Transdermal System is a prescription medicine used to treat:    Mild, moderate, and severe memory problems (dementia) associated with Alzheimer’s disease.    Mild-to-moderate memory problems (dementia) associated with Parkinson’s disease (PD). Based on clinical trials conducted over 6 to 12 months, Rivastigmine Transdermal System was shown to help with cognition which includes (memory, understanding communication, and reasoning) and with doing daily tasks. Rivastigmine Transdermal System does not work the same in all people. Some people treated with Rivastigmine Transdermal System may: Seem much better Get better in small ways or stay the same Get worse but slower than expected Not change and then get worse as expected Some patients will not benefit from treatment with Rivastigmine Transdermal System. Rivastigmine Transdermal System does not cure Alzheimer’s disease. All patients with Alzheimer’s disease get worse over time. Rivastigmine Transdermal System comes as a transdermal system that delivers rivastigmine (the medicine in Rivastigmine Transdermal System) through the skin. It is not known if Rivastigmine Transdermal System is safe or effective in children under 18 years of age. Who should not use Rivastigmine Transdermal System? Do not use Rivastigmine Transdermal System if you: are allergic to rivastigmine, carbamate derivatives, or any of the ingredients in Rivastigmine Transdermal System. See the end of this leaflet for a complete list of ingredients in Rivastigmine Transdermal System. have had a skin reaction that: spread beyond the Rivastigmine Transdermal System size had blisters, increased skin redness, or swelling did not get better within 48 hours after you removed the Rivastigmine Transdermal System Ask your healthcare provider if you are not sure if you should use Rivastigmine Transdermal System. What should I tell my healthcare provider before using Rivastigmine Transdermal System? Before you use Rivastigmine Transdermal System, tell your healthcare provider if you: have or have had a stomach ulcer are planning to have surgery have or have had problems with your heart have problems passing urine have or have had seizures have problems with movement (tremors) have asthma or breathing problems have a loss of appetite or are losing weight have had a skin reaction to rivastigmine (the medicine in Rivastigmine Transdermal System) in the past have any other medical conditions are pregnant or plan to become pregnant. It is not known if the medicine in Rivastigmine Transdermal System will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if the medicine in Rivastigmine Transdermal System passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take Rivastigmine Transdermal System. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: a medicine used to treat inflammation [nonsteroidal anti-inflammatory drugs (NSAIDs)] other medicines used to treat Alzheimer’s or Parkinson’s disease an anticholinergic medicine, such as an allergy or cold medicine, a medicine to treat bladder or bowel spasms, or certain asthma medicines, or certain medicines to prevent motion or travel sickness metoclopramide, a drug given to relieve symptoms of nausea, gastroesophageal reflux disease (GERD), or nausea and vomiting after surgery or chemotherapy treatment If you are undergoing surgery while using Rivastigmine Transdermal System, inform your doctor because Rivastigmine Transdermal System may exaggerate the effects of anesthesia, or the effects of a beta-blocker, a type of medicine given for high blood pressure, heart disease, and other medical conditions Ask your healthcare provider if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I use Rivastigmine Transdermal System? Use Rivastigmine Transdermal System exactly as your healthcare provider tells you to use it. Rivastigmine Transdermal System comes in 3 different dosage strengths. Your healthcare provider may change your dose as needed. Wear only 1 Rivastigmine Transdermal System at a time.  Rivastigmine Transdermal System is for skin use only. Only apply Rivastigmine Transdermal System to healthy skin that is clean, dry, hairless, and free of redness, irritation, burns or cuts.    Avoid applying Rivastigmine Transdermal System to areas on your body that will be rubbed against by tight clothing. Do not apply Rivastigmine Transdermal System to skin that has cream, lotion, or powder on it. Change your Rivastigmine Transdermal System every 24 hours at the same time of day. You may write the date and time you put on the Rivastigmine Transdermal System with a ballpoint pen before applying the Transdermal System to help you   remember when to remove it. Change your application site every day to avoid skin irritation. You can use the same area, but do not use the exact same spot for at least 14 days after your last application. Check to see if the Rivastigmine Transdermal System has become loose when you are bathing, swimming, or showering. Rivastigmine Transdermal System is designed to deliver medication during the time it is worn. If your Rivastigmine Transdermal System falls off before its usual replacement time, put on a new Rivastigmine Transdermal System right away. Replace the new patch the next day at the same time as usual. Do not use overlays, bandages, or tape to secure a Rivastigmine Transdermal System that has become loose or try to reapply a Rivastigmine Transdermal System that has fallen off.         If you miss a dose or forget to change your Rivastigmine Transdermal System, apply your next Rivastigmine Transdermal System as soon as you remember. Do not apply 2 Rivastigmine Transdermal Systems to make up for the missed dose. If you miss more than 3 doses of applying Rivastigmine Transdermal System, call your healthcare provider before putting on a new Rivastigmine Transdermal System. You may need to restart Rivastigmine at a lower dose. Always remove the old Rivastigmine Transdermal System from the previous day before you apply a new one. Having more than 1 Rivastigmine Transdermal System on your body at the same time can cause you to get too much       medicine. If you accidentally use more than 1 Rivastigmine Transdermal System at a time, call your healthcare provider right away. If you are unable to reach your healthcare provider, call your local Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.  What should I avoid while using Rivastigmine Transdermal System? Do not touch your eyes after you touch the Rivastigmine Transdermal System. In case of accidental contact with your eyes or      if your eyes become red after handling the patch, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.  Rivastigmine Transdermal System can cause drowsiness, dizziness, weakness, or fainting. Do not drive, operate heavy machinery, or do other dangerous activities until you know how Rivastigmine Transdermal System affects you. Avoid exposure to heat sources, such as excessive sunlight, saunas, or sunrooms for long periods of time. What are the possible side effects of Rivastigmine Transdermal System? Rivastigmine Transdermal System may cause serious side effects, including: Medication overdose. Hospitalization and rarely death may happen when people accidently wear more than 1 patch at the same time. It is important that the old Rivastigmine Transdermal System be removed before you apply a new one. Do not wear more than 1 Rivastigmine Transdermal System at a time. Stomach or bowel (intestinal) problems, including: nausea vomiting diarrhea dehydration loss of appetite weight loss bleeding in your stomach (ulcers) Skin reactions. Some people have had a serious skin reaction called allergic contact dermatitis (ACD) when using Rivastigmine Transdermal System. Stop using Rivastigmine Transdermal System and call your healthcare provider right    away if you experience reactions that spread beyond the patch size, are intense in nature and do not improve within 48 hours after the patch is removed. Symptoms of ACD may be intense and include: itching, redness, swelling, warmth or tenderness of the skin peeling or blistering of the skin that may ooze, drain or crust over Heart problems Seizures Problems with movement (tremors) The most common side effects of Rivastigmine Transdermal System include: depression headache anxiety dizziness stomach pain urinary tract infections muscle weakness tiredness trouble sleeping Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Rivastigmine Transdermal System. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should I store Rivastigmine Transdermal System? Store Rivastigmine Transdermal System between 68°F to 77°F (20°C to 25°C). Keep Rivastigmine Transdermal System in the sealed pouch until ready to use. Keep Rivastigmine Transdermal System and all medicines out of the reach of children. General information about the safe and effective use of Rivastigmine Transdermal System. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Rivastigmine Transdermal System for a condition for which it was not prescribed. Do not give Rivastigmine Transdermal System to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about Rivastigmine Transdermal System. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Rivastigmine Transdermal System that is written for health professionals. For more information, contact Alvogen at 1-866-770-3024. What are the ingredients of Rivastigmine Transdermal System ? Active ingredient: rivastigmine Excipients include: colloidal silicon dioxide, light mineral oil, polyisobutylene adhesive, acrylate-vinylacetate pressure sensitive adhesive, aluminum coated polyester backing Made in Germany Distributed by: Alvogen, Inc. Morristown, NJ 07960 USA PL304-07 Revised: 05/2024

Discarding Rivastigmine Transdermal Patch