Summary Basis of Decision for Exelon Patch
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Exelon Patch
Rivastigmine, 9 mg/5 cm2, 18 mg/10 cm2, patch, Transdermal
Novartis Pharmaceuticals Canada Inc.
Submission control no: 109513
Date issued: 2008-06-22
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Health Products and Food Branch
Également disponible en français sous le titre :Sommaire des motifs de décision (SMD), PrEXELON* PATCH, rivastigmine, 9 mg/5 cm2, 18 mg/10 cm2, timbre, Novartis Pharmaceuticals Canada Inc., No de contrôle de la présentation 109513
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
18 mg/10 cm2 (Exelon* Patch 10)
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02302845 - 9 mg/5 cm2
- 02302853 - 18 mg/10 cm2
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
*EXELON is a registered trademark
2 Notice of decision
On November 29, 2007, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product, Exelon* Patch.
Exelon* Patch is a transdermal patch containing the medicinal ingredient rivastigmine, a cholinesterase inhibitor. Rivastigmine is also found in Exelon* capsules and solution, which have been marketed in Canada since 2000 and 2002, respectively.
Exelon* Patch is indicated for the symptomatic treatment of patients with mild to moderate dementia of the Alzheimer's type. Rivastigmine is thought to have its therapeutic effect by enhancing cholinergic neurotransmission by slowing the degradation of acetylcholine released by cholinergic neurons through the inhibition of acetylcholinesterase. Exelon* Patch has not been studied in controlled clinical trials for longer than 6 months. Exelon* Patch should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of Alzheimer's disease.
The market authorization was based on quality, non-clinical, and clinical information submitted. A 24-week Phase III, randomized, double-blind, placebo and active-controlled study, along with its open-label extension phase provided the safety and efficacy data for this New Drug Submission. Patients with mild to moderate Alzheimer's disease treated with Exelon* Patch 10 demonstrated statistically significant improvements in cognition and clinical global impression of change (cognition, behavior, and functioning) compared to the placebo group. The most common types of adverse reactions observed with Exelon* Patch 10 were similar to the most common adverse reactions known to be associated with the capsules and oral solution in Alzheimer's disease patients.
Two strengths of Exelon* Patch (rivastigmine) are available, Exelon* Patch 5 (9 mg/5 cm2, in vivo release rate of 4.6 mg/24 h) and Exelon* Patch 10 (18 mg/10 cm2, in vivo release rate of 9.5 mg/24 h). Treatment is started with Exelon* Patch 5 once a day. After a minimum of four weeks of treatment and if well tolerated, this dose should be increased to Exelon* Patch 10. Exelon* Patch 10 is the recommended maintenance daily dose which can be continued as long as therapeutic benefits exist. Dosing guidelines are available in the Product Monograph.
Exelon* Patch is contraindicated for patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation. Exelon* Patch should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Exelon* Patch are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Exelon* Patch is favourable for the symptomatic treatment of patients with mild to moderate dementia of the Alzheimer's type.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
Currently, there are two oral dosage forms of Exelon* marketed in Canada. Exelon* capsules and the bioequivalent oral solution received market authorization for the symptomatic treatment of mild to moderate Alzheimer's dementia. Exelon* capsules and oral solution are also approved in Canada for the symptomatic treatment of mild to moderate dementia associated with Parkinson's disease. The capsule and oral solution contain rivastigmine hydrogen tartrate as the medicinal ingredient.
In April 2006, the sponsor presented the Exelon* Patch to Health Canada. This product uses a different medicinal ingredient; rivastigmine, free base, as opposed to rivastigmine hydrogen tartrate. It was proposed that this new dosage form would improve compliance, tolerability of the drug, and be useful for patients with swallowing difficulties.
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Rivastigmine, the medicinal ingredient of the Exelon* Patch, is a cholinesterase inhibitor. Rivastigmine is thought to enhance cholinergic neurotransmission by slowing the degradation of acetylcholine released by cholinergic neurons through the inhibition of cholinesterases.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of rivastigmine is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of rivastigmine are considered acceptable. The validation reports are considered satisfactory for all analytical procedures used for release and stability testing of rivastigmine.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period and recommended storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Exelon* Patch (rivastigmine) is a transdermal patch for transdermal administration. Each patch is a thin, matrix-type transdermal system consisting of three layers when worn by the patient. A fourth layer, the release liner, covers the adhesive layer prior to use and is removed at the time the system is applied to the skin.
Exelon* Patch 5: each patch of 5 cm2 contains 9 mg rivastigmine base, with an in vivo release rate of 4.6 mg/24 hours. The outside of the backing layer is beige and labelled with "PrEXELON* PATCH 5 (rivastigmine) 4.6 mg/24 h" and "AMCX".
Exelon* Patch 10: each patch of 10 cm2 contains 18 mg rivastigmine base, with an in vivo release rate of 9.5 mg/24 hours. The outside of the backing layer is beige and labelled with "PrEXELON* PATCH 10 (rivastigmine) 9.5 mg/24 h" and "BHDI".
Each patch is individually sealed in a separate pouch and is available in cartons of 30 or 60.
Non-medicinal ingredients include: acrylic copolymer, poly(butylmethacrylate, methyl-methacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of rivastigmine with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are considered acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Exelon* Patch is tested to verify that the identity, appearance, content uniformity, peel force, adhesion force, release rate, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits. The validation process is considered to be complete. No deficiencies were found with respect to the batch analysis.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°C for Exelon* Patch is considered acceptable.
The container closure system is acceptable.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. No excipients of human or animal origin are used in the manufacture of Exelon* Patch.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Exelon* Patch has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Rivastigmine has been shown to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. In vitro and in vivo studies have been performed to evaluate the action of the drug. Rivastigmine inhibited AChE activity in various brain regions which resulted in increased accumulation of acetylcholine (ACh) levels in the rat brain.
3.2.2 Pharmacokinetics
The absorption, distribution, metabolism, and excretion of radiolabelled rivastigmine was studied in minipigs following oral, intravenous, and dermal administration. Absorption was slower with the patch compared to oral administration and approximately ⅔ of the dose remained within the patch after 24 hours, however, bioavailability of parent rivastigmine was much higher due to the absence of the extensive first-pass metabolism that occurred after oral administration. Absorption was approximately 2-fold higher from skin that was abraded by prior applications of placebo patches. Concentrations of the non-pharmacologically active metabolite NAP226-90 were much higher than rivastigmine levels after oral rivastigmine administration, but significantly lower than rivastigmine levels after dermal rivastigmine patch application. Excretion was mainly urinary via the sulfate conjugate of NAP226-90. Biliary/gastrointestinal excretion was a minor route, regardless of means of administration.
After an oral dose of radiolabelled rivastigmine in rats, rivastigmine and its metabolites were transferred into rat milk with radioactivity levels approximately 1.9 fold higher in milk than in maternal plasma. Rivastigmine and/or its metabolites were also distributed to the placenta, but were not readily transferred to fetal rats.
Rivastigmine is poorly metabolized by human skin (in vitro), but is extensively metabolized by the liver and to some extent the intestine. Metabolism is generally similar in rats and humans with all significant metabolites formed by human liver, apart from a minor amount of direct rivastigmine glucuronic acid conjugate, also formed by rat liver. The main metabolite was NAP226-90 formed by esterase-mediated decarbamylation of rivastigmine. Minipigs also formed NAP226-90 as well as other metabolites.
The potential for metabolic interactions appears to be low based on lack of effect on various CYP isoforms and the lack of effect that butyrylcholinesterase-inhibiting antidepressant and neuroleptic drugs had on hepatic rivastigmine hydrolysis. However, cholinesterase-inhibiting drugs do inhibit hydrolysis of rivastigmine to NAP226-90 in plasma which may be a relatively more important metabolic pathway when the drug is administered dermally and not subject to the extensive esterase-mediated first-pass metabolism in the liver.
3.2.3 Toxicology
The non-clinical safety program for rivastigmine tartrate (in support of Exelon* oral capsules) consisted of a full range of acute, subchronic, and chronic toxicology studies in mice, rats, dogs, and monkeys, as well as genotoxicity, carcinogenicity, reproductive and sensitization studies. In these studies, no systemic/organ toxicity was seen. Dosing in animals was limited by acute signs of cholinergic hyperactivity. The mechanism of rivastigmine toxicity was related to inhibition of cholinesterase activity and secondarily increased activity of intrinsic cholinergic agonists at the synapses. Differences in sensitivity and metabolism of cholinesterase inhibitors are known to occur between different species, with dogs and minipigs being similar to man, and rodents differing due to their high first-pass metabolism after oral administration.
To support the Exelon* Patch, a comprehensive toxicity program was conducted in mice, rats, guinea pigs, rabbits, and minipigs using topical routes of administration. The minipig is an appropriate species for dermal toxicity studies since its skin properties are close to those of humans.
Single-Dose Toxicity
No specific topical single-dose toxicity studies other than local tolerance studies were conducted with rivastigmine. Adequate toxicity studies were conducted with the oral administration.
Repeat-Dose Toxicity
No significant systemic effects were demonstrated other than decreased plasma and erythrocyte cholinesterase activities. Clinical signs were typical of cholinesterase inhibition, and occasional secondary effects on body weight and food consumption were observed. There were no treatment-related hematology, routine clinical chemistry, organ weight, gross or microscopic findings indicative of overt toxicity.
The cholinergic signs were occasionally dose-limiting. Mortality or euthanasia occasionally occurred after a high dose and were considered due to hypercholinergic activity. Specifically, mortality/euthanasia occurred in mice after the first high dose of 1.0 mg/kg (that was subsequently lowered) in the 13-week study; in rabbits given 0.1 mL of rivastigmine in the eye irritation study which represented a dose of almost 40 mg/kg; and in guinea pigs given an 18 mg patch in a contact hypersensitivity study that would have represented an applied dose of approximately 60 mg/kg. Minipigs in a 4-week study were also euthanized due to the severity of skin reactions to placebo and rivastigmine patches applied in the same region daily for 12-19 applications, however this was not a drug-related phenomenon.
Reproductive and Developmental Toxicity
No reproductive and developmental toxicity studies were conducted by the dermal route. Adequate toxicology studies were conducted to support the oral route of administration.
Carcinogenicity
A single carcinogenicity study was conducted in mice by the dermal route of administration which showed that rivastigmine was not tumorigenic when given for 98-99 weeks at daily dermal doses up to 0.75 mg/kg.
Local Tolerance
In dermal studies with minipigs, mild erythema was somewhat dose-dependent and greater with the 6-site rotation than the 12-site rotation regimen.
Rivastigmine transdermal patches did not elicit a phototoxic response in guinea pigs.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered acceptable. The dermal toxicology studies were adequately conducted and no unanticipated toxicities were identified. The clinical signs observed would be expected based on the cholinergic pharmacology of rivastigmine. Overall, the pharamacology and toxicology studies support the use of Exelon* Patch for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Rivastigmine, the medicinal ingredient of the Exelon* Patch, is a cholinesterase inhibitor. Rivastigmine inhibits acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. By inhibiting the degradation of acetylcholine, rivastigmine is thought to enhance cholinergic transmission in the brain.
The Exelon* Patch was developed as an alternative dosage form to the two dosage forms of Exelon* that are presently available in Canada. Exelon* capsules and Exelon* oral solution are presently being marketed for the symptomatic treatment of patients with mild to moderate dementia of the Alzheimer type. Exelon* capsules and oral solution are also approved in Canada for the symptomatic treatment of mild to moderate dementia associated with Parkinson's disease. The medicinal ingredient in both oral dosage forms is rivastigmine tartrate. Adequate pharmacodynamic studies for rivastigmine were conducted for the previous Exelon* drug submissions.
3.3.2 Pharmacokinetics
Several Phase I and Phase II studies were conducted with various dosage strengths of the final marketing image (FMI) of Exelon* Patch in healthy volunteers and patients with Alzheimer's Disease (AD). Most of these studies were open-label, but they were evaluated for the comparative bioavailability, pharmacokinetic and additional safety data they provided. Overall, the safety profile for Exelon* Patch in these studies was similar to what was observed in the Phase III pivotal study (described in section 3.3.3 Clinical Efficacy).
The following findings were noted:
- Pharmacokinetic studies demonstrated that rivastigmine was well released from the patch and that the plasma concentrations of rivastigmine remained steady, with significantly reduced fluctuations in plasma concentrations compared to oral dosing. Lower inter-individual variability was also observed with the patch compared to the oral formulations.
- The highest drug exposure levels (AUC and Cmax) were obtained when the patch was applied to the upper back, chest, and upper arm, for both rivastigmine and the main (pharmacologically inactive) metabolite. For the abdomen and outer thigh, bioavailability was reduced 20-30% and application to these areas was more likely to cause erythema. The observations regarding the lower bioavailability and increased potential for skin irritation following application to the outer thigh and abdomen have been incorporated into the Exelon* Patch Product Monograph.
- Studies evaluating allergic sensitization and phototoxicity in healthy subjects did not suggest evidence of either type of reaction with the Exelon* Patch.
- Pharmacokinetic behavior of rivastigmine patches was similar in Caucasians and Japanese individuals. However, a slower titration regimen seemed to improve tolerability to the Exelon* Patch in a Japanese AD patient population. Generally, the tolerability findings with Japanese patients appeared to be consistent with what has been observed for patients with low body weight using Exelon* capsules and Exelon* Patch. Appropriate precautions for careful titration of patients with low body weight have been incorporated in the Exelon* Patch Product Monograph.
3.3.3 Clinical Efficacy
The clinical efficacy and safety of Exelon* Patch were evaluated in a 24-week pivotal Phase III, multi-centre, randomized, double-blind, placebo and active-controlled study, along with its 28-week open-label extension (up to 52 weeks of treatment). The design, diagnostic criteria, inclusion/exclusion criteria, staging of disease severity [baseline Mini Mental State Examination (MMSE) scores ≥10 and ≤20 required], and efficacy assessment scales are all considered standard, valid, and are internationally accepted for clinical trials evaluating the efficacy and safety of therapeutic products for the symptomatic treatment of mild to moderate AD.
A total of 1195 patients were randomized to four treatment arms: Exelon* Patch 10 (9.5 mg/24 hours patch and placebo capsules), Exelon* Patch 20 (17.4 mg/24 hours patch and placebo capsules), Exelon* capsules [6 mg twice a day (BID) and placebo patch], and placebo (placebo patches and placebo capsules). Due to the known cholinergic-mediated adverse effects associated with oral rivastigmine (e.g., gastrointestinal adverse events, dizziness), patients were slowly titrated to target doses of Exelon* Patch 10, Exelon* Patch 20, and Exelon* capsules (6 mg BID) with 4-week intervals between each dose increase. Exelon* Patch 5 and Exelon* Patch 15 were interim doses used for the purpose of titration.
The primary efficacy of Exelon* Patch was evaluated using a dual outcome assessment strategy (co-primary endpoints). The co-primary efficacy variables were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). With each primary endpoint, the change in function was evaluated from baseline to Week 24.
Secondary efficacy variables measured change in total scores from baseline to Week 24 in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), MMSE, Ten Point Clock Test, and Trail Making Test Part A.
For both primary efficacy measures (ADAS-Cog and ADCS-CGIC) at Week 24, the differences between Exelon* Patch 10 vs. placebo and Exelon* capsules vs. placebo were statistically significant. Treatment effects achieved with Exelon* Patch 10 were similar to those achieved with capsules.
A key secondary efficacy measure, the ADCS-ADL showed that patients in all Exelon* treatment groups had significantly less deterioration in activities of daily living at Week 24 compared to patients who received placebo.
3.3.4 Clinical Safety
The majority of the safety data for this submission was taken from the single Phase III, 24-week, pivotal study described in section 3.3.3 Clinical Efficacy. Additional safety data from the extension of that study and the Phase I and Phase II studies showed a similar safety profile.
In all of the Exelon* treatment groups approximately 80% of the patients completed treatment compared to 88% in the placebo group. Approximately 80% of patients in the Exelon* Patch 10 group, and 30% of patients in both the Exelon* Patch 20 and capsule groups received their target dose for ‑12 weeks. Adverse events (AEs) and withdrawal of consent were the main reasons for discontinuation of treatment in all groups. Overall, 9-11% of patients treated with Exelon* patches or capsules compared to 6% of patients treated with placebo, discontinued due to AEs. Discontinuations due to AEs were more frequent during the titration phase than during the maintenance phase for all treatment groups.
The most frequent adverse events (AEs) leading to discontinuation (defined as those occurring in ≥1% of patients treated with Exelon* Patch 10 or Exelon* Patch 20, and more frequently occurring than in the placebo group) were nausea, vomiting, anorexia, decreased weight, asthenia, application site pruritus, cerebrovascular accident, dizziness, syncope, agitation, anxiety, delirium, erythema and pruritus. Only nausea and vomiting resulted in discontinuation of >1% of patients in any treatment group (2% in Exelon* Patch 20).
The AE profile for Exelon* Patch was qualitatively similar to the known safety profile for Exelon* capsules in patients with AD. The most common AEs were cholinergic-mediated gastrointestinal AEs (nausea, vomiting, diarrhea, weight loss), dizziness, and other central nervous system, psychiatric and cardiovascular events that are known to occur due to advanced age and AD disease. Although exposure levels of rivastigmine are similar with Exelon* Patch 10 and capsules (6 mg BID), tolerability was generally improved with Exelon* Patch 10.
In the Phase III study, one patient (0.3%) developed pancreatitis during double-blind treatment with Exelon* capsules, and one patient (0.2%) developed pancreatitis during open-label treatment with Exelon* Patch 15. In a previous study with Exelon* capsules in patients with dementia associated with Parkinson's disease, elevations in serum amylase and lipase levels were reported more frequently in patients treated with Exelon* compared to placebo, but there were no clinical consequences (i.e., no pancreatitis). There were also several post-marketing reports of pancreatitis for which association with Exelon* capsule treatment could not be excluded. Consequently, a precaution for pancreatitis has been included in the Exelon* Patch Product Monograph.
Consistent with results from Phase I and Phase II studies in healthy volunteers and AD patients, patients treated with Exelon* and placebo patches in the pivotal study experienced slight or mild skin irritations. Skin irritation was mostly considered related to mechanical stress caused by adhesion and removal of patches, but was exacerbated by rivastigmine. Patients treated with Exelon* patches experienced slight or mild skin irritation more frequently than placebo-treated patients, with the most common types of irritation being transient erythema and pruritus at the patch application site. Severe skin irritations were reported in ≤2% of patients treated with Exelon* patches and in ≤1% of patients treated with placebo patches. Skin irritation leading to discontinuation (mostly moderate or severe erythema, pruritus, or dermatitis that was limited to the patch area) was reported for 2% of patients in each of the Exelon* patch groups, 1% of patients in the capsule group, and 0.3% of patients in the placebo group.
There were 14 deaths (Exelon* Patch 20, n=5; Exelon* Patch 10, n=4; Exelon* capsule, n=2; placebo, n=3). The most common causes of death were cardiac disorders (cardiac failure, congestive cardiac failure) and nervous system disorders (cerebrovascular accident). The AEs leading to death are consistent with common causes of death in an elderly AD population, and there was no evidence to suggest a relationship to any treatment. Serious AE (SAE) incidences were highest in the Exelon* Patch 20 group (36 patients, 12%). Incidences of SAEs in the Exelon* Patch 10 (8%) and Exelon* capsule (7%) groups were similar to incidences in the placebo group (9%). SAEs affecting the nervous system, cardiovascular system and gastrointestinal system occurred more frequently with Exelon* Patch 20 (≤2-3%) than in the placebo and the other Exelon* treatment groups. Exelon* Patch 20 did not confer appreciable additional therapeutic benefit and was associated with significant increases in AEs.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Exelon* Patch has demonstrated similar treatment effects (changes in cognitive function and global change) for patients with mild to moderate dementia of the Alzeimer's type, as those achieved by Exelon* capsule which is currently marketed in Canada for the identical indication.
The formulation of rivastigmine in the Exelon* Patch allows for once daily dosing, without the need for oral administration with food. Tolerability was acceptable during titration with Exelon* Patch 5 and with the maximum recommended maintenance dose of Exelon* Patch 10 compared to oral rivastigmine. Under the recommended conditions of use, the risk-benefit ratio for the use of Exelon* Patch 5 and Exelon* Patch 10 in the management of mild to moderate AD is considered favourable at this time.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Exelon* Patch is favourable in the treatment of patients with mild to moderate dementia of the Alzeimer's type. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Exelon Patch
| Submission Milestone | Date |
|---|---|
| Submission filed | 2006-11-01 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2006-12-15 |
| Response filed | 2006-12-27 |
| Screening Acceptance Letter issued | 2007-02-02 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | 2007-11-08 |
| Quality Evaluation complete | 2007-11-28 |
| Clinical Evaluation complete | 2007-11-27 |
| Labelling Review complete | 2007-11-27 |
| NOC issued by Director General | 2007-11-29 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EXELON PATCH 5 | 02302845 | KNIGHT THERAPEUTICS INC. | RIVASTIGMINE 4.6 MG / 24 HOUR |
| EXELON PATCH 10 | 02302853 | KNIGHT THERAPEUTICS INC. | RIVASTIGMINE 9.5 MG / 24 HOUR |