Rivastigmine Actavis

Pharmacotherapeutic group: psychoanaleptics, anticholinesterases, ATC code: N06DA03 Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by oral rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by oral rivastigmine was similar to the inhibition of AChE activity. Clinical studies in Alzheimer's dementia The efficacy of rivastigmine transdermal patches in patients with Alzheimer's dementia has been demonstrated in a 24-week double-blind, placebo-controlled core study and its open-label extension phase and in a 48-week double-blind comparator study. 24-week placebo-controlled study Patients involved in the placebo-controlled study had an MMSE (Mini-Mental State Examination) score of 10–20. Efficacy was established by the use of independent, domain-specific assessment tools which were applied at regular intervals during the 24-week treatment period. These include the ADAS-Cog (Alzheimer's Disease Assessment Scale – Cognitive subscale, a performance-based measure of cognition) and the ADCS-CGIC (Alzheimer's Disease Cooperative Study – Clinician's Global Impression of Change, a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the ADCS-ADL (Alzheimer's Disease Cooperative Study – Activities of Daily Living, a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities related to finances). The 24-week results for the three assessment tools are summarised in Table 2. ITT-LOCF population Rivastigmine transdermal patches 9.5 mg/24 h N=251 Rivastigmine capsules 12 mg/day N= 256 Placebo N=282 ADAS-Cog Mean baseline ± SD Mean change at week 24 ± SD p-value versus placebo (n=248) 27.0 ± 10.3 -0.6 ± 6.4 0.005* 1 (n=253) 27.9 ± 9.4 -0.6 ± 6.2 0.003* 1 (n=281) 28.6 ± 9.9 1.0 ± 6.8 ADCS-CGIC Mean score ± SD p-value versus placebo (n=248) 3.9 ± 1.20 0.010* 2 (n=253) 3.9 ± 1.25 0.009* 2 (n=278) 4.2 ± 1.26 ADCS-ADL Mean baseline ± SD Mean change at week 24 ± SD p-value versus placebo (n-247) 50.1 ± 16.3 -0.1 ± 9.1 0.013* 1 (n=254) 49.3 ± 15.8 -0.5 ± 9.5 0.039* 1 (n=281) 49.2 ± 16.0 -2.3 ± 9.4 * p≤0.05 versus placebo ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward 1 Based on ANCOVA with treatment and country as factors and baseline value as a covariate. Negative ADAS-Cog changes indicate improvement. Positive ADCS-ADL changes indicate improvement. 2 Based on CMH test (van Elteren test) blocking for country. ADCS-CGIC scores <4 indicate improvement. The results for clinically relevant responders from the 24-week placebo-controlled study are provided in Table 3. Clinically relevant improvement was defined a priori as at least 4-point improvement on the ADAS-Cog, no worsening on the ADCS-CGIC, and no worsening on the ADCS-ADL. Patients with clinically significant response (%) ITT-LOCF population Rivastigmine transdermal patches 9.5 mg /24 h N=251 Rivastigmine capsules 12 mg/day N= 256 Placebo N=282 At least 4 points improvement on ADAS-Cog with no worsening on ADCS-CGIS and ADCS-ADL p-value versus placebo 17.4 0.037* 19.0 0.004* 10.5 * p<0.05 versus placebo As suggested by compartmental modelling, 9.5 mg/24 h transdermal patches exhibited exposure similar to that provided by an oral dose of 12 mg/day. 48-week active comparator controlled study Patients involved in the active comparator controlled study had an initial baseline MMSE score of 10-24. The study was designed to compare the efficacy of the 13.3 mg/24 h transdermal patch against the 9.5 mg/24 h transdermal patch during a 48-week double-blind treatment phase in Alzheimer's disease patients who demonstrated functional and cognitive decline after an initial 24-48 week open-label treatment phase while on a maintenance dose of 9.5 mg/24 h transdermal patch. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of >2 points from the previous visit or a decrease of >3 points from baseline. Efficacy was established by the use of ADAS-Cog (Alzheimer's Disease Assessment Scale – Cognitive subscale, a performance-based measure of cognition) and the ADCS-IADL (Alzheimer's Disease Cooperative Study – Instrumental Activities of Daily Living) assessing instrumental activities which include maintaining finances, meal preparation, shopping, ability to orient oneself to surroundings, ability to be left unattended. The 48-week results for the two assessment tools are summarised in Table 4. Population visit Rivastigmine 15cm2 Rivastigmine 10cm2 Rivastigmine 15cm2 Rivastigmine 10cm2 N=256 N=271 n Mean n Mean DLSM 95% CI P-value ADAS-Cog LOCF Baseline 264 34.4 268 34.9 DB-week 48 Value 264 38.5 268 39.7 Change 264 4.1 268 4.9 -0.8 (-2.1, 0.5) 0.227 ADAS-IADL LOCF Baseline 265 27.5 271 25.8 Week48 Value 265 23.1 271 19.6 change 265 -4.4 271 -6.2 2.2 (0.8, 3.6) 0.002* CI – confidence interval. DLSM – difference in least square means. LOCF – Last Observation Carried Forward. ADAS-cog scores: A negative difference in DLSM indicates greater improvement in rivastigmine 15 cm2 as compared to rivastigmine 10 cm2. ADCS-IADL scores: A positive difference in DLSM indicates greater improvement in rivastigmine 15 cm2 as compared to rivastigmine 10 cm2. N is the number of patients with an assessment at baseline (last assessment in the initial open- label phase) and with at least 1 post-baseline assessment (for the LOCF). The DLSM, 95% CI, and p-value are based on an ANCOVA (analysis of covariance) model adjusted for country and baseline ADAS-cog score. * p<0.05 Source: Study D2340-Table 11-6 and Table 11-7 The European Medicines Agency has waived the obligation to submit the results of studies with rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer's dementia (see section 4.2 for information on paediatric use).