Memantine hydrochloride, tablet 10 mg, and oral solution 10 mg per mL, Ebixa, March 2008
Public summary document for Memantine hydrochloride, tablet 10 mg, and oral solution 10 mg per mL, Ebixa, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Memantine hydrochloride, tablet 10 mg, and oral solution 10 mg per mL, Ebixa
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The re-submission sought listing an Authority Required benefit for the treatment of moderately severe Alzheimer’s disease (AD).
2. Background
Memantine has been considered several times previously by the PBAC.
At the most recent consideration in March 2007 meeting, the PBAC rejected the submission
for listing on a cost-minimisation basis compared to donepezil. The PBAC noted that
listing was sought for the treatment of moderately severe AD in patients who have
a baseline (Standardised) Mini-Mental State Examination ((S)MMSE) score of 10-14 and
considered the submission did not provide sufficiently comprehensive Mini-Mental State
Examination (MMSE) data for memantine. The MMSE was not a primary or secondary outcome
measure in the four memantine trials included in the submission.
3. Registration Status
Memantine was TGA registered on 17 April 2003 for treatment of the symptoms of moderately severe to severe Alzheimer’s disease.
4. Listing Requested and PBAC’s View
The requested listing for memantine has similar Authority requirements to the anti-cholinesterase
inhibitors but with the requirement that the baseline (Standardised) Mini Mental State
Examination ((S)MMSE) score must be 10-14.
For the complete restriction, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
Memantine would provide an alternative treatment to donepezil, galantamine and rivastigmine for the treatment of patients with moderately severe Alzheimer’s disease.
6. Comparator
The re-submission nominated donepezil, galantamine and rivastigmine as the main comparators.
The PBAC accepted this as appropriate.
7. Clinical Trials
The basis of the re-submission was an indirect meta-analysis of four randomised trials
of memantine and 12 donepezil, three galantamine and seven rivastigmine trials with
placebo as the common comparator.
The data presented included:
- Memantine – (4 trials): 99679, MD-01, MD-10, 9605 @ 5-20 mg/d (24-28 wks)
- Donepezil – (12 trials) @ 2-10 mg/day (24-27 wks)
- Galantamine – (3 trials) @ 24(32) mg/day (24-26 wks)
- Rivastigmine – (7 trials) @ 2-12 mg/day (and patches) (26 wks)
Studies published at the time of the submission are presented in the table below.
|
Trial |
Publication title/Publication citation |
|---|---|
|
Memantine |
|
|
MEM-MD-01 |
Trial MEM-MD-01: A randomized, double-blind, placebo-controlled evaluation of the
safety and efficacy of memantine in patients with moderate to severe dementia of the
Alzheimer’s type. |
|
MEM-MD-10 |
Trial MEM-MD-10: A randomized, double-blind, placebo-controlled evaluation of the
safety and efficacy of memantine in patients with mild to moderate dementia of the
Alzheimer’s type. |
|
MRZ-9605 |
Trial MRZ-9605: Efficacy and long-term tolerability of memantine in patients with
moderately severe to severe Alzheimer’s disease (AD). |
|
Donepezil |
|
|
Burns (1999) |
Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Moller HJ, Rogers SL, Friedhoff
LT. 1999. The effects of donepezil in Alzheimer's disease - results from a multinational
trial. Dementia & Geriatric Cognitive Disorders 10:237-244. |
|
Feldman (2001) |
Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E, Donepezil MSAD. 2001.
A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's
disease.[erratum appears in Neurology 2001 Dec 11;57(11):2153]. Neurology 57:613-620. |
|
Homma (1998) |
Homma A, Imai Y, Hariguchi S, Hasegawa K, Kameyama M, Nishimura T. 1998. Late Phase II Clinical Study of Acetylcholinesterase Inhibitor E2020 in Patients with Alzheimer-type Dementia -24-48-weeks Double-blind, Placebo-Controlled Study-. Rinsho Hyoka 26:209-231. |
|
Homma (2000) |
Homma A, Imai Y, Hariguchi S, Hasegawa K, Kameyama M, Nishimura T. 1998. Late Phase II Clinical Study of Acetylcholinesterase Inhibitor E2020 in Patients with Alzheimer-type Dementia -24-48-weeks Double-blind, Placebo-Controlled Study-. Rinsho Hyoka 26:209-231. |
|
Krishnan (2003) |
Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, Perdomo C, Ieni JR, Rogers S. 2003. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease. American Journal of Psychiatry 160:2003-2011. |
|
Mazza (2006) |
Mazza M, Capuano A, Bria P, Mazza S. 2006. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. European Journal of Neurology 13:981-985. |
|
Moraes (2006) |
Moraes W, Poyares DR, Guilleminault C, Ramos LR, Bertolucci PH, Tufik S. 2006. The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study. Sleep 29(2):199-205. |
|
Rogers (1998a) |
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. 1998. A 24-week, double-blind,
placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil
Study Group.[see comment]. Neurology 50:136-145. |
|
Selzer (2004) |
Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, Richardson S, Donepezil
4S. 2004. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled
trial.[erratum appears in Arch Neurol. 2005 May;62(5):825]. Archives of Neurology
61:1852-1856. |
|
Tariot (2001) |
Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E. 2001.
A randomized, double-blind, placebo-controlled study of the efficacy and safety of
donepezil in patients with Alzheimer's disease in the nursing home setting.[see comment].
Journal of the American Geriatrics Society 49:1590-1599. |
|
Tune (2003) |
Tune L, Tiseo PJ, Ieni J, Perdomo C, Pratt RD, Votaw JR, Jewart RD, Hoffman JM. 2003.
Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer
disease: results of a 24-week, double-blind, placebo-controlled study. American Journal
of Geriatric Psychiatry 11:169-177. |
|
Winblad (2006) |
Winblad B, Kilander L, Eriksson S, Minthon L, Batsman S, Wetterholm AL, Jansson-Blixt C, Haglund A, Severe A. 2006. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study.[see comment]. Lancet 367:1057-1065. |
|
Galantamine |
|
|
Brodaty (2005) |
Brodaty H, Corey-Bloom J, Potocnik FC, Truyen L, Gold M, Damaraju CR. 2005. Galantamine
prolonged-release formulation in the treatment of mild to moderate Alzheimer's disease.
Dementia & Geriatric Cognitive Disorders #2005. |
|
Raskind (2000) |
Raskind MA, Peskind ER, Wessel T, Yuan W. 2000. Galantamine in AD: A 6-month randomized,
placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.
Neurology 54:2261-2268. |
|
Wilcock (2000) |
Wilcock GK, Lilienfeld S, Gaens E. 2000. Efficacy and safety of galantamine in patients
with mild to moderate Alzheimer's disease: multicentre randomised controlled trial.
Galantamine International-1 Study Group.[see comment][erratum appears in BMJ 2001
Feb 17;322(7283):405]. BMJ 321:1445-1449. |
|
Rivastigmine |
|
|
Ballard (2005) |
Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, O'Brien J, Everratt A, Sadler S, Maddison C, Lee L, Bannister C, Elvish R, Jacoby R. 2005. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial.[see comment]. BMJ 330:874. |
|
Corey-Bloom (1998) |
Corey-Bloom J, Anand R, Veach J. 1998. A randomized trial evaluating the efficacy
and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor,
in patients with mild to moderately severe Alzheimer's disease. International Journal
of Geriatric Psychopharmacology 1. |
|
Feldman (2007) |
Feldman HH, Lane R. Rivastigmine: A placebo-controlled trial of BID and TID regimens
in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007 Mar 12. |
|
RIV-B351 |
Data obtained from Cochrane review; Birks J. 2006. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database of Systematic Reviews (1):CD005593. |
|
Rosler (1999) |
Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal Bianco P, Stahelin HB, Hartman
R, Gharabawi M. 1999. Efficacy and safety of rivastigmine in patients with Alzheimer's
disease: international randomised controlled trial.[see comment][comment][erratum
appears in BMJ 2001 Jun 16;322(7300):1456]. BMJ 318:633-638. |
|
Tai (2000) |
Tai CT, Liu CK, Sung SM, Pai MC, Hsu CY. 2000. The safety and efficacy of exelon in Alzheimer's patients: a multicentre, randomized, 26-week study in Taiwan. International Journal of Neuropsychopharmacology 3:S356. |
|
Winblad (2007) |
Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S,
Nagel J, Lane R. A six-month double-blind, randomized, placebo-controlled study of
a transdermal patch in Alzheimer's disease-- rivastigmine patch versus capsule. Int
J Geriatr Psychiatry. 2007 Mar 22. |
8. Results of Trials
In general, there was no statistically significant difference in any outcome between
memantine and placebo. The only statistically significant differences (p<0.05) were
Alzheimer’s Disease Assessment Scale – cognitive (ADAS-Cog) responder (99769), ADAS-cog
(MD-10), and Severe Impairment Battery (SIB), Functional Assessment Staging (FAST),
and Alzheimer’s Disease Cooperative Study – Activities of Daily Living – change in
sum (ADCS-ADL-css) (9605), favouring memantine. There was no significant difference
in MMSE score in study 9605.
The individual trial results for donepezil, galantamine and rivastigmine were presented
in the submission. There were statistically significant differences in most, but not
all, outcomes in favour of donepezil in the donepezil trials, but the effect size
again was small (2-3 points on the 70 point ADAS-Cog scale). The placebo response
was much greater than the difference between the active and placebo treatment effect
sizes. Similar comments apply to galantamine and rivastigmine.
The re-submission grouped the outcomes from the trials into several ‘domains’ as outlined
in the table below.
Outcome measures classified into ‘domains’
|
Domain |
Outcome |
|---|---|
|
“GLOBAL” |
Clinician’s global impression of change (higher score, greater deficity) |
|
Clinical Global Impression of Change scale (CGIC) and the global improvement index with interviewing of patients. Clinician Interview-Based Impression of Change (CIBIC) and with caregiver input (CIBIC-M or –Plus) |
|
|
Clinician’s global impression of severity (higher score, greater deficity) |
|
|
Clinical Dementia Rating (CDR) and Clinical Dementia Rating Sum of Boxes (CDR-SB) |
|
|
Global Deterioration Scale (GDS) |
|
|
Gottfries-Br宥-Steen (GBS) |
|
|
Mental Function Impairment Scale (MENFIS) |
|
|
“COGNITION” |
Alzheimer’s Disease Assessment Scale cognitive (ADAS-cog) and ADAS-Jcog |
|
Mini-Mental State Examination (MMSE) |
|
|
Severe Impairment Battery (SIB) |
|
|
“DISABILITY” |
Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS/ADL23) |
|
Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS/ADL19) |
|
|
Behavioural Rating Scale for Geriatric Patients (BGP) |
|
|
Disability Assessment for Dementia (DAD) |
|
|
Instrumental Activities of Daily Living (IADL) |
|
|
Physical Self-Maintenance Scale (PSMS) |
|
|
The Progressive Deterioration Scale (PDS) |
|
|
“BEHAVIOUR” |
Neuropsychiatric Inventory (NPI) |
The table below summarises the main results from the meta-analyses of the randomised trials for the four domains.
Meta-analyses results for the four domains (change from baseline)
|
Domain |
Trials |
Mem |
Pbo |
AChEIs |
SMD |
Difference (95%CI) |
p value |
|---|---|---|---|---|---|---|---|
|
Global |
4 |
311 |
266 |
-0.36 (-0.52, -0.19) F |
0.098 |
0.481 |
|
|
5 |
785 |
1080 |
-0.33 (-0.46, -0.20) R |
||||
|
Cognition |
4 |
303 |
264 |
-0.32 (-0.57, -0.16) R |
-0.114 |
0.388 |
|
|
10 |
1542 |
2467 |
-0.43 (-0.54, -0.31) R |
||||
|
Disability |
4 |
312 |
267 |
-0.24 (-0.41, -0.08) F |
0.107 |
0.252 |
|
|
6 |
941 |
1640 |
-0.13 (-0.22, -0.05) F |
||||
|
Behaviour |
4 |
308 |
266 |
-0.17 (-0.34, -0.01) F |
0.082 |
0.449 |
|
|
2 |
355 |
582 |
-0.09 (-0.23, 0.04) F |
Notes: F = fixed effects; R = random effects meta-analysis; † error – difference should
be ~0.03; Bold = favours AChEIs; ** = a one-sided confidence interval was used for
which the upper bound is not informative and results in a bias towards a non-inferiority
result.
The PBAC noted that in contrast to the results of the individual trials, which suggested
that there are only a few statistically significant differences between memantine
and placebo and the effect sizes were small, the grouping of outcomes into domains
produced statistically significant differences between memantine and placebo.
The PBAC noted that the results of the meta-analysis must be interpreted with caution,
given the poorly justified exclusion of many trials. There were also significant statistical
and methodological issues in relation to the meta-analysis itself. A major issue was
the definition of a “minimum clinically detectable difference” in the absence of MMSE
data. The choice made by the sponsor was a statistical concept rather than a clinical
one relevant to Alzheimer disease. A further important methodological issue was the
correction of the significance level to account for multiple comparisons. In summary,
the method of meta-analysis is subject to significant uncertainty and insufficient
detail was provided in the re-submission.
In relation to safety, the PBAC had previously accepted that memantine is better tolerated
than AChEIs.
9. Clinical Claim
The submission claimed memantine is non-inferior in terms of comparative effectiveness
and “better” in terms of comparative safety over the AChEIs (donepezil, galantamine
and rivastigmine).
Based on the evidence presented, the PBAC considered that memantine had a ‘better’
safety profile but lesser efficacy, associated with some uncertainty, than the anticholinesterases.
10. Economic Analysis
The submission presented a cost minimisation analysis. The equi-effective doses were estimated as memantine 20 mg/day and donepezil 10 mg/day. This was unchanged from the previous submissions. Given the PBAC’s views with respect to the clinical claim, this approach was not accepted as valid. However, the PBAC considered that based on the lower price proposed in the Pre-PBAC Response, listing on the basis of acceptable cost-effectiveness at that price was appropriate.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed as up to between 10,000 and 50,000 in Year 4. The estimated financial cost per year to the PBS was less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of memantine as monotherapy for the treatment of
moderately severe Alzheimer’s disease on the basis of acceptable cost-effectiveness
compared to donepezil, galantamine and rivastigmine.
The PBAC noted limited data were available comparing memantine to the acetylcholinesterase
inhibitors (AChEIs) and although MMSE was used to establish the baseline characteristics
of the patients enrolled in the four memantine trials, MMSE results are only available
for trial 9605. The PBAC also noted that there was selective use of trials in the
re-submission compared to previous submissions. The PBAC was advised that given the
issues of trial selection, and the use of “lumped” endpoints, the evidence to support
non-inferiority remains very uncertain.
The PBAC noted the Pre-Sub-Committee response stated that “although MMSE data were
not included in memantine trials due to the lack of reliability in more severe Alzheimer’s
disease, this should not preclude the use of MMSE for initiation and continuation
of memantine for moderately severe Alzheimer’s disease.” The Committee agreed that
MMSE remained an appropriate means of determining eligibility for initial and continuing
treatment for the anti-dementia drugs.
With respect to the trial data presented the PBAC noted that in the memantine studies
versus placebo, in general there were no statistically significant differences in
most of the outcomes between treatments. The only statistically significant differences
(p<0.05) were ADAS-Cog responder (99769), ADAS-cog (MD-10), and SIB (Severe Impairment
Battery), FAST (Functional Assessment Staging), ADCS-ADL-css (9605), favouring memantine.
There was however, no significant difference in MMSE score in study 9605. For donepezil,
galantamine and rivastigmine, in trials versus placebo there were statistically significance
differences in most, but not all outcomes, favouring the active arms.
The PBAC also noted that in contrast to the results of the individual trials, which
suggested that there were only a few statistically significant differences between
memantine and placebo and the effect sizes were small, the grouping of outcomes into
domains (global, cognition, disability, behaviour) produced statistically significant
differences between memantine and placebo and no significant differences between memantine
and the AChEIs, except on the “cognition domain”. The PBAC considered the results
of the meta-analysis must be interpreted with caution, given the poorly justified
exclusion of many trials. There were also some statistical and methodological issues
in relation to the meta-analysis itself.
Overall, the PBAC considered that in the context of moderately severe Alzheimer’s
disease compared to mild disease that greater weight that could be attributed to the
non-cognitive domains and a recommendation to list memantine as an additional treatment
option for the treatment of moderately severe Alzheimer’s disease on the basis of
a ‘better’ safety profile but lesser efficacy associated with some uncertainty compared
with the AChEIs, was acceptable.
Recommendation
MEMANTINE HYDROCHLORIDE, tablet, 10 mg, and oral solution, 10 mg per mL,
50 mL.
Restriction:
Authority required
INITIAL APPLICATION FOR THE TREATMENT OF MODERATELY SEVERE ALZHEIMER'S DISEASE — Patients
with an (S)MMSE of 10-14.
Initial treatment, as the sole PBS-subsidised therapy, of moderately severe Alzheimer's
disease. Confirmation of this diagnosis must be made by a specialist/consultant physician
(including a psychiatrist).
The authority application must include the result of the baseline Mini-Mental State
Examination (MMSE) or Standardised Mini-Mental State Examination (SMMSE). This baseline
(S)MMSE must be a score of 10 -14;
This application must be made in writing, but initial supply may be sought by telephone.
For telephone applications, up to a maximum of 2 months' initial therapy will be authorised.
This telephone application must be followed by a written authority application for
no more than 1 month's therapy and sufficient repeats to complete a maximum of up
to 6 months' initial treatment.
For written applications where no prior telephone approval has been issued, up to
a maximum of 1 month's therapy plus 5 repeats will be authorised.
CONTINUING TREATMENT — (S)MMSE
Continuing treatment, as the sole PBS-subsidised therapy, following initial PBS-subsidised
therapy, of moderately severe Alzheimer's disease in patients with demonstrated improvement
in cognitive function as measured by an increase of at least 2 points from baseline
on the Mini-Mental State Examination (MMSE) or Standardised Mini-Mental State Examination
(SMMSE);
The initial authority application for continuing treatment must include the relevant
result from the (S)MMSE and must be in writing.
Subsequent applications for continuing treatment can be made by telephone.
Authority required
INITIAL APPLICATION FOR THE TREATMENT OF MODERATELY SEVERE ALZHEIMER'S DISEASE — Patients
with an (S)MMSE of 9 or less who require a clinician's assessment.
Initial treatment, as the sole PBS-subsidised therapy, of moderately severe Alzheimer's
disease of patients with a baseline Mini-Mental State Examination (MMSE) or Standardised
Mini-Mental State Examination (SMMSE) score of 9 or less, who are unable to register
a score of 10-14 for reasons other than their Alzheimer's disease, as specified below.
Confirmation of this diagnosis must be made by a specialist/consultant physician (including
a psychiatrist).
Such patients will need to be assessed using the Clinicians Interview Based Impression
of Severity (CIBIS) scale. The authority application must include the result of the
baseline (S)MMSE and specify to which group(s) (see below) the patient belongs.
This application must be made in writing, but initial supply may be sought by telephone.
For telephone applications, up to a maximum of 2 months' initial therapy will be authorised.
This telephone application must be followed by a written authority application for
no more than 1 month's therapy and sufficient repeats to complete a maximum of up
to 6 months' initial treatment.
For written applications where no prior telephone approval has been issued, up to
a maximum of 1 month's therapy plus 5 repeats will be authorised.
Patients who qualify under this criterion are from 1 or more of the following groups:
(1) Unable to communicate adequately because of lack of competence in English, in
people of non-English speaking background;
(2) Limited education, as defined by less than 6 years of education, or who are illiterate
or innumerate;
(3) Aboriginal or Torres Strait Islanders who, by virtue of cultural factors, are
unable to complete an (S)MMSE test;
(4) Intellectual (developmental or acquired) disability, eg Down's syndrome;
(5) Significant sensory impairment despite best correction, which precludes completion
of an (S)MMSE test;
(6) Prominent dysphasia, out of proportion to other cognitive and functional impairment.
CONTINUING TREATMENT — Clinician assessed improvement.
Continuing treatment, as the sole PBS-subsidised therapy, following initial PBS-subsidised
therapy, of moderately severe Alzheimer's disease in patients with demonstrated improvement
in function, based on a rating of "very much improved" or "much improved" on the Clinicians
Interview Based Impression of Change (CIBIC) scale, which must be assessed by the
same clinician who initiated treatment.
The initial authority application for continuing treatment must state the improvement
achieved on the CIBIC scale and must be in writing.
Subsequent applications for continuing treatment can be made by telephone.
Authority required
APPLICATION FOR THE TREATMENT OF MODERATELY SEVERE ALZHEIMER'S DISEASE — Patients
who commenced treatment prior to 1 March 2008.
Continuing treatment, as the sole PBS-subsidised therapy, of a patient commenced on
memantine prior to 1 March 2008.
Applications for continuing treatment can be made by telephone.
Maximum quantity: 56 (tablet), 1 (oral solution)
Repeats: 5 (both forms)
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
Lundbeck Australia welcomes the PBAC’s decision to recommend Ebixa for listing on
the PBS for the treatment of moderately severe Alzheimer’s disease. However, the Sponsor
contends that Ebixa is equivalent to the acetylcholinesterase inhibitors in this spectrum
of the Alzheimer’s disease population.
