Treatment of patients with moderate to severe Alzheimer’s disease.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and
treatment of Alzheimer’s dementia. Therapy should only be started if a caregiver is available who w
regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made
according to current guidelines. The tolerance and dosing of memantine should be reassessed on a
regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit
memantine and the patient’s tolerance of treatment should be reassessed on a regular basis according
to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic
benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of
memantine should be considered when evidence of a therapeutic effect is no longer present or if the
patient does not tolerate treatment.
Ebixa should be administered once a day and should be taken at the same time every day. The filmcoated
tablets can be taken with or without food.
Adults:
Dose titration
The maximum daily dose is 20 mg per day. In order to reduce the risk of undesirable effects, the
maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows
Week 1 (day 1-7):
The patient should take half a 10 mg film-coated tablet (5 mg) per day for 7 days.
Week 2 (day 8-14):
The patient should take one 10 mg film-coated tablet (10 mg) per day for 7 days.

Week 3 (day 15-21):
The patient should take one and a half 10 mg film-coated tablets (15 mg) per day for 7 days.
From Week 4 on:
The patient should take two 10 mg film-coated tablets (20 mg) per day.
Maintenance dose
The recommended maintenance dose is 20 mg per day.
Elderly: On the basis of the clinical studies, the recommended dose for patients over the age of 65
years is 20 mg per day (two 10 mg film-coated tablets once a day) as described above.
Children and adolescents: Ebixa is not recommended for use in children below 18 years due to a lac
of data on safety and efficacy.
Renal impairment: In patients with mildly impaired renal function (creatinine clearance 50 – 80
ml/min) no dose adjustment is required. In patients with moderate renal impairment (creatinine
clearance 30 – 49 ml/min) daily dose should be 10 mg per day. If tolerated well after at least 7 day
of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In
patients with severe renal impairment (creatinine clearance 5 – 29 ml/min) daily dose should be 10 m
per day.

Hepatic impairment: In patients with mild or moderate hepatic impaired function (Child-Pugh A an
Child-Pugh B), no dose adjustment is needed. No data on the use of memantine in patients with seve
hepatic impairment are available. Administration of Ebixa is not recommended in patients with seve
hepatic impairment.

Caution is recommended in patients with epilepsy, former history of convulsions or patients with
predisposing factors for epilepsy.
Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or
dextromethorphan should be avoided. These compounds act at the same receptor system as
memantine, and therefore adverse reactions (mainly central nervous system (CNS)-related) may be
more frequent or more pronounced (see also section 4.5).
Some factors that may raise urine pH (see section 5.2 “Elimination”) may necessitate careful
monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a
vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated
states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria
In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart
failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited
data are available and patients with these conditions should be closely supervised.

Due to the pharmacological effects and the mechanism of action of memantine the following
interactions may occur:

• The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and
anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as
memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant
administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modi
their effects and a dose adjustment may be necessary.
• Concomitant use of memantine and amantadine should be avoided, owing to the risk of
pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The
same may be true for ketamine and dextromethorphan (see also section 4.4). There is one
published case report on a possible risk also for the combination of memantine and phenytoin
• Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and
nicotine that use the same renal cationic transport system as amantadine may also possibly
interact with memantine leading to a potential risk of increased plasma levels.
• There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when
memantine is co-administered with HCT or any combination with HCT.
• In post-marketing experience, isolated cases with international normalized ratio (INR) increas
have been reported in patients concomitantly treated with warfarin. Although no causal
relationship has been established, close monitoring of prothrombin time or INR is advisable fo
patients concomitantly treated with oral anticoagulants.
In single-dose pharmacokinetic (PK) studies in young healthy subjects, no relevant active substance
active substance interaction of memantine with glyburide/metformin or donepezil was observed.
In a clinical study in young healthy subjects, no relevant effect of memantine on the pharmacokineti
of galantamine was observed.

Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase,
epoxide hydrolase or sulphation in vitro.

For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a
potential for reducing intrauterine growth at exposure levels, which are identical or slightly higher
than at human exposure (see section 5.3). The potential risk for humans is unknown. Memantine
should not be used during pregnancy unless clearly necessary.
It is not known whether memantine is excreted in human breast milk but, taking into consideration t
lipophilicity of the substance, this probably occurs. Women taking memantine should not breast-fee

Moderate to severe Alzheimer’s disease usually causes impairment of driving performance and
compromises the ability to use machinery. Furthermore, Ebixa has minor to moderate influence on t
ability to drive and use machines such that outpatients should be warned to take special care.

In clinical trials in mild to severe dementia, involving 1,784 patients treated with Ebixa and 1,595
patients treated with placebo, the overall incidence rate of adverse reactions with Ebixa did not diffe
from those with placebo; the adverse reactions were usually mild to moderate in severity. The most
frequently occurring adverse reactions with a higher incidence in the Ebixa group than in the placeb
group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs
2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%).
The following Adverse Reactions listed in the Table below have been accumulated in clinical studie
with Ebixa and since its introduction in the market. Within each frequency grouping, undesirable
effects are presented in order of decreasing seriousness.

Adverse reactions are ranked according to system organ class, using the following convention: very
common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥1/10,000 to
1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

1 Hallucinations have mainly been observed in patients with severe Alzheimer’s disease.
2 Isolated cases reported in post-marketing experience.

Alzheimer’s disease has been associated with depression, suicidal ideation and suicide. In postmarketing
experience these events have been reported in patients treated with Ebixa.

Only limited experience with overdose is available from clinical studies and post-marketing
experience.

Symptoms: Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been
associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In th
overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervou
system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait
disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).
In the most extreme case of overdose, the patient survived the oral intake of a total of 2000 mg
memantine with effects on the central nervous system (coma for 10 days, and later diplopia and
agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered
without permanent sequelae.
In another case of a large overdose, the patient also survived and recovered. The patient had receive
400 mg memantine orally. The patient experienced central nervous system symptoms such as
restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and
unconsciousness.
Treatment: In the event of overdose, treatment should be symptomatic. No specific antidote for
intoxication or overdose is available. Standard clinical procedures to remove active substance mater
e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation),
acidification of urine, forced diuresis should be used as appropriate.
In case of signs and symptoms of general central nervous system (CNS) overstimulation, careful
symptomatic clinical treatment should be considered.

Pharmacotherapeutic group: Other Anti-dementia drugs, ATC code: N06DX01.
There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular a
NMDA-receptors, contributes to both expression of symptoms and disease progression in
neurodegenerative dementia.
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It
modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal
dysfunction.
Clinical studies: A pivotal monotherapy study in a population of patients suffering from moderate to
severe Alzheimer’s disease (mini mental state examination (MMSE) total scores at baseline of 3 - 14
included a total of 252 outpatients. The study showed beneficial effects of memantine treatment in
comparison to placebo at 6 months (observed cases analysis for the clinician´s interview based
impression of change (CIBIC-plus): p=0.025; Alzheimer’s disease cooperative study – activities of
daily living (ADCS-ADLsev): p=0.003; severe impairment battery (SIB): p=0.002).
A pivotal monotherapy study of memantine in the treatment of mild to moderate Alzheimer’s diseas
(MMSE total scores at baseline of 10 to 22) included 403 patients. Memantine-treated patients show
a statistically significantly better effect than placebo-treated patients on the primary endpoints:
Alzheimer’s disease assessment scale (ADAS-cog) (p=0.003) and CIBIC-plus (p=0.004) at week 24
(last observation carried forward (LOCF)). In another monotherapy study in mild to moderate
Alzheimer’s disease a total of 470 patients (MMSE total scores at baseline of 11-23) were randomis
In the prospectively defined primary analysis statistical significance was not reached at the primary
efficacy endpoint at week 24.
A meta-analysis of patients with moderate to severe Alzheimer’s disease (MMSE total scores < 20)
from the six phase III, placebo-controlled, 6-month studies (including monotherapy studies and stud

with patients on a stable dose of acetylcholinesterase inhibitors) showed that there was a statistically
significant effect in favour of memantine treatment for the cognitive, global, and functional domains
When patients were identified with concurrent worsening in all three domains, results showed a
statistically significant effect of memantine in preventing worsening, as twice as many placebo-treat
patients as memantine-treated patients showed worsening in all three domains (21% vs. 11%,
p<0.0001).

Absorption: Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 an
8 hours. There is no indication that food influences the absorption of memantine.
Distribution: Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging
from 70 to 150 ng/ml (0.5 - 1 μmol) with large interindividual variations. When daily doses of 5 to
30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The
volume of distribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.
Biotransformation: In man, about 80% of the circulating memantine-related material is present as th
parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4
and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhib
NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro
In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered withi
20 days, more than 99% being excreted renally.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to
100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to
170 ml/min/1.73 m² and part of total renal clearance is achieved by tubular secretion.
Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. T
renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7
9 (see section 4.4). Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivo
to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 t
40 mg.
Pharmacokinetic/pharmacodynamic relationship: At a dose of memantine of 20 mg per day the CSF
levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 μmol in human fronta
cortex.

vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum
concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As t
effects have neither been observed in long term studies in rodents nor in non-rodents, the clinical
relevance of these findings is unknown.
Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, but
not in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did not
disclose any ocular changes.
Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes was
observed in rodents. This effect is known from other active substances with cationic amphiphilic
properties. There is a possible relationship between this accumulation and the vacuolisation observe

in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these
findings is unknown.
No genotoxicity has been observed following testing of memantine in standard assays. There was no
evidence of any carcinogenicity in life long studies in mice and rats. Memantine was not teratogenic
rats and rabbits, even at maternally toxic doses, and no adverse effects of memantine were noted on
fertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightly
higher than at human exposure.

Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Tablet coat:
Hypromellose
Macrogol 400
Titanium dioxide (E 171)
Iron oxide yellow (E 172)

Not applicable.

This medicinal product does not require any special storage conditions.

Blister packs containing either 7, 10, 14 or 20 tablets per blister strip. Pack sizes of 14, 28, 30, 42, 4
1, 50, 56, 56 x 1, 70, 84, 98, 98 x 1, 100, 100 x 1, 112, 980 (10 x 98) or 1000 (20 x 50) tablets are
presented. The pack sizes 49 x 1, 56 x1, 98 x 1 and 100 x 1 film-coated tablets are presented in unit
dose blister.
Not all pack sizes may be marketed.

No special requirements.