Spc-axura-en with marked changes.doc

SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Axura 10 mg film-coated tablets.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg of memantine hydrochloride (equivalent to 8.31 mg memantine).
For excipients, see section 6.1.
3.
PHARMACEUTICAL FORM

Film-coated tablets.
The film-coated tablets are white to off-white, centrally tapered oblong, biconvex, with a
single breakline on both sides.
4.
CLINICAL PARTICULARS

4.1 Therapeutic indications
Treatment of patients with moderately severe to severe Alzheimer’s disease.
4.2 Posology and method of administration
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 will regularly monitor drug intake by the patient. Diagnosis should be made according to
current guidelines.
Adults: The maximum daily dose is 20 mg per day. In order to reduce the risk of side effects the
maintenance dose is achieved by upward titration 5 mg per week over the first 3 weeks as
follows: Treatment should be started with 5 mg daily (half a tablet in the morning) during the
1st week. In the 2nd week 10 mg per day (half a tablet twice a day) and in the 3rd week 15 mg
per day is recommended (one tablet in the morning and half a tablet in the afternoon). From the
4th week on, treatment can be continued with the recommended maintenance dose of 20 mg per
day (one tablet twice a day).
The tablets can be taken with or without food.
Elderly: On the basis of the clinical studies the recommended dose for patients over the age of
65 years is 20 mg per day (10 mg twice a day) as described above.

Children and adolescents under the age of 18 years: The safety and efficacy of memantine in
children and adolescents have not been established.

Renal impairment: In patients with normal to mildly impaired renal function (serum
creatinine levels of up to 130 µmol/l) no dose reduction is needed. In patients with moderate
renal impairment (creatinine clearance 40 - 60 ml/min/1.73 m²) daily dose should be reduced
to 10 mg per day. No data are available for patients with severely reduced kidney function
(see sections 4.4 and 5.2).

Hepatic impairment: There are no data on the use of memantine in patients with hepatic
impairment (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
As no data are available for patients with severe renal impairment (creatinine clearance less than
9 ml/min/1.73 m²) therapy is not recommended (see section 4.2).
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 drug reactions (mainly 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 by 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), and uncontrolled hypertension were excluded. As a
consequence, only limited data are available and patients with these conditions should be
closely supervised.
4.5 Interaction with other medicinal products and other forms of interaction
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 modify their effects and a dosage 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 drugs 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.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing
monooxygenase, epoxide hydrolase and sulphation in vitro.
4.6 Pregnancy and lactation
Pregnancy: 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.
Lactation: It is not known whether memantine is excreted in humans breast milk but, taking
into consideration the lipophilicity of the substance, this probably occurs. Women taking
memantine should not breast-feed.
4.7 Effects on ability to drive and use machines
Moderately severe to severe Alzheimer’s disease usually causes impairment of driving
performance and compromises the ability to use machinery. Furthermore, memantine may
change reactivity such that outpatients should be warned to take special care when driving a
vehicle or operating machinery.
4.8 Undesirable effects

In clinical trials in moderately severe to severe dementia, overall incidence rates for adverse
events did not differ from placebo treatment and adverse events were usually mild to moderate
in severity.
The following table gives an overview of the most frequent (> 4% for memantine) adverse
events (irrespective of causal relationship) that were observed in the trial population of
patients with moderately severe to severe dementia.
Common adverse reactions (1 - 10% and more frequent than with placebo) for memantine and
placebo patients respectively were: hallucinations (2.0 vs. 0.7%), confusion (1.3 vs. 0.3%),
dizziness (1.7 vs. 1.0%), headache (1.7 vs. 1.4%) and tiredness (1.0 vs. 0.3%).
Uncommon adverse reactions (0.1 - 1% and more frequent than with placebo) were anxiety,
hypertonia (increased muscle tone), vomiting, cystitis and increased libido.
Based on spontaneous reports, seizures have been reported, mostly in patients with a history
of convulsions.
4.9 Overdose
In one case of suicidal overdosage the patient survived the oral intake of up to 400 mg
memantine with effects on the central nervous system (e. g. restlessness, psychosis, visual
hallucinations, proconvulsiveness, somnolence, stupor and unconsciousness) which resolved
without permanent sequelae.
Treatment of overdosage should be symptomatic.
5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-dementia drugs, ATC code: N06DX01.
There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in
particular at 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 blocks the effects of pathologically elevated tonic levels of glutamate that may
lead to neuronal dysfunction.
Clinical studies: A clinical trial in a population of patients suffering from moderately severe
to severe Alzheimer's disease (MMSE total scores at baseline of 3 - 14) showed beneficial
effects of memantine treatment in comparison to placebo over a treatment period of 6 months.
In this multicenter, double-blind, randomised, placebo-controlled study, a total of 252
outpatients (33% male, 67% female, mean age 76 years) were included. The dosing was
10 mg memantine twice a day. Primary outcome parameters included assessment of the global
domain (using the Clinicians Interview-Based Impression of Change (CIBIC-Plus)) and the
functional domain (using the Activities of Daily Living Inventory (ADCS-ADLsev)).
Cognition was assessed as a secondary endpoint with the Severe Impairment Battery (SIB).
The results in these domains favoured memantine over placebo (Observed Cases Analysis for
CIBIC-Plus: p=0.025; ADCS-ADLsev: p=0.003; SIB: p=0.002).
After 6 months, the rate of individual responders (response prospectively defined as
stabilisation or improvement in two independent domains) was 29% for the memantine group
versus 10% for placebo (p=0.0004). With a triple criterion (response defined as stabilisation
or improvement in all three domains: cognition, functional and global domain), there were
11% responders for memantine versus 6% for placebo (p=0.17).

5.2 Pharmacokinetic properties
Absorption: Memantine has an absolute bioavailability of approximately 100%. tmax is
between 3 and 8 hours. There is no indication that food influences the absorption of
memantine.

Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range
of 10 to 40 mg.
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 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 the 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 exhibit 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 within 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. The renal elimination rate of memantine under alkaline urine conditions may be
reduced by a factor of 7 to 9 (see section 4.4). Alkalisation of urine may result from drastic
changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of
alkalising gastric buffers.
Specific patient population: In elderly volunteers with normal and reduced renal function
(creatinine clearance of 50 - 100 ml/min/1.73 m²), a significant correlation was observed
between creatinine clearance and total renal clearance of memantine (see section 4.2).
The effect of liver disease on the pharmacokinetics of memantine has not been studied. As
memantine is metabolised to a minor extent only, and into metabolites with no NMDA-
antagonistic activity, clinically relevant changes in the pharmacokinetics are not expected in
mild to moderate liver impairment.
Pharmacokinetic/pharmacodynamic relationship: At a dose of memantine of 20 mg per day
the cerebrospinal fluid (CSF) levels match the ki-value (ki = inhibition constant) of
memantine, which is 0.5 µmol in human frontal cortex.
5.3 Preclinical safety data
In short term studies in rats memantine like other NMDA-antagonists have induced neuronal
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 the 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 drugs with cationic amphiphilic
properties. There is a possible relationship between this accumulation and the vacuolisation
observed 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 in 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.
6.
PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Colloidal anhydrous silica
Talc
Magnesium stearate
Tablet coat:
Methacrylic acid - ethyl acrylate copolymer (1:1)
Sodium lauryl sulphate
Polysorbate 80
Talc
Triacetin
Simethicone emulsion
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
Blister packs containing either 7, 10, 14 or 20 tablets per blister strip (Alu/PP). Pack sizes of
28, 30, 50, 56, 100, 112 or 1000 (20 x 50) tablets are presented.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
No special requirements.
7.
MARKETING AUTHORISATION HOLDER

Merz Pharmaceuticals GmbH
Eckenheimer Landstr. 100
D-60318 Frankfurt/Main
Germany
8.
MARKETING AUTHORISATION NUMBER(S)

EU/1/02/218/001
EU/1/02/218/002
EU/1/02/218/003
EU/1/02/218/007
EU/1/02/218/008
EU/1/02/218/009
EU/1/02/218/010
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/05/2002
10. DATE OF REVISION OF THE TEXT
SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Axura 10 mg/g oral drops, solution.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of solution contains 10 mg of memantine hydrochloride (equivalent to 8.31 mg memantine).
For excipients, see section 6.1.
3.
PHARMACEUTICAL FORM

Oral drops, solution.
The solution is clear and colourless to light yellowish.
4.
CLINICAL PARTICULARS

4.1 Therape utic indications
Treatment of patients with moderately severe to severe Alzheimer’s disease.
4.2 Posology and method of administration
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 will regularly monitor drug intake by the patient. Diagnosis should be made according to
current guidelines.
Adults: The maximum daily dose is 20 mg per day. In order to reduce the risk of side effects the
maintenance dose is achieved by upward titration 5 mg per week over the first 3 weeks as
follows: Treatment should be started with 5 mg daily (10 drops in the morning) during the 1st
week. In the 2nd week 10 mg per day (10 drops twice a day) and in the 3rd week 15 mg per day
is recommended (20 drops in the morning and 10 drops in the afternoon). From the 4th week
on, treatment can be continued with the recommended maintenance dose of 20 mg per day
(20 drops twice a day).
The drops can be taken with or without food.
Elderly: On the basis of the clinical studies the recommended dose for patients over the age of
65 years is 20 mg per day (10 mg twice a day) as described above.

Children and adolescents under the age of 18 years: The safety and efficacy of memantine in
children and adolescents have not been established.

Renal impairment: In patients with normal to mildly impaired renal function (serum
creatinine levels of up to 130 µmol/l) no dose reduction is needed. In patients with moderate
renal impairment (creatinine clearance 40 - 60 ml/min/1.73 m²) daily dose should be reduced
to 10 mg per day. No data are available for patients with severely reduced kidney function
(see sections 4.4 and 5.2).
Hepatic impairment: There are no data on the use of memantine in patients with hepatic
impairment (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
As no data are available for patients with severe renal impairment (creatinine clearance less than
9 ml/min/1.73 m²) therapy is not recommended (see section 4.2).
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 drug reactions (mainly 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 by 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), and uncontrolled hypertension were excluded. As a
consequence, only limited data are available and patients with these conditions should be
closely supervised.
4.5 Interaction with other medicinal products and other forms of interaction
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 modify their effects and a dosage 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 drugs 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.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing
monooxygenase, epoxide hydrolase and sulphation in vitro.
4.6 Pregnancy and lactation
Pregnancy: 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.
Lactation: It is not known whether memantine is excreted in humans breast milk but, taking
into consideration the lipophilicity of the substance, this probably occurs. Women taking
memantine should not breast-feed.
4.7 Effects on ability to drive and use machines
Moderately severe to severe Alzheimer’s disease usually causes impairment of driving
performance and compromises the ability to use machinery. Furthermore, memantine may
change reactivity such that outpatients should be warned to take special care when driving a
vehicle or operating machinery.
4.8 Undesirable effects

In clinical trials in moderately severe to severe dementia, overall incidence rates for adverse
events did not differ from placebo treatment and adverse events were usually mild to moderate
in severity.
The following table gives an overview of the most frequent (> 4% for memantine) adverse
events (irrespective of causal relationship) that were observed in the trial population of
patients with moderately severe to severe dementia.
Common adverse reactions (1 - 10% and more frequent than with placebo) for memantine and
placebo patients respectively were: hallucinations (2.0 vs. 0.7%), confusion (1.3 vs. 0.3%),
dizziness (1.7 vs. 1.0%), headache (1.7 vs. 1.4%) and tiredness (1.0 vs. 0.3%).
Uncommon adverse reactions (0.1 - 1% and more frequent than with placebo) were anxiety,
hypertonia (increased muscle tone), vomiting, cystitis and increased libido.
Based on spontaneous reports, seizures have been reported, mostly in patients with a history
of convulsions.
4.9 Overdose
In one case of suicidal overdosage the patient survived the oral intake of up to 400 mg
memantine with effects on the central nervous system (e. g. restlessness, psychosis, visual
hallucinations, proconvulsiveness, somnolence, stupor and unconsciousness) which resolved
without permanent sequelae.
Treatment of overdosage should be symptomatic.
5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-dementia drugs, ATC code: N06DX01.
There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in
particular at 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 blocks the effects of pathologically elevated tonic levels of glutamate that may
lead to neuronal dysfunction.
Clinical studies: A clinical trial in a population of patients suffering from moderately severe
to severe Alzheimer's disease (MMSE total scores at baseline of 3 - 14) showed beneficial
effects of memantine treatment in comparison to placebo over a treatment period of 6 months.
In this multicenter, double-blind, randomised, placebo-controlled study, a total of 252
outpatients (33% male, 67% female, mean age 76 years) were included. The dosing was
10 mg memantine twice a day. Primary outcome parameters included assessment of the global
domain (using the Clinicians Interview-Based Impression of Change (CIBIC-Plus)) and the
functional domain (using the Activities of Daily Living Inventory (ADCS-ADLsev)).
Cognition was assessed as a secondary endpoint with the Severe Impairment Battery (SIB).
The results in these domains favoured memantine over placebo (Observed Cases Analysis for
CIBIC-Plus: p=0.025; ADCS-ADLsev: p=0.003; SIB: p=0.002).
After 6 months, the rate of individual responders (response prospectively defined as
stabilisation or improvement in two independent domains) was 29% for the memantine group
versus 10% for placebo (p=0.0004). With a triple criterion (response defined as stabilisation
or improvement in all three domains: cognition, functional and global domain), there were
11% responders for memantine versus 6% for placebo (p=0.17).
5.2 Pharmacokinetic properties
Absorption: Memantine has an absolute bioavailability of approximately 100%. tmax is
between 3 and 8 hours. There is no indication that food influences the absorption of
memantine.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range
of 10 to 40 mg.
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 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 the 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 exhibit 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 within 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. The renal elimination rate of memantine under alkaline urine conditions may be
reduced by a factor of 7 to 9 (see section 4.4). Alkalisation of urine may result from drastic
changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of
alkalising gastric buffers.
Specific patient population: In elderly volunteers with normal and reduced renal function
(creatinine clearance of 50 - 100 ml/min/1.73 m²), a significant correlation was observed
between creatinine clearance and total renal clearance of memantine (see section 4.2).
The effect of liver disease on the pharmacokinetics of memantine has not been studied. As
memantine is metabolised to a minor extent only, and into metabolites with no NMDA-
antagonistic activity, clinically relevant changes in the pharmacokinetics are not expected in
mild to moderate liver impairment.
Pharmacokinetic/pharmacodynamic relationship: At a dose of memantine of 20 mg per day
the cerebrospinal fluid (CSF) levels match the ki-value (ki = inhibition constant) of
memantine, which is 0.5 µmol in human frontal cortex.
5.3 Preclinical safety data
In short term studies in rats memantine like other NMDA-antagonists have induced neuronal
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 the 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 drugs with cationic amphiphilic
properties. There is a possible relationship between this accumulation and the vacuolisation
observed 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 in 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.
6.
PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Potassium sorbate
Sorbitol
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
Once opened, the contents of the bottle should be used within 3 months.
6.4 Special precautions for storage
Do not store above 30ºC.
6.5 Nature and contents of container
Brown glass bottles (Hydrolytic Class III) with dropper containing either 20, 50, 100 g or 10 x
50 g solution.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
No special requirements.
MARKETING AUTHORISATION HOLDER

Merz Pharmaceuticals GmbH
Eckenheimer Landstr. 100
D-60318 Frankfurt/Main
Germany
8.
MARKETING AUTHORISATION NUMBER(S)

EU/1/02/218/004
EU/1/02/218/005
EU/1/02/218/006
EU/1/02/218/011
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/05/2002
10. DATE OF REVISION OF THE TEXT

Source: http://download.merz.de/axura-info/pdf/memantine_product_characteristics.pdf