Skip to Content

UK Edition. Click here for US version.

MEMANTINE SANDOZ 10 MG/ML ORAL SOLUTION

Active substance(s): MEMANTINE HYDROCHLORIDE / MEMANTINE HYDROCHLORIDE

View full screen / Print PDF » Download PDF ⇩
Transcript
SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Memantine Sandoz 10 mg/ml Oral Solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of memantine oral solution contains 10 mg memantine hydrochloride
which is equivalent to 8.31 mg of memantine.
Excipient(s) with known effect: each ml contains 89 mg sorbitol, liquid (non
crystallising).
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Oral Solution.
Colourless and clear solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of patients with moderate 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 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 of 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.
Memantine tablets should be administered once a day and should be taken at the same
time every day.
Memantine oral solution should be taken once daily at the same time each day. The
prescribed amount of solution withdrawn from the bottle with the oral syringe may be
swallowed directly from the oral syringe or mixed in a small glass of water before
intake. For detailed instructions on the preparation and handling of the product see
section 6.6.
The solution and film-coated tablets can be taken with or without food.
Adults:
Dose titration
The recommended starting dose is 5 mg per day, which is stepwise increased over the
first 4 weeks of treatment reaching the recommended maintenance dose as follows:
Week 1 (day 1-7):
The patient should take half a 10 mg tablet or quarter of a 20 mg tablet or 0.5 ml of
the solution, equivalent to 5 mg per day, for 7 days.
Week 2 (day 8-14):
The patient should take one 10 mg tablet or half a 20 mg tablet or 1 ml of the
solution, equivalent to 10 mg per day, for 7 days.
Week 3 (day 15-21):
The patient should take one and a half 10 mg tablet or three quarters of a 20 mg tablet
or 1.5 ml of the solution, equivalent to 15 mg per day, for 7 days.
From Week 4 on:
The patient should take one 20 mg tablet or two 10 mg tablets or 2 ml of the solution
equivalent to 20 mg per day, once a 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 (one 20 mg tablet/two 10 mg tablets/2 ml from
the solution) as described above.
Paediatric population: Memantine is not recommended for use in children below 18
years due to a lack of data on safety and efficacy.
Renal impairment: In patients with mildly impaired renal function (creatinine
clearance 50 - 80 ml/min) no dosage adjustment is required. In patients with moderate
renal impairment (creatinine clearance 30 - 49 ml/min) daily dose should be 10 mg (1

ml from the solution). If tolerated well after at least 7 days 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 mg (1 ml from the solution) per day.
Hepatic impairment: In patients with mild or moderate hepatic impaired function
(Child-Pugh A and Child-Pugh B) no dosage adjustment is needed. No data on the
use of memantine in patients with severe hepatic impairment are available.
Administration of memantine is not recommended in patients with severe hepatic
impairment.

4.3

Contraindications
Hypersensitivity to the active substance memantine or to any of the excipients listed
in section 6.1.

4.4

Special warnings and precautions for use
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 CNSrelated) 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), or uncontrolled hypertension were excluded.
As a consequence, only limited data are available and patients with these conditions
should be closely supervised.
The oral solution contains sorbitol (E 420). Patients with rare hereditary problems of
fructose intolerance should not take this medicine.

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 NMDAantagonists. 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 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) increases 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 for patients concomitantly treated with oral
anticoagulants.
In single dose PK studies in young healthy subjects no relevant drug-drug interaction
of memantine with glyburide/metformin or donepezil was observed.
In a clinical study in young healthy volunteers no relevant effect of memantine on the
pharmacokinetics of galantamine was observed.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing
monooxygenase, epoxide hydrolase or sulphation in vitro.

4.6

Fertility, 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
that 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.
Breastfeeding: It is not known whether memantine is excreted in human 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
Moderate to severe Alzheimer's disease usually causes impairment of driving
performance and compromises the ability to use machinery. Furthermore, memantine
has minor or moderate influence on the ability to drive and use machines, such that
outpatients should take special care.

4.8

Undesirable effects
In clinical trials in mild to severe dementia, involving 1,784 patients treated with
memantine and 1,595 patients treated with placebo, the overall incidence rate of
adverse events with memantine did not differ from those with placebo; the adverse
events were usually mild to moderate in severity. The most frequently occurring
adverse events with a higher incidence in the memantine group than in the placebo
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 Drug Reactions listed in the Table below have been
accumulated in clinical studies with memantine 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)

Infections and infestations

Uncommon

Fungal infections

Immune system disorders
Psychiatric disorders

Common
Common

Drug Hypersensitivity
Somnolence

Uncommon

Confusion

Uncommon

Hallucinations1

Not known
Common

Psychotic reactions2
Dizziness

Common

Balance disorders

Uncommon

Gait abnormal

Very rare

Seizures

Uncommon
Common

Cardiac failure
Hypertension

Uncommon

Venous
thrombosis/thromboembolism

Common

Dyspnoea

Nervous system disorders

Cardiac disorders
Vascular disorders

Respiratory, thoracic and
mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders

Common

Constipation

Uncommon

Vomiting

Not known

Pancreatitis2

Common

Elevated liver function test

Not Known

Hepatitis

General disorders and administration Common
site conditions
Uncommon

Headache
Fatigue

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 post-marketing experience these events have been reported in patients
treated with memantine.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9

Overdose
Only limited experience with overdose is available from clinical studies and postmarketing experience.
Symptoms: Relatively 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 the overdose cases below 140 mg or unknown
dose the patients revealed symptoms from central nervous 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 overdosage, 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 received 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 overdosage, treatment should be symptomatic. No specific
antidote for intoxication or overdose is available. Standard clinical procedures to
remove active substance material, 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 CNS overstimulation, careful symptomatic
clinical treatment should be considered.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Psychoanaleptics, 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.
Pharmacodynamic effects
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 efficacy and safety
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 disease (MMSE total scores at baseline of 10 to 22) included 403
patients. Memantine-treated patients showed 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 randomised. 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 studies 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-treated patients as memantine-treated patients showed worsening in all
three domains (21% vs. 11%, p<0.0001).

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.
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 the parent compound. Main human metabolites are N-3,5-dimethylgludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5dimethyl-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.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the
dose range of 10 to 40 mg.
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 that are identical or slightly higher
than at human exposure.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Potassium sorbate
Sorbitol, liquid (non crystallising) (E420)
Sodium hydroxide (for pH adjustment)
Hydrochlorid acid (for pH adjustment)
Purified water

6.2

Incompatibilities
Not applicable

6.3

Shelf life
4 years
Shelf life after first opening container: 6 months.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container
The oral solution is packed in amber glass bottles type III closed with a HDPE screw
cap with tamper-evident ring. The bottle is packed in a carton box together with a 2
ml oral syringe (LDPE and PS) connected to a press-in bottle adapter (LDPE). The
oral syringe has a main graduation in steps of 0.5 ml and 5 mg (0.5, 1, 1.5 2 ml
respectively 5, 10, 15, 20 mg) and a fine graduation in steps of 0.1 ml (= 1 mg).
Pack sizes:
20 ml, 50 ml or 100 ml oral solution
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
Instructions on the preparation and handling of the oral solution
The medicine-kit consists of three parts:


a bottle containing solution



a plastic adapter, connected to



a 2 ml oral syringe, with 0.5 ml graduations

Before the first use
Hold the open bottle upright on a table. Remove the plastic adapter from the oral
syringe and push it firmly into the neck of the bottle, as far as you can. The adapter
must be kept in the bottle until the last dose is withdrawn. To dispense a dose, please
follow all instructions in "Preparing a dose" up to "Cleaning".

Preparing a dose
Turn the cap to open the bottle. Check the plunger is fully down inside the barrel of
the oral syringe.
Keep the bottle upright and insert the oral syringe firmly into the plastic adapter, as
shown in the picture.

Withdrawing the dose
Hold the oral syringe in place and carefully turn the bottle upside down. Slowly pull
the plunger of the syringe down fully so that the oral syringe fills with solution. Push
the plunger back up completely to expel any large air bubbles that may be trapped
inside the oral syringe.
Slowly pull the plunger down until the barrel ring reaches the mark corresponding to
the number of milliliters or milligrams you need to take (0.5 ml = 5 mg, 1 ml = 10
mg, 1.5 ml = 15 mg, 2 ml = 20 mg).

Carefully turn the bottle the right way up. Disconnect the oral syringe by gently
twisting it out of the plastic adapter.

Administering the dose
The solution can be swallowed directly from the oral syringe. The patient must be
sitting upright and the plunger must be pushed slowly to allow the patient to swallow.
Alternatively, the dose can be mixed in a small glass of water just prior to
administration. Stir and drink the entire mixture right away.

The oral solution can be taken with or without food.
Replace the cap after use, leaving the adapter in place.

Cleaning
After use, wipe the outside of the oral syringe with a dry, clean tissue.

7

MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park, Frimley,
Camberley, Surrey, GU16 7SR
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1357

9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/07/2013

10

DATE OF REVISION OF THE TEXT
04/07/2013

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide