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Memantine ratiopharm (memantine hydrochloride) – Summary of product characteristics - N06DX01

Updated on site: 08-Oct-2017

Medication nameMemantine ratiopharm
ATC CodeN06DX01
Substancememantine hydrochloride
ManufacturerRatiopharm GmbH

1.NAME OF THE MEDICINAL PRODUCT

Memantine ratiopharm 10 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg of memantine hydrochloride equivalent to 8.31 mg memantine.

Excipients with known effect

Lactose (80 mg/film-coated tablet) and soya lecithin (0.13 mg/film-coated tablet).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet (tablet)

The 10 mg film-coated tablets are white to off-white, capsule shaped (12.5 x 5.6 mm), biconvex tablets with a break score on one side and embossed with “10” on the other side.

The tablet can be divided into equal doses.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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

4.2Posology 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.

Posology

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.

Paediatric population

Memantine ratiopharm 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 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 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 per day.

Hepatic impairment

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

Method of administration

Memantine ratiopharm should be administered once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food.

4.3Contraindications

Hypersensitivity to the active substance, peanut or soya or to any of the excipients listed in section 6.1.

4.4Special 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 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 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.

Excipients

Memantine ratiopharm contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Memantine ratiopharm contains soya lecithin, see section 4.3.

4.5Interaction 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 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) 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 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 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.

4.6Fertility, 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.

Breast-feeding

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.

Fertility

No adverse effects of memantine were noted on fertility in rats and rabbits (see section 5.3).

4.7Effects 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 ratiopharm has minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.

4.8Undesirable effects

Summary of the safety profile

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 reactions with memantine did not differ 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 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%).

Tabulated list of adverse reactions

The following Adverse 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

Common

Drug hypersensitivity

Psychiatric disorders

Common

Somnolence

 

Uncommon

Confusion

 

Uncommon

Hallucinations1

 

Not known

Psychotic reactions2

Nervous system disorders

Common

Dizziness

 

Common

Balance disorders

 

Uncommon

Gait abnormal

 

Very rare

Seizures

Cardiac disorders

Uncommon

Cardiac failure

Vascular disorders

Common

Hypertension

 

Uncommon

Venous

 

 

thrombosis/thromboembolism

Respiratory, thoracic and

Common

Dyspnoea

mediastinal disorders

 

 

Gastrointestinal disorders

Common

Constipation

 

Uncommon

Vomiting

 

Not known

Pancreatitis2

Hepatobiliary disorders

Common

Elevated liver function test

 

Not known

Hepatitis

General disorders and

Common

Headache

administration site conditions

Uncommon

Fatigue

1Hallucinations have mainly been observed in patients with severe Alzheimer’s disease.

2Isolated 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 national reporting system listed in Appendix V.

4.9Overdose

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 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 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 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 overdose, 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 central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Other 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 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 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).

5.2Pharmacokinetic 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-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.

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 CSF levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 μmol in human frontal cortex.

5.3Preclinical 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 active substances 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

6.1List of excipients

Tablet core

Cellulose microcrystalline (E 460)

Starch pregelatinised (E 1404)

Lactose anhydrous

Colloidal anhydrous silica (E 551)

Magnesium stearate (E 470b)

Coating

Polysorbate 80 (E 433)

Polyvinyl alcohol (E 1203)

Titanium dioxide (E 171)

Talc (E 553b)

Soya lecithin (E 322)

Xanthan gum (E 415)

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years

HDPE bottles:

Shelf life after first opening: 6 months

6.4Special precautions for storage

Blister packs:

Do not store above 25°C.

HDPE bottles:

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

PVC/PVDC-Aluminium foil blister packs

Pack sizes of 10, 14, 21, 28, 30, 42, 50, 56, 98, 100, 112 film-coated tablets.

HDPE (high-density polyethylene) bottles with PP (polypropylene) caps

Pack sizes of 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

ratiopharm GmbH Graf-Arco-Straße 3 89079 Ulm Germany

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/13/836/001

EU/1/13/836/002

EU/1/13/836/003

EU/1/13/836/004

EU/1/13/836/005

EU/1/13/836/006

EU/1/13/836/007

EU/1/13/836/008

EU/1/13/836/009

EU/1/13/836/010

EU/1/13/836/011

EU/1/13/836/012

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 June 2013

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Memantine ratiopharm 20 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg of memantine hydrochloride equivalent to 16.62 mg memantine.

Excipients with known effect

Lactose (160 mg/film-coated tablet) and soya lecithin (0.26 mg/film-coated tablet).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

The 20 mg film-coated tablets are white to off-white, capsule shaped (15.6 x 8.0 mm), biconvex tablets with a break score on one side and embossed with “20” on the other side.

The tablet can be divided into equal doses.

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.

Posology

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. For up-titration other tablet strengths are available.

Week 1 (day 1-7):

The patient should take one 5 mg film-coated tablet per day for 7 days.

Week 2 (day 8-14):

The patient should take one 10 mg film-coated tablet per day for 7 days.

Week 3 (day 15-21):

The patient should take one 15 mg film-coated tablet per day for 7 days.

From Week 4 on:

The patient should take one 20 mg film-coated tablet 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 as described above.

Paediatric population

Memantine ratiopharm 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 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 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 per day.

Hepatic impairment

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

Method of administration

Memantine ratiopharm should be administered once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance, peanut or soya 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 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 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.

Excipients

Memantine ratiopharm contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Memantine ratiopharm contains soya lecithin, see section 4.3.

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 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) 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 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 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, 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.

Breast-feeding

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.

Fertility

No adverse effects of memantine were noted on fertility in rats and rabbits (see section 5.3).

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 ratiopharm has minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.

4.8 Undesirable effects

Summary of the safety profile

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 reactions with memantine did not differ 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 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%).

Tabulated list of adverse reactions

The following Adverse 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

Common

Drug hypersensitivity

Psychiatric disorders

Common

Somnolence

 

Uncommon

Confusion

 

Uncommon

Hallucinations1

 

Not known

Psychotic reactions2

Nervous system disorders

Common

Dizziness

 

Common

Balance disorders

 

Uncommon

Gait abnormal

 

Very rare

Seizures

Cardiac disorders

Uncommon

Cardiac failure

Vascular disorders

Common

Hypertension

 

Uncommon

Venous

 

 

thrombosis/thromboembolism

Respiratory, thoracic and

Common

Dyspnoea

mediastinal disorders

 

 

Gastrointestinal disorders

Common

Constipation

 

Uncommon

Vomiting

 

Not known

Pancreatitis2

Hepatobiliary disorders

Common

Elevated liver function test

 

Not known

Hepatitis

General disorders and

Common

Headache

administration site conditions

Uncommon

Fatigue

1Hallucinations have mainly been observed in patients with severe Alzheimer’s disease.

2Isolated 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 national reporting system listed in Appendix V.

4.9 Overdose

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 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 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 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 overdose, 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 central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other 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 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 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-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.

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 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 active substances 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

Cellulose microcrystalline (E 460)

Starch pregelatinised (E 1404)

Lactose anhydrous

Colloidal anhydrous silica (E 551)

Magnesium stearate (E 470b)

Coating

Polysorbate 80 (E 433)

Polyvinyl alcohol (E 1203)

Titanium dioxide (E 171)

Talc (E 553b)

Soya lecithin (E 322)

Xanthan gum (E 415)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

HDPE bottles:

Shelf life after first opening: 6 months

6.4 Special precautions for storage

Blister packs:

Do not store above 25°C.

HDPE bottles:

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC-Aluminium foil blister packs

Pack sizes of 10, 14, 21, 28, 30, 42, 56, 98, 100 film-coated tablets.

HDPE (high-density polyethylene) bottles with PP (polypropylene) caps

Pack sizes of 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

ratiopharm GmbH Graf-Arco-Straße 3 89079 Ulm Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/836/013

EU/1/13/836/014

EU/1/13/836/015

EU/1/13/836/016

EU/1/13/836/017

EU/1/13/836/018

EU/1/13/836/019

EU/1/13/836/020

EU/1/13/836/021

EU/1/13/836/022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 June 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Memantine ratiopharm 5 mg film-coated tablets

Memantine ratiopharm 10 mg film-coated tablets

Memantine ratiopharm 15 mg film-coated tablets

Memantine ratiopharm 20 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg of memantine hydrochloride equivalent to 4.15 mg memantine. Each film-coated tablet contains 10 mg of memantine hydrochloride equivalent to 8.31 mg memantine.

Each film-coated tablet contains 15 mg of memantine hydrochloride equivalent to 12.46 mg memantine.

Each film-coated tablet contains 20 mg of memantine hydrochloride equivalent to 16.62 mg memantine.

Excipients with known effect

Lactose (40 mg/film-coated tablet) and soya lecithin (0.065 mg/film-coated tablet). Excipients with known effect

Lactose (80 mg/film-coated tablet) and soya lecithin (0.13 mg/film-coated tablet). Excipients with known effect

Lactose (120 mg/film-coated tablet) and soya lecithin (0.195 mg/film-coated tablet). Excipients with known effect

Lactose (160 mg/film-coated tablet) and soya lecithin (0.26 mg/film-coated tablet).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

The 5 mg film-coated tablets are white to off-white, capsule shaped (9.6 x 4.54 mm), biconvex tablets plain on one side and embossed with “5” on the other side.

The 10 mg film-coated tablets are white to off-white, capsule shaped (12.5 x 5.6 mm), biconvex tablets with a break score on one side and embossed with “10” on the other side.

The 15 mg film-coated tablets are white to off-white, capsule shaped (14.0 x 6.0 mm), biconvex tablets plain on one side and embossed with “15” on the other side.

The 20 mg film-coated tablets are white to off-white, capsule shaped (15.6 x 8.0 mm), biconvex tablets with a break score on one side and embossed with “20” on the other side.

The 10 mg and 20 mg tablet can be divided into equal doses.

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.

Posology

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 one 5 mg film-coated tablet per day (white to off-white, capsule shaped, biconvex tablets plain on one side and embossed with “5” on the other side) for 7 days.

Week 2 (day 8-14):

The patient should take one 10 mg film-coated tablet per day (white to off-white, capsule shaped, biconvex tablets with a break score on one side and embossed with “10” on the other side.) for 7 days.

Week 3 (day 15-21):

The patient should take one 15 mg film-coated tablet per day (white to off-white, capsule shaped, biconvex tablets plain on one side and embossed with “15” on the other side.) for 7 days.

Week 4 (day 22-28):

The patient should take one 20 mg film-coated tablet per day (white to off-white, capsule shaped, biconvex tablets with a break score on one side and embossed with “20” on the other side.) for 7 days. The maximum daily dose is 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 (20 mg once a day) as described above.

Paediatric population

Memantine ratiopharm 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 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 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 per day.

Hepatic impairment

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

Method of administration

Memantine ratiopharm should be administered once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance, peanut or soya 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 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 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.

Excipients

Memantine ratiopharm contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Memantine ratiopharm contains soya lecithin, see section 4.3.

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 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) 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 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 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, 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.

Breast-feeding

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.

Fertility

No adverse effects of memantine were noted on fertility in rats and rabbits (see section 5.3).

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 ratiopharm has minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.

4.8 Undesirable effects

Summary of the safety profile

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 reactions with memantine did not differ 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 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%).

Tabulated list of adverse reactions

The following Adverse 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

Common

 

Drug hypersensitivity

Psychiatric disorders

Common

 

Somnolence

 

Uncommon

 

Confusion

 

Uncommon

 

Hallucinations1

 

Not known

 

Psychotic reactions2

Nervous system disorders

Common

 

Dizziness

 

 

 

 

Common

Balance disorders

 

Uncommon

Gait abnormal

 

Very rare

Seizures

Cardiac disorders

Uncommon

Cardiac failure

Vascular disorders

Common

Hypertension

 

Uncommon

Venous

 

 

thrombosis/thromboembolism

Respiratory, thoracic and

Common

Dyspnoea

mediastinal disorders

 

 

Gastrointestinal disorders

Common

Constipation

 

Uncommon

Vomiting

 

Not known

Pancreatitis2

Hepatobiliary disorders

Common

Elevated liver function test

 

Not known

Hepatitis

General disorders and

Common

Headache

administration site conditions

Uncommon

Fatigue

1Hallucinations have mainly been observed in patients with severe Alzheimer’s disease.

2Isolated 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 national reporting system listed in Appendix V.

4.9 Overdose

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 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 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 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 overdose, 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 central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other 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 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 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-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.

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 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 active substances 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

Cellulose microcrystalline (E 460)

Starch pregelatinised (E 1404)

Lactose anhydrous

Colloidal anhydrous silica (E 551)

Magnesium stearate (E 470b)

Coating

Polysorbate 80 (E 433)

Polyvinyl alcohol (E 1203)

Titanium dioxide (E 171)

Talc (E 553b)

Soya lecithin (E 322)

Xanthan gum (E 415)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/PVDC-Aluminium foil blister packs

Pack sizes of 28 (7 +7 +7 + 7) film-coated tablets.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

ratiopharm GmbH Graf-Arco-Straße 3 89079 Ulm Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/836/023

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 June 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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