EBIXA 20mg tablets medication leaflet

Ebixa 10 mg film-coated tablets

Ebixa 20 mg film-coated tablets

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

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

For the full list of excipients, see section 6.1.

Film-coated tablet

Ebixa 10 mg film-coated tablets

Pale yellow to yellow, oval shaped film-coated tablets with breaking line and imprint “1 0” on oneside and “M M” on the other side. The tablet can be divided into equal doses.

Ebixa 20 mg film-coated tablets

Pale red to grey-red, oval-oblong film-coated tablets with imprint “20” on one side and “MEM” on theother side

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

Treatment should be initiated and supervised by a physician experienced in the diagnosis andtreatment of Alzheimer’s dementia.

Therapy should only be started if a caregiver is available who will regularly monitor the intake of themedicinal product by the patient. Diagnosis should be made according to current guidelines. Thetolerance and dosing of memantine should be reassessed on a regular basis, preferably within threemonths after start of treatment. Thereafter, the clinical benefit of memantine and the patient’stolerance 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 thepatient tolerates treatment with memantine. Discontinuation of memantine should be considered whenevidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Dose titration

The maximum daily dose is 20 mg per day. In order to reduce the risk of undesirable effects, themaintenance 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) or one 20 mg film-coated tablet per day.

The recommended maintenance dose is 20 mg per day.

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is20 mg per day (two 10 mg film-coated tablets or one 20 mg film-coated tablet once a day) as describedabove.

In patients with mildly impaired renal function (creatinine clearance 50 - 80 ml/min) no doseadjustment 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 withsevere renal impairment (creatinine clearance 5 - 29 ml/min) daily dose should be 10 mg per day.

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

No data available.

Ebixa should be administered orally once a day and should be taken at the same time every day. Thefilm-coated tablets can be taken with or without food.

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

Caution is recommended in patients with epilepsy, former history of convulsions or patients withpredisposing factors for epilepsy.

Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine ordextromethorphan should be avoided. These compounds act at the same receptor system asmemantine, and therefore adverse reactions (mainly central nervous system (CNS)-related) may bemore frequent or more pronounced (see also section 4.5).

Some factors that may raise urine pH (see section 5.2 “Elimination”) may necessitate carefulmonitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to avegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated bystates 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 heartfailure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limiteddata are available and patients with these conditions should be closely supervised.

Ebixa contains Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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

* The mode of action suggests that the effects of L-dopa, dopaminergic agonists, andanticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such asmemantine. The effects of barbiturates and neuroleptics may be reduced. Concomitantadministration of memantine with the antispasmodic agents, dantrolene or baclofen, can modifytheir effects and a dose adjustment may be necessary.

* Concomitant use of memantine and amantadine should be avoided, owing to the risk ofpharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. Thesame may be true for ketamine and dextromethorphan (see also section 4.4). There is onepublished case report on a possible risk also for the combination of memantine and phenytoin.

* Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine andnicotine that use the same renal cationic transport system as amantadine may also possiblyinteract with memantine leading to a potential risk of increased plasma levels.

* There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) whenmemantine is co-administered with HCT or any combination with HCT.

* In post-marketing experience, isolated cases with international normalized ratio (INR) increaseshave been reported in patients concomitantly treated with warfarin. Although no causalrelationship has been established, close monitoring of prothrombin time or INR is advisable forpatients 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 pharmacokineticsof galantamine was observed.

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

There are no or limited amount of data from the use of memantine in pregnant women. Animal studiesindicate a potential for reducing intrauterine growth at exposure levels, which are identical or slightlyhigher than at human exposure (see section 5.3). The potential risk for humans is unknown.

Memantine should not be used during pregnancy unless clearly necessary.

It is not known whether memantine is excreted in human breast milk but, taking into consideration thelipophilicity of the substance, this probably occurs. Women taking memantine should not breast-feed.

No adverse reactions of memantine were noted on male and female fertility.

Moderate to severe Alzheimer’s disease usually causes impairment of driving performance andcompromises the ability to use machinery. Furthermore, Ebixa has minor to moderate influence on theability to drive and use machines such that outpatients should be warned to take special care.

In clinical trials in mild to severe dementia, involving 1,784 patients treated with Ebixa and 1,595patients treated with placebo, the overall incidence rate of adverse reactions with Ebixa did not differfrom those with placebo; the adverse reactions were usually mild to moderate in severity. The mostfrequently occurring adverse reactions with a higher incidence in the Ebixa group than in the placebogroup were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%).

The following Adverse Reactions listed in the Table below have been accumulated in clinical studieswith Ebixa and since its introduction in the market.

Adverse reactions are ranked according to system organ class, using the following convention: verycommon (≥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). Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness.

SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION

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 Venousthrombosis/thromboembolism

Respiratory, thoracic and mediastinal Common Dyspnoeadisorders

Gastrointestinal disorders Common Constipation

Uncommon Vomiting

Not known Pancreatitis2

Hepatobiliary disorders Common Elevated liver function test

Not known Hepatitis

General disorders and administration Common Headachesite conditions

Uncommon Fatigue1 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 reactions have been reported in patients treated with Ebixa.

Reporting suspected adverse reactions after authorisation of the medicinal product isimportant. 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 nationalreporting system listed in Appendix V

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

Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated witheither only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdose casesbelow 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 mgmemantine with effects on the central nervous system (coma for 10 days, and later diplopia andagitation). The patient received symptomatic treatment and plasmapheresis. The patient recoveredwithout permanent sequelae.

In another case of a large overdose, the patient also survived and recovered. The patient had received400 mg memantine orally. The patient experienced central nervous system symptoms such asrestlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, andunconsciousness.

In the event of overdose, treatment should be symptomatic. No specific antidote for intoxication oroverdose is available. Standard clinical procedures to remove active substance material, e.g. gastriclavage, 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, carefulsymptomatic clinical treatment should be considered.

Pharmacotherapeutic group: Psychoanaleptics. 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 inneurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. Itmodulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronaldysfunction.

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 incomparison to placebo at 6 months (observed cases analysis for the clinician´s interview basedimpression of change (CIBIC-plus): p=0.025; Alzheimer’s disease cooperative study - activities ofdaily 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 showeda 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 primaryefficacy 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 studieswith patients on a stable dose of acetylcholinesterase inhibitors) showed that there was a statisticallysignificant 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 astatistically significant effect of memantine in preventing worsening, as twice as many placebo-treatedpatients as memantine-treated patients showed worsening in all three domains (21% vs. 11%,p0.0001).

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.

Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to150 ng/ml (0.5 - 1 µmol) with large interindividual variations. When daily doses of 5 to 30 mg wereadministered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume ofdistribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.

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 within20 days, more than 99% being excreted renally.

Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. Involunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m² and partof total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. Therenal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to9 (see section 4.4). Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivoreto a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.

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.

In short term studies in rats, memantine like other NMDA-antagonists have induced neuronalvacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serumconcentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As theeffects have neither been observed in long term studies in rodents nor in non-rodents, the clinicalrelevance of these findings is unknown.

Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, butnot in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did notdisclose any ocular changes.

Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes wasobserved in rodents. This effect is known from other active substances with cationic amphiphilicproperties. There is a possible relationship between this accumulation and the vacuolisation observedin lungs. This effect was only observed at high doses in rodents. The clinical relevance of thesefindings is unknown.

No genotoxicity has been observed following testing of memantine in standard assays. There was noevidence of any carcinogenicity in life long studies in mice and rats. Memantine was not teratogenic inrats and rabbits, even at maternally toxic doses, and no adverse effects of memantine were noted onfertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightlyhigher than at human exposure.

Tablet cores for 10/20 mg film-coated tablets:

Microcrystalline cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Tablet coat for 10/20 mg film-coated tablets:

Hypromellose

Macrogol 400

Titanium dioxide

Additional for 10 mg film-coated tablets:

Iron oxide yellow

Additional for 20 mg film-coated tablets:

Iron oxide yellow and red

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

Blister: PVDC/PE/PVC/Al-blister or PP/Al-blister

Ebixa 10 mg film-coated tablets:

Pack sizes of 14, 28, 30, 42, 50, 56, 70, 84, 98, 100,112 film-coated tablets.

Multipack containing 980 (10 packs of 98) and 1000 (20 packs of 50) film-coated tablets.

Perforated unit dose blister: PVDC/PE/PVC/Al-blister or PP/Al-blister

Pack sizes 49 x 1, 56 x1, 98 x 1 and 100 x 1 film-coated tablets .

Ebixa 20 mg film-coated tablets:

Pack sizes of 14, 28, 42, 56, 70, 84, 98, 112 film-coated tablets.

Multipack containing 840 (20 x 42) film-coated tablets

Perforated unit dose blister: PVDC/PE/PVC/Al-blister or PP/Al-blister

Pack sizes 49 x 1, 56 x1, 98 x 1 and 100 x 1 film-coated tablets

Not all pack sizes may be marketed.

No special requirements.

H. Lundbeck A/S

Ottiliavej 92500 Valby

Denmark

EU/1/02/219/001-003

EU/1/02/219/007-012

EU/1/02/219/014-021

EU/1/02/219/023-035

EU/1/02/219/037-049

Date of first authorisation: 15 May 2002

Date of latest renewal: 15 May 2007

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu