4.1. Therapeutic indications

Treatment of adult 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.

Posology

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.

Adults

Dose titration

The maximum daily dose is 20 mg once daily. 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 0.5 ml solution (5 mg) equivalent to one pump actuation per day for 7 days.

Week 2 (day 8-14)

The patient should take 1 ml solution (10 mg) equivalent to two pump actuations per day for 7 days.

Week 3 (day 15-21)

The patient should take 1.5 ml solution (15 mg) equivalent to three pump actuations per day for 7 days.

From Week 4 on

The patient should take 2 ml solution (20 mg) equivalent to four pump actuations 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 (2 ml solution, equivalent to four pump actuations) as described above.

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 (1 ml solution, equivalent to two pump actuations). 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 solution, equivalent to two pump actuations) 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 Ebixa is not recommended in patients with severe hepatic impairment.

Paediatric population

No data are available.

Method of administration

Ebixa should be taken orally once daily at the same time each day. The solution can be taken with or without food. The solution must not be poured or pumped into the mouth directly from the bottle or the pump, but should be dosed onto a spoon or into a glass of water using the pump.

For detailed instructions on the preparation and handling of the product see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance 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 other 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.

Ebixa contains Sorbitol and Potassium

This medicine contains 100 mg sorbitol in each gram which is equivalent to 200 mg /4 pump actuation. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Furthermore, this medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially potassium-free.

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

There are no or limited amount of data from the use of memantine in pregnant women. 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 reactions of memantine were noted on male and female fertility.

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, Ebixa has minor or 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 Ebixa and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with Ebixa 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 Ebixa 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 Ebixa and since its introduction in the market.

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). Within each frequency 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

Venous thrombosis/thromboembolism

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Gastrointestinal disorders

Common

Constipation

Uncommon

Vomiting

Not known

Pancreatitis2

Hepatobiliary disorders

Common

Elevated liver function test

Not known

Hepatitis

General disorders and administration site conditions

Common

Headache

Uncommon

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 reactions have been reported in patients treated with Ebixa.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.