NEMDATINE Film-coated tablets Ref.[6963] Active ingredients: Memantine

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.

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

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.

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.

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

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.

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.

Infections and infestations

Uncommon: Fungal infections

Immune system disorders

Common: Drug hypersensitivity

Psychiatric disorders

Common: Somnolence

Uncommon: Confusion, Hallucinations¹

Not known Psychotic reactions²

Nervous system disorders

Common: Dizziness, 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 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.

Not applicable.