Memantine

The effects of barbiturates and neuroleptics may be reduced by concomitant treatment with memantine.

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.

Concomitant use of memantine and 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.

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.

Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dose adjustment may be necessary.

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

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.

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.

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

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. 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 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, memantine 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%).

List of adverse reactions

The following Adverse Reactions listed 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.