Anti-dementia drugs

Memantine Hydrochloride (memantine)

Oral drops, solution 1 g of solution contains 10 mg of memantine hydrochloride (equivalent to 8.31 mg memantine). One drop of solution is equivalent to 0.5 mg memantine hydrochloride. Excipients: 1 g of solution contains 100 mg of sorbitol E420 and 0.5 mg of potassium

The solution is clear and colourless to light yellowish.

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

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.

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

Children and adolescents under the age of 18 years: The safety and efficacy of memantine in children and adolescents have not been established.

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (10 mg twice a day) as described above.

Hypersensitivity to the active substance or to any of the excipients.

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 drug reactions (mainly CNS-related) may be more frequent or more pronounced.

Some factors that may raise urine pH 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– oral drops: The oral drops contain sorbitol. Patients with rare hereditary problems of fructose intolerance 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 dosage 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. There is one published case report on a possible risk also for the combination of memantine and phenytoin.

• Other active substances such as 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 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 PK studies in young healthy subjects no relevant drug-drug interaction of memantine with glyburide/metformin or donepezil was observed.

In a clinical study in young healthy volunteers 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.

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 events with Ebixa did not differ from those with placebo; the adverse events were usually mild to moderate in severity. The most frequently occurring adverse events 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% ).

The following Adverse Drug Reactions listed in the Table below have been accumulated in clinical studies with Ebixa 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).

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 events have been reported in patients treated with Ebixa.

H. Lundbeck A/S

(POM)

11 August 2009