Anti-dementia

Memantine Hydrochloride (memantine)

Each 5 mg film-coated tablet contains 5 mg of memantine hydrochloride equivalent to 4.15 mg memantine. Each 10 mg film-coated tablet contains 10 mg of memantine hydrochloride equivalent to 8.31 mg memantine. Each 15 mg film-coated tablet contains 15 mg of memantine hydrochloride equivalent to 12.46 mg memantine. Each 20 mg film-coated tablet contains 20 mg of memantine hydrochloride equivalent to 16.62 mg memantine. Excipient: The 10 mg film-coated tablet contains 166 mg lactose

The 5 mg film-coated tablets are white to off-white, oval-oblong film-coated tablets with imprint '5' on one side and imprint 'MEM' on the other side. The 10 mg film-coated tablets are white to off-white film-coated tablets, centrally tapered oblong, biconvex, with a single breakline on both sides. The tablet can be divided into equal halves. The 15 mg film-coated tablets are orange to grey-orange, oval-oblong film-coated tablets with imprint '15' on one side and imprint 'MEM' on the other side. The 20 mg film-coated tablets are pale red to grey-red, oval-oblong film-coated tablets with imprint '20' on one side and imprint 'MEM' on the other side.

Treatment of patients with moderately severe to severe Alzheimers disease.

Dose titration

Treatment Initiation Pack:

The recommended starting dose is 5 mg per day, which is stepwise increased over the first 4 weeks of treatment reaching the recommended maintenance dose as follows:

Week 1 (day 1-7):

The patient should take one 5 mg film-coated tablet per day (white to off-white, oval-oblong) for 7 days.

Week 2 (day 8-14):

The patient should take one 10 mg film-coated tablet per day (white to off-white, centrally tapered oblong, biconvex, with a single breakline on both sides) for 7 days.

Week 3 (day 15-21):

The patient should take one 15 mg film-coated tablet per day (grey-orange, oval-oblong film) for 7 days.

Week 4 (day 22-28):

The patient should take one 20 mg film-coated tablet per day (grey-red, oval-oblong film) for 7 days.

The maximum daily dose is 20 mg per day.

Tablet packs of 10 mg and 20 mg and Dropper pack of 10mg/g:

The maximum daily dose is 20 mg per day. 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 17):

The patient should take one 5 mg tablet/half a 10 mg tablet/10 drops per day (5 mg) for 7 days.

Week 2 (day 814):

The patient should take one 10 mg tablet/20 drops (10 mg) per day for 7 days.

Week 3 (day 1521):

The patient should take one 15 mg tablet/one and a half 10 mg tablets/30 drops (15 mg) per day for 7 days.

From Week 4 on:

The patient should take one 20 mg tablet/two 10 mg tablets/40 drops (20 mg) 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 (one 20 mg tablet/two 10 mg tablets/40 drops) as described above.

Children and adolescents under the age of 18 years: Ebixa is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Renal impairment: In patients with mildly impaired renal function (creatinine clearance 50 – 80 ml/min) no dosage adjustment 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 with severe renal impairment (creatinine clearance 5 – 29 ml/min) daily dose should be 10 mg per day.

Hepatic impairment: In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dosage 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.

Not recommended.

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– tablets: The 10 mg tablets contain lactose monohydrate. 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 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.

Lundbeck

(POM)

11 August 2009