COMPOSITION:

Active substance:

memantine;

1 tablet contains 5 mg or 10 мг of Memantine hydrochloride;

Excipients:

Mannitol (E 421), Microcrystalline cellulose, Croscarmallose sodium, Povidone K 30, Colloidal silicon Dioxide anhydrous, Magnesium Stearate, Opadry Pink 03F84827 (talc, Titanium Dioxide (E 171), Hypromellose, Iron Oxide red (E 172), Polyethylene Glycol).

INDICATIONS:

Moderate to severe Alzheimer’s disease.

DOSAGE:

Treatment should be initiated and supervised by a physician. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient.

Tablets should be administered once a day and should be taken at the same time every day. These tablets can be taken with or without food.

Adults.

The maximum dose is 20 mg. To decrease the risk of adverse reactions, the maintenance dose is determined by gradually increasing the dose by 5 mg per week during the first three weeks as follows:

1st week (day 1-7): take 5 mg per day during the week;

2nd week (day 8-14): take 10 mg per day during the week;

3rd week (day 15-21): take 15 mg per day during the week;

starting from the 4th week take 20 mg per day every day.

The recommended maintenance dose is 20 mg per day.

The duration of treatment is individually determined by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia.

Elderly patients.

The recommended dose for patients over the age of 65 years is 20 mg per day (2 tablets 10 mg 1 time per day), as described above.

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) the daily dose should be decreased to 10 mg. 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 decreased to 10 mg.

Hepatic impairment.

In patients with mild or moderate hepatic impaired function (Child-Pugh A, B) no dosage adjustment is needed. Administration of memantine is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS:

In clinical trials of memantine the overall incidence rate of adverse events did not differ from the one with placebo, and the adverse events were usually mild to moderate in severity.

The Adverse Drug Reactions listed in the Table below, observed in clinical studies and medical use, are ranked according to the frequency as follows: very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1,000 to <1/100), rare ( 1/10000 to < 1/1000), very rare (< 1/10000), 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 medical use.

Alzheimer’s disease is associated with depression, suicidal ideas and suicide. Such cases are known in medical use of memantine.

Drug interactions:

Concomitant administration of NMDA-antagonists (amantadine, ketamine or dextromethorphan) should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may be more common or more pronounced. In one published report it was also noted about the possible risk of memantine and phenytoin combination.

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, may modify their effects and a dosage adjustment may be necessary.

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.

Concomitant administration of memantine with hydrochlorothiazide or any other combined drug containing hydrochlorothiazide, may reduce the serum levels of the latter.

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 pharmakokinetic studies in healthy subjects, no relevant drug-drug interaction of memantine with glyburide/metformin, donepezil or galantamine was observed.

Memantine does not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase or sulphation in vitro.

Pregnancy and lactation:

For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels that 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.

Children:

The drug is not used in children due to the lack of data on safety and efficacy.

PRECAUTIONS:

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

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.

Ability to influence reaction velocity while driving or operating any other mechanisms.

Patients who have visual impairment, dizziness, vertigo, or other central nervous system disorders during treatment should refrain from diving motor transport or operating mechanisms.

Overdose:

The experience is limited.

Symptoms

Relatively 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, such as confusion, drowsiness, vertigo, agitation, aggression, hallucination, gait disturbance and/or of gastrointestinal origin (vomiting and diarrhoea).

After the intake of 2000 mg memantine, the patient developed coma (10 days), later diplopia and agitation. After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.

Treatment

The treatment is symptomatic, there is no specific antidote. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbo medicinalis, acidification of urine, forced diuresis should be used as appropriate.

In case of general overstimulation of the central nervous system, careful symptomatic clinical treatment should be considered. Ability to influence reaction velocity while driving or operating any other mechanisms.

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 reaction rate in humans; therefore, outpatients should be warned about the necessity to take special care when driving or using machines.

CONTRAINDICATIONS:

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

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics.

Malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. Memantine modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.

Pharmacokinetics.

Absorption.

Memantine has an absolute bioavailability of approximately 100%; time to reach maximum plasma concentration (tmax) is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.

Distribution.

Daily dose of 20 mg leads to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5-1 µmol) with large interindividual variations. When daily doses of 5 to 30 mg are administered, a mean cerebrospinal fluid (CSF)/serum ratio is 0.52. About 45 % of memantine is bound to plasma-proteins.

Biotransformation.

In human body, about 80 % of the circulating memantine is present as the parent compound; the main metabolites do not exhibit NMDA-antagonistic activity. No cytochrome P450 catalysed metabolism has been detected in vitro.

Elimination.

Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73m² and part of total renal clearance is achieved by tubular secretion. Renal stage of pharmacokinetics of memantine includes tubular reabsorption.

The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.

Linearity.

Pharmacokinetics is linear in the dose range of 10 to 40 mg.

Pharmacokinetic/pharmacodynamic relationship.

At a dose of memantine of 20 mg per day the cerebrospinal fluid levels match the ki-value (inhibition constant) of memantine, which is 0.5 µmol in human frontal cortex.

PHARMACEUTICAL CHARACTERISTICS:

General physic-chemical properties:

oval shaped pink coated tablets, plain on both sides.

Shelf-life:

3 years.

Storage:

Store below 25 °С. Keep out of reach of children.

Package:

14 tablets in a blister, 1 blister in a carton package.No14 or 10 carton packages in a carton box No 140 (14×10).

Conditions of supply:

By prescription.