Product Overview

Composition

Dosage 20 mg

1 film-coated tablet, 20 mg contains:

active substance:

memantine hydrochloride 20 mg;

Excipients:

calcium hydrogen phosphate dihydrate 55 mg,

silicon dioxide colloidal 5.2 mg,

croscarmellose sodium 7.5 mg,

lactose monohydrate 161.1 mg,

magnesium stearate 1.8 mg,

povidone K-30 9.4 mg;

film sheath :

Opadry White 8 mg, including: hypromellose (hydroxypropyl methylcellulose) 2.7 mg, hyprolysis (hydroxypropyl cellulose) 2.7 mg, talc 1.6 mg, titanium dioxide 1 mg.

pharmachologic effect

Pharmacodynamics

Memantine is a voltage-dependent, non-competitive NMDA receptor blocker with moderate affinity for them. It modulates the effect of pathologically increased tonic glutamate content, which can lead to neuronal dysfunction.

Pharmacokinetics

Absorption: memantine is rapidly and completely absorbed from the gastrointestinal tract (GIT), has an absolute bioavailability of about 100%. Eating does not affect absorption. The average time to reach maximum plasma concentration (Tmax) is from 3 to 8 hours. With normal renal function, no cumulation of memantine was noted.

Distribution: a daily dose of 20 mg creates a constant concentration of memantine in blood plasma in the range of 70-150 ng / ml (0.5-1 mmol) with large individual variations. The distribution volume of memantine is 10 l / kg. About 45% of memantine binds to plasma proteins.

Metabolism: about 80% of memantine is excreted unchanged. The main metabolites in humans are N-3,5-dimethylgludantan, a mixture of 4- and 6-hydroxyemantine isomers and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites has pharmacological activity. In in vitro studies, metabolism catalyzed by cytochrome P-450 was not detected. In the study, when 14 C-memantine was taken orally, an average of 84% of the oral dose was excreted within 20 days, with more than 99% excreted by the kidneys.

Excretion: memantine is excreted from the body by the kidneys monoexponentially. The elimination half-life (T1 / 2) makes 60 - 100 hours. It is excreted by the kidneys. In volunteers with normal renal function, the total clearance is 170 ml / min / 1.73 m2, part of the total renal clearance is achieved due to tubular secretion. Renal excretion also includes tubular reabsorption, possibly mediated by cationic transport proteins. The rate of renal elimination of memantine under conditions of an alkaline urine reaction may decrease by 7–9 times. Alkalization of urine can be caused by a sharp change in diet, for example, a transition from a diet including animal products to a vegetarian diet, or due to the intensive use of alkaline gastric buffers.

Linearity

Studies conducted in volunteers showed linear pharmacokinetics in the dose range of 10-40 mg.

Pharmacokinetic / pharmacodynamic dependence

When using memantine at a dose of 20 mg / day, the concentration level in the cerebrospinal fluid corresponds to the inhibition constant (ki), which for memantine is 0.5 μmol in the frontal cortex.

Indications

Moderate and severe Alzheimer's type dementia.

Contraindications

Hypersensitivity to the active substance or any of the components of the drug;
Severe liver failure (class C according to the Child-Pugh classification);
Congenital galactose intolerance, lactose deficiency or glucose / galactose malabsorption syndrome;
Pregnancy;
Period of breastfeeding;
Children under 18 years of age (efficacy and safety not established).

Carefully:

Epilepsy, a history of convulsive syndrome;
A history of myocardial infarction;
Heart failure (NYHA grades III-IV);
Uncontrolled arterial hypertension;
The simultaneous use of NMDA receptor antagonists (amantadine, ketamine, dextromethorphan);
Factors that increase the pH of urine (a sharp change in diet (switching from meat to vegetarian), heavy intake of alkaline gastric buffers, renal tubular acidosis, or severe urinary tract infections caused by Proteus spp.);
Renal failure;
Liver failure.

Side effects

Below are undesirable reactions obtained both in the course of research and from spontaneous reports.
WHO classification of the frequency of adverse reactions: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rare (<1/10000),

the frequency is unknown - according to available data, it is not possible to establish the frequency of occurrence.

Infectious and parasitic diseases
Infrequently: fungal infections.

Frequency unknown: candidiasis.

Disorders from the immune system
Often: hypersensitivity to the components of the drug.

Frequency unknown: allergic reactions, Stevens-Johnson syndrome.

Mental disorders
Infrequently: hallucinations (observed mainly in patients with severe Alzheimer's disease).

Frequency unknown: psychotic reactions, irritability, depression, anxiety, suicidal thoughts.

Disturbances from the nervous system
Often: headache, dizziness, drowsiness, imbalance.
Infrequently: impaired gait, confusion.
Very rare: cramps.

Frequency unknown: impaired consciousness, increased intracranial pressure, muscle hypertonicity.

Heart disorders

Infrequently: heart failure.

Disorders from the vessels.
Often: increased blood pressure.

Infrequently: venous thrombosis and / or thromboembolism.

Disorders of the respiratory system, chest and mediastinal organs

Often: shortness of breath.

Gastrointestinal Disorders
Often: constipation.
Infrequently: nausea, vomiting.

Frequency unknown: pancreatitis.

Violations of the liver and biliary tract:

Frequency unknown: hepatitis.

Disorders of the skin and subcutaneous tissue

Frequency unknown: thrombocytopenic purpura.

Genitourinary Disorder

The frequency is not known: acute renal failure, cystitis, increased libido.

General disorders

Infrequently: fatigue, general weakness.

Laboratory and instrumental data:
Often: increased activity of liver enzymes.
Frequency unknown: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia.

Interaction

Levodopa, dopamine receptor agonists and m-anticholinergic drugs. With the simultaneous use of memantine with levodopa drugs, dopamine receptor antagonists, m-anticholinergic agents, the effect of the latter can be enhanced, as with the simultaneous use of other NMDA receptor antagonists.

Barbiturates and antipsychotics. With simultaneous use with barbiturates, antipsychotics, the effect of the latter may decrease. When combined, it can change (strengthen or reduce) the effect of dantrolene or baclofen, so the doses of drugs should be selected individually.

Amantadine, ketamine, dextromethorphan. Concomitant use with amantadine, ketamine, phenytoin, and dextromethorphan should be avoided because of the increased risk of developing psychosis. These drugs are chemically

related NMDA receptor antagonists.

Phenytoin. The combined use of memantine with phenytoin should be avoided.

Cimetidine, ranitidine, procainamide, quinidine, quinine, nicotine. Possible increase in plasma concentrations of cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine while taking with memantine due to the use of the same renal cationic transport system.

Hydrochlorothiazide. A decrease in the concentration of hydrochlorothiazide or any combination with hydrochlorothiazide is possible while taking it with memantine.

Indirect anticoagulants. May increase the international normalized ratio (MHO) in patients taking indirect anticoagulants (warfarin). Despite the absence of a causal relationship, careful monitoring of prothrombin time and INR is recommended in patients taking warfarin and memantine at the same time.

Antidepressants. The simultaneous use of antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors requires careful monitoring of patients.

Lack of interactions. In pharmacokinetic studies after a single dose of memantine, no interactions of memantine with glibenclamide, metformin, donepezil, or galantamine were detected. Memantine does not inhibit the isoenzymes of CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP3A, flavin-containing monoxidase, epoxide hydrolase or in vitro sulfation.

How to take, course of administration and dosage

Therapy should be under the supervision of a physician with experience in the diagnosis and treatment of dementia in Alzheimer's disease. Therapy should be started if the patient (or the person who is constantly caring for the patient) is ready to regularly monitor the intake of the drug.

The diagnosis should be made in accordance with current recommendations. The tolerability and dose of Memantine Canon should be regularly evaluated, preferably within three months after initiation of therapy. Then, the clinical efficacy of the drug and the tolerability of the therapy should be regularly evaluated in accordance with current clinical guidelines. Maintenance therapy can be continued indefinitely if there is a positive effect and good tolerability of the drug Memantine Canon. The use of the drug should be discontinued if the positive therapeutic effect is no longer observed or if the patient does not tolerate therapy.

The drug should be used orally, once a day, at the same time, without chewing, drinking plenty of fluids, regardless of food intake. The maximum daily dose is 20 mg.

The dosage regimen is set individually. It is recommended to start treatment with the appointment of minimally effective doses. To reduce the risk of unwanted side effects, the selection of a constant dose is carried out by increasing titration of 5 mg per week for the first three weeks according to the following scheme:

1st week (days 1-7): 5 mg every day for seven days.
2nd week (days 8-14): 10 mg every day for seven days.
3rd week (days 15-21): 15 mg every day for seven days.

Starting from the 4th week: 20 mg every day.

Use in individual patient groups

Elderly patients

For patients over 65 years of age, the recommended dose is 20 mg per day.

Patients with impaired renal function

In patients with mild impaired renal function (creatinine clearance of 50-80 ml / min) dose adjustment is not required.

In patients with moderate impaired renal function (creatinine clearance 30-49 ml / min), the dose should be 10 mg per day. If this dose is well tolerated for at least 7 days of treatment, then it can be increased to 20 mg per day in accordance with the standard dosage regimen.

In patients with severe renal impairment (creatinine clearance 5-29 ml / min), the dose should not exceed 10 mg per day.

Patients with impaired liver function

Patients with mild or moderate hepatic impairment (Child-Pugh classes A and B) do not require dose adjustment.

In patients with severe hepatic insufficiency (class C according to the Child-Pugh classification), the use of the drug Memantine Canon is contraindicated.

Overdose

During clinical trials and post-marketing studies of the drug Memantine Canon, a limited amount of information about overdoses was obtained.

Symptoms: In case of sufficiently large overdoses (200 mg once or more than 100 mg per day for 3 days), the following symptoms were identified: weakness, fatigue, diarrhea, or lack of symptoms. With an overdose of less than 140 mg or with an unknown overdose, the following adverse events were revealed from the nervous system: confusion, drowsiness, dizziness, agitation, aggression, hallucinations and impaired gait and from the gastrointestinal tract: vomiting and diarrhea.

In the most serious cases of overdose, the patient survived after taking more than 2000 mg of memantine with adverse effects from the nervous system (coma for 10 days, diplopia, agitation). The patient received symptomatic therapy and plasmapheresis and recovered without any consequences.

Another described case of a serious overdose is 400 mg once. The patient recovered without consequences. Reactions from the nervous system were noted: anxiety, psychosis, visual hallucinations, stupor, drowsiness, unconsciousness.
Treatment: in case of overdose, symptomatic treatment is necessary. There is no specific antidote for intoxication with memantine. Carry out standard procedures for the evacuation of the drug by washing, using activated carbon, forced diuresis, urine alkalizing agents.

In case of symptoms of super irritation of the central nervous system, symptomatic therapy should be selected very carefully.

Special instructions

It is recommended to use with caution in patients with epilepsy, a history of seizures or in patients with a predisposition to epilepsy.

The appointment of memantine along with other NMDA receptor antagonists (amantadine, ketamine, dextromethorphan) should be avoided, since undesirable reactions can occur more often and at a higher intensity, mainly at the central nervous system.

The presence of factors affecting the increase in urine pH (dramatic changes in diet, for example, a switch from a diet including animal products to a vegetarian diet, or an intensive consumption of alkaline gastric buffers), as well as renal tubular acidosis or severe urinary tract infections, caused by Proteus spp., require careful monitoring of the patient's condition.

Of the majority of clinical trials, patients with a history of myocardial infarction, decompensated chronic heart failure (NYHA class III-IV functional class), or uncontrolled hypertension were excluded. Therefore, data on the use of memantine in such patients are limited, the drug should be administered under close medical supervision.

Effects on ability to drive vehicles and engage in other potentially dangerous activities
Patients with Alzheimer's disease at the stage of moderate and severe dementia usually have impaired ability to drive vehicles and manage complex mechanisms. In addition, memantine can cause a change in the reaction rate, so patients need to refrain from driving and working with complex mechanisms.