Memantine - instructions for use, dose, side effects, contraindications

Pharmacodynamics:The adamantane derivative, by chemical structure and pharmacological properties, is close to amantadine. It is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) -receptors (including in black matter), thereby reducing the excessive stimulating effect of cortical glutamate neurons on the neostriatum, which develops against a background of insufficient dopamine excretion. Improves the process of nerve impulse transmission. Improves cognitive processes, increases daily activity.

Pharmacokinetics:

Eating does not affect absorption. After oral administration, it is quickly and completely absorbed from the gastrointestinal tract. The maximum concentration is achieved 3-8 hours after administration. Pharmacokinetics is linear in the dose range of 10-40 mg. A daily dose of 20 mg results in an equilibrium plasma concentration of 70 to 150 ng / ml. The volume of distribution is about 10 l / kg. About 45% of memantine binds to blood plasma proteins. With normal renal function, no cumulation of memantine was observed. 80% of memantine circulating in the blood is unchanged substance. The main metabolites are K-3,5-dimethylgludantan, an isomeric mixture of 4- and 6-hydroxymemanthine and 1-nitroso-3,5-dimethyladamantane.None of the metabolites has antagonistic activity with respect to NMDA receptors. The involvement of cytochrome P450 in in vitro metabolism has not been revealed.

In studies in which¹⁴C -memantine was taken orally, on average 84% of the dose was excreted for 20 days, while> 99% was excreted in the urine. Memantine is excreted mainly by the kidneys. Excretion occurs single-phase, the half-life is 60-100 h; clearance is 170 ml / min / 1.73 m², partially secreted by the renal tubules.

With an alkaline urine reaction, the removal of memantine is slowed (on average by 80% with a pH of 8).

Pharmacodynamic and pharmacokinetic connection

When memantine is used at a dose of 20 mg / day, the level of concentration in the cerebrospinal fluid corresponds to the value of Ki (pressure constant), which for memantine is 0.5 μmol in the region of the frontal cortex of the brain.

Indications:Dementia of the Alzheimer's type of moderate and severe degree.

Contraindications:

Hypersensitivity to any of the components of the drug, severe hepatic insufficiency (class C according to the Child-Pugh classification), breastfeeding, children under 18 (due to insufficient data).

If you have any of the listed conditions, always consult a doctor before taking the drug.

Pregnancy and lactation:

Data on the use of pregnancy are limited.

Experimental studies conducted on animals indicate the possibility of slowing intrauterine growth at a level of exposure to identical or slightly higher concentrations of memantine compared to such in humans. A potential risk to a person is not known. The use of the drug in pregnancy is not recommended and is only possible if the expected benefit to the mother exceeds the possible risk to the fetus.

It is not known whether excretion of memantine occurs in breast milk, therefore, women taking memantine, you should refrain from breastfeeding.

There is no data on the effect on fertility.

Dosing and Administration:

Therapy with memantine should be initiated and conducted under the supervision of a physician with experience in the diagnosis and treatment of Alzheimer's dementia. Before the start of treatment it is necessary to provide care for the patient with a view to regular monitoring of the patient's drug intake. The diagnosis is made in accordance with the current recommendations.The tolerability and dosage of memantine should be reviewed regularly, preferably within the first three months after initiation of treatment. After that, the clinical effectiveness of memantine and the patient's tolerability of treatment should be reviewed according to current clinical guidelines. Supportive treatment can continue until a positive therapeutic effect is achieved, and while the patient normally tolerates memantine treatment. Remission of memantine should be discontinued in the absence of a positive therapeutic effect or if the patient is intolerant of the drug.

The drug should be taken orally once a day and always at the same time, regardless of food intake. Begin treatment memantine recommended with the appointment of minimally effective doses.

The estimated value of the maintenance dose is 20 mg / day.

Treatment schedule: during the first week of therapy (days 1-7) at a dose of 5 mg / day, during the second week (days 8-14) at a dose of 10 mg / day, during the third week (days 15-21) in a dose 15 mg / day, starting with the fourth week at a dose of 20 mg / day (considering the impossibility of dividing the pill, it is recommended to use the drug memantine in tablets of 5 mg or 10 mg with a risk during the dose-escalating step).

The maximum daily dose of 20 mg.

Dose adjustments in elderly patients (over 65 years) are not required.

With moderate renal failure (creatinine clearance 50-80 ml / min), dose adjustment is usually not required. With creatinine clearance of 30-49 ml / min, the daily dose initially does not exceed 10 mg, then after 7 weeks, with good tolerability, the dose can be increased up to 20 mg according to the standard schedule. In severe renal failure (creatinine clearance 5-29 ml / min) daily dose should not exceed 10 mg.

In patients with mild and moderate liver disorders (class A and B according to the Child-Pugh classification) correction of the dosing regimen is not required.

Side effects:

In clinical studies in patients with dementia, adverse reactions were observed from mild to moderate severity and occurred with a higher incidence in the memantine group compared with placebo: dizziness (6.3% versus 5.6%), headache (5 , 2% vs. 3.9%), constipation (4.6% vs. 2.6%), drowsiness (3.4% vs. 2.2%) and hypertension (4.1% vs. 2.8%).

Adverse reactions are classified according to the clinical manifestations (in accordance with the damage of certain organ systems) and the frequency of occurrence:

very often - ≥ 1/10;

often - ≥1 / 100 to <1/10;

infrequently - ≥1 / 1000 to <1/100;

rarely - ≥1 / 10000 to <1/1000;

very rarely - <1/10000, including individual messages.

From the central and peripheral nervous system:

Often: headache, dizziness, drowsiness, imbalance;

Infrequent: gait disturbance;

Rarely: increased fatigue;

Very rarely: epileptic seizures, convulsions.

Disorders from the psyche:

Infrequently: depression, increased excitability, sleep disturbance, confusion, agitation, hallucinations;

The frequency is unknown: psychotic reactions, suicidal thoughts.

From the cardiovascular system:

Often: increased blood pressure;

Infrequent: venous thrombosis / thromboembolism, heart disease, heart failure.

From the gastrointestinal tract:

Often: constipation;

Infrequent: nausea, vomiting;

Frequency unknown: pancreatitis.

From the side of the liver and bile ducts

Often: violation of functional liver tests;

Frequency unknown: hepatitis.

From the respiratory system:

Often: shortness of breath.

Infections:

Infrequently: fungal infections.

From the immune system:

Often: hypersensitivity to the drug.

Common reactions:

Infrequent: general weakness, allergic reactions.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

In Alzheimer's disease, depression, suicidal ideation and suicide were recorded in post-marketing studies.

There are some reports of the occurrence of adverse reactions when the drug is used in clinical practice: dizziness, drowsiness, increased intracranial pressure, nausea, hallucinations, headache, impaired consciousness, hypertonic muscle, gait disorders, depression, seizures, psychotic reactions, suicidal thoughts, constipation, nausea, pancreatitis, candidamycosis, increased blood pressure, vomiting, cystitis, increased libido, venous thrombosis, thromboembolism, allergic reactions.

Overdose:

Clinical experience with memantine has shown a limited amount of information about overdoses.

Symptoms: fatigue, weakness, diarrhea, confusion, drowsiness, dizziness, aggression, agitation, hallucinations, gait disturbance, nausea.

Treatment: In case of an overdose, symptomatic treatment should be performed. There is no specific antidote for memantine intoxication. Carry out standard procedures for evacuating the drug by washing the stomach, using activated charcoal (to prevent further absorption of the drug in the intestine), forced diuresis, methods of acidifying the urine reaction. In the case of symptoms of over-irritation of the central nervous system, symptomatic therapy should be carefully chosen and justified.

In overdoses of 200 mg once or more than 100 mg per day for 3 days, the following symptoms were identified: weakness, fatigue, diarrhea, or absence of symptoms. An overdose of less than 140 mg or an overdose of an unknown amount of memantine revealed the following adverse effects on the part of the nervous system: confusion, lethargy, drowsiness, dizziness, agitation, aggression, hallucinations, gait abnormalities and gastrointestinal tract: vomiting and diarrhea.

In the most serious cases of overdose, the patient survived after taking more than 2000 mg memantine with adverse effects from the nervous system (coma for 10 days, later - 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. There were reactions from the nervous system: anxiety, psychosis, visual hallucinations, stupor, seizures, drowsiness, unconsciousness.

Interaction:

With the simultaneous use with preparations of levodopa, dopamine receptor agonists, m-holinoblokatorami action of the latter can be strengthened.

With simultaneous use with barbiturates, neuroleptics, the effect of the latter may decrease.

When combined, the effect of spasmolytic drugs, dantrolene or baclofen may be altered (enhanced or decreased), so the dosage of the drugs should be selected individually. Simultaneous administration with amantadine, phenytoin, ketamine and dextromethorphan should be avoided because of the increased risk of developing pharmacotoxic psychosis.

Other medicines, such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotinewhich use the same cationic kidney transport system as memantine, can also interact with memantine, causing a potential risk of elevated levels in the blood plasma.

It is possible to reduce the concentration of hydrochlorothiazide when taken concomitantly with memantine. Memantine can increase the excretion of hydrochlorothiazide.

There are cases of an increase in INR (an international normalized ratio) in patients taking indirect anticoagulants simultaneously (warfarin). It is recommended that prothrombin time or INR is monitored regularly.

In pharmacological studies in healthy young volunteers with a single administration of memantine with glibenclamide / metformin or donepezil, no interaction effects were recorded. Also in such studies, no interaction with galantamine was found.

In the event that you are taking other medicines, be sure to consult a doctor before taking the drug.

Special instructions:

An alkaline urine reaction requires a more careful observation of such patients because of the slower release of memantine. Some factors that cause an increase in the pH of the urine may necessitate careful monitoring of the patient.These factors include dramatic changes in diet, such as replacing a meat-rich diet for vegetarian or intensive use of antacid agents. In addition, urine pH may increase due to tubular renal acidosis or a severe urinary tract infection caused by Proteus spp.

Data on the use of memantine in patients with a history of myocardial infarction, with chronic heart failure (NYHA class III-IV functional class) or uncontrolled hypertension are limited, and careful medical supervision of the patient is therefore necessary.

With caution appoint a patient with thyrotoxicosis, epilepsy, convulsions (including in the anamnesis), as well as patients with a predisposition to epilepsy.

Memantine should be avoided together with other NMDA receptor antagonists (amantadine, ketamine, dextromethorphan), since adverse reactions can occur more often and more intensively, mainly at the level of the central nervous system.

Effect on the ability to drive transp. cf. and fur:Patients with Alzheimer's disease in the stage of moderate and severe dementia are usually disruptedability to drive vehicles and manage complex machinery. Besides, memantine can cause a change in the reaction rate, so patients need to refrain from driving vehicles and working with complex mechanisms.

Form release / dosage:Tablets, film-coated, 10 mg.

Packaging:

For 7 or 10 tablets in a contour mesh box made of polyvinyl chloride film and aluminum foil.

By 2, 4, 8 or 14 contour cell packs of 7 tablets or 3, 6 or 9 contour cell packs of 10 tablets together with instructions for use in a pack of cardboard.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002810

Date of registration:12.01.2015 / 25.01.2018

Expiration Date:12.01.2020

The owner of the registration certificate:FARMZASCHITA NPC, FSUE FARMZASCHITA NPC, FSUE Russia

Manufacturer: & nbsp

FARMZASCHITA NPC, FSUE Russia

Information update date: & nbsp23.04.2018

Illustrated instructions

Instructions

Memantine (Memantin)