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

Excipients: lactose monohydrate 169 mg, microcrystalline cellulose 40 mg, silicon dioxide colloid 1.2 mg, sodium starch glycolate (type A) 10 mg, hydroxypropylcellulose 7.4 mg, magnesium stearate 2.4 mg;

Shell composition: Opaprai II white OY-L-28900 (lactose monohydrate - 36%, hypromellose -28%, titanium dioxide 26%, macrogol 4000-10%) 7 mg.

Description:Oblong biconvex tablets, coated with a white film shell, engraved with "g" and "Ph" and the risk between the letters on each side. The tablet is white or almost white in color.

Pharmacotherapeutic group:Dementia remedy

ATX: & nbsp

N.06.D.X.01 Memantine

N.06.D.X Other drugs for the treatment of dementia

Pharmacodynamics:Memantine is a potential-dependent non-competitive inhibitor of NMDA receptors with moderate affinity for them. It modulates the effect of the pathologically increased tonic content of glutamate, which can lead to neuronal dysfunction.

Pharmacokinetics:

After oral administration, it is quickly and completely absorbed. The maximum concentration in blood plasma is reached in 3-8 hours after administration.

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

Daily intake of a daily dose of 20 mg leads to an equilibrium plasma concentration of 70 to 150 ng / ml (0.5-1 μmol) with pronounced individual variations. 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 the drug was noted. About 80% of memantine is present in the circulating blood as an unchanged compound. The main metabolites are N-3,5-dimethyl-glutananthane, a mixture of isomers of 4- and 6-hydroxy-memantine and 1-nitroso-3,5-dimethyl-adamantane.None of these metabolites has antagonistic activity against NMDA receptors. The involvement of cytochrome P450 in metabolism in in vitro studies has not been revealed.

In studies with admission¹⁴C-memantine orally on average 84% of the dose was excreted for 20 days, while more than 99% of the drug was excreted by the kidneys.

Memantine is excreted mainly by the kidneys. Excretion occurs monoexponentially, the half-life is 60 to 100 hours. In studies with volunteers with normal renal function, the total clearance was 170 ml / min / 1.73 m², part of the total renal clearance was achieved due to secretion of the renal tubules.

Renal excretion also includes tubular reabsorption, which, possibly, is carried out by means of cationic transport proteins. The rate of renal elimination in conditions of alkaline urine reaction can decrease by 7-9 times.

The alkalinization of urine can be the result of a dramatic change in diet, for example, the transition from the consumption of predominantly meat products to vegetarianism, or due to the intensive use of alkaline gastric buffers.

Pharmacokinetic-pharmacodynamic relationship:

When taking a maintenance dose of 20 mg / day, the concentration level of memantine in the cerebrospinal fluid corresponds to the value of k_i (k_iconstants of inhibition) that for memantine is 0.5 μmol in the frontal cortex of the human brain.

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

Contraindications:Individual hypersensitivity to memantine or any of the components included in the formulation; pregnancy and the period of breastfeeding; age under 18 years (effectiveness and safety not established); deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome, since the composition of the drug MEMANTINOL® includes lactose.

Carefully:Thyrotoxicosis, epilepsy, a predisposition to the development of seizures (including in the anamnesis), the simultaneous use of NMDA receptor antagonists (amantadine, ketamine, dextromethorphan), the presence of factors that increase the pH of urine (a sudden change in diet, for example, the transition to vegetarianism, a copious intake of alkaline gastric buffers), renal tubular acidosis, severe urinary tract infections caused by bacteria of the genus Proteus,myocardial infarction (history), cardiac insufficiency III-IV functional class (according to NYHA classification), uncontrolled arterial hypertension, renal failure, hepatic insufficiency.

Pregnancy and lactation:Contraindicated in pregnancy, because there is no clinical data on the effect of memantine on pregnancy. Studies conducted on animals indicate the possibility of the drug to cause a delay in intrauterine development 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. It is not known whether the excretion of memantine occurs in breast milk, so women receiving memantine, you should refrain from breastfeeding.

Dosing and Administration:

Treatment with memantine should be started and carried out under the supervision of a physician who has experience in diagnosing and treating dementia in Alzheimer's disease. The diagnosis should be made in accordance with the current recommendations. Treatment should be started only if the person who is in constant care of the patient will regularly monitor the patient taking the drug.The tolerability and dosage of memantine should be reviewed on a regular basis, preferably within the first three months after initiation of therapy. After this period, the clinical effectiveness of memantine and the patient's tolerability should be regularly reviewed in accordance with current clinical guidelines. Supportive treatment can be continued indefinitely if there is a positive effect of the therapy and good tolerability of treatment. Reception memantine should be discontinued in the absence of a positive therapeutic effect or patient intolerance of treatment.

The drug should be taken orally once a day and always at the same time, regardless of food intake.

Adults:

Dose titration:

The maximum daily dose of 20 mg / day. In order to reduce the risk of adverse reactions, the dose of the drug is titrated by sequentially increasing it by 5 mg every week for the first three weeks:

During the first week of therapy (days 1-7), the patient should take memantine in a dose of 5 mg / day (half a tablet of 10 mg), during the 2nd week (days 8-14) - at a dose of 10 mg / day (one tablet of 10 mg), during the 3rd week (days 15-21 ) - in a dose of 15 mg / day (one and a half tablets of 10 mg).Starting with the 4th week, the patient is prescribed memantine at a dose of 20 mg / day (two tablets of 10 mg).

The recommended maintenance dose is 20 mg per day.

Special patient groups

Patients of advanced age (over 65 years)

Correction of the dose is not required.

Patients with impaired renal function

In patients with a creatinine clearance of 50-80 ml / min, dose adjustment is not required. For patients with moderate renal insufficiency (creatinine clearance 30-49 ml / min), the recommended daily dose is 10 mg / day. If the dose is well tolerated for 7 days, the dose can be increased to 20 mg / day in accordance with the standard titration scheme. In patients with severe renal failure (creatinine clearance 5-29 ml / min) daily dose should not exceed 10 mg / day.

Patients with impaired hepatic function

In patients with mild and moderate impairment of liver function (class A and class B on the Child-Pugh scale), dose adjustment is not required. Data on the use of memantine in patients with severe impairment of liver function, no, therefore, memantine is not recommended for such patients.

Side effects:

Adverse reactions are classified according to clinical manifestations (according toand the frequency of occurrence according to the classification of the World Health Organization (WHO): 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), the frequency is not established (can not be estimated from the data available).

In clinical studies with moderate and severe dementia, including 1784 patients who received memantine, and 1595 patients receiving placebo, the overall incidence of adverse reactions with memantine was not different from that of placebo. As a rule, adverse reactions of mild or moderate severity were observed. The most frequent adverse reactions in the memantine group compared with the placebo group were: dizziness (6.3% versus 5.6%, respectively), 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%, respectively). Adverse reactions are presented in tabular form:

Infectious and parasitic diseases	Infrequently	Fungal infections
Immune system disorders	Often	Hypersensitivity to the drug components
Violations psyche	Often	Drowsiness
	Infrequently	Confusion consciousness, hallucinations¹
	Frequency not set	Psychotic reactions²
Disturbances from the nervous system	Often	Dizziness, imbalance
	Infrequently	Violation gait
	Rarely	Convulsions
Hcrochetingno-vascular system	Often	Increase arterial pressures
Hcrochetingno-vascular system	Infrequently	Venous thrombosis / thromboembolism
Disturbances from the respiratory system, chest and mediastinal organs	Often	Dyspnea
Disorders from the gastrointestinal tract	Often	Constipation
	Infrequently	Nausea, vomiting
	Frequency not set	Pankreatitis
Disorders from the liver and fелчевыводящих ways	Often	Phigh liver function samples
Disorders from the liver and fелчевыводящих ways	Frequency not set	Hepatitis
General reactions	Often	Headache
General reactions	Infrequently	Fatigability

¹Hallucinations were observed, mainly, in patients with Alzheimer's disease at the stage of severe dementia

²Separate reports received during the period of post-registration experience of memantine use.

In the post-marketing application, the following adverse reactions were reported: dizziness, drowsiness, increased excitability, increased fatigue,anxiety, increased intracranial pressure, nausea, hallucinations, headache, impaired consciousness, muscle hypertonia, gait disturbance, depression, seizures, psychotic reactions, suicidal thoughts, constipation, nausea, pancreatitis, candidiasis, increased blood pressure, vomiting, cystitis, increased libido , venous thrombosis, thromboembolism, allergic reactions, agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura, hepatitis, acute renal failure, Stevens syndrome -Dzhonsona.

Overdose:

There are limited data on overdose obtained in the course of clinical trials and post-registration experience with the use of memantine.

Symptoms:

With relatively large overdoses (200 mg once and 105 mg / day for 3 days), the following symptoms were noted: fatigue, weakness and / or diarrhea or symptoms were absent. In cases of overdose in a dose of less than 140 mg once or in the case of taking an unknown dose, patients experienced side reactions from the central nervous system: confusion, hypersomnia, drowsiness, dizziness,aggression, hallucinations, gait disturbance) and / or the digestive system: vomiting, diarrhea.

In the most severe case of overdose, the patient survived after taking a dose of 2000 mg memantine, he had adverse reactions from the central nervous system (coma for 10 days, then diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without further complications.

In another case of severe overdose, the patient survived and recovered after taking memantine at a dose of 400 mg once. The patient experienced adverse reactions from the central nervous system: anxiety, psychosis, visual hallucinations, lowering the threshold of convulsive readiness, drowsiness, stupor and loss of consciousness.

Treatment:

In case of an overdose, treatment is symptomatic. There is no specific antidote. It is necessary to conduct standard medical measures aimed at removing substances from the stomach, for example, gastric lavage, taking activated charcoal, urine acidification, it is possible to perform forced diuresis.

Interaction:

With the simultaneous use of levodopa drugs, dopamine receptor agonists, anticholinergic drugs, the effect of the latter may be enhanced.

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

When used simultaneously with dantrolene or baclofen, as well as with antispasmodics, their effect may change (increase or decrease), so the dosage of the drugs should be adjusted.

Simultaneous use of memantine with amantadine should be avoided in connection with the risk of developing psychosis. Memantine and amantadine belong to the group of NMDA receptor antagonists. The risk of developing psychosis is also increased with simultaneous use with ketamine, dextromethorphan and phenytoin.

With simultaneous admission with cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, an increase in the plasma concentration of memantine is possible.

It is possible to reduce the level of hydrochlorothiazide while taking it with memantine at the expense of increasing its excretion from the body.

It is possible to increase the INR (international normalized ratio) in patients concurrently taking oral indirect anticoagulants (warfarin). It is recommended to constantly monitor prothrombin time or INR.Simultaneous use with antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors requires close monitoring of patients.

According to the results of pharmacokinetic studies in young healthy volunteers, single-time simultaneous administration of memantine with glyburide / metformin or donepezil did not reveal the effects of drug interaction.

Clinical studies also did not reveal the effect of memantine on the pharmacokinetics of galantamine in young healthy volunteers.

In vitro studies memantine did not inhibit the isoenzymes CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, monooxygenase containing flavin, epoxide hydrolase or sulfation.

Special instructions:

It is recommended to be used with caution in patients with thyrotoxicosis, epilepsy, convulsions (including in anamnesis), as well as patients with predisposition to epilepsy. Simultaneous use of NMDA receptor antagonists (amantadine, ketamine, dextromethorphan) and memantine should be avoided. These compounds act on the same receptor system as memantine, and therefore, adverse reactions (mainly from the central nervous system) can occur more often and be more pronounced.

Given the slower release of memantine in patients with alkaline urine, more careful observation requires patients with factors that affect the increase in urine pH (a dramatic change in diet, for example, when switching from the consumption of predominantly meat products to vegetarianism, intensive consumption of alkaline gastric buffers), and also in cases of renal tubular acidosis or a severe urinary tract infection caused by bacteria of the genus Proteus.

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

Effect on the ability to drive transp. cf. and fur:In patients with Alzheimer's disease, the ability to drive vehicles and manage complex mechanisms is usually impaired in the stage of moderate and severe dementia. Besides, memantine can cause a change in the reaction rate, so patients need to refrain from managing motor vehicles or working with complex mechanisms.

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

Packaging:

10 tablets per contour cell packaging made of polyvinylchloride film and aluminum foil. By 2, 3, 6, 9 or 12 contour mesh packages together with the instruction for use are placed in a cardboard box.

For 30 or 90 tablets per can of polymer for medicinal purposes

means, each bank along with the instruction for use is placed in a cardboard box.

Storage conditions:

Keep in dry the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002450

Date of registration:06.05.2014 / 04.03.2015

Expiration Date:06.05.2019

The owner of the registration certificate:Farm-Holding, CJSCFarm-Holding, CJSC Russia

Manufacturer: & nbsp

GEROPHARM, LLC Russia

Information update date: & nbsp27.04.2018

Illustrated instructions

Instructions

Memantinol® (Memantinol)