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

Excipients: cellulose microcrystalline, type 102 107.05 mg; cellulose microcrystalline, type 101 30,00 mg; croscarmellose sodium 1.20 mg; silicon colloidal dioxide 0.75 mg; magnesium stearate 1.50 mg.

Film Sheath: Deficient white * 4.50 mg [hypromellose-6sp 2,81250 mg, titanium dioxide 1.40625 mg, macrogol-400 0.28125 mg].

* -code falling 03B28796

Description:Oval, biconvex tablets covered with a film shell, white, with a risk on one side and engraving "N93" on the other.

Pharmacotherapeutic group:Drugs for the treatment of dementia

ATX: & nbsp

N.06.D.X.01 Memantine

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

Pharmacodynamics:

There is increasing evidence that disrupting the work of glutamatergic neurotransmission, in particular N-methyl-D-aspartate receptors (NMDA receptors), contributes to both the onset of symptoms, the onset and progression of neurodegenerative dementia.

Memantine is a potential-dependent, non-competitive antagonist of NMDA receptors with moderate affinity for them. It has a modulating effect with pathologically increased tonic concentrations of glutamate, which can lead to neuronal dysfunction. It regulates ion transport, blocks calcium channels, normalizes the membrane potential and improves the process of nerve impulse transmission. Improves cognitive processes and increases daily activity.

Pharmacokinetics:

Suction: After oral administration memantine quickly and completely absorbed. Absolute bioavailability is approximately 100%. The mean time to reach the maximum plasma concentration (T_max) is from 3 to 8 hours. There are no data on the effect of food on the absorption of memantine.

Distribution: A daily dose of 20 mg creates an equilibrium concentration of memantine in the blood plasma in the range of 70-150 ng / ml (0.5-1 μmol / l) with large individual variations. The ratio of the average concentration of memantine in the cerebrospinal fluid (CSF) to plasma concentration when administered at a daily dose of 5-30 mg is 0.52. The determination volume is about 10 l / kg. Approximately 45% of memantine binds to plasma proteins.

Metabolism: In the body, about 80% of circulating memantine-related compounds are present in the form of the ancestors of the class. The main metabolites are: N-3,5-dimethyl-gludananthane, isomer mixture of 4- and 6-hydroxymemanthine and 1-nitroso-3,5-dimethyladamantane. None of these metabolites is active against NMDA receptors. In a laboratory environment (in vitro), the metabolism mediated by cytochrome P450 is not detected.

Excretion: In the study with oral administration¹⁴C-memantine averaged 84% of the ingested dose was withdrawn within 20 days, with more than 99% excreted by the kidneys.

In patients with normal renal function, no cumulation of the drug was noted. Memantine is displayed monoexponentially with a half-life (t_1/2 ) - 60-100 hours. Memantine is excreted in the urine, and 57-82% is excreted unchanged.In healthy volunteers with normal renal function, total clearance (Cl_tot) is 173 ml / min / 1.73 m², part of which is due to tubular secretion. Renal excretion also includes tubular reabsorption, mediated, possibly, by cationic transport proteins. The rate of renal clearance of memantine may decrease with alkalinization of urine (pH 7-9). The alkalinization of urine can be caused by a dramatic change in diet, for example, when switching from meat to vegetarian food or from excessive intake of alkaline gastric buffers.

Linearity / nonlinearity: In the range of doses of 10-40 mg in healthy volunteers, linearity of pharmacokinetics was revealed.

Pharmacokinetic-pharmacodynamic relationship: With a daily intake of 20 mg memantine, its concentration in the CSF is equal to the value of ki (inhibition constant), which in the frontal cortex is 0.5 μmol / l.

Indications:Dementia in Alzheimer's disease of moderate and severe severity.

Contraindications:Hypersensitivity to any of the components that make up the drug; severe hepatic insufficiency (class C according to the Child-Pugh classification), age under 18 (due to insufficient clinical data).

Carefully:Patients with epilepsy, convulsions (including seizures in the history or in patients with predisposition to epilepsy), myocardial infarction and decompensated chronic heart failure (III-IV functional class according to MYHA classification) or with uncontrolled hypertension.

Pregnancy and lactation:

Clinical data obtained from pregnant women are not available.

The results of studies in animals show that at concentrations equivalent to therapeutic or slightly higher, it is possible to slow the intrauterine growth of the fetus. The potential risk to humans is unknown. The use of Memantine-Richter during pregnancy is not recommended and is only possible if the expected benefit for the mother exceeds the possible risk to the fetus.

Data on the penetration of memantine into breast milk are not available, however, taking into account the lipophilicity of the substance, this can not be ruled out. Women taking Memantine-Richter should not breast-feed.

Clinical data on the effect on fertility are not available.

Dosing and Administration:

Treatment should be conducted under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should be started only in case of constant care of the patient and control over the intake of the drug. The diagnosis should be made in accordance with the current guidelines.

Memantine-Richter should be taken once a day, preferably at the same time every day, inside, regardless of food intake.

It is necessary to regularly assess the sufficiency of the dose and the tolerability of the Memantine-Richter drug, especially during the first three months after initiation of therapy. Further, the clinical benefit of the drug and the patient's tolerability should be assessed in accordance with the current guidelines. Supportive therapy should be continued as long as there is a therapeutic benefit and a satisfactory tolerability of the drug. With the disappearance of the therapeutic effect or intolerance of the drug treatment is canceled.

Adult patients with dementia

Week 1 (days 1-7):

The recommended dose is 5 mg (1/2 tablet) per day for 7 days. Week 2 (days 8-14):

The recommended dose is 10 mg (1 tablet) per day for 7 days.

Week 3 (days 15-21):

The recommended dose is 15 mg (1 1/2 tablets) per day for 7 days.

Starting from 4 weeks:

The recommended dose is 20 mg (2 tablets) per day.

To reduce the risk of unwanted reactions titration of the dose to the optimum - 20 mg is made by a weekly increase of 5 mg.

The recommended maintenance dose is 20 mg (2 tablets) per day.

The maximum daily dose is 20 mg (2 tablets) per day.

Special patient groups

Patients with impaired function of night

Patients with mild renal impairment (creatinine clearance 50-80 ml / min) do not need to change the dose.

In patients with impaired renal function of medium degree (creatinine clearance 30-49 ml / min) daily dose is 10 mg. If it is well tolerated for at least 7 days, it can be increased to 20 mg / day according to the standard schedule.

In patients with severe renal impairment (creatinine clearance 5-29 ml / min), the daily dose is 10 mg.

Patients with impaired hepatic function

In patients with a mild or moderate liver function disorder (Child-Pugh class A and B classes), dose adjustment is not required.

Data on the use of memantine in patients with severe liver dysfunction are absent. It is not recommended to appoint Memantine-Richter to patients with severe liver dysfunction.

Elderly patients

Based on clinical data, the recommended dose for patients older than 65 years, as described above, is 20 mg (2 tablets) per day.

Children and teens

Memantine-Richter is not recommended for children under 18 years old (due to insufficient data on efficacy and safety).

Side effects:

The undesirable phenomena presented below are distributed according to the system-organ classes and frequency of occurrence. The frequency is defined as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1 / 1000), very rarely (<1/10000), the frequency is unknown (the frequency can not be estimated based on the available data). Frequency categories were formed on the basis of clinical studies of mepantine and post-registration observation.

Infections and invasions

Infrequently: fungal infections.

Immune system disorders

Often: hypersensitivity reactions.

Mental disorders

Often: drowsiness;

Infrequently: confusion, hallucinations¹;

The frequency is unknown: psychotic reactions².

Disturbances from the nervous system

Often: imbalance, dizziness, headache; Infrequent: gait disturbances;

Very rarely: epilepsy.

Heart Disease

Infrequent: heart failure.

Disorders from the vascular system

Often: increased blood pressure;

Infrequent: venous thrombosis / thromboembolism.

Disturbances from the respiratory system, chest and mediastinal organs

Often: shortness of breath.

Disorders from the digestive system

Often: constipation;

Infrequent: vomiting;

Frequency unknown: pancreatitis².

Disturbances from the liver and bile ducts

Often: violation of functional liver tests;

Frequency unknown: hepatitis.

Systemic disorders and complications at the site of administration

Uncommon: fatigue.

¹Hallucinations were observed predominantly in patients with severe Alzheimer's disease.

²In the post-marketing period, separate messages were received.

Alzheimer's can cause depression, suicidal thoughts and attempts.As part of post-marketing application, such phenomena occurred in patients who took memantine.

If you noted any other undesirable reactions not listed in the instructions, please contact your doctor.

Overdose:

There are only limited data on overdose from clinical research and post-marketing experience.

Symptoms: A relatively large overdose (200 mg and 105 mg / day for 3 days, respectively) was manifested only by fatigue, weakness and / or diarrhea, or no symptoms. In patients with an overdose of less than 140 mg or with an unknown dose, symptoms such as confusion, hypersomnia, drowsiness, vestibular dizziness, agitation, aggression, hallucinations, gait disturbance, vomiting and diarrhea have been observed.

Admission 2000 mg memantine did not lead to death, but was accompanied by violations from the central nervous system (coma for 10 days followed by diplopia and agitation). After the symptomatic treatment and plasmapheresis, there was a recovery without persistent adverse effects.

In another reported case, the patient also recovered.After taking 400 mg of memantine, he had the following violations in the central nervous system: anxiety, psychosis, visual hallucinations, a tendency to convulsive reactions, drowsiness, stupor and loss of consciousness.

Treatment: In case of an overdose, symptomatic treatment is performed. There is no specific antidote for overdose or intoxication. Use standard clinical procedures to remove the active substance, for example, agitated charcoal (disrupts possible intestinal hepatic recirculation), urine acidification, forced diuresis.

In the presence of signs and symptoms of general hyperstimulation of the central nervous system should be symptomatic treatment.

Interaction:

Pharmaceutical interaction

Not applicable.

Pharmacokinetic interaction

In pharmacokinetic studies, a single administration of memantine in healthy volunteers did not lead to pharmacokinetic interaction with glibenclamide, metformin or dopepezil. Clinical studies in healthy volunteers did not reveal the effect of memantine on the pharmacokinetics of galantamine.

Memantine does not inhibit the isoenzymes CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxyhydrolase or in vitro sulphation.

Pharmacodynamic interaction

Levodopa, dopamine receptor agonists and m-cholinoblocking agents

Simultaneous administration of the drug with levodopa, dopamine receptor agonists and m-holinoblocking agents may enhance their effect.

Barbiturates and antipsychotics

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

Anticonvulsants, dantrolene and baclofen

The simultaneous use of memantine and anticonvulsants, dantrolene or baclofen may alter their effect, so an individual dose adjustment may be required.

Amantadine, ketamine, dextromethorphan and phenytoin

Memantine and amantadine belong to the group of NMDA receptor antagonists. Due to the risk of pharmacotoxic psychosis, simultaneous use of memantine with amantadine should be avoided. This risk is also characteristic of ketamine and dextromethorphan. The case of such interaction between memantine and phenytoin is described.

Cimetidine, ranigidine, procainamide, quinidine, quinine and nicotine

For the transportation of cimetidine, ranitidine, quinidine, quinine and nicotine, the same renal cation system is used in the body, which can cause the interaction of these drugs with memantine, leading to an increase in its concentration in the blood plasma. Simultaneous reception with memantine can lead to an increase in the concentration of cimetidine, ranitidine, procainamide, quinidia, quinine and nicotine.

Hydrochlorothiazide

Simultaneous administration of memantine can lead to a decrease in the concentration of hydrochlorothiazide.

Indirect anticoagulants

In post-marketing studies, individual cases of an increase in the international normalized ratio (INR, ratio of prothrombin time of the patient and prothrombin time of a standard plasma adjusted for the activity of the thromboplastin used) in patients simultaneously taking warfarin and memantine.

Despite the absence of a cause-and-effect relationship, careful monitoring of prothrombin time or INR in patients taking indirect anticoagulants is recommended.

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

Special instructions:

Care should be taken when used in patients with epilepsy, history of seizures, or in patients with a predisposition to epilepsy, simultaneous use of the drug with other NMDA receptor blockers should be avoided, including amantadine, ketamine and dextromethorphan. These compounds act on the same receptor system as memantine, so that unwanted reactions (mainly from the central nervous system) may be more frequent or more pronounced.

Due to some factors that can increase the pH of urine, careful follow-up of the patient is required. Such factors include: dramatic changes in the diet, for example, the transition from a meat diet to a vegetarian diet, or excessive consumption of alkaline gastric buffers. Also, urine pH can be increased by renal tubular acidosis (PTA) or severe urinary tract infections caused by Proteus spp.

Of the majority of clinical studies, patients with a history of myocardial infarction were excluded,decompensated chronic heart failure (NYHA III-IV functional class) or uncontrolled hypertension.

Data on such patients are limited, so they require careful monitoring of the doctor.

If you were hospitalized, inform your doctor about whether you are taking Memantine-Richter.

If you forget to take another pill of the Memantine-Richter drug, you should wait for the next pill at the usual time. Do not take a double dose to compensate for the missed pill.

Effect on the ability to drive transp. cf. and fur:

Alzheimer's disease of moderate or severe severity usually disrupts the ability to drive vehicles and mechanisms.

Memantine can cause unwanted reactions from the central nervous system (confusion, hallucinations, psychotic reactions, dizziness, headache, drowsiness, paroxysms), which can also affect these abilities. Thus, it is not recommended to engage in these activities; for outpatients should be established special care.

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

Packaging:For 15 tablets in a blister of PVC / PE / PVDC - aluminum foil. For 2 or 4 blisters in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003102

Date of registration:21.07.2015 / 23.01.2017

Expiration Date:21.07.2020

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER POLAND, Co. Ltd. Poland

GEDEON RICHTER-RUS, CJSC Russia

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp23.04.2018

Illustrated instructions

Instructions

Memantine Richter (Memantin-Richter)