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

Excipients: lactose monohydrate (sugar milk) - 64.5 mg, microcrystalline cellulose - 14.0 mg, croscarmellose sodium - 4.0 mg, povidone-K25 - 3.0 mg, silicon dioxide colloid - 0.5 mg, magnesium stearate - 1 , 0 mg.

Shell composition: hypromellose - 1.7 mg, macrogol-4000 - 0.4 mg, titanium dioxide - 0.9 mg.

Dosage of 20.0 mg

Active substance: memantine hydrochloride - 20.0 mg.

Excipients: lactose monohydrate (sugar milk) - 129.0 mg, microcrystalline cellulose 28.0 mg, croscarmellose sodium 8.0 mg, povidone-K25 6.0 mg, silicon colloidal dioxide - 1,0 mg, magnesium stearate-2,0 mg.

Shell composition: hypromellose - 3,4 mg, macrogol-4000 - 0,8 mg, titanium dioxide - 1,8 mg.

Description:

Round, biconvex tablets with a risk on one side, covered with a film shell of white or almost white color. On the cross section of the tablet, two layers are visible: a white or almost white core and a film membrane.

Pharmacotherapeutic group:Dementia remedy

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 the disruption of the work of glutamatergic neurotransmission, in particular M-methyl-Daspartate receptors (NMDA-receptors) contributes to both the onset of symptoms and the progression of neurodegenerative dementia.

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

Pharmacokinetics:

Suction

Memantine has an absolute bioavailability of about 100%. The mean time to reach the maximum concentration in the blood plasma (t_m_Oh) 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. With the appointment of a daily dose of 5-30 mg, the ratio of the mean concentration in the cerebrospinal fluid (CSF) to the plasma concentration equal to 0.52 was calculated. The volume of distribution 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-4-3,5-dimethylgludantan, an isomeric mixture of 4- and 6hydroxymemanthine and 1-nitroso-3,5-dimethyladamantane. None of these metabolites is active against NMDAreceptors. In the laboratory (in vitro) mediated by cytochrome P450 metabolism is not detected.

In the study with ingestion of a labeled ¹⁴C-memantine more than 84% of the dose was excreted for 20 days, more than 99% excreted by the kidneys.

Excretion

Memantine is excreted monoexponentially with a half-life (t₁_/₂) 60-100 h. In healthy volunteers with normal renal function, the total clearance (Cl_total) is 170 ml / min / 1.73 m², part of which is due to tubular secretion.

Renal excretion also includes tubular reabsorption, mediated, perhaps, by cationic transport proteins. The rate of renal clearance of memantine may decrease with alkalinization of urine to pH 7-9 (see section "Specific guidance"). The alkalinization of urine can be caused by a dramatic change in the diet, for example, when switching from meat to vegetarian, or because of excessive intake of alkaline gastric buffers.

Linearity

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

Pharmacokinetic-pharmacodynamic relationship

With daily intake of 20 mg memantine, its concentration in the CSF is equal to the value of k_i(inhibition constant), which in the frontal cortex is 0.5 μmol / l.

Indications:

Treatment of Alzheimer's disease from medium to severe.

Contraindications:

- Hypersensitivity to any of the components that make up the drug;

- severe hepatic insufficiency (class C according to the Child-Pugh classification);

- pregnancy, the period of breastfeeding;

- children under 18 years of age (efficacy and safety not established).

- intolerance to galactose, deficiency of lactase, lactase deficiency.

Carefully:

Epilepsy, a history of convulsive syndrome; a history of myocardial infarction; heart failure (III-IV Classes by classification NYHA); uncontrolled arterial hypertension; simultaneous use of antagonists NMDA-receptors (amantadine, ketamine, dextromethorphan); factors that increase the pH of urine (a dramatic change in diet (the transition from meat to vegetarian), copious intake of alkaline gastric buffers, renal tubular acidosis, or severe urinary tract infections caused by Proteus spp.); kidney failure; hepatic insufficiency (class A and B according to the Child-Pugh classification).

Pregnancy and lactation:

Pregnancy

Clinical data obtained from pregnant women are not available. The results of 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. Memantine should not be used during pregnancy in the absence of obvious need.

Breast-feeding

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 receiving memantine, you should stop breastfeeding.

Fertility

In preclinical studies of male and female fertility, the undesirable effects of memantine were not identified.

Dosing and Administration:

Dosing regimen

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 if there is a carer who will regularly monitor the patient taking the medication. The diagnosis should be made in accordance with current recommendations.

It is necessary to regularly assess the sufficiency of the dose and the tolerability of memantine, preferably within three months after initiation of therapy. Further, the clinical benefit of the drug and the patient's tolerability should be assessed in accordance with current recommendations. Supportive therapy should be continued as long as there is a therapeutic benefit and a satisfactory drug tolerance is observed.With the disappearance of the therapeutic effect or intolerance of the drug treatment is canceled.

Adults

Dose selection

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the maintenance dose is achieved by selecting 5 mg per week for the first three weeks according to the following scheme:

Week 1 (days 1-7):

The recommended dose is 5 mg (1/2 tablets with a dosage of 10 mg) per day for 7 days.

A week 2 (days 8-14):

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

Week 3 (days 15-21):

The recommended dose is 15 mg (1 1 /2 tablets with a dosage of 10 mg) per day for 7 days.

Starting from 4 weeks:

The recommended dose is 20 mg per day.

Maintenance dose

The recommended maintenance dose is 20 mg per day.

Elderly patients

Based on the clinical data, the recommended dose for patients over 65 years of age is 20 mg per day in accordance with the above.

Patients with impaired renal function

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), the dose is 10 mg / day.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 dysfunction (creatinine clearance 5-29 ml / min), the dose is 10 mg / day.

Patients with impaired hepatic function

In patients with mild or moderate degree of impaired liver function (classes A and B according to the Child-Pugh classification), a dose change is not required. Data on the use of memantine in patients with severe liver dysfunction are absent. It is not recommended to appoint memantine patients with severe impairment of liver function.

Children and teens

Due to the lack of data on efficiency and safety memantine is not recommended for children under 18 years of age.

Mode of application

Memantine is taken once a day, preferably at the same time every day. Tablets, covered with a film membrane, can be taken regardless of food intake.

Side effects:

Security Profile Summary

In clinical studies of mild to moderate dementia, including 1,784 patients who received memantine, and 1595 patients who received a placebo, the overall incidence of adverse reactions with memantine notwas different from that for placebo; The severity of adverse reactions tended to range from mild to moderate.

The most private adverse reactions with a frequency of occurrence more frequent than the placebo group were dizziness (6.3 and 5.6%, respectively), headache (5.2 and 3.9%), constipation (4.6 and 2.6 %), drowsiness (3,4 and 2,2%) and arterial hypertension (4,1 and 2,8%). The list of undesirable reactions listed below includes the experience of clinical trials and post-registration data. In each frequency group, unwanted reactions are listed in order of decreasing severity.

The undesirable phenomena presented below are distributed according to the system-organ classes and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10,000 and < 1/1000), very rarely (<1/10 000, including individual cases), is unknown (can not be estimated from the data available).

Infections and infestations: infrequently - fungal infections.

From the immune system: often hypersensitivity to the drug.

Mental disorders: often - drowsiness; infrequently - confusion, hallucinations¹; frequency unknown - psychotic reactions².

Co side of the nervous system: often - dizziness, imbalance; infrequently - gait disturbance; very rarely - cramps.

From the heart: infrequently - heart failure.

Co the sides of the vessels: often - increased blood pressure; infrequently - venous thrombosis / thromboembolism.

From the respiratory system, chest and mediastinum: often - shortness of breath.

From the gastrointestinal tract: often constipation; infrequently - vomiting; frequency unknown - pancreatitis².

Co side of the liver and bile ducts: often - increased functional liver tests; frequency is unknown - hepatitis.

General disorders and disorders at the site of administration: often - headache; infrequently - 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.

Overdose:

According to the results of clinical studies and post-registration monitoring, only limited data on overdose were obtained.

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. Symptoms from the central nervous system (confusion, hypersomnia, drowsiness, vestibular dizziness, agitation, aggression, hallucinations, gait disturbance) and / or gastrointestinal tract (vomiting and diarrhea) were observed in patients with an overdose of <140 mg or with an unknown dose ).

In the most severe case - taking 2000 mg memantine - no lethal outcome occurred, but it was accompanied by violations from the central nervous system: coma for 10 days followed by diplopia and agitation. Patient was prescribed symptomatic treatment and plasmapheresis. There was a recovery without persistent adverse effects.

In another reported case, the patient also survived and 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 intoxication or overdose. Use standard clinical procedures to remove the active substance, for example, Activated carbon (disrupts possible intestinal-hepatic recirculation), urine acidification, forced diuresis.

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

Interaction:

Due to the pharmacological effects and mechanism of action of memantine, the following interactions can occur:

- The mechanism of action suggests that, when used simultaneously with antagonists NMDA-receptors, to which memantine, the action of levodopa, dopamine receptor agonists and m-holinoblockers can be enhanced. With the simultaneous use of memantine with barbiturates and neuroleptics, the effect of the latter may decrease. The simultaneous use of memantine and anticonvulsants, dantrolene or baclofen may alter their effect, so a dose adjustment may be required.

- Due to the risk of pharmacotoxic psychosis, simultaneous use of memantine with amantadine should be avoided. These drugs are chemically related antagonists NMDAreceptors. This risk is also characteristic of ketamine and dextromethorphan (see section "Special instructions"). A case of a risk of similar interaction between memantine and phenytoin is described.

- Other active substances, such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which use the same renal cationic transport system as amantadine, probably can interact with memantine, leading to a potential risk of an increase in the content of these substances in the blood plasma.

- It is possible to reduce the concentration of hydrochlorothiazide in the blood serum when used simultaneously with memantine or any combination containing hydrochlorothiazide.

- In post-registration studies, individual cases of an increase in the international normalized relationship (INR) in patients taking concomitantly 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.

In pharmacokinetic studies, a single administration of memantine by healthy volunteers did not lead to pharmacokinetic interaction with glibenclamide / metformin or donepezil.

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

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

Special instructions:

Caution should be exercised when used in patients with epilepsy, history of seizures, or in patients with a predisposition to epilepsy.

It should avoid simultaneous use of the drug with other blockers NMDA-receptors, 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 (see also the section "Interaction with other drugs").

Some factors that can raise the pH of the urine (see the section "Pharmacokinetics") require careful monitoring of the patient.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, urinary 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, decompensated by chronic heart failure (III-IV functional class for NYHA) or uncontrolled hypertension. Data on such patients are limited, so they require careful monitoring of the doctor.

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 driving vehicles and working with complex mechanisms.

Form release / dosage:Tablets, film-coated, 10 mg and 20 mg.

Packaging:

For 10, 25, 30, 50 tablets in a contour mesh package made of a polyvinyl chloride film and aluminum foil printed lacquered.

10, 25, 30, 40, 50, 60, 90 or 100 tablets in cans of polyethylene terephthalate for medicinal products sealed with screw caps with a first opening control or a "push-turn" system of polypropylene or polyethylene or polypropylene cans for medicines, sealed with caps tightened with the control of the first opening of polyethylene or cans of polypropylene for medicinal products sealed with lids pulled with the control of the first opening of high pressure polyethylene.

One bank or 1,2, 3, 4, 5, 6, 9 or 10 contour cellular packs, together with the instruction for use, are placed in a cardboard package (bundle).

Storage conditions:

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-004105

Date of registration:26.01.2017

Expiration Date:26.01.2022

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp02.03.2017

Illustrated instructions

Instructions

Memantine (Memantin)