Mentavistin film-coated tablets 10 mg blister No. 30

Instructions Mentavistin film-coated tablets 10 mg blister No. 30

Composition

active ingredient: memantine;

1 tablet contains memantine hydrochloride 10 mg or 20 mg, equivalent to 8.31 mg or 16.62 mg of memantine;

excipients: lactose monohydrate, microcrystalline cellulose, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

film shell:

for 10 mg dosage: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000; for 20 mg dosage: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide yellow (E 172), iron oxide red (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

10 mg tablets: White, round, biconvex, film-coated tablets with a wide pressure-sensitive score on one side and embossed with “M9MN” and “10” on the other side.

20 mg tablets: Pink, oval, biconvex, film-coated tablets with a wide pressure-sensitive score on one side and embossed with “M9MN 20” on the other side.

Pharmacotherapeutic group

Psychoanaleptics. Other agents for use in dementia. Memantine. ATX code N06D X01.

Pharmacological properties

Pharmacodynamics.

Disturbances in glutamatergic neurotransmission, especially involving NMDA (N-methyl-D-aspartate) receptors, play an important role in the manifestation of symptoms and progression of neurodegenerative dementia.

Memantine is a potential-dependent, medium-affinity, non-competitive NMDA receptor antagonist. Memantine modulates the effects of pathologically elevated glutamate levels, which can lead to neuronal dysfunction.

Clinical trials

The pivotal monotherapy study in patients with moderate to severe Alzheimer's disease (MMSE score 3–14) included a total of 252 outpatients. The beneficial effect of memantine treatment is evident after 6 months of treatment compared to placebo treatment (observed case analysis for the clinician interview based on changes in CIBIC-plus (p = 0.025); ADCS-ADLsev (p = 0.003) and SIB (p = 0.002)). The pivotal monotherapy study of memantine in the treatment of mild to moderate Alzheimer's disease (MMSE total score at baseline from 10 to 22) included 403 patients. Patients treated with memantine showed statistically significantly better results than patients treated with placebo on the primary endpoints ADAS-cog (p = 0.003) and CIBIS-plus (p = 0.004) at 24 weeks (LOCF). In another monotherapy study in mild to moderate Alzheimer's disease, a total of 470 patients (baseline MMSE total score 11–23) were randomized. In the prospectively defined primary analysis, statistical significance was not reached for the primary efficacy endpoint at 24 weeks.

A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total score) from six phase III placebo-controlled 6-month studies (including monotherapy studies and studies in patients taking a stable dose of acetylcholinesterase inhibitors) showed a statistically significant effect of memantine treatment on cognitive, general and functional domains.

When a patient experienced concomitant deterioration in all three domains, the results demonstrated a statistically significant effect of memantine in preventing deterioration; patients in the placebo group experienced deterioration in all three domains twice as often as patients taking memantine (21% vs. 11%, p 0.0001).

Pharmacokinetics.

Absorption

The absolute bioavailability of memantine is approximately 100%, the time to peak plasma concentration (Tmax) is 3 to 8 hours. There is no evidence of an effect of food intake on absorption.

Distribution

A daily dose of 20 mg results in steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5–1 μmol) with significant interindividual variation. At daily doses of 5 to 30 mg, the ratio of the drug content in the cerebrospinal fluid to the serum is 0.52. The volume of distribution is approximately 10 l/kg. Approximately 45% of memantine is bound to plasma proteins.

Biotransformation

In humans, approximately 80% of memantine circulates as the parent compound, the major metabolites do not have NMDA antagonistic properties. Cytochrome P450 involvement in metabolism has not been demonstrated in vitro.

In a study with oral administration of 14C-memantine, an average of 84% of the dose was eliminated within 20 days, with more than 99% of the dose excreted by the kidneys.

Elimination

Linearity

According to studies in volunteers, the pharmacokinetics of memantine are linear in the dose range of 10–40 mg.

Pharmacodynamic/pharmacokinetic relationship

At a dose of 20 mg of memantine per day, its content in the cerebrospinal fluid corresponds to the ki value (inhibition constant) of memantine, which is 0.5 μmol in the frontal cortex of the human brain.

Indication

Alzheimer's disease from moderate to severe forms.

Contraindication

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other types of interactions

Concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may be true for ketamine and dextromethorphan. One published report also noted the possible risk of the combination of memantine and phenytoin.

The mechanism of action suggests that the effects of L-dopa, dopaminergic agonists and anticholinergics may be potentiated by concomitant use of NMDA antagonists such as memantine. The effects of barbiturates and neuroleptics may be attenuated. Concomitant use of memantine and the antispasmodics dantrolene or baclofen may modify their effects, which may require dose adjustment.

Other drugs, such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which use the same renal cation transport system as amantadine, may also be able to interact with memantine, leading to a potential risk of increased plasma levels.

When memantine is co-administered with hydrochlorothiazide (HCTZ) or any combination with HCTZ, a decrease in serum HCTZ levels is possible.

There have been isolated reports of increased international normalized ratio (INR) with memantine in patients taking warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is necessary in patients taking concomitant oral anticoagulants.

In pharmacokinetic studies in healthy volunteers, no significant interaction effects of memantine with glyburide/metformin, donepezil, or galantamine were observed. Memantine is not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation in vitro.

Application features

Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizures, as well as patients with risk factors for epilepsy. Concomitant use with N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine, and therefore adverse reactions (mainly related to the central nervous system) may be more frequent or more pronounced.

Several factors that may increase urine pH may warrant close monitoring. These include major dietary changes, such as changing from a meat-rich diet to a vegetarian diet, or heavy use of antacids. In addition, urine pH may be elevated due to conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.

In most clinical trials, patients with recent myocardial infarction, decompensated congestive heart failure (New York Heart Association grades III–IV), and uncontrolled hypertension were excluded from the study. As a result, only limited data are available and patients with these conditions require close monitoring.

Important information about excipients.

The medicinal product contains lactose, therefore it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

There are no data on the effects of memantine when used during pregnancy. Experimental studies in animals indicate the possibility of intrauterine growth retardation at memantine exposure levels identical to or slightly higher than those used in humans. The potential risk for humans is unknown. The drug Mentavistin should not be used during pregnancy, except in cases of clear and obvious necessity.

It is not known whether memantine is excreted in breast milk, which is, however, possible given the lipophilicity of the substance. Women taking memantine should refrain from breastfeeding.

Fertility.

In preclinical studies, no negative effect of memantine on male or female fertility was observed.

Ability to influence reaction speed when driving vehicles or other mechanisms

Moderate to severe Alzheimer's disease usually causes impairment of the ability to drive and use machines. Memantine also has minor or moderate influence on the ability to drive and use machines, so outpatients should exercise caution when performing the above-mentioned operations.

Method of administration and doses

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Treatment should only be initiated in the presence of a caregiver who will monitor the patient's medication intake. Diagnosis should be made in accordance with current guidelines. Tolerability and dosage of memantine should be assessed regularly, preferably within 3 months of initiating therapy. Thereafter, the clinical benefit of memantine and the patient's tolerability should be reassessed regularly in accordance with current clinical guidelines. Maintenance treatment may be continued as long as the therapeutic effect remains favourable and the patient is tolerating memantine. The decision to discontinue memantine should be considered in the absence of therapeutic effect or if the patient is not tolerating the medication. The tablets should be taken once daily at the same time each day, regardless of food intake.

Adults.

Dose titration

The maximum daily dose is 20 mg. In order to reduce the risk of adverse reactions, the maintenance dose should be determined by gradually increasing the dosage by 5 mg per week during the first 3 weeks as follows:

Week 1 (days 1-7):

take 5 mg per day for a week;

2nd week (day 8-14):

take 10 mg per day for a week;

Week 3 (days 15-21):

take 15 mg per day for a week.

Starting from week 4:

take 20 mg per day for a week.

Maintenance dose

The recommended maintenance dose is 20 mg per day.

Elderly patients

The recommended dose for patients aged 65 years and over is 20 mg per day, as stated above.

Kidney dysfunction

For patients with mild renal impairment (creatinine clearance 50-80 ml/min), no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance 30-49 ml/min), a daily dose of 10 mg should be used. If this dose is well tolerated by the patient for at least 7 days of treatment, it may be increased to 20 mg per day according to the standard dose selection scheme. For patients with severe renal impairment (creatinine clearance 5-29 ml/min), a daily dose of 10 mg should be prescribed.

Liver dysfunction

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A and B). There are no data on the use of memantine in patients with severe hepatic impairment, therefore, memantine is not recommended for use in patients with severe hepatic impairment.

Children.

The drug is not used in children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose

Data on overdose are limited.

Symptoms.

Relatively large overdoses (200 mg and 105 mg per day for 3 days, respectively) were either associated with symptoms of fatigue, weakness and/or diarrhea, or were asymptomatic. Overdoses up to 140 mg or an unknown dose have been associated with symptoms of central nervous system disorders (confusion, lethargy, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disorders (vomiting and diarrhea).

In the most severe known case of overdose, a patient survived after oral administration of a total dose of 2000 mg of memantine and developed central nervous system disorders (coma for 10 days, later diplopia and agitation). The patient was treated symptomatically and underwent plasmapheresis. The patient recovered completely without any permanent sequelae.

In another case of a large overdose (400 mg memantine orally), the patient also survived and recovered. He experienced central nervous system disorders such as anxiety, psychosis, visual hallucinations, convulsive readiness, drowsiness, stupor, and unconsciousness.

Treatment.

Treatment is symptomatic, there is no specific antidote. Standard clinical procedures should be used to remove the active substance from the body, such as gastric lavage, administration of activated charcoal, methods of acidifying the urine reaction, forced diuresis. In case of excessive general stimulation of the central nervous system, symptomatic treatment measures should be carried out with caution.

Adverse reactions

General safety profile data

The most common adverse reactions, which occurred more frequently in the memantine group than in the placebo group, were dizziness (6.3% vs. 5.6%, respectively), headache (5.2% vs. 3.9%), constipation (4.6% vs. 2.6%), somnolence (3.4% vs. 2.2%), and hypertension (4.1% vs. 2.8%).

The following table lists adverse reactions observed during clinical trials and post-marketing use, defined by frequency as: very common (≥ 1/10), common (≥ 1/100 to < 1/1000), uncommon0 to < 1/

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

2Separate messages for medical use.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have been reported with the medical use of memantine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

This medicinal product does not require any special storage conditions. Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a pack.

Vacation category

According to the recipe.

Producer

Synthon Hispania, SL

Location of the manufacturer and address of its place of business

Calle Castello, no. 1, Sant Boi de Llobregat, Barcelona, 08830, Spain/

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.