Instructions for use Mematon IC film-coated tablets 20 mg blister No. 30
Composition
active ingredient: memantine;
1 tablet contains memantine hydrochloride 10 mg or 20 mg;
excipients: croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), polyethylene glycol, talc, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, film-coated, white; one surface of the 10 mg tablet has a dividing line.
Pharmacotherapeutic group
Psychoanaleptics. Drugs used in dementia. Memantine. ATX code N06D X01.
Pharmacological properties
Pharmacodynamics.
Disturbances in glutamatergic neurotransmission, especially involving N-methyl-D-aspartate (NMDA) receptors, play an important role in the manifestation of symptoms and progression of neurodegenerative dementia.
Memantine is a voltage-gated, medium-affinity, noncompetitive NMDA receptor antagonist. Memantine modulates the effects of pathologically elevated glutamate levels, which can lead to neuronal dysfunction.
Clinical trials
In a pivotal study of 252 outpatients with moderate to severe Alzheimer's disease [baseline MMSE score 3–14], patients receiving memantine monotherapy demonstrated a beneficial effect of the drug after 6 months of treatment compared with patients receiving placebo [observed-case analysis using the following scales: Clinician's Impression of Change Interview-Based Scale (CIBIC-plus): p = 0.025; Alzheimer's Disease Collaborative Study – Activities of Daily Living (ADCS-ADLsev): p = 0.003; Severe Dementia Cognitive Score (SIB): p = 0.002].
The results of the main study of memantine as monotherapy in 403 patients with mild to moderate Alzheimer's disease (baseline MMSE score 10–22) showed that patients receiving memantine had a statistically significant greater effect on the primary endpoints: Alzheimer's Disease Assessment Scale (ADAS-cog) (p = 0.003) and CIBIC-plus (p = 0.004) at week 24 of the study [according to the last observation carried forward (LOCF) method]. According to a prospective primary analysis of the results of another study of memantine as monotherapy in 470 patients with mild to moderate Alzheimer's disease (baseline MMSE score 10–23), no statistically significant difference in the primary efficacy endpoint was achieved in the groups of patients receiving memantine or placebo at week 24 of the study.
A meta-analysis of pooled data from patients with moderate to severe Alzheimer's disease (baseline MMSE < 20) who participated in 6 placebo-controlled phase III clinical trials of 6 months duration (including studies of patients treated with memantine as monotherapy and studies of patients receiving maintenance doses of acetylcholinesterase inhibitors) showed a statistically significant beneficial effect of memantine treatment on cognitive, functional and global domains. In patients with simultaneous deterioration in all three domains, the results showed a statistically significant positive effect of memantine on preventing further deterioration; patients in the placebo group experienced deterioration in all three domains twice as often as patients treated with memantine (21% vs. 11%, p < 0.0001).
Pharmacokinetics.
Absorption
The absolute bioavailability of memantine is approximately 100%. The time to reach 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 intersubject variability. At daily doses of 5 to 30 mg, the ratio of memantine concentration in the cerebrospinal fluid to serum is on average 0.52. The volume of distribution is approximately 10 l/kg. Approximately 45% of memantine is bound to plasma proteins.
Metabolism
In humans, about 80% of memantine circulates unchanged. The main metabolites, N-3,5-dimethylgludantan, a mixture of 4- and 6-hydroxymemantine isomers, and 1-nitroso-3,5-dimethyladamantane, do not have NMDA antagonistic activity. The involvement of the cytochrome P450 system in the metabolism of memantine in vitro has not been demonstrated.
Elimination
Memantine is eliminated monoexponentially with a half-life (T1/2) of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cltot) is 170 ml/min/1.73 m2, with part of the total renal clearance being achieved by tubular secretion. There is also tubular reabsorption in the kidneys, which is probably mediated by the cation transport system. The rate of renal elimination of memantine may be reduced by alkalinization of the urine to pH 7-9 (see section "Special instructions"). Alkalinization of the urine may occur as a result of abrupt changes in the diet, for example, by replacing a diet rich in meat with a vegetarian diet or by intensive intake of alkaline gastric buffers.
Linearity
According to studies in volunteers, the pharmacokinetics of memantine are linear in the dose range of 10–40 mg.
Relationship between pharmacokinetics and pharmacodynamics
When using memantine at a dose of 20 mg per day, its concentration in the cerebrospinal fluid corresponds to the inhibition constant (ki), 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 memantine or to any of the excipients of the drug.
Interaction with other medicinal products and other types of interactions
The mechanism of action of memantine and its pharmacological effects determine the following interactions.
The concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA receptor antagonists. The risk of psychosis is also increased when memantine is used concomitantly with ketamine and dextromethorphan (see section 4.4). One published report also reported a risk of psychosis with the combined use of memantine and phenytoin.
Other drugs such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which are transported by the same renal cation transport system as amantadine, may also be able to interact with memantine, leading to a potential risk of increased plasma concentrations.
Concomitant use of NMDA receptor antagonists such as memantine with levodopa, dopaminergic agonists and anticholinergics may potentiate the effects. The effects of barbiturates and neuroleptics may be reduced. Concomitant use of memantine with dantrolene, baclofen and antispasmodics may modify their effects and require dose adjustment.
Concomitant use of memantine with hydrochlorothiazide (HCTZ) or any combination containing HCTZ may result in decreased serum HCTZ levels.
In the post-marketing period, isolated cases of increased international normalized ratio (INR) have been reported in patients receiving concomitant warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is necessary in patients receiving concomitant oral anticoagulants.
Pharmacokinetic studies in young healthy volunteers revealed no drug interaction effects when memantine was co-administered with glyburide/metformin or donepezil as a single dose.
In a clinical study in young healthy volunteers, no significant effect of memantine on the pharmacokinetics of galantamine was observed.
In in vitro studies, memantine did not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation.
Application features
Caution should be exercised when prescribing memantine to patients with epilepsy, a history of seizures, or risk factors for developing epilepsy.
The concomitant use of memantine with NMDA receptor antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine and therefore side effects (mainly central nervous system) may be more frequent or more severe (see section 4.5).
The presence of certain factors that increase urine pH (see section "Pharmacological properties") may require careful monitoring of the patient. Such factors include abrupt changes in diet, such as replacing a diet rich in meat with a vegetarian diet or intensive intake of alkaline gastric buffers. In addition, urine pH may increase in renal tubular acidosis or severe urinary tract infections caused by bacteria of the genus Proteus.
Most clinical studies excluded patients with recent myocardial infarction, patients with decompensated congestive heart failure (New York Heart Association (NYHA) functional class III-IV for chronic heart failure), and patients with uncontrolled hypertension. As a result, only limited data are available in patients with these conditions, and this group of patients should be closely monitored.
Use during pregnancy or breastfeeding
Pregnancy period
There are no clinical data on the use of memantine during pregnancy. Animal studies have shown a potential for intrauterine growth retardation at doses similar to or slightly higher than those used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
Breastfeeding period
It is not known whether memantine is excreted in human milk, but this is likely due to the lipophilicity of the substance. Women taking memantine should not breast-feed.
Fertility
No negative effects of memantine on male and female fertility have been identified.
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. In addition, memantine has minor to moderate influence on the ability to drive and use machines, so outpatients should be warned to exercise special caution when performing the above operations.
Method of administration and doses
Treatment with the medicinal product should be initiated and supervised by a physician experienced in the diagnosis and treatment of dementia due to Alzheimer's disease. The disease should be diagnosed in accordance with current guidelines.
Therapy should only be initiated in the presence of a caregiver who will regularly monitor the patient's medication intake. The patient's tolerance of the treatment and the dose of memantine used should be reassessed regularly, preferably within the first 3 months after the start of treatment. In the future, the clinical efficacy of memantine and the tolerability of the treatment should be reassessed regularly in accordance with current clinical guidelines. The duration of treatment is determined by the physician individually. Maintenance treatment can be continued as long as the therapeutic effect remains favorable and the patient's tolerability of memantine is good. Discontinuation of memantine treatment should be considered in the event of loss of therapeutic effect or deterioration in patient tolerability.
The medicine should be taken orally once a day at the same time every day, regardless of meals.
Adults
Dose titration
The maximum daily dose is 20 mg. In order to reduce the risk of undesirable effects, the maintenance dose should be achieved by gradually increasing the dose by 5 mg per week during the first 3 weeks according to the following scheme:
Week 1 (days 1–7):
take 5 mg (½ tablet of 10 mg dosage) once a day for 7 days;
Week 2 (days 8–14):
take 10 mg (1 tablet with a dosage of 10 mg) once a day for 7 days;
Week 3 (days 15–21):
take 15 mg (1½ tablets of 10 mg) once a day for 7 days;
starting from the 4th week:
take 20 mg (2 tablets of 10 mg or 1 tablet of 20 mg) once a day.
Maintenance dose
The recommended maintenance dose is 20 mg per day.
Elderly patients
Based on the results of clinical studies, the recommended dose for patients aged 65 years and older is 20 mg per day (2 tablets of 10 mg or 1 tablet of 20 mg once a day), as indicated above.
Patients with renal impairment
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), the recommended daily dose is 10 mg. The dose may be increased to 20 mg per day according to the standard titration regimen if the patient tolerates memantine well for at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5–29 ml/min), the daily dose should not exceed 10 mg.
Patients with hepatic impairment
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. Memantine is not recommended for use in this patient group.
Children
The drug should not be used in children (under 18 years of age) due to insufficient data on the safety and efficacy of memantine in this group of patients.
Overdose
Limited data on overdose with memantine have been obtained during clinical trials and the post-marketing period.
Overdose with relatively high doses of memantine (200 mg and 105 mg per day for 3 days, respectively) was associated with symptoms such as fatigue, weakness and/or diarrhea, or clinical signs of overdose were not observed. In overdose caused by taking a dose below 140 mg or taking an unknown dose, patients experienced central nervous system disorders (confusion, lethargy, drowsiness, vertigo, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disorders (vomiting and diarrhea).
In the most severe known case of overdose, a patient survived after taking a total oral dose of 2000 mg of memantine, but developed central nervous system disorders (coma for 10 days, later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis and recovered without any permanent complications.
In another case of severe overdose due to oral ingestion of 400 mg of memantine, the patient also survived and recovered. The patient experienced central nervous system disorders such as anxiety, psychosis, visual hallucinations, increased seizure activity, drowsiness, stupor, and loss of consciousness.
Treatment
In case of overdose, symptomatic treatment should be carried out. There is no specific antidote for intoxication or overdose. Standard clinical procedures should be carried out to remove the active substance from the body, such as gastric lavage, administration of activated charcoal (to prevent potential enterohepatic recirculation), methods of acidification of urine, forced diuresis.
If symptoms of general central nervous system hyperstimulation appear, symptomatic therapy should be carried out with caution.
Adverse reactions
In clinical trials of memantine in patients with mild to severe dementia (1784 patients received memantine and 1595 received placebo), the overall incidence of adverse reactions in patients taking memantine did not differ from that in patients taking placebo; adverse reactions were usually mild to moderate in severity. The most common adverse reactions, which occurred at a higher frequency in the memantine group than in patients taking placebo, 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 adverse reactions listed below were observed during clinical trials and in the post-marketing period.
Adverse reactions are classified by system organ class and frequency. Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
From the nervous system: often - dizziness, balance disorders; infrequently - gait disturbances; very rarely - convulsions.
Psychiatric disorders: common: drowsiness; uncommon: confusion, hallucinations*; frequency unknown: psychotic reactions**.
Cardiovascular system: often - arterial hypertension; infrequently - heart failure, venous thrombosis/thromboembolism.
On the part of the respiratory system: often - shortness of breath.
Gastrointestinal tract: often - constipation; infrequently - vomiting; frequency unknown - pancreatitis**.
On the part of the hepatobiliary system: often - increased biochemical indicators of liver function; frequency unknown - hepatitis.
Immune system disorders: often – hypersensitivity reactions.
Infectious and parasitic diseases: uncommon - fungal diseases.
General disorders: often - headache; infrequently - increased fatigue.
* Hallucinations were observed mainly in patients with severe Alzheimer's disease.
** Isolated cases reported in the post-marketing period.
Depression, suicidal ideation and suicide attempts may occur in patients with Alzheimer's disease. Such cases have been reported in the post-marketing period in patients receiving memantine.
Reporting of suspected adverse reactions
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system in order to monitor the benefit/risk balance of the medicinal product.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
Additional Liability Company "INTERCHEM".
Location of the manufacturer and address of its place of business.
Ukraine, 65025, Odessa, 21st km. Starokyivska Road, 40-A.
