Memamed film-coated tablets 20 mg blister No. 30

Instructions for use Memamed film-coated tablets 20 mg blister No. 30

Composition

active ingredient: memantine;

1 tablet contains memantine hydrochloride 10 mg or 20 mg;

excipients: microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silicon dioxide, magnesium stearate;

shell: hypromellose, titanium dioxide (E 171), macrogol 400, iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

10 mg tablets: film-coated tablets, oblong, biconvex, yellow, with a break line on both sides, with a core diameter of 5.6x11.1 mm;

20 mg tablets: film-coated tablets, round, biconvex, yellow in color, with a core diameter of 10.3 mm.

The tablet can be divided into two equal parts.

Pharmacotherapeutic group

Psychoanaleptics. Other drugs 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 studies: 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 was evident after 6 months of treatment compared with placebo (observed case analysis for 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 mild to moderate Alzheimer's disease (baseline MMSE total score 10 to 22) enrolled 403 patients. Patients treated with memantine showed statistically significant improvement over patients treated with placebo on the primary endpoints of 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 were randomized (baseline MMSE total score 11 to 23). 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 < 20) from six phase III placebo-controlled 6-month studies (including monotherapy studies and studies in patients on 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 reach maximum plasma concentration (Tmax) is from 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 in cerebrospinal fluid to 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 main metabolites do not have NMDA antagonistic properties. Cytochrome P450 has not been shown to be involved in in vitro metabolism. In a study of oral administration of 14C-memantine, an average of 84% of the dose was eliminated within 20 days, with more than 99% excreted by the kidneys.

Elimination: Memantine is eliminated monoexponentially with a t1/2 of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cltot) is 170 ml/min/1.73 m2 and part of the total renal clearance is achieved by tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, which is probably mediated by a cationic transport system.

The rate of renal elimination of memantine in conditions of alkaline urine may be reduced by 7-9 times. Alkalinization of urine may occur as a result of profound changes in diet, for example, changing from a meat-rich diet to a vegetarian diet or as a result of intensive intake of antacid gastric preparations.

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

Indication

Alzheimer's disease from moderate to severe forms.

Contraindication

Hypersensitivity to the active substance or to any component of the drug.

Interaction with other medicinal products and other types of interactions

The 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 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 seizure episodes, as well as patients with risk factors for developing 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 side effects (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 significant 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 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.

Use during pregnancy or breastfeeding

There are no data on the effects of memantine during pregnancy. Experimental studies in animals indicate the possibility of intrauterine growth retardation when the drug is used in concentrations identical to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Moderate to severe Alzheimer's disease usually impairs the ability to drive and use machines. Also, memantine has a minor to moderate effect on the reaction time, so outpatients should be warned about the need to exercise special caution when driving or operating machinery.

Method of administration and doses

Treatment should be initiated and continued under the supervision of a physician. Therapy should only be initiated in the presence of a caregiver who will regularly monitor the patient's intake of the drug. The drug should be taken once a day at the same time each day. The tablets can be taken with or without food.

Adults. 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:

1st week (day 1-7): take ½ tablet (5 mg per day) for a week;

2nd week (day 8-14): take 1 tablet (10 mg per day) for a week;

Week 3 (days 15-21): take 1½ tablets (15 mg per day) for a week;

starting from the 4th week: take 20 mg per day (2 tablets of 10 mg or 1 tablet of 20 mg) every day.

The recommended maintenance dose is 20 mg per day.

The duration of treatment should be determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. The tolerability and dosage of memantine should be assessed regularly, preferably within 3 months of starting treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be assessed regularly in accordance with current clinical guidelines. Maintenance treatment may be continued as long as the therapeutic effect remains favourable and the patient's tolerance of memantine is good. Discontinuation of memantine should be considered if signs of therapeutic effect disappear or the patient's tolerance of treatment deteriorates.

Elderly patients: Based on clinical trial results, the recommended dose for patients aged 65 years and over is 20 mg per day, as stated above.

Renal impairment. For patients with mild renal impairment (creatinine clearance 50-80 ml/min), no dose reduction is required. For patients with moderate renal impairment (creatinine clearance 30-49 ml/min), the daily dose should be reduced to 10 mg. The dose may be increased to 20 mg per day according to the standard regimen if there are no adverse reactions after at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5-29 ml/min), the daily dose should be reduced to 10 mg.

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

Children.

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

Overdose

Experience is limited.

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

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: Symptomatic, no specific antidote exists. 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 used with caution.

Side effects

During clinical trials of memantine, the overall incidence of adverse events did not differ from that seen with placebo, and adverse events were usually mild or moderate in severity.

The adverse reactions observed during clinical trials and medical use are listed in the table below and are defined by frequency as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), unknown (cannot be determined from the available data).

often

often

infrequently

very rare

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

2 Separate 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.

Expiration date

2 years.

Storage conditions

Store in original packaging out of the reach of children.

Packaging

10 tablets in a blister, 3 or 6 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Medochemie LTD (Central Factory).

Location of the manufacturer and address of its place of business

1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.

Address

1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.

In case of adverse reactions and questions regarding the safety of the drug, please contact us via the feedback form on the website: www.ukraine.medochemie.com