Mematon® is

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEMATON® IS

Composition:

Active substance: memantine;

1 tablet contains memantine hydrochloride 10 mg or 20 mg;

Excipients: sodium croscarmellose, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), polyethylene glycol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets; the 10 mg tablet has a score line on one side.

Pharmacotherapeutic group.

Psychoanaleptics. Medicinal products used in dementia. Memantine. ATC code N06DX01.

Pharmacological Properties

Pharmacodynamics

Glutamatergic neurotransmission, particularly involving N-methyl-D-aspartate (NMDA) receptors, plays a significant role in the symptoms and progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. Memantine modulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.

Clinical Studies

In the main study involving 252 outpatients with Alzheimer’s disease of moderate to severe severity [baseline Mini-Mental State Examination (MMSE) scores of 3–14 points], patients treated with memantine as monotherapy showed a favorable effect after 6 months of treatment compared to placebo group patients [observed case analysis using the following scales: Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus): p = 0.025; Alzheimer's Disease Cooperative Study–Activities of Daily Living scale for severe impairment (ADCS-ADLsev): p = 0.003; Severe Impairment Battery (SIB): p = 0.002].

In another pivotal study of memantine monotherapy involving 403 patients with Alzheimer’s disease of mild to moderate severity (baseline MMSE scores of 10–22 points), patients receiving memantine showed statistically significant greater improvement compared to the placebo group in the primary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) (p = 0.003) and CIBIC-plus (p = 0.004) at week 24 [using the last observation carried forward (LOCF) method]. However, in a prospective primary analysis of another monotherapy study involving 470 patients with mild to moderate Alzheimer’s disease (baseline MMSE scores of 10–23 points), no statistically significant difference in the primary efficacy endpoint was observed between the memantine and placebo groups at week 24.

In a meta-analysis of pooled data from patients with moderate to severe Alzheimer’s disease (baseline MMSE < 20 points) who participated in six 6-month placebo-controlled phase III clinical trials (including studies of memantine monotherapy and studies of patients receiving a maintenance dose of acetylcholinesterase inhibitors), memantine treatment showed statistically significant beneficial effects on cognitive, functional, and global domains. In patients experiencing deterioration in all three domains, results demonstrated a statistically significant positive effect of memantine in preventing further worsening; deterioration in all three domains was observed twice as frequently in the placebo group compared to the memantine group (21% vs. 11%, p < 0.0001).

Pharmacokinetics

Absorption

The absolute bioavailability of memantine is approximately 100%. The time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food effects on absorption.

Distribution

A daily dose of 20 mg results in a steady-state plasma concentration of memantine ranging from 70 to 150 ng/mL (0.5–1 µmol), with considerable inter-individual variability. When daily doses of 5 to 30 mg are administered, the ratio of memantine concentration in cerebrospinal fluid to that in blood serum averages 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is bound to plasma proteins.

Metabolism

In humans, approximately 80% of memantine circulates in unchanged form. The main metabolites—N-3,5-dimethylgludantan, a mixture of 4- and 6-hydroxymemantine isomers, and 1-nitroso-3,5-dimethyladamantane—lack NMDA-antagonistic activity. In vitro studies have shown no involvement of the cytochrome P450 system in memantine metabolism.

Elimination

In a study following oral administration of 14C-memantine, approximately 84% of the administered dose was eliminated within 20 days, with over 99% excreted via the kidneys.

Memantine elimination follows a monoexponential pattern with a half-life (T1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m², with a significant portion of renal clearance achieved through tubular secretion. Tubular reabsorption also occurs in the kidneys, possibly mediated by a cation-transport system. The rate of renal elimination of memantine may decrease when urine pH is alkalinized to pH 7–9 (see section "Special Instructions"). Urine alkalinization may occur due to drastic dietary changes, such as switching from a meat-rich diet to a vegetarian diet, or due to intensive intake of alkaline gastric buffers.

Linearity

Pharmacokinetic studies in volunteers indicate that memantine exhibits linear pharmacokinetics within the dose range of 10–40 mg.

Pharmacokinetic/Pharmacodynamic Relationship

When memantine is administered at a dose of 20 mg per day, its concentration in cerebrospinal fluid corresponds to the inhibition constant (Ki) of 0.5 µmol in the frontal cortex region of the human brain.

Clinical characteristics.

Indications.

Alzheimer's disease of moderate to severe degree of severity.

Contraindications.

Hypersensitivity to memantine or to any excipient of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The mechanism of action of memantine and its pharmacological effects determine the following interactions.

Concomitant use of memantine and amantadine should be avoided due to the risk of developing a pharmacotoxic psychosis. Both compounds are chemically related antagonists of NMDA receptors. The risk of developing psychosis is also increased when memantine is used concomitantly with ketamine and dextromethorphan (see section "Special precautions for use"). In one published report, the risk of developing psychosis was also reported with combined use of memantine and phenytoin.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which are transported by the same renal cation transport system as amantadine, may also potentially interact with memantine, leading to a potential risk of increased plasma concentration of memantine.

When NMDA receptor antagonists such as memantine are used concomitantly with levodopa, dopaminergic agonists, and anticholinergic agents, an enhanced effect is possible. Effects of barbiturates and neuroleptic agents may be diminished. Concomitant use of memantine with dantrolene, baclofen, and muscle relaxants may modify their effects and require dose adjustment.

Concomitant use of memantine with hydrochlorothiazide (HCT) or any combination containing HCT may result in decreased serum levels of HCT.

In the post-marketing period of memantine use, isolated cases of increased international normalized ratio (INR) have been reported in patients who were concurrently receiving warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is necessary in patients who are concurrently taking oral anticoagulants.

Pharmacokinetic studies involving young healthy volunteers showed no drug interaction effects when memantine was administered concomitantly as a single dose with glimepiride/metformin or donepezil.

In a clinical study involving young healthy volunteers, no significant influence of memantine on the pharmacokinetics of galantamine was observed.

In vitro studies showed that memantine did not inhibit the isoenzymes CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation.

Special precautions for use

Caution should be exercised when prescribing memantine to patients with epilepsy, a history of seizures, or risk factors for developing epilepsy.

Concomitant use of memantine with other NMDA receptor antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may occur more frequently or be more pronounced (see section "Interaction with other medicinal products and other types of interactions").

The presence of certain factors that may increase urine pH (see section "Pharmacological properties") may require careful monitoring of the patient. Such factors include significant dietary changes, for example switching from a meat-rich diet to a vegetarian diet, or intensive use of alkaline gastric buffers. Additionally, urine pH may increase in renal tubular acidosis or in severe urinary tract infections caused by Proteus species bacteria.

Most clinical trials excluded patients who had recently experienced myocardial infarction, patients with decompensated congestive heart failure (functional class III–IV according to the New York Heart Association (NYHA) classification of chronic heart failure), and patients with uncontrolled arterial hypertension. Therefore, data regarding these patient groups are limited, and such patients should be closely monitored.

Use during pregnancy or breastfeeding

Pregnancy

Clinical data on the use of memantine during pregnancy are lacking. Animal studies indicate a potential for delayed intrauterine growth when memantine is administered at doses equal to or slightly exceeding those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy except in cases of clear medical necessity.

Breastfeeding

It is unknown whether memantine is excreted in human breast milk; however, excretion is likely due to the lipophilic nature of the substance. Women taking memantine should not breastfeed.

Fertility

No adverse effects of memantine on male or female fertility have been observed.

Ability to affect reaction speed when driving or operating machinery

Moderate to severe Alzheimer's disease typically impairs the ability to drive a vehicle or operate machinery. In addition, memantine may have a slight or moderate influence on the ability to drive vehicles or operate machinery. Therefore, outpatients should be advised to exercise particular caution when performing these activities.

Method of Administration and Dosage

Treatment with the medicinal product should be initiated and conducted under the supervision of a physician experienced in the diagnosis and treatment of dementia associated with Alzheimer's disease. The condition must be diagnosed according to current guidelines.

Treatment may only be initiated if a caregiver is available who will regularly supervise the patient's intake of the medicinal product. The patient's tolerance to treatment and the dose of memantine used should be regularly reassessed, preferably within the first 3 months after starting treatment. Thereafter, the clinical efficacy of memantine and treatment tolerance should be regularly reassessed according to current clinical guidelines. The duration of treatment is determined individually by the physician. Maintenance therapy may be continued as long as a favorable therapeutic effect persists and the patient tolerates memantine well. Consideration should be given to discontinuing memantine treatment if the therapeutic effect disappears or if treatment tolerance worsens.

The medicinal product should be taken orally once daily at the same time each day, independent of food intake.

Adults

Dose Titration

Maximum daily dose – 20 mg. To reduce the risk of adverse effects, the maintenance dose should be reached gradually by increasing the dose by 5 mg weekly over the first 3 weeks according to the following schedule:

Week 1 (Days 1–7):
Take 5 mg (½ tablet of 10 mg strength) once daily for 7 days;

Week 2 (Days 8–14):
Take 10 mg (1 tablet of 10 mg strength) once daily for 7 days;

Week 3 (Days 15–21):
Take 15 mg (1½ tablets of 10 mg strength) once daily for 7 days;

From Week 4 onwards:
Take 20 mg (2 tablets of 10 mg strength or 1 tablet of 20 mg strength) once daily.

Maintenance Dose

The recommended maintenance dose is 20 mg per day.

Elderly Patients

Based on clinical study results, the recommended dose for patients aged 65 years and older is 20 mg daily (2 tablets of 10 mg strength or 1 tablet of 20 mg strength once daily), as stated above.

Patients with Renal Impairment

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), dose adjustment is not 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 daily according to the standard titration schedule 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 of the medicinal product should not exceed 10 mg.

Patients with Hepatic Impairment

For patients with mild to moderate hepatic impairment (Child–Pugh class A and B), dose adjustment is not required. Data on the use of memantine in patients with severe hepatic impairment are lacking. The use of memantine in this patient group is not recommended.

Children

The medicinal product should not be used in children (under 18 years of age) due to insufficient data on safety and efficacy of memantine in this patient group.

Overdose

Limited data on memantine overdose were obtained during clinical trials and the post-marketing period.

Symptoms

Overdose following ingestion of relatively high doses of memantine (200 mg and 105 mg daily for 3 days, respectively) was associated with symptoms such as increased fatigue, weakness and/or diarrhea, or no clinical signs of overdose were observed. In cases of overdose caused by ingestion of doses below 140 mg or an unknown dose, patients experienced central nervous system disturbances (confusion, lethargy, somnolence, vertigo, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disturbances (vomiting, diarrhea).

In the most severe known case of overdose, a patient survived after ingesting a total dose of 2000 mg of memantine, experiencing central nervous system disturbances (coma for 10 days, followed by diplopia and agitation). The patient received symptomatic treatment and plasmapheresis and recovered without any permanent complications.

In another case of severe overdose following ingestion of 400 mg of memantine, the patient also survived and recovered. The patient experienced central nervous system disturbances such as anxiety, psychosis, visual hallucinations, increased seizure susceptibility, somnolence, stupor, and loss of consciousness.

Treatment

Symptomatic treatment should be administered in case of overdose. There is no known specific antidote for intoxication or overdose. Standard clinical procedures for elimination of the active substance from the body should be performed, such as gastric lavage, administration of activated charcoal (to prevent potential enterohepatic recirculation), urinary acidification methods, and forced diuresis.

Symptomatic therapy should be administered cautiously in the presence of symptoms indicating generalized central nervous system hyperstimulation.

Adverse Reactions

In clinical trials involving patients with mild to severe dementia (1784 patients received memantine and 1595 received placebo), the overall incidence of adverse reactions in patients treated with memantine was not different from that in patients receiving placebo. Adverse reactions were generally mild to moderate in severity. The most common adverse reactions observed 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 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. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Nervous system disorders: common – dizziness, balance disorder; uncommon – gait disturbance; very rare – seizures.

Psychiatric disorders: common – somnolence; uncommon – confusion, hallucinations*; frequency not known – psychotic reactions**.

Cardiac disorders: common – hypertension; uncommon – heart failure, venous thrombosis/thromboembolism.

Respiratory system disorders: common – dyspnea.

Gastrointestinal disorders: common – constipation; uncommon – vomiting; frequency not known – pancreatitis**.

Hepatobiliary disorders: common – increased liver function biochemical parameters; frequency not known – hepatitis.

Immune system disorders: common – hypersensitivity reactions.

Infections and infestations: uncommon – fungal infections.

General disorders: common – headache; uncommon – fatigue.

* Hallucinations were primarily observed in patients with severe Alzheimer's disease.

** Isolated cases reported during 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 requested to report any suspected adverse reactions via the national reporting system to ensure ongoing monitoring of the benefit-risk balance of the medicinal product.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

10 tablets per blister; 3 blisters per carton.

Prescription status

Prescription only.

Manufacturer

"INTERSIM" Limited Liability Company.

Manufacturer's address

40-A, 21st km of Starokyivska Road, Odesa, Ukraine, 65025.