Memtek

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Mемtek® (Memtec)

Composition:

Active substance: memantine;

One orodispersible tablet contains 10 mg of memantine hydrochloride, equivalent to 8.31 mg of memantine;

Excipients: polacrilin, sodium hydroxide, purified water\1, lactose monohydrate, microcrystalline cellulose, mannitol (E 421), sodium croscarmellose, aspartame (E 951), colloidal anhydrous silicon dioxide, iron oxide red (E 172), peppermint flavor2, magnesium stearate.

\1The majority is removed during the manufacturing process;

\2Peppermint flavor contains: maltodextrin, modified starch (E 1450), peppermint oil.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties: light pink tablets with specks, round-shaped, flat surface, beveled edges, and engraved "10" on one side.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Disturbances in glutamatergic neurotransmission, particularly involving N-methyl-D-aspartate (NMDA) receptors, play 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.

Pharmacokinetics

Absorption. Absolute bioavailability of memantine is approximately 100%. Time to reach maximum plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food effect 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 individual variability. When daily doses of 5 to 30 mg are administered, the ratio of drug concentration in cerebrospinal fluid to that in blood plasma is 0.52. Approximately 45% of memantine is bound to plasma proteins.

Biotransformation. In humans, approximately 80% of memantine circulates in its unchanged form. The main metabolites lack NMDA-antagonistic properties. No involvement of cytochrome P450 in memantine metabolism has been observed in vitro.

Elimination. Memantine is eliminated in a monoexponential manner, with a half-life (T1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is approximately 170 mL/min/1.73 m². The renal phase of memantine pharmacokinetics includes tubular reabsorption.

Renal elimination of memantine may decrease by 7–9 times under alkaline urine conditions. Urinary alkalinization may occur due to significant dietary changes, such as switching from a meat-rich diet to a vegetarian diet, or as a result of intensive use of antacid gastric medications.

Linearity. Pharmacokinetics are linear within the dose range of 10–40 mg.

Pharmacodynamic/pharmacokinetic relationship. At a daily dose of 20 mg, memantine concentration in cerebrospinal fluid corresponds to the inhibition constant (ki) of memantine, which is 0.5 μmol in the frontal cortex region of the human brain.

Clinical characteristics.

Indications.

Alzheimer's disease of moderate to severe degree.

Contraindications.

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 apply to ketamine and dextromethorphan. One published report also indicated a potential risk of combining memantine with phenytoin.

The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when co-administered with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant use of memantine with the muscle relaxants dantrolene or baclofen may modify their effects, possibly necessitating dose adjustments.

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

When memantine is co-administered with hydrochlorothiazide (HCTZ) or any combination containing HCTZ, a decreased serum level of HCTZ may occur.

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

In pharmacokinetic studies in healthy volunteers, no significant interaction effects were observed between memantine and glipizide/metformin, donepezil, or galantamine.

In vitro, memantine is not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase.

Special precautions for use.

Caution should be exercised when prescribing the medicinal product to patients with epilepsy, those with a history of seizures, as well as patients with risk factors for developing epilepsy.

Concomitant use of the medicinal product with N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine; therefore, adverse reactions (mainly related to the central nervous system) may be more frequent or more pronounced. Certain factors that cause an increase in urine pH may necessitate careful patient monitoring. Such factors include significant dietary changes, for example, switching from a meat-rich diet to a vegetarian one, or intensive use of antacid gastric agents. In addition, urine pH may increase in conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.

Patients who have recently experienced myocardial infarction, those with decompensated congestive heart failure (NYHA class III–IV), and those with uncontrolled arterial hypertension were not included in clinical studies; therefore, data regarding these patient groups are limited. Close monitoring is required for patients with these conditions.

Important information about excipients.

The medicinal product contains aspartame, a phenylalanine derivative, which may be harmful for patients with phenylketonuria. It also 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 clinical data on the effects of memantine when used during pregnancy. Animal studies indicate a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy except in cases where clearly and explicitly necessary.

It is unknown whether memantine is excreted in human breast milk, although excretion may occur considering the lipophilic nature of the substance. Women receiving memantine should avoid breastfeeding.

Fertility.

No negative effects of memantine on fertility in men or women have been observed.

Ability to influence reaction speed when driving or operating machinery.

Alzheimer’s disease, from moderate to severe stages, typically impairs the ability to drive a vehicle or operate machinery. In addition, memantine may have a slight or moderate effect on human reaction speed. Therefore, outpatients should be advised to exercise particular caution when driving or operating machinery.

Method of Administration and Dosage

Treatment should be initiated and conducted under the supervision of a physician. Therapy should be started only if a caregiver is available who will regularly monitor the patient's intake of the medicinal product.

The tablets should be taken once daily at the same time each day. The tablets may be taken with or without food.

The maximum daily dose is 20 mg.

To reduce the risk of adverse reactions, the maintenance dose should be established by gradually increasing the dosage by 5 mg per week over the first 3 weeks as follows:

1st week (days 1–7):

the patient should take 5 mg* daily for one week;

2nd week (days 8–14):

the patient should take 10 mg daily for one week;

3rd week (days 15–21):

the patient should take 15 mg* daily for one week;

from week 4 onwards: take 20 mg daily.

*Use memantine preparations at the corresponding dosage.

The recommended maintenance dose is 20 mg per day. The duration of treatment is determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. Tolerance and dosage of memantine should be regularly evaluated, especially during the first 3 months of treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly assessed according to current clinical guidelines. Maintenance therapy may be continued as long as the therapeutic effect remains favorable and the tolerability of memantine is good.

Consideration should be given to discontinuing memantine treatment if signs of therapeutic benefit disappear or if tolerability worsens.

Elderly patients.

Based on clinical trial results, the recommended dose for patients aged 65 years and older is 20 mg per day (2 tablets of 10 mg once daily), as stated above.

Renal impairment.

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), dose reduction is not 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 daily following the standard titration schedule if no adverse reactions occur 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.

For patients with mild to moderate hepatic impairment (Child-Pugh class A, B), dose adjustment is not required. Memantine is not recommended in patients with severe hepatic impairment.

Children

The medicinal product is not used in children due to insufficient data on safety and efficacy.

Overdose

Experience is limited.

Symptoms

Significant overdoses (200 mg and 105 mg daily 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 with an unknown dose, symptoms of central nervous system disturbances (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disturbances (vomiting, diarrhea) were observed.

In the most severe known case of overdose, a patient survived after oral intake of a total dose of 2000 mg of memantine and experienced central nervous system disturbances (coma lasting 10 days, followed by diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. Full recovery occurred without any permanent sequelae.

In another case of massive overdose (400 mg of memantine orally), the patient also survived and recovered. Central nervous system disturbances were observed, including restlessness, psychosis, visual hallucinations, seizure readiness, somnolence, stupor, and unconsciousness.

Treatment

Symptomatic; there is no specific antidote. Standard clinical procedures for elimination of the active substance from the body should be used, such as gastric lavage, activated charcoal, acidification of urine, and forced diuresis.

In cases of excessive central nervous system stimulation, symptomatic treatment measures should be used with caution.

Adverse reactions.

According to available data, during clinical trials of memantine, the overall incidence of adverse reactions did not differ from that observed with placebo, and adverse events were generally of mild to moderate severity.

The adverse reactions listed below, observed during clinical trials and post-marketing use, are categorized by frequency as follows: 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), and not known (cannot be estimated from the available data).

1Hallucinations were predominantly observed in patients with severe forms of Alzheimer's disease.

2Individual reports during post-marketing use.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have been reported during post-marketing use of memantine.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and/or lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

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. 15 tablets in a blister; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. GenePharm S.A.

Manufacturer's address and location of operations.

18 Km Meresono Avenue, Pallini, 153 51, Greece.

Marketing Authorization Holder. JSC "Pharmaceutical company "Darnytsia".

Address and location of operations of the Marketing Authorization Holder.

13 Boryspylska Street, Kyiv, 02093, Ukraine.