Memox 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEMOX 10 (MEMOX 10) MEMOX 20 (MEMOX 20)

Composition:

Active substance: memantine;

1 tablet contains 10 mg or 20 mg of memantine hydrochloride;

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

Film-coating mixture: lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol 4000 (macrogol); for 20 mg tablets: iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

"MEMOX 10": white, round, biconvex film-coated tablets, engraved with "M9MN" and "10" on one side and a breakline on the other;

"MEMOX 20": red-brown, oval, biconvex film-coated tablets, engraved with "M9MN 20" on one side and a breakline on the other.

Pharmacotherapeutic group.

Drugs used in dementia. ATC code N06DX01.

Pharmacological Properties.

Pharmacodynamics.

Glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) 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.

Pharmacokinetics.

Absorption.

The absolute bioavailability of memantine is approximately 100%. The time to reach maximum plasma concentration (tmax) ranges from 3 to 8 hours. There is no evidence of food effects on drug 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 memantine concentration in cerebrospinal fluid to that in blood plasma is 0.52. The mean volume of distribution of memantine is 10 L/kg. Approximately 45% of memantine is protein-bound in plasma.

Metabolism.

Approximately 80% of circulating compounds related to memantine hydrochloride in the human body are present as the parent substance. The main metabolites in humans are N-3,5-dimethyl-gludantane, an isomeric mixture of 4- and 6-hydroxymemantines, and 1-nitroso-3,5-dimethyladamantane. None of these metabolites exhibit antagonistic activity at NMDA receptors. In vitro studies have shown no involvement of cytochrome P450 in memantine metabolism. In a study using 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 via the kidneys.

Elimination.

Memantine is eliminated according to a monoexponential decay curve, with a half-life (t1/2) ranging from 60 to 100 hours. In individuals with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m². The renal phase of memantine pharmacokinetics includes tubular reabsorption.

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

Linearity.

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

Pharmacodynamic/pharmacokinetic relationship.

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

Clinical characteristics.

Indications.

Alzheimer's disease from mild to severe stages.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Due to the pharmacological effects and mechanism of action of memantine hydrochloride, the following interactions may occur:

• 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 with the combination of memantine and phenytoin;
• due to its mechanism of action, a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents may occur when co-administered with NMDA antagonists such as memantine. A possible reduction in the effects of barbiturates and neuroleptic agents may also occur. Concomitant administration of memantine with muscle relaxants, dantrolene, or baclofen may modify their effects, potentially 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 these drugs;
• when memantine is co-administered with hydrochlorothiazide or any combination product containing hydrochlorothiazide, a decreased serum concentration of hydrochlorothiazide may occur;
• there have been reports of isolated cases of increased international normalized ratio (INR) in patients receiving memantine while taking warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is recommended in patients receiving oral anticoagulants concomitantly with memantine.

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

According to available clinical study data in young healthy volunteers, no significant effect of memantine hydrochloride on the pharmacokinetics of galantamine was observed. Memantine is in vitro 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 drug to patients with epilepsy, patients with a history of seizures, and patients with risk factors for developing epilepsy.

Concomitant use of the drug with NMDA antagonists such as amantadine, ketamine, and 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 be more frequent or more pronounced.

Certain factors that cause an increase in urine pH may necessitate 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 antacid gastric medications. In addition, urine pH may increase due to conditions such as renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria.

Data are limited in patients who have recently experienced myocardial infarction, patients with decompensated congestive heart failure (NYHA class III–IV), and patients with uncontrolled arterial hypertension. Therefore, careful monitoring is required in patients with these conditions.

The drug contains lactose; therefore, it should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the effects of memantine when used during pregnancy.

Animal studies have indicated that exposure to concentrations equal to or slightly higher than those used in humans may result in delayed intrauterine growth. The potential risk to humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.

Breastfeeding

It is unknown whether memantine is excreted in human milk; however, considering the lipophilic nature of the substance, women taking memantine should avoid breastfeeding.

Fertility

No adverse effects of memantine on reproductive function in men or women have been observed.

Ability to influence reaction speed when driving or operating machinery

Moderate to severe Alzheimer's disease generally impairs the ability to drive a car or operate machinery. Moreover, memantine may have a minor or moderate influence on human reaction speed. Therefore, outpatients should be warned to exercise particular caution when driving vehicles or operating machinery.

Method of Administration and Dosage

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

The tablets should be taken once daily at the same time each day. Tablets may be taken with food or independently of food intake.

The duration of treatment is determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. Diagnosis should be established according to current clinical guidelines. Tolerability and dosage of the medicinal product should be regularly evaluated, preferably within 3 months after initiation of treatment. Thus, the clinical benefits of using memantine hydrochloride and the patient's tolerability to the drug should be regularly reviewed according to current clinical recommendations. Maintenance therapy may continue as long as a favorable therapeutic effect is observed and the patient tolerates treatment with memantine hydrochloride. Discontinuation of therapy should be considered if the therapeutic effect is lost or the patient poorly tolerates treatment with the drug.

Adults.

The recommended initial dose is 5 mg once daily, which should be gradually increased over the first 4 weeks of treatment to reach the recommended maintenance dose as follows:

Week 1 (days 1–7):
The patient should take 5 mg once daily for the week;

Week 2 (days 8–14):
The patient should take 10 mg once daily for the week;

Week 3 (days 15–21):
The patient should take 15 mg once daily for the week;

Starting from week 4:
The patient should take 20 mg once daily every day.

The recommended maintenance dose is 20 mg once daily.

Elderly Patients.

The recommended dose for patients aged 65 years and older is 20 mg once daily, as described 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 once 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 A, B), dose adjustment is not required. Data on the use of the medicinal product in patients with severe hepatic impairment are lacking. The use of memantine in patients with severe hepatic impairment is not recommended.

Children.

The drug should not be 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) were accompanied by symptoms of increased fatigue, weakness, and/or diarrhea, or were asymptomatic. Following overdoses of up to 140 mg or of unknown amount, symptoms of central nervous system disturbances were observed, such as confusion, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbances, and/or gastrointestinal disorders (vomiting and diarrhea).

After ingestion of 2000 mg of memantine, a patient developed coma (lasting 10 days), lateral diplopia, and agitation. The patient recovered fully after symptomatic treatment and plasmapheresis.

In another case, after ingestion of 400 mg of memantine, a patient developed symptoms of central nervous system disturbances, including restlessness, psychosis, visual hallucinations, psychomotor retardation, drowsiness, stupor, and loss of consciousness.

Treatment.

Symptomatic treatment; there is no specific antidote. Standard clinical procedures for elimination of the active substance from the body should be applied, such as gastric lavage, administration of activated charcoal, acidification of urine, and forced diuresis. In cases of excessive central nervous system stimulation, symptomatic therapeutic measures should be carried out with caution.

Adverse reactions.

It is known that during clinical studies of memantine, the overall incidence of adverse events did not differ from that observed with placebo, and adverse events were generally mild to moderate in severity.

The adverse reactions observed, listed in the table below, are presented according to the following classification of frequency of occurrence: 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), frequency not known (cannot be estimated from the available data).

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

2 Individual 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.

Shelf life. 3 years.

Storage conditions. Store out of reach of children in the original packaging at a temperature not exceeding 25 °C.

Packaging. Memox 10: 10 tablets in a blister; 3 or 6 blisters in a cardboard box.

Memox 20: 10 tablets in a blister; 3 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start" (packaging and repackaging from bulk supplied by Synthon España, S.L., Spain).

Manufacturer's address and location of business activity.

8, Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or for any safety-related questions regarding the use of the medicinal product, please contact the pharmacovigilance department of LLC "ASINO UKRAINE" at 8, Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.