Memantine-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

N06DX01 (Memantine)

Active Substance

Memantine (Rec.INN registered by WHO)

Dosage Forms

	Memantine-SZ	Film-coated tablets, 10 mg: 30, 60, or 90 pcs.
		Film-coated tablets, 20 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with a score on one side; the core of the tablet on the cross-section is white or almost white.

Excipients: microcrystalline cellulose 102, croscarmellose sodium (primellose), colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171).

30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Film-coated tablets pink, round, biconvex; the core of the tablet on the cross-section is white or almost white.

Excipients: microcrystalline cellulose 102, croscarmellose sodium (primellose), colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), dye carmoisine (azorubine) (E122).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Glutamate NMDA-receptor blocker. Drug for the treatment of dementia

Pharmacotherapeutic Group

Psychoanaleptics; agents for the treatment of dementia; other agents for the treatment of dementia

Pharmacological Action

Impairment of glutamatergic neurotransmission, especially the function of NMDA receptors, contributes to both the manifestation of symptoms and the progression of neurodegenerative dementia.

The drug Memantine-SZ is a voltage-dependent, moderately affine, non-competitive antagonist of NMDA receptors. The drug modulates the pathological increase in glutamate levels, which can lead to neuronal dysfunction. It improves cognitive processes and increases daily activity.

Pharmacokinetics

Absorption

Memantine has an absolute bioavailability of approximately 100%. C_max in blood plasma is reached within 3-8 hours. There are no indications that food intake affects the absorption of memantine.

Distribution

Daily doses of 20 mg lead to a steady-state plasma concentration of memantine in the range of 70-150 ng/ml (0.5-1 μmol) with large interindividual variations. When using daily doses from 5 to 30 mg, the average ratio of the drug content in cerebrospinal fluid to serum was 0.52.

V_d – about 10 L/kg. The binding of memantine to plasma proteins is approximately 45%.

Metabolism

About 80% of orally administered memantine circulates unchanged. The main metabolites in humans are N-3,5-dimethylgludantan, a mixture of 4- and 6-hydroxymemantine isomers, and 1-nitroso-3,5-dimethyladamantane. None of these metabolites have NMDA-antagonistic activity. Biotransformation catalyzed by the cytochrome P450 system was not detected in vitro.

In a study of oral administration of ¹⁴C-memantine, an average of 84% of the administered dose was excreted within 20 days, with more than 99% via the kidneys.

Excretion

The elimination of memantine is monoexponential with a T_1/2 of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cl_tot) is 170 ml/min/1.73 m², with part of the total renal clearance achieved through tubular secretion.

Tubular reabsorption also occurs in the kidneys, likely mediated by proteins involved in cation transport. The rate of renal clearance of memantine may decrease when urine is alkalized to pH 7-9. Alkalization of urine can result from drastic changes in diet, such as switching to a vegetarian diet or abundant intake of alkaline gastric buffers.

Linearity

Studies involving volunteers demonstrated linear pharmacokinetics in the dose range from 10 to 40 mg.

Pharmacokinetic-pharmacodynamic relationship

When memantine is used at a dose of 20 mg/day, the drug content in the cerebrospinal fluid corresponds to the ki (inhibition constant) of memantine, which is 0.5 μmol of the drug in the frontal cortex of the human brain.

Indications

Adults aged 18 years and over

• For the treatment of moderate to severe dementia in Alzheimer’s disease.

ICD codes

Dosage Regimen

Orally, once a day, at the same time, regardless of meals.

The 10 mg tablet can be divided along the score into equal doses.

Treatment should be initiated and conducted under the supervision of a physician experienced in the diagnosis and treatment of dementia in Alzheimer’s disease. Therapy should only be initiated if there is a caregiver who will regularly monitor the patient’s intake of the medication. Diagnosis of the disease should be made according to current guidelines. The tolerability and dosage of Memantine-SZ should be reviewed regularly, preferably within 3 months after initiation of treatment. Thereafter, the clinical benefit of the drug and the patient’s tolerability of treatment should be reviewed regularly in accordance with current clinical guidelines. Maintenance treatment can be continued indefinitely as long as the therapeutic effect is favorable and the patient tolerates the treatment well. In the absence of signs of therapeutic efficacy or if the patient does not tolerate the treatment, discontinuation of the drug should be considered.

To reduce the risk of adverse reactions, the initial dose is increased to the maintenance dose by titration in 5 mg increments per week over the first 3 weeks as follows

Week 1 (day 1-7): 5 mg/day is prescribed.

Week 2 (day 8-14): 10 mg/day is prescribed.

Week 3 (day 15-21): 15 mg/day is prescribed.

Week 4 and beyond: 20 mg/day is prescribed.

Recommended maintenance dose is 20 mg/day.

Maximum daily dose of memantine is 20 mg.

Special patient groups

Elderly patients (over 65 years)

According to clinical studies, the recommended dose for patients over 65 years is 20 mg/day.

Patients with renal impairment

In patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required. In patients with moderate renal failure (CrCl 30-49 ml/min) the daily dose is 10 mg. If the drug is well tolerated for at least 7 days of treatment, the dose can be increased to 20 mg/day according to the standard titration scheme. In patients with severe renal failure (CrCl 5-29 ml/min) the daily dose is 10 mg.

Patients with hepatic impairment

In patients with mild or moderate hepatic impairment (Child-Pugh class A and B) no dose adjustment is required. There are no data on the use of memantine in patients with severe hepatic insufficiency. The use of Memantine-SZ in patients with severe hepatic insufficiency (Child-Pugh class C) is contraindicated (see section “Contraindications”).

Children

The safety and efficacy of Memantine-SZ in children aged 0 to 18 years have not been established to date. Memantine-SZ should not be used in children under 18 years of age due to the lack of data on safety and efficacy.

Adverse Reactions

Summary of the safety profile

In clinical studies of mild to severe dementia involving 1784 patients receiving Memantine and 1595 patients receiving placebo, the overall incidence of adverse reactions with Memantine did not differ from that with placebo; adverse reactions were usually mild or moderate in severity. The most common adverse reactions, the incidence of which was higher in the memantine treatment group compared to the placebo group, were dizziness (6.3% vs. 5.6%, respectively), headache (5.2% vs. 3.9%, respectively), constipation (4.6% vs. 2.6%, respectively), somnolence (3.4% vs. 2.2%, respectively), and increased blood pressure (4.1% vs. 2.8%, respectively).

Tabulated summary of adverse reactions

Adverse reactions observed in clinical studies of memantine and post-marketing are distributed by system-organ class in descending order of their severity, with the frequency of their occurrence indicated according to the WHO classification: very common (≥1/10); common (≥1/100 but <1/10); uncommon (≥1/1000 but <1/100); rare (≥1/10000 but <1/1000); very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Table 1. Tabulated summary of adverse reactions

¹ Hallucinations were observed mainly in patients with Alzheimer’s disease at the severe dementia stage.

² Isolated cases reported in the post-marketing period.

Description of selected adverse reactions

There are isolated reports of the following adverse reactions occurring with the use of the drug (data obtained post-marketing): agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura, acute renal failure, Stevens-Johnson syndrome.

In Alzheimer’s disease, patients may experience depression, suicidal thoughts, and suicide attempts. In the context of post-marketing use, these adverse reactions have been reported in patients taking Memantine.

Contraindications

• Hypersensitivity to memantine or to any of the excipients included in the drug;
• Severe hepatic insufficiency.

With caution in patients with thyrotoxicosis, epilepsy, seizures (including history) and patients with risk factors for developing epilepsy.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of memantine in pregnant women. Animal studies indicate a possible delay in intrauterine development when memantine is used in doses similar to or slightly exceeding doses used in humans. The potential risk to humans is unknown. The use of Memantine-SZ during pregnancy is not recommended.

Breastfeeding

There is no information on the penetration of memantine into human breast milk. However, given its lipophilicity, this possibility exists. Memantine-SZ should not be used during breastfeeding. Breastfeeding should be discontinued during treatment with Memantine-SZ.

Fertility

No adverse effects of memantine use were identified in studies of male and female fertility.

Use in Hepatic Impairment

The use of Memantine-SZ in patients with severe hepatic insufficiency (Child-Pugh class C) is contraindicated.

Use in Renal Impairment

In patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required. In patients with moderate renal failure (CrCl 30-49 ml/min) the daily dose is 10 mg. In patients with severe renal failure (CrCl 5-29 ml/min) the daily dose is 10 mg.

Pediatric Use

Memantine-SZ should not be used in children under 18 years of age due to the lack of data on safety and efficacy.

Geriatric Use

According to clinical studies, the recommended dose for patients over 65 years is 20 mg/day.

Special Precautions

Concomitant use of NMDA receptor antagonists such as amantadine, ketamine, dextromethorphan should be avoided, as these compounds affect the same receptor system as Memantine, so more frequent or more pronounced adverse reactions, mainly from the CNS, may develop (see section “Drug Interactions”).

The presence of factors that increase urine pH (see section “Pharmacokinetics”) may require careful monitoring of the patient. Such factors include a drastic change in diet, such as switching to a vegetarian diet, or abundant intake of alkaline gastric buffers. In addition, urine pH may increase in renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria.

Patients who had recently experienced myocardial infarction or had uncompensated congestive heart failure (NYHA class III-IV), uncontrolled hypertension, mild to moderate hepatic insufficiency (Child-Pugh classes A and B) were excluded from most clinical trials. Therefore, there are only limited data regarding patients with these conditions, and such patients should be carefully monitored.

Excipients

Memantine-SZ in the 20 mg dosage contains the dye carmoisine (azorubine) E 122, which may cause allergic reactions.

Effect on ability to drive vehicles and machinery

Memantine may cause changes in reaction speed, so patients should exercise particular caution when driving vehicles and operating machinery.

In addition, patients with Alzheimer’s disease at the moderate and severe dementia stage usually have impaired ability to drive vehicles and operate complex machinery.

Overdose

There are only limited data on overdose obtained during clinical studies and in the post-marketing period.

Symptoms

Cases of relatively large overdose (200 mg and 105 mg per day for 3 days, respectively) were accompanied either only by symptoms of fatigue, weakness and/or diarrhea, or were not accompanied by any symptoms at all. In cases of overdose with a dose of less than 140 mg or an unknown dose, patients experienced symptoms of CNS involvement (confusion, lethargy, drowsiness, dizziness, agitation, aggressiveness, hallucinations, and gait disturbances) and/or gastrointestinal tract (vomiting and diarrhea).

In the most severe case of overdose, the patient survived after ingesting 2000 mg of memantine, accompanied by CNS involvement (coma for 10 days, later – diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without irreversible consequences.

In another case of large overdose, the patient also survived and recovered. The patient took 400 mg of memantine orally. The patient developed CNS symptoms such as anxiety, psychosis, visual hallucinations, seizure readiness, drowsiness, stupor, and loss of consciousness.

Treatment

In case of overdose, treatment should be symptomatic. There is no specific antidote for intoxication or overdose. If necessary, standard therapeutic measures aimed at removing the active substance from the body, such as gastric lavage, administration of activated charcoal (to prevent potential recirculation in the intestine and liver), acidification of urine, forced diuresis, are carried out.

If signs and symptoms of general CNS hyperstimulation appear, symptomatic therapy should be administered with caution.

Drug Interactions

Pharmacodynamic interaction

Levodopa, dopamine receptor agonists and anticholinergic agents

The mechanism of action suggests an enhancement of the effects of levodopa, dopamine receptor agonists, and anticholinergic drugs when used concomitantly with NMDA antagonists such as Memantine.

Barbiturates and neuroleptics

When used concomitantly with barbiturates or neuroleptics, the effect of the latter may be reduced.

Antispasmodics, dantrolene and baclofen

Concomitant use of memantine with antispasmodics, dantrolene, or baclofen may alter their effect and require dose adjustment.

Amantadine, ketamine, dextromethorphan and phenytoin

Concomitant administration of memantine with amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both substances are chemically related NMDA antagonists. The same applies to ketamine and dextromethorphan (see section “Special Precautions”). One report has also been published on the possible risk of combined use of memantine and phenytoin.

Cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine

Other active substances, such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cation transport system as amantadine, may possibly interact with memantine, creating a potential risk of increased plasma concentrations.

Hydrochlorothiazide

A decrease in the serum level of hydrochlorothiazide is possible with simultaneous administration with memantine.

Anticoagulants

Isolated cases of increased INR have been reported in patients concurrently receiving treatment with warfarin. Although a causal relationship has not been established, it is recommended to carefully monitor prothrombin time or INR in patients simultaneously taking oral anticoagulants.

Pharmacokinetic Interaction

Glibenclamide, Metformin, and Donepezil

Pharmacokinetic studies of single doses in young healthy volunteers revealed no interactions between memantine and glibenclamide/ metformin or donepezil.

Galantamine

A clinical study involving young healthy volunteers revealed no significant effect of memantine on the pharmacokinetics of galantamine.

Other Interactions

Memantine does not inhibit the activity of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin monooxygenase, epoxide hydrolase, and sulfation in vitro.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.