Mentavistin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MENTAVISTIN (MENTAVISTIN)

Composition:

Active substance: memantine;

One tablet contains 10 mg or 20 mg of memantine hydrochloride, equivalent to 8.31 mg or 16.62 mg of memantine;

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

Film coating:

for 10 mg dosage: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000;
for 20 mg dosage: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: White, round, biconvex, film-coated tablets with a wide, pressure-sensitive score line on one side and embossing "M9MN" and "10" on the other side.

20 mg tablets: Pink, oval, biconvex, film-coated tablets with a wide, pressure-sensitive break line on one side and embossing "M9MN 20" on the other side.

Pharmacotherapeutic group.

Psychoanaleptics. Other agents used in dementia. Memantine. ATC code N06DX01.

Pharmacological Properties

Pharmacodynamics

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

Clinical Studies

The main monotherapy study in patients with moderate to severe Alzheimer’s disease (Mini-Mental State Examination (MMSE) score of 3–14) included a total of 252 outpatients. A positive effect of memantine therapy was observed after 6 months of treatment compared to placebo (observed case analysis of clinician interview-based assessment using CIBIC-plus (p = 0.025); ADCS-ADLsev scale (p = 0.003); and SIB scores (p = 0.002)). The primary monotherapy study of memantine in the treatment of mild to moderate Alzheimer’s disease (baseline MMSE total score from 10 to 22) included 403 patients. Patients receiving memantine treatment showed statistically significant better outcomes than those receiving placebo on the primary endpoints of the ADAS-cog scale (p = 0.003) and CIBIC-plus (p = 0.004) at week 24 (using LOCF). In another monotherapy study in patients with mild to moderate Alzheimer’s disease, a total of 470 patients were randomized (baseline MMSE total score 11–23). In the prospectively defined primary analysis, statistical significance was not achieved at the primary efficacy endpoint at week 24.

A meta-analysis of patients with moderate to severe Alzheimer’s disease (baseline MMSE total score < 20) from six Phase III placebo-controlled 6-month studies (including both monotherapy trials and trials in patients receiving stable doses of acetylcholinesterase inhibitors) demonstrated statistically significant benefits of memantine treatment in cognitive, global, and functional domains.

When deterioration across all three domains was assessed, results showed a statistically significant effect of memantine in preventing decline; deterioration across all three domains occurred 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 drug concentration in cerebrospinal fluid to plasma is 0.52. The volume of distribution is approximately 10 L/kg. Approximately 45% of memantine is protein-bound in plasma.

Metabolism

In humans, approximately 80% of memantine circulates as the parent compound; the major metabolites lack NMDA-antagonistic activity. In vitro studies show no involvement of the cytochrome P450 system in memantine metabolism.

In a study using oral administration of 14C-labeled memantine, an average of 84% of the dose was eliminated within 20 days, with over 99% of the dose excreted renally.

Elimination

Memantine is eliminated in a mono-exponential manner, 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, and renal clearance is achieved partly through tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, possibly mediated by a cationic transport system. The rate of renal elimination of memantine may be reduced by 7–9 fold under alkaline urine conditions. Urine alkalinization may occur as a result of profound dietary changes, such as switching from a meat-rich diet to a vegetarian diet, or due to intensive use of antacid gastric medications.

Linearity

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

Pharmacodynamic/Pharmacokinetic Relationship

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

Clinical characteristics.

Indications.

Moderate to severe Alzheimer's disease.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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 indicated a possible risk with the combination of memantine and phenytoin.

The mechanism of action suggests a potential enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when used concomitantly 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, which could necessitate dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which utilize 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 concurrently with memantine.

In pharmacokinetic studies in healthy volunteers, no significant interaction effects were observed between memantine and glipizide/metformin, donepezil, or galantamine. Memantine is in vitro not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation.

Special precautions for use

Caution is required when prescribing the medicinal product to patients with epilepsy, those with a history of seizures, and patients with risk factors for developing epilepsy. Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse reactions (mainly related to the central nervous system) may occur more frequently or be more pronounced.

Certain factors that may increase urine pH require careful patient monitoring. 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. Additionally, urine pH may rise due to conditions such as tubular renal acidosis (TRA) or severe urinary tract infections caused by Proteus bacteria.

During most clinical trials, patients who had recently suffered a myocardial infarction, those with decompensated congestive heart failure (NYHA class III–IV), and those with uncontrolled arterial hypertension were excluded from participation. Therefore, only limited relevant data are available, and patients with these conditions require careful monitoring.

Important information about excipients

The medicinal product contains lactose and therefore 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 data on the effects of memantine when used during pregnancy. Animal experimental studies indicate a potential for delayed intrauterine growth at exposure levels equal to or slightly higher than those used in humans. The potential risk for humans is unknown. The medicinal product Mentavistin should not be used during pregnancy, except in cases where clearly necessary.

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

Fertility

In preclinical studies, no negative effects of memantine on fertility in either men or women were observed.

Ability to influence reaction speed when driving or operating machinery

Moderate to severe Alzheimer's disease typically impairs the ability to drive a car and operate machinery. Additionally, memantine has a minor or moderate effect on the ability to drive vehicles and operate machinery. Therefore, outpatients should exercise particular caution when performing these activities.

Method of Administration and Dosage

Treatment should be initiated and conducted under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should be initiated only if a caregiver is available who will supervise the patient’s intake of the medication. Diagnosis is established according to current guidelines. Tolerability and dosing of memantine should be regularly evaluated, preferably within 3 months after initiation of therapy. Thereafter, clinical benefit of memantine treatment and patient tolerability should be periodically reassessed on a regular basis in accordance with current clinical guidelines. Maintenance therapy may be continued as long as a favorable therapeutic effect is maintained and the patient tolerates memantine well. The decision to discontinue memantine treatment should be considered in cases of lack of therapeutic effect or if the patient does not tolerate the medication.

Tablets should be taken once daily at the same time each day, independent of food intake.

Adults

Dose Titration

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the maintenance dose should be achieved by gradually increasing the dose by 5 mg per week over the first 3 weeks as follows:

Week 1 (days 1–7):
Take 5 mg once daily for one week.

Week 2 (days 8–14):
Take 10 mg once daily for one week.

Week 3 (days 15–21):
Take 15 mg once daily for one week.

Starting from Week 4:
Take 20 mg once daily.

Maintenance Dose

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 stated above.

Renal Impairment

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance 30–49 mL/min), a daily dose of 10 mg is recommended. If this dose is well tolerated for at least 7 days of treatment, it may be increased to 20 mg daily according to the standard dose titration schedule. For patients with severe renal impairment (creatinine clearance 5–29 mL/min), a daily dose of 10 mg is recommended.

Hepatic Impairment

For patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), no dose adjustment is required. There are no data on the use of memantine in patients with severe hepatic impairment; therefore, memantine is not recommended in patients with severe hepatic impairment.

Children

The medicinal product is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose

Data on overdose are 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 reported 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 such as restlessness, psychosis, visual hallucinations, seizure readiness, somnolence, stupor, and loss of consciousness were observed.

Treatment

Treatment is symptomatic; there is no specific antidote. Standard clinical procedures for removing the active substance from the body should be applied, such as gastric lavage, administration of activated charcoal, urinary acidification, and forced diuresis. In cases of excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Adverse Reactions

General information on safety profile

During clinical studies of memantine involving patients with mild to severe dementia (1784 patients receiving memantine and 1595 receiving placebo), the overall incidence of adverse reactions was not different from that observed with placebo, and adverse reactions were generally of mild or moderate severity.

The most common adverse reactions observed more frequently in the group of patients receiving memantine 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, observed during clinical studies and post-marketing use, are classified 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), frequency not known (cannot be estimated from available data).

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

2Spontaneous reports in post-marketing experience.

Alzheimer's disease has been 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 medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription-only medicine.

Manufacturer. Sínton Hispania, S.L./Synthon Hispania, S.L.

Address of the manufacturer and location of the site where its operations are conducted.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.