Memamed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEAMED® (MEMAMED)

Composition:

Active ingredient: memantine;

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

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, yellow iron oxide (E 172).

Pharmaceutical form.
Film-coated tablets.

Main physicochemical properties:

10 mg tablets: film-coated, elongated, biconvex tablets, yellow in color, with a score line on both sides, core diameter 5.6x11.1 mm;

20 mg tablets: film-coated, round, biconvex tablets, yellow in color, core diameter 10.3 mm.

The tablet may be divided into two equal parts.

Pharmacotherapeutic group.
Psychoanaleptics. Other agents used in dementia. Memantine.

ATC code N06D X01.

Pharmacological Properties.

Pharmacodynamics.

Disruption of 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.

Clinical Studies. The main monotherapy study in patients with moderate to severe stages of 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 cases analysis of clinician interview based on change scores in CIBIC-plus \[p = 0.025\], ADCS-ADLsev \[p = 0.003\], and SIB \[p = 0.002\]).

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 treated with memantine showed statistically significantly better outcomes than those receiving placebo on primary endpoints: ADAS-cog scale [p = 0.003], 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 for 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 a statistically more significant treatment effect of memantine on cognitive, global, and functional domains.

When deterioration in all three domains was assessed, results showed a statistically significant effect of memantine in preventing decline; 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.
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 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. With daily doses ranging from 5 to 30 mg, 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.

Biological Transformation.
In humans, approximately 80% of memantine circulates as the parent compound; the main metabolites lack NMDA-antagonistic activity. 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 over 99% of the dose excreted via the kidneys.

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, which may be mediated by a cationic transport system.

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

Linearity.
According to studies in volunteers, the pharmacokinetics of memantine are linear 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 apply to ketamine and dextromethorphan. One published report also indicated a potential risk with the combination of memantine and phenytoin.

The mechanism of action suggests a possible 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, potentially necessitating dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cation transport system as amantadine, may also interact with memantine, potentially increasing the risk of elevated plasma levels.

When memantine is used concomitantly 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 and memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly.

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

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

Special precautions for use.

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

Concomitant use of the drug 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 effects (mainly related to the central nervous system) may occur more frequently or be more pronounced.

Certain factors that may increase urine pH may necessitate 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 agents. In addition, urine pH may increase in conditions such as renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria.

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

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

There are no data on the effects of memantine when used during pregnancy. Animal experimental studies indicate a possibility of delayed intrauterine growth at exposure levels of memantine equal to or slightly higher than those used in humans. The potential risk for 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 breast milk; however, excretion is possible due to 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 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. Additionally, memantine may have a slight to moderate influence on the ability to drive vehicles or operate machinery. Therefore, outpatients should exercise particular caution when performing the aforementioned activities.

Method of Administration and Dosage

Treatment should be initiated and supervised by a physician. Therapy should only be started if a caregiver is available who will regularly monitor the patient's intake of the medication. The drug should be taken once daily at approximately the same time each day. Tablets may be taken with or without food.

Adults
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:

Week 1 (days 1–7): take ½ tablet (5 mg once daily) for one week;
Week 2 (days 8–14): take 1 tablet (10 mg once daily) for one week;
Week 3 (days 15–21): take 1½ tablets (15 mg once daily) for one week;
Starting from week 4: take 20 mg once daily (2 tablets of 10 mg or 1 tablet of 20 mg).

The recommended maintenance dose is 20 mg daily.

The duration of treatment is determined individually by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerability and dosage of memantine should be regularly assessed, preferably within 3 months after initiation of treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly evaluated according to current clinical guidelines. Maintenance therapy may be continued as long as a favorable therapeutic effect persists and the patient tolerates the treatment well. Discontinuation of memantine therapy should be considered if therapeutic benefits disappear or if tolerability deteriorates.

Elderly patients
Based on clinical trial data, the recommended dose for patients aged 65 years and older is 20 mg daily, as described 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), 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 classes A and B), dose adjustment is not required. There is no data available on the use of memantine in patients with severe hepatic impairment. Memantine is not recommended in patients with severe hepatic impairment.

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

Overdose

Experience is limited.

Symptoms
Relatively high 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. Following overdoses up to 140 mg or of 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 and fully recovered without any permanent sequelae.

In another case of significant overdose (400 mg of memantine orally), the patient also survived and recovered. Symptoms included central nervous system disturbances such as restlessness, psychosis, visual hallucinations, seizure readiness, somnolence, stupor, and loss of consciousness.

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

Adverse Reactions.

Safety Profile Overview

During clinical trials 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 events were generally mild to moderate in severity. The most commonly reported adverse reactions occurring more frequently in patients receiving memantine than in those receiving placebo 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 trials and post-marketing experience, are categorized by frequency 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 the available data).

System, organ, class	Frequency	Adverse reactions
Infections	uncommon	fungal infections
Immune system disorders	common	hypersensitivity
Psychiatric disorders	common uncommon uncommon frequency not known	somnolence; confusion; hallucinations1; psychotic reactions2
Nervous system disorders	common common uncommon very rare	dizziness; impaired balance; gait disturbance; seizures
Cardiac disorders	uncommon	heart failure
Vascular disorders	common uncommon	arterial hypertension; venous thrombosis/thromboembolism
Respiratory system disorders	common	dyspnea
Gastrointestinal disorders	common uncommon frequency not known	constipation; vomiting; pancreatitis2
Hepatobiliary disorders	common frequency not known	increased liver function tests; hepatitis
General disorders	common uncommon	headache; increased fatigue

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

2 Spontaneous reports from post-marketing experience.

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

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

Shelf life.
4 years.

Storage conditions.
Store in the original packaging in a place inaccessible to children.

Packaging.
10 tablets per blister, 3 or 6 blisters per cardboard box.

Prescription status.
Prescription only.

Manufacturer.

1. Medochemie Ltd (Central Factory)/Medochemie LTD (Central Factory).
2. Medochemie Limited/Medochemie Limited.

Manufacturer's address and place of business.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.
2. Michail Irakleous 2, Agios Athanassios Industrial Area, Agios Athanassios, Limassol, 4101, Cyprus.