Mexia 10

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEXIA 10, MEXIA 20 (MEXIA 10, MEXIA 20)

Composition:

Active substance: memantine;

One film-coated tablet contains 10 mg or 20 mg of memantine hydrochloride;

Excipients:

10 mg tablets: microcrystalline cellulose, lactose DC (containing lactose monohydrate, povidone); colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating Opadry Y-1-7000 White (containing hypromellose, titanium dioxide (E 171), polyethylene glycol);

20 mg tablets: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium croscarmellose, talc, magnesium stearate, coating Opadry Pink 20 A34056 (containing hypromellose, hydroxypropylcellulose, talc, titanium dioxide (E 171), red iron oxide (E 172), black iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: elongated, biconvex tablets, tapered towards the center, film-coated, white to almost white in color, with a break line on both sides;

20 mg tablets: elongated oval film-coated tablets, light pink in color, with "20" engraved on one side.

Pharmacotherapeutic group.

Agents used in dementia. 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.

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 individual variability. With daily doses of 5 to 30 mg, the ratio of drug concentration in cerebrospinal fluid to plasma is 0.52. Approximately 45% of memantine is protein-bound in plasma.

Biotransformation

In humans, about 80% of memantine circulates as the unchanged parent compound. The main metabolites lack NMDA-antagonistic activity. No involvement of cytochrome P450 in 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. Renal handling of memantine includes tubular reabsorption.

The rate of renal elimination of memantine may decrease by 7- to 9-fold under alkaline urine conditions. Urinary alkalinization may occur due to significant dietary changes (e.g., switching from a meat-rich diet to a vegetarian diet) or from 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, the concentration of memantine in cerebrospinal fluid corresponds to the ki (inhibition constant) value of 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.

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 also possible.

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 applies to ketamine and dextromethorphan. Combined administration of memantine with muscle relaxants, dantrolene or baclofen may modify their effects, possibly necessitating dose adjustments. One published report also indicated a potential risk associated with the combination of memantine and phenytoin.

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 risk of increased plasma levels.

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

There have been reports of isolated cases of increased international normalized ratio (INR) in patients receiving memantine and warfarin. 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 involving 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 sulfation.

Special precautions for use.

Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizures, as well as 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 effects (mainly related to the central nervous system (CNS)) 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 agents. In addition, urine pH may increase due to conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.

Patients who have recently experienced myocardial infarction, as well as patients with decompensated congestive heart failure (NYHA class III-IV) or uncontrolled arterial hypertension, were not included in clinical trials; therefore, data regarding these patients are limited. Close monitoring is required for patients with these conditions.

The medicinal product contains lactose. If a patient has known intolerance to certain sugars, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

There are no data on the effects of memantine when used during pregnancy. The potential risk to humans is unknown. Animal studies indicate a possibility of delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. Memantine should not be used during pregnancy except in cases where clearly necessary.

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

Ability to influence reaction rate while driving or operating machinery.

Moderate to severe Alzheimer's disease 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. Outpatients should be advised 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 only be initiated if a caregiver is available who will regularly monitor the patient's medication intake.

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

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 dose 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 2 tablets (20 mg once daily) every day.

The recommended maintenance dose is 20 mg once daily.

The duration of treatment is determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. Tolerability 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 tolerability of memantine is good. Consideration should be given to discontinuing memantine treatment if therapeutic benefits 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 daily (2 tablets of 10 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 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. The use of memantine is not recommended in patients with severe hepatic impairment.

Children

The drug is not recommended for use 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. Following overdoses of up to 140 mg or of unknown quantity, symptoms of central nervous system disturbances (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disturbances (vomiting, diarrhea) were observed.

After ingestion of 2000 mg of memantine, a patient developed coma lasting 10 days, followed by diplopia and agitation. The patient recovered without sequelae following symptomatic treatment and plasmapheresis.

Treatment

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

In cases of excessive general CNS stimulation, symptomatic therapeutic measures should be applied with caution.

Adverse reactions.

Infections and infestations: fungal infections.

Immune system disorders: hypersensitivity.

Psychiatric disorders: somnolence, confusion, hallucinations (mainly observed in patients with severe Alzheimer's disease), psychotic reactions (isolated reports).

Nervous system disorders: dizziness, impaired balance, gait disturbance, seizures.

Cardiac disorders: heart failure, arterial hypertension, venous thrombosis/thromboembolism.

Respiratory system disorders: dyspnea.

Gastrointestinal disorders: constipation, vomiting, pancreatitis (isolated reports).

Hepatobiliary disorders: increased liver function tests, hepatitis.

General disorders: headache, increased fatigue.

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

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 mg tablets: 10 tablets in a blister pack, 5 or 10 blisters in a cardboard box;

25 tablets in a blister pack, 2 or 4 blister packs in a cardboard box;

14 tablets in a blister pack, 2 blister packs in a cardboard box.

20 mg tablets: 14 tablets in a blister pack, 2 or 6 blister packs in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of business.

Sankaklar Quarter, Eskikarakodja Avenue, No. 299, 81100, Duzce, Turkey.