Maruksa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Maruxa® (Maruxa®)

Composition:

Active substance: memantine;

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

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, methacrylate copolymer (1:1) dispersion 30 % (methacrylic acid, ethacrylate copolymer, purified water, sodium lauryl sulfate, polysorbate 80), triacetin, simethicone emulsion (dimethicone, aqueous colloidal silicon dioxide, stearic acid polyglycol ether, hydrogen peroxide, sorbic acid, purified water).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg: white, oval, biconvex film-coated tablets with a score line on one side;

20 mg: white, oval, biconvex film-coated tablets.

Pharmacotherapeutic group. Psychoanaleptics. Agents used in dementia.

ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Dysfunction of glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays an important 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) is 3 to 8 hours. There are no signs of food intake affecting 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 drug concentration in cerebrospinal fluid to serum is 0.52. The volume of distribution is approximately 10 L/kg. Approximately 45% of memantine is bound to plasma proteins.

Biotransformation

In the human body, approximately 80% of memantine circulates as the parent compound. None of the major metabolites of memantine (N-3,5-dimethyl-adamantane, a mixture of 4- and 6-hydroxymemantines, and 1-nitroso-3,5-dimethyl-adamantane) possess NMDA-antagonist properties. In vitro studies have shown no involvement of cytochrome P450 in memantine metabolism. In a study using oral administration of 14C-memantine, on average 84% of the dose was recovered within 20 days, with more than 99% excreted via the kidneys.

Elimination

Memantine is eliminated in a monoexponential manner with a half-life (t1/2) of 60 to 100 hours. In healthy adult volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m². The renal phase of memantine pharmacokinetics also includes tubular reabsorption.

The rate of renal elimination of memantine may be reduced by 7 to 9 times under conditions of alkaline urine pH. Alkalinization of urine may occur as a result of significant dietary changes, for example, switching from a meat-rich diet to a vegetarian diet, or due to 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 of memantine, the concentration in cerebrospinal fluid corresponds 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.

The pharmacological effects and mechanism of action of memantine determine the following interactions:

• The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when co-administered with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant use of memantine with muscle relaxants, dantrolene, or baclofen may modify their effects, which may necessitate dose adjustment.
• 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 (see section "Special precautions for use"). One published report also mentioned 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 cation transport system as amantadine, may also interact with memantine, potentially increasing memantine plasma levels.
• Concomitant administration of memantine with hydrochlorothiazide (HCTZ) or with any combination containing HCTZ may lead to a reduction in serum levels of HCTZ.
• There have been reports of isolated cases of increased international normalized ratio (INR) in patients receiving warfarin while taking 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 between memantine and glimepiride/metformin or donepezil were observed. In healthy volunteers, no pharmacokinetic interaction effects with galantamine were 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, as well as patients with risk factors for developing epilepsy.

Concomitant use of this medicinal product with N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine; therefore, adverse reactions (mainly related to the central nervous system) may occur more frequently or be more pronounced (see section "Adverse reactions").

Certain factors that may increase urinary pH (see section "Pharmacodynamics") 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, urinary 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, patients with decompensated congestive heart failure (NYHA class III-IV), and patients with uncontrolled arterial hypertension were excluded from participation. Therefore, data in these patient populations are limited, and careful monitoring of such patients is required.

Special warnings regarding excipients.

The product contains lactose and therefore should not be administered to patients with rare hereditary galactose intolerance, Lapp 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 indicate a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. The potential risk in humans is unknown. Memantine should not be used during pregnancy except in cases where clearly necessary.

Breastfeeding

It is unknown whether memantine is excreted in human breast milk, although this is possible considering the lipophilic nature of the substance. Women taking memantine should avoid breastfeeding.

Fertility

No adverse effects on fertility in males or females were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

Alzheimer's disease, from moderate to severe stages, typically impairs the ability to drive a car and operate machinery. Additionally, memantine may have a minor or moderate effect on human reaction speed. Therefore, outpatients should be advised to exercise particular caution when driving vehicles or operating machinery.

Method of Administration and Dosage

Treatment should be initiated and managed under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's disease. Therapy should only be initiated if a caregiver is available who will regularly supervise the patient's intake of the medication. Diagnosis should be established according to current guidelines. Tolerance and dosage of memantine should be regularly evaluated, preferably within three months after starting treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly assessed in accordance with current clinical recommendations. Maintenance therapy may be continued as long as the therapeutic effect remains favorable and the patient tolerates the treatment well. Consideration should be given to discontinuing memantine therapy if signs of therapeutic benefit disappear or if tolerance to treatment worsens.

Adults

Dosage Titration

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

1st week (days 1–7):
Take half a tablet (5 mg) once daily for 7 days;

2nd week (days 8–14):
Take 1 tablet (10 mg) once daily for 7 days;

3rd week (days 15–21):
Take 1½ tablets (15 mg) once daily for 7 days;

Starting from week 4:
Take 2 tablets of 10 mg (20 mg) or 1 tablet of 20 mg once daily.

The recommended maintenance dose is 20 mg once daily.

Elderly Patients

The recommended dose for patients aged 65 years and older is 20 mg daily (2 tablets of 10 mg or 1 tablet of 20 mg once daily), as described above.

Renal Impairment

In 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

Dose adjustment is not required in patients with mild or moderate hepatic impairment (Child Pugh A, B). There are no available data on the use of memantine in patients with severe hepatic impairment. The use of Maruxa® in patients with severe hepatic impairment is not recommended.

Method of Administration

Maruxa® tablets should be taken once daily at the same time each day. Tablets may be taken with or without food.

The 10 mg tablet may be divided into equal parts.

Children

Not recommended for use in children (under 18 years of age) 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 fatigue, weakness, and/or diarrhea, or were asymptomatic. Following 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 disorders (vomiting, diarrhea) were observed.

In more severe cases, coma lasting 10 days developed in a patient after ingestion of 2000 mg of memantine, followed later by diplopia and agitation. The patient recovered fully after symptomatic treatment and plasmapheresis. After oral administration of 4000 mg of memantine, symptoms of CNS disturbances such as agitation, psychosis, visual hallucinations, seizure predisposition, somnolence, stupor, and loss of consciousness were observed. In this case, the patient survived and recovered.

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, activated charcoal administration, urine acidification, and forced diuresis.

In cases of excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Adverse reactions.

The adverse reactions listed in the table below were observed during clinical trials and medical use. The adverse reactions are grouped by frequency in decreasing order of severity.

The reactions are presented according to the frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), including isolated cases; frequency not known (cannot be estimated based on available data).

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

2 Spontaneous reports in clinical use.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack, 2 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

TAD Pharma GmbH.

Address of manufacturer and location of its manufacturing site.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.