Membral

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

Composition:

Active ingredient: memantine;

1 tablet contains 10 mg of memantine hydrochloride;

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

coating: film-coating mixture Opadry II White (lactose monohydrate; hypromellose (hydroxypropylmethylcellulose); polyethylene glycol; titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, round-shaped, biconvex, with a break line on one side.

Pharmacotherapeutic group. Medicinal product for the treatment of dementia. 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.

Pharmacokinetics.

The absolute bioavailability of memantine is approximately 100%. The time to reach peak plasma concentration is 3 to 8 hours. There is no evidence of food 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 that in plasma is 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is bound to plasma proteins.

Biotransformation. 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. The primary metabolites are N-3,5-dimethyl-gludantan, an isomeric mixture of 4- and 6-hydroxymemantine, and 1-nitroso-3,5-dimethyl-adamantane.

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 is approximately 170 mL/min/1.73 m². The renal phase of memantine pharmacokinetics 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 as a result of significant dietary changes, such as 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, the concentration of memantine 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.

Alzheimer's type dementia, from mild to severe stages.

Contraindications.

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

Severe renal impairment.

Paediatric population (under 18 years of age).

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. A potential risk has also been reported for 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 co-administered with NMDA antagonists such as memantine. A possible reduction in the effects of barbiturates and neuroleptic agents may occur. Concomitant administration of memantine with muscle relaxants, dantrolene, or baclofen may modify their effects, possibly necessitating dose adjustments.

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 potential risk of increased plasma levels.

When memantine is co-administered with hydrochlorothiazide (HCTZ) or any combination containing HCTZ, a decreased serum concentration 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.

Pharmacokinetic studies in healthy volunteers revealed no significant interaction effects 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 should be exercised when prescribing the medicinal product 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) may be more frequent or more pronounced.

Certain factors that may increase 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 in conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.

Patients who recently suffered myocardial infarction, those with decompensated congestive heart failure (NYHA class III–IV), and those with uncontrolled arterial hypertension were excluded from most clinical trials. Therefore, data in these patient populations are limited, and careful monitoring is required.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of memantine during pregnancy. Experimental animal studies indicate a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy except in cases of extreme necessity.

Lactation period. It is unknown whether memantine passes into breast milk, although this is possible considering the lipophilicity 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.

Patients with Alzheimer's disease at the stage of moderate to severe dementia generally have impaired ability to drive or operate machinery. In addition, memantine may affect reaction speed; therefore, patients receiving treatment on an outpatient basis should exercise particular caution when driving or operating machinery.

Method of Administration and Dosage

Orally. The dosage regimen should be individually determined by a physician.

Treatment should be initiated and conducted under medical supervision. Therapy should be initiated only if a caregiver is available who will regularly monitor the patient's medication intake.

Tablets should be taken once daily at the same time each day. 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 during the first 3 weeks as follows:

Week 1 (days 1–7): take ½ tablet (5 mg daily) for one week;

Week 2 (days 8–14): take 1 tablet (10 mg daily) for one week;

Week 3 (days 15–21): take 1½ tablets (15 mg daily) for one week;

Starting from week 4: take 2 tablets (20 mg daily) every day.

The recommended maintenance dose is 20 mg daily.

The duration of treatment should be individually determined by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Tolerance and memantine dosage should be regularly evaluated, preferably within 3 months after initiation 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 a favorable therapeutic effect and good tolerability are maintained. Consideration should be given to discontinuing memantine treatment 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 (2 tablets of 10 mg once daily), as stated above.

Renal impairment

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), dose reduction is not 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 according to 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 class A, B), dose adjustment is not required. Memantine is not recommended for patients with severe hepatic impairment.

Children

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

Overdose

Data on overdose are limited.

Symptoms. Overdose with relatively large amounts (200 mg and 105 mg/day for 3 days) has been associated either with symptoms such as increased fatigue, weakness, and/or diarrhea, or with complete absence of any symptoms. With doses below 140 mg or with unknown doses, patients have experienced central nervous system disorders (confusion, lethargy, somnolence, vertigo, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disorders (vomiting, diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disturbances (coma lasting 10 days, followed by diplopia and agitation). The patient recovered fully after symptomatic treatment and plasmapheresis.

In another case of overdose with a high dose of memantine (400 mg), central nervous system disturbances were observed, including restlessness, psychosis, visual hallucinations, seizure predisposition, somnolence, stupor, and loss of consciousness. The patient recovered.

Treatment. Symptomatic treatment should be administered in case of overdose. There is no specific antidote. If necessary, standard clinical procedures should be performed to remove the active substance from the body, such as gastric lavage, administration of activated charcoal (to interrupt possible enterohepatic recirculation), acidification of urine, and forced diuresis.

If clinical signs or symptoms indicate excessive stimulation of the central nervous system, symptomatic treatment measures should be applied with caution.

Adverse Reactions

In clinical studies involving patients with mild to severe dementia treated with memantine, the overall incidence of adverse effects was found to be similar to that observed with placebo. Adverse reactions were generally mild to moderate in severity. The most commonly reported adverse reactions included dizziness, headache, constipation, somnolence, and arterial hypertension.

Infections and infestations: Fungal infections.

Immune system disorders: Hypersensitivity.

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

Cardiovascular disorders: Arterial hypertension, venous thrombosis/thromboembolism, heart failure.

Respiratory system disorders: Dyspnea.

Gastrointestinal disorders: Constipation, nausea, vomiting, pancreatitis (isolated reports).

Central nervous system disorders: Dizziness, gait disturbance, impaired balance, seizures.

Hepatobiliary disorders: Increased liver function parameters, hepatitis.

General disorders: Headache, increased fatigue.

Hepatic dysfunction and/or jaundice may occur, accompanied by elevated levels of aspartate aminotransferase (glutamate oxaloacetate transaminase), alanine aminotransferase (glutamate pyruvate transaminase), alkaline phosphatase, and bilirubin. Careful monitoring of patients is required. If any abnormal findings occur, the drug should be discontinued and appropriate measures taken.

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

Reporting suspected adverse reactions

It is important to report any suspected adverse reactions during the use of this medicinal product. This enables continuous monitoring of the benefit-risk balance of the drug.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters per carton.

10 tablets in a blister; 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of operations.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Website: www.vitamin.com.ua