Memantin asino
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEMANTINE ACINO (MEMANTINE ACINO)
Composition:
Active substance: memantine;
One tablet contains 10 mg of memantine hydrochloride;
Excipients: microcrystalline cellulose, crospovidone, talc, magnesium stearate;
Tablet coating: Opadry II White 33G28435: hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin.
Dosage form. Film-coated tablets.
Main physicochemical properties: white, oval-shaped, biconvex film-coated tablets with the markings “M” and “10” on one side separated by a break line.
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 regulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.
In patients with moderate to severe Alzheimer's disease, favorable effects such as stabilization or improvement in global and functional status and cognitive performance have been observed after administration of memantine at a dose of 20 mg over a six-month period.
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 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 plasma is 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is bound to plasma proteins.
Biotransformation
In the human body, approximately 80% of memantine circulates as the parent compound; the main metabolites do not exhibit NMDA-antagonistic activity. In vitro studies have shown no involvement of cytochrome P450 in its metabolism.
After oral administration of 14C-labeled memantine, on average 84% of the dose is eliminated within 20 days, with more than 99% of the dose being excreted by the kidneys.
Elimination
Memantine is eliminated according to a monoexponential decay curve, 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. Renal elimination of memantine also involves tubular reabsorption, which may be mediated by a cationic transport system.
The rate of renal elimination of memantine may decrease by 7–9 times under alkaline urine conditions. Urine alkalinization may occur due to sudden 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) value 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 N-methyl-D-aspartate (NMDA) antagonists (e.g., amantadine, ketamine, or dextromethorphan) should be avoided due to the risk of pharmacotoxic psychosis. 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. Published data indicate a potential risk when memantine is used concomitantly with 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 administration of memantine with 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 utilize the same renal cationic transport system as amantadine, may also interact with memantine, potentially increasing plasma concentrations.
Concomitant use of memantine with hydrochlorothiazide or any combination product containing hydrochlorothiazide may lead to decreased serum levels of the latter.
Isolated cases of increased international normalized ratio (INR) have been reported in patients taking warfarin concomitantly with memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is recommended in patients receiving oral anticoagulants concurrently.
Pharmacokinetic studies in healthy volunteers have not revealed significant interaction effects 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 sulfotransferase.
Special precautions for use.
Patients who recently suffered myocardial infarction, patients with decompensated congestive heart failure (NYHA class III-IV), as well as those with uncontrolled arterial hypertension were excluded from most clinical trials. Therefore, relevant data are limited, and patients with these conditions require careful monitoring.
Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizures, and patients with risk factors for developing epilepsy.
Concomitant use of N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Certain factors that may increase urine pH require careful patient monitoring. These factors include sudden changes in diet, such as switching from a meat-rich diet to a vegetarian one, and intensive use of antacid gastric medications. In addition, urine pH may increase due to renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.
The drug 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.
There are no clinical data on the effects of memantine when used during pregnancy. Animal experimental studies indicate a potential for delayed intrauterine growth at concentrations 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 necessary.
It is unknown whether memantine is excreted in human breast milk, although excretion is possible considering the lipophilic nature of the substance. Women taking memantine should avoid breastfeeding.
Fertility
No adverse effects of memantine on fertility in men or women have been 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 or operate complex machinery. Additionally, memantine has a minor or moderate effect on human reaction speed. Therefore, outpatients should be warned to exercise particular caution when driving or operating complex machinery.
Method of Administration and Dosage
Treatment should be initiated and conducted under the supervision of a physician. Therapy should be initiated only if a caregiver is available who will regularly monitor the patient's intake of the medication.
The tablets should be taken once daily at the same time each day. The tablets may be taken independently of food intake.
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 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 is determined individually by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerability and memantine dosage should be regularly evaluated, preferably every three 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 the therapeutic effect remains favorable and the patient tolerates the medication well. Discontinuation of memantine therapy should be considered if therapeutic benefits disappear or if tolerability deteriorates.
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 stated 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 according to the standard titration schedule if no adverse reactions occur within 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 and class B), dose adjustment is not required. There are no data on the use of memantine in patients with severe hepatic impairment. The use of memantine in patients with severe hepatic impairment is not recommended.
Children.
The drug should not be used in children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose.
Experience with overdose 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 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 case of the largest reported overdose after oral intake of 2000 mg of memantine, the patient developed coma (lasting 10 days), lateral diplopia, and agitation. After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.
In another case of significant overdose after oral intake of 400 mg of memantine, central nervous system disturbances occurred, including restlessness, psychosis, visual hallucinations, seizure predisposition, somnolence, stupor, and loss of consciousness. The patient recovered without sequelae.
Treatment
Symptomatic treatment; 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, urinary acidification, and forced diuresis.
In cases of excessive central nervous system stimulation, symptomatic treatment measures should be applied with caution.
Adverse reactions.
The overall frequency of adverse events during memantine use was not different from that observed with placebo, and negative events were usually mild or moderate in severity.
The most commonly reported adverse effects that occurred more frequently in the memantine group than in the placebo group were: dizziness, headache, constipation, somnolence, and hypertension.
The adverse reactions listed below are categorized by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).
Infections:
uncommon – fungal infections.
Immune system disorders:
common – hypersensitivity.
Psychiatric disorders:
common – somnolence;
uncommon – confusion, hallucinations (mainly observed in patients with severe Alzheimer's disease);
not known – psychotic reactions (isolated reports from post-marketing experience).
Nervous system disorders:
common – dizziness, impaired balance;
uncommon – gait disturbance;
very rare – seizures.
Cardiac disorders:
uncommon – heart failure.
Vascular disorders:
common – hypertension;
uncommon – venous thrombosis/thromboembolism.
Respiratory system disorders:
common – dyspnoea.
Gastrointestinal disorders:
common – constipation;
uncommon – vomiting;
not known – pancreatitis.
Hepatobiliary disorders:
common – increased liver function tests;
not known – hepatitis.
General disorders:
common – headache;
uncommon – fatigue.
Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have also been reported during treatment with memantine.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging.
14 tablets in a blister, 2 blisters per cardboard pack.
Prescription status. Prescription only.
Manufacturer.
Actavis Ltd
Actavis Ltd
Manufacturer's location and address of place of business.
BLB 015-016 Bulebel Industrial Estate, Zejtun, ZTN 3000, Malta.
BLB 015-016 Bulebel Industrial Estate, Zejtun, ZTN 3000, Malta.