Instructions Membral film-coated tablets 10 mg blister No. 60
Composition
active ingredient: memantine;
1 tablet contains memantine hydrochloride 10 mg;
excipients: lactose monohydrate; microcrystalline cellulose; colloidal anhydrous silica; talc; magnesium stearate;
shell: Opadry II White film-coating mixture (lactose monohydrate; hypromellose (hydroxypropylmethylcellulose); polyethylene glycol; titanium dioxide (E 171)).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, white or almost white in color, round in shape with a biconvex surface with a score on one side.
Pharmacotherapeutic group
A remedy for the treatment of dementia. ATX code N06D X01.
Pharmacological properties
Pharmacodynamics
Disturbances in glutamatergic neurotransmission, especially involving NMDA (N-methyl-D-aspartate) receptors, play an important role in the manifestation of symptoms and progression of neurodegenerative dementia.
Memantine is a potential-dependent, medium-affinity, non-competitive NMDA receptor antagonist. Memantine modulates the effects of pathologically elevated levels of glutamate, which can lead to neuronal dysfunction.
Pharmacokinetics
The absolute bioavailability of memantine is approximately 100%, the time to peak plasma concentration is 3 to 8 hours. There is no evidence of an effect of food intake on absorption.
Distribution. A daily dose of 20 mg results in steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5-1 μmol) with significant interindividual variation. At daily doses of 5 to 30 mg, the ratio of the drug content in the cerebrospinal fluid to the serum is 0.52. The volume of distribution is approximately 10 l/kg. Approximately 45% of memantine is bound to plasma proteins.
Biotransformation. In humans, about 80% of memantine circulates as the parent compound, the main metabolites do not have NMDA-antagonistic properties. Cytochrome P450 has not been shown to be involved in in vitro metabolism. The main metabolites are N-3,5-dimethylgludantan, an isomeric mixture of 4- and 6-hydroxymemantine, and 1-nitroso-3,5-dimethyladamantane.
Elimination: Memantine is eliminated monoexponentially with a t1/2 of 60 to 100 hours. In volunteers with normal renal function, total clearance was 170 ml/min/1.73 m2. The renal phase of memantine pharmacokinetics also includes tubular reabsorption.
The rate of renal elimination of memantine in conditions of alkaline urine may be reduced by a factor of 7-9. Alkalinization of urine may occur as a result of significant changes in diet, such as replacing a diet rich in meat with a vegetarian diet or as a result of intensive intake of antacids.
Linearity: Pharmacokinetics are linear in the dose range of 10–40 mg.
Pharmacodynamic/pharmacokinetic relationship.
At a dose of 20 mg memantine per day, the level of content in the cerebrospinal fluid corresponds to the ki value (inhibition constant) of memantine, which is 0.5 μmol in the frontal cortex of the human brain.
Indication
Alzheimer's-type dementia, from mild to severe forms.
Contraindication
Hypersensitivity to the active substance or to any component of the medicinal product.
Severe renal dysfunction.
Children's age (up to 18 years).
Interaction with other medicinal products and other types of interactions
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 be true for ketamine and dextromethorphan. A possible risk of the combination of memantine and phenytoin has been reported.
The mechanism of action suggests that the effects of L-dopa, dopaminergic agonists and anticholinergics may be potentiated by concomitant use of NMDA antagonists such as memantine. The effects of barbiturates and neuroleptics may be attenuated. Concomitant administration of memantine and antispasmodics, dantrolene or baclofen may modify their effects, which may require dose adjustment.
Other drugs such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which use the same renal cation transport system as amantadine, may also be able to interact with memantine, leading to a potential risk of increased plasma levels.
When memantine is co-administered with hydrochlorothiazide (HCTZ) or any combination with HCTZ, a decrease in serum HCTZ levels is possible.
There have been isolated reports of increased international normalized ratio (INR) with memantine in patients taking warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is necessary in patients taking concomitant oral anticoagulants.
In pharmacokinetic studies in healthy volunteers, no significant interaction effects of memantine with glyburide/metformin, donepezil, or galantamine were observed.
Memantine is not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation in vitro.
Application features
Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizure episodes, as well as patients with risk factors for developing epilepsy.
Concomitant use with N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine and therefore side effects (mainly related to the central nervous system) may be more frequent or more pronounced.
Several factors that may increase urine pH may warrant close monitoring. These include major dietary changes, such as changing from a meat-rich diet to a vegetarian diet, or heavy use of antacids. In addition, urine pH may be elevated due to conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.
In most clinical trials, patients with recent myocardial infarction, decompensated congestive heart failure (stage III-IV), and uncontrolled hypertension were excluded from the study. As a result, only limited data are available and patients with these conditions require close monitoring.
The medicine contains lactose, therefore patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use it.
Use during pregnancy or breastfeeding
Pregnancy. There are no data on the use of memantine during pregnancy. Experimental studies in animals indicate the possibility of intrauterine growth retardation at exposure concentrations identical to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
Breastfeeding: It is not known whether memantine passes into breast milk, but it is possible given the lipophilicity of the substance. Women taking memantine should refrain from breastfeeding.
Fertility.
No negative effects of memantine on male or female fertility were observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients with moderate to severe Alzheimer's disease usually have impaired ability to drive or operate machinery. In addition, memantine may cause changes in reaction time, so patients receiving treatment in an outpatient setting should exercise special caution when driving or operating machinery.
Method of administration and doses
Internally. The dosage regimen is set by the doctor individually.
Treatment should be initiated and continued under the supervision of a physician. Therapy should only be initiated with a caregiver who will regularly monitor the patient's medication intake.
The tablets should be taken once a day at the same time each day. The tablets can be taken with or without food.
Adults.
The maximum daily dose is 20 mg. In order to reduce the risk of adverse reactions, the maintenance dose should be determined by gradually increasing the dose by 5 mg per week during the first 3 weeks as follows:
Week 1 (day 1–7): take ½ tablet (5 mg per day) for a week;
Week 2 (days 8–14): take 1 tablet (10 mg per day) for a week;
Week 3 (days 15–21): take 1½ tablets (15 mg per day) for a week;
starting from week 4: take 2 tablets (20 mg per day) every day.
The recommended maintenance dose is 20 mg per day.
The duration of treatment should be determined individually by a physician experienced in the diagnosis and treatment of dementia in Alzheimer's disease. The tolerability and dosage of memantine should be assessed regularly, preferably within 3 months of starting treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be assessed regularly in accordance with current clinical guidelines.
Maintenance treatment can be continued as long as the therapeutic effect remains favorable and the patient tolerates memantine well. Discontinuation of memantine should be considered if signs of therapeutic effect disappear or the patient's tolerance of treatment deteriorates.
Elderly patients.
Based on the results of clinical studies, the recommended dose for patients aged 65 years and over is 20 mg per day (2 tablets of 10 mg once a day), as indicated above.
Kidney dysfunction.
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 per day according to the standard regimen if there are no adverse reactions 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.
No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh A, B). The use of memantine in patients with severe hepatic impairment is not recommended.
Children
The drug should not be prescribed to children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose
Data on overdose are limited.
Symptoms: Overdoses in relatively large volumes (200 mg and 105 mg/day for 3 days) were associated either with only symptoms such as increased fatigue, weakness and/or diarrhea, or with a complete absence of any symptoms. When taking doses less than 140 mg or unknown doses, patients experienced disorders of the central nervous system (confusion, lethargy, drowsiness, vertigo, agitation, aggression, hallucinations and gait disturbances) and/or gastrointestinal tract (vomiting and diarrhea).
In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disorders (the patient was in a coma for 10 days, and later experienced diplopia and agitation). After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.
In another case of overdose with a high dose of memantine (400 mg), central nervous system disorders such as anxiety, psychosis, visual hallucinations, seizure tendency, drowsiness, stupor and loss of consciousness were observed. The patient recovered.
Treatment. In case of overdose, symptomatic treatment should be carried out. There is no specific antidote. If necessary, standard clinical procedures should be carried out to remove the active substance from the body, such as gastric lavage, administration of activated charcoal (to disrupt possible enterohepatic recirculation), acidification of urine, forced diuresis.
In the event of clinical signs or symptoms suggestive of excessive general central nervous system stimulation, symptomatic treatment should be used with caution.
Side effects
In studies involving patients with mild to severe dementia treated with memantine and placebo, the overall incidence of adverse events with memantine was no different from that in patients treated with placebo; adverse events were mild to moderate in severity. The most commonly observed adverse events were dizziness, headache, constipation, somnolence and hypertension.
Infections and infestations: fungal infections.
Immune system disorders: hypersensitivity.
On the part of the psyche: drowsiness, confusion, hallucinations (mainly observed in patients with severe Alzheimer's disease), psychotic reactions (isolated reports).
Cardiovascular system: arterial hypertension, venous thrombosis/thromboembolism, heart failure.
Respiratory system: shortness of breath.
On the part of the digestive tract: constipation, nausea, vomiting, pancreatitis (isolated reports).
From the side of the central nervous system: dizziness, gait disturbance, balance disturbance, convulsions.
From the hepatobiliary system: increased liver function tests, hepatitis.
General disorders: headache, fatigue.
Liver dysfunction and/or jaundice may occur with elevations in aspartate aminotransferase (glutamate oxaloacetate transaminase), alanine aminotransferase (glutamate pyruvate transaminase), alkaline phosphatase, and bilirubin. Patients should be closely monitored. If any atypical findings are observed, 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 with the use of memantine.
Reporting of suspected adverse reactions
It is important to report any suspected adverse reactions while using the drug. This allows for continuous monitoring of the benefit/risk ratio of the drug.
Expiration date
4 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
10 tablets in a blister; 6 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and address of its place of business.
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
Address
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
