Instructions Memox 10 film-coated tablets 10 mg blister No. 60
Composition
active ingredient: memantine;
1 tablet contains memantine hydrochloride 10 mg or 20 mg;
excipients: lactose monohydrate, microcrystalline cellulose, talc, colloidal anhydrous silicon dioxide, magnesium stearate;
film coating mixture: lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol 4000 (macrogol), for 20 mg tablets: iron oxide yellow (E 172), iron oxide red (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
"Memox 10": round tablets with a biconvex surface, coated with a white shell, engraved with "M9MN" and "10" on one side and a score on the other;
"Memox 20": oval-shaped tablets with a biconvex surface, coated with a red-brown shell, engraved with "M9MN 20" on one side and a score on the other.
Pharmacotherapeutic group
Drugs used in dementia. ATX code N06D X01.
Pharmacological properties
Pharmacodynamics
Disturbances in glutamatergic neurotransmission, especially involving NMDA receptors (N-methyl-D-aspartate), 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
Absorption.
The absolute bioavailability of memantine is approximately 100%, the time to reach maximum plasma concentration (tmax) is from 3 to 8 hours. There is no evidence of the effect of food intake on the absorption of the drug.
Distribution.
A daily dose of 20 mg provides stable plasma concentrations of memantine in the range of
70 to 150 ng/mL (0.5>1 μmol) with significant individual variation.
When using daily doses of 5 to 30 mg, the ratio of the drug content in the cerebrospinal fluid to the blood serum is 0.52. The average volume of distribution of memantine is 10 l/kg. Approximately 45% of memantine binds to blood plasma proteins.
Biotransformation.
About 80% of the circulating compounds related to memantine hydrochloride in humans are present as the parent compound. The main metabolites in humans are
N-3,5-dimethyl-gludantan, an isomeric mixture of 4- and 6-hydroxymemantine, as well as 1-nitroso-
3,5-dimethyladamantane. None of these metabolites show antagonistic activity at NMDA receptors. Cytochrome P450 has not been shown to be involved in in vitro metabolism. In a study of oral administration of 14C-memantine, an average of 84% of the dose was eliminated within 20 days, with more than 99% excreted by the kidneys.
Elimination.
Memantine is eliminated in a monoexponential manner with a t1/2 half-life ranging from 60 to 100 hours. In subjects with normal renal function, the 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 a factor of 7-9 in alkaline urine. Alkalinization of urine may occur as a result of significant dietary changes, such as replacing a meat-rich diet with a vegetarian diet or as a result of intensive use 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 disease from mild to severe forms.
Contraindication
Hypersensitivity to the active substance or to any component of the drug.
Interaction with other medicinal products and other types of interactions
Given the pharmacological effects and mechanism of action of memantine hydrochloride, the following interactions may occur:
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. One published report also noted the possible risk of the combination of memantine and phenytoin;
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;
when memantine is co-administered with hydrochlorothiazide or any combination drug containing hydrochlorothiazide, a decrease in the serum level of the latter 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 single-dose pharmacokinetic studies in young healthy volunteers, no significant interaction effects of memantine with glyburide/metformin or donepezil were observed.
Based on available clinical trial data in young healthy volunteers, no significant effect of memantine hydrochloride on the pharmacokinetics of galantamine was 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 of the drug with (NMDA) antagonists such as amantadine, ketamine and dextromethorphan should be avoided. These compounds affect 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 in conditions of renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria.
There are only limited data in patients with recent myocardial infarction, patients with decompensated congestive heart failure (New York Heart Association stage III-IV), and patients with uncontrolled hypertension. Therefore, careful monitoring is necessary in patients with these conditions.
The drug contains lactose, so it should not be taken by patients with rare hereditary problems of galactose intolerance, 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 have been reported to indicate a potential for intrauterine growth retardation at exposure concentrations similar to or slightly higher than those used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
Breast-feeding
It is not known whether memantine is excreted in breast milk, however, given the lipophilicity of the substance, women taking memantine should refrain from breastfeeding.
Fertility
No adverse effects of memantine on male or female reproductive function were noted.
Ability to influence reaction speed when driving vehicles or other mechanisms
Moderate to severe Alzheimer's disease usually impairs the ability to drive and use machines. Furthermore, memantine has a minor to moderate effect on the reaction time, so outpatients should be warned to exercise caution when driving or operating machinery.
Method of administration and doses
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.
The duration of treatment should be determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. The diagnosis should be made in accordance with current practice guidelines. The tolerability and dosage of the medicinal product should be assessed regularly, preferably within 3 months of starting treatment. Therefore, the clinical benefits of memantine hydrochloride and the patient's tolerability of the medicinal product should be reviewed regularly in accordance with current clinical guidelines. Maintenance treatment may be continued as long as the therapeutic effect is considered to be favourable and the patient tolerates memantine hydrochloride treatment. Discontinuation of medicinal product should be considered in the event of loss of therapeutic effect or poor patient tolerance.
Adults.
The recommended starting dose is 5 mg per day, which is gradually increased during the first
4 weeks of treatment, reaching the recommended maintenance dose as follows:
Week 1 (days 1-7):
the patient needs to take 5 mg per day for a week;
the patient needs to take 10 mg per day for a week;
Week 3 (days 15-21):
the patient needs to take 15 mg per day for a week;
starting from the 4th week:
the patient needs to take 20 mg per day every day.
The recommended maintenance dose is 20 mg per day.
Elderly patients.
The recommended dose for patients aged 65 years and over is 20 mg per day, as stated 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.
Liver dysfunction.
No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh A, B). There are no data on the use of the drug 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 due to insufficient data on the safety and effectiveness of its use.
Overdose
Experience is limited.
Symptoms.
Relatively large overdoses (200 mg and 105 mg per day for 3 days) were accompanied by symptoms of increased fatigue, weakness and/or diarrhea or were asymptomatic. With overdoses up to 140 mg or an unknown dose, symptoms of central nervous system disorders were observed, such as confusion, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbances and/or gastrointestinal disorders (vomiting and diarrhea).
After taking 2000 mg of memantine, the patient developed coma (10 days), lateral diplopia, and agitation. After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.
In another case, after taking 400 mg of memantine, a patient developed symptoms of central nervous system impairment, such as restlessness, psychosis, visual hallucinations, slow movements, drowsiness, stupor, and loss of consciousness.
Treatment.
Symptomatic, no specific antidote exists. Standard clinical procedures should be used to remove the active substance from the body, such as gastric lavage, activated charcoal, acidification of the urine reaction, forced diuresis. In case of excessive general stimulation of the central nervous system, symptomatic treatment should be carried out with caution.
Side effects
It is known that during clinical trials of memantine, the overall incidence of adverse events did not differ from that observed with placebo, and adverse events were usually mild or moderate in severity.
The adverse reactions observed in the table are listed according to the following frequency classification: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10000 to < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
| Organ system class | Frequency | Adverse reactions |
| Infections | Infrequently | Fungal diseases |
| On the part of the immune system | Often | Hypersensitivity |
| From the psyche | Often Infrequently Frequency unknown | Drowsiness Confusion of consciousness Hallucinations1 Psychotic reactions2 |
| From the nervous system | Often Infrequently Very rare | Dizziness Disequilibrium Gait disturbance Convulsive seizures |
| Cardiovascular system | Often Infrequently | Arterial hypertension Heart failure Venous thrombosis/thromboembolism |
| Respiratory system | Often | Dyspnea |
| From the digestive system | Often Infrequently Frequency unknown | Constipation Vomiting Pancreatitis2 |
| Liver and biliary tract disorders | Often Frequency unknown | Increased liver function tests Hepatitis |
| General violations | Often Infrequently | Headache Increased fatigue |
1 Hallucinations were mainly observed in patients with severe Alzheimer's disease.
2 Separate messages for medical use.
Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have been reported with the medical use of memantine.
Expiration date
3 years.
Storage conditions
Store out of the reach of children in the original packaging at a temperature not exceeding 25 °C.
Packaging
Memox 10: 10 tablets in a blister; 3 or 6 blisters in a cardboard pack.
Memox 20: 10 tablets in a blister; 3 or 6 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Location of the manufacturer and address of its place of business.
Ukraine, 03124, Kyiv, Vaclav Havel Boulevard, 8.
In case of side effects and questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at the address: Vaclav Havel Boulevard, 8, Kyiv, 03124, tel/fax: +38 044 281 2333.
