Akatinol Memantine (Tablets, Tablet kit) Instructions for Use

ATC Code

N06DX01 (Memantine)

Active Substance

Memantine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Glutamate NMDA-receptor blocker. Drug for the treatment of dementia

Pharmacotherapeutic Group

Other drugs for the treatment of dementia

Pharmacological Action

Pharmacodynamics

Impairment of glutamatergic neurotransmission, particularly the function of NMDA receptors, contributes to both the manifestation of symptoms and the progression of neurodegenerative dementia. Memantine is a voltage-dependent, moderately affine, non-competitive NMDA receptor antagonist. The drug modulates the pathological increase in glutamate levels, which can lead to neuronal dysfunction. It improves cognitive processes and increases daily activity.

Pharmacokinetics

Absorption

Memantine has an absolute bioavailability of approximately 100%. C_max in blood plasma is reached within 3-8 hours. There is no evidence that food intake affects the absorption of memantine.

Distribution

Daily doses of 20 mg lead to a steady-state plasma concentration of memantine in the range of 70 to 150 ng/ml (0.5-1 μmol/l) with large interindividual variations. With daily doses from 5 to 30 mg, the mean ratio of drug concentration in cerebrospinal fluid to serum concentration was 0.52. V_d is about 10 L/kg. Approximately 45% of memantine is bound to plasma proteins.

Biotransformation

Approximately 80% of orally administered memantine circulates unchanged. The main metabolites in humans are N-3,5-dimethylgludantan, a mixture of 4- and 6-hydroxymemantine isomers, and 1-nitroso-3,5-dimethyladamantane. None of these metabolites have NMDA-antagonistic activity. Metabolism catalyzed by the cytochrome P450 system was not detected in vitro.

In a study of oral administration of ¹⁴C-memantine, an average of 84% of the administered dose was excreted within 20 days, with more than 99% excreted via the kidneys.

Excretion

The elimination of memantine is monoexponential with a T_1/2 of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cl_tot) is 170 ml/min/1.73 m², with part of the total renal clearance achieved through tubular secretion.

Tubular reabsorption also occurs in the kidneys, likely mediated by proteins involved in cation transport. The rate of renal clearance of memantine may decrease when urine is alkalized to pH 7-9. Urine alkalization can result from drastic changes in diet, such as switching to a vegetarian diet or abundant intake of alkaline gastric buffers.

Linearity

Studies involving volunteers demonstrated linear pharmacokinetics in the dose range from 10 to 40 mg.

Pharmacokinetic-Pharmacodynamic Relationship

When memantine is used at a dose of 20 mg/day, the drug concentration in the cerebrospinal fluid corresponds to the ki value (ki – inhibition constant) of memantine, which is 0.5 μmol/l of the drug in the frontal cortex of the human brain.

Indications

• Dementia in Alzheimer’s disease of moderate and severe degree;
• Moderate and moderately severe vascular dementia.

ICD codes

Dosage Regimen

Tablets

Treatment should be initiated and conducted under the supervision of a physician experienced in the diagnosis and treatment of dementia in Alzheimer’s disease and vascular dementia. Therapy should only be initiated if there is a caregiver who will regularly monitor the patient’s intake of the medication. Diagnosis of the disease should be made in accordance with current guidelines. The tolerability and dosage of memantine should be reviewed regularly, preferably within 3 months after starting treatment. Thereafter, the clinical benefit of memantine and the patient’s tolerability of treatment should be reviewed regularly in accordance with current clinical guidelines. Maintenance treatment can be continued indefinitely as long as the therapeutic effect is favorable and the patient tolerates memantine treatment well. In the absence of signs of therapeutic efficacy or if the patient is intolerant to treatment, discontinuation of memantine should be considered.

The drug should be taken orally once a day, at the same time, regardless of meals.

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the initial dose is increased to the maintenance dose by titration in 5 mg increments per week over the first 3 weeks as follows:

Week 1 (day 1-7): 5 mg/day is prescribed.

Week 2 (day 8-14): 10 mg/day is prescribed.

Week 3 (day 15-21): 15 mg/day is prescribed.

Week 4 and beyond: 20 mg/day is prescribed.

The recommended maintenance dose is 20 mg/day.

Tablets with other dosages are available for dose titration.

Special patient groups

Elderly patients

According to clinical studies, the recommended dose for patients over 65 years of age is 20 mg/day.

Renal impairment

In patients with mild renal impairment (creatinine clearance 50-80 ml/min), no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance 30-49 ml/min), the daily dose is 10 mg. If the drug is well tolerated for at least 7 days of treatment, the dose can be increased to 20 mg/day according to the standard titration schedule. In patients with severe renal impairment (creatinine clearance 5-29 ml/min), the daily dose is 10 mg.

Hepatic impairment

In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), no dose adjustment is required. There are no data on the use of memantine in patients with severe hepatic impairment. It is not recommended for use in patients with severe hepatic impairment.

Tablet kit

When taken orally, the initial dose for adults is 5 mg/day. Subsequently, the dose can be increased weekly by 5 mg. The average maintenance dose is 10-20 mg/day. Maximum dose is 20 mg/day.

Adverse Reactions

Brief overview of the safety profile

In clinical studies of mild to severe dementia involving 1784 patients receiving Akatinol Memantine and 1595 patients receiving placebo, the overall incidence of adverse reactions (AR) with Akatinol Memantine did not differ from that with placebo; ARs were usually mild or moderate in severity. The most common ARs, the incidence of which was higher in the Akatinol Memantine treatment group compared to the placebo group, were dizziness (6.3% vs. 5.6%, respectively), headache (5.2% vs. 3.9%), constipation (4.6% vs. 2.6%), drowsiness (3.4% vs. 2.2%, respectively) and increased blood pressure (4.1% vs. 2.8%, respectively). The table below lists ARs that were observed in clinical studies of Akatinol Memantine and in the post-registration period. Within each frequency category, ARs are presented in order of decreasing severity.

Adverse reactions are classified by clinical manifestations (according to affected organs and organ systems) and by frequency: 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 not known (currently there is no data on the prevalence of adverse reactions).

¹ Hallucinations were observed mainly in patients with Alzheimer’s disease at the severe dementia stage.
² Isolated cases reported during the post-registration period.

There are isolated reports of the following adverse reactions occurring with the use of the drug in clinical practice (data obtained after the drug was marketed): agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura, acute renal failure, Stevens-Johnson syndrome.

In Alzheimer’s disease, patients may experience depression, suicidal thoughts and suicide attempts. In the context of post-registration use, these adverse reactions have been reported in patients taking Akatinol Memantine.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Individual hypersensitivity to the components of the drug;
• Severe hepatic impairment;
• Age under 18 years (due to insufficient data on safety and efficacy).

Use with caution in patients with epilepsy, seizures (including history) and in patients with factors predisposing to epilepsy. Simultaneous use of NMDA receptor antagonists such as amantadine, ketamine, dextromethorphan should be avoided. These compounds act on the same receptor system as Memantine, so more frequent or more pronounced adverse reactions (mainly from the CNS) may develop.

The presence of factors that increase urine pH may require careful monitoring of the patient. Such factors include a drastic change in diet, such as switching to a vegetarian diet, or abundant intake of alkaline gastric buffers. In addition, urine pH may increase in renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria.

Patients who had recently experienced myocardial infarction or had uncompensated congestive heart failure (NYHA class III-IV), uncontrolled arterial hypertension were excluded from most clinical trials. Therefore, there is only limited data regarding patients with these conditions, and such patients should be under careful observation.

Use in Pregnancy and Lactation

Pregnancy

There are no clinical data on the use of memantine during pregnancy. Animal studies indicate a possible delay in intrauterine development when the drug is used in doses similar to or slightly exceeding doses used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy except in cases of clear necessity.

Lactation period

It is not known whether Memantine passes into breast milk, however, given the lipophilic properties of the substance, this is likely. Women taking Memantine should not breast-feed their child.

Fertility

Preclinical studies of male and female fertility did not reveal any adverse effects of memantine use.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment. The use of the drug in patients with severe hepatic impairment is contraindicated.

Use in Renal Impairment

Use with caution in patients with renal impairment.

Pediatric Use

Contraindicated in patients under 18 years of age.

Geriatric Use

According to clinical studies, the recommended dose for patients over 65 years of age is 20 mg/day.

Special Precautions

Use with caution in patients with thyrotoxicosis, epilepsy, seizures (including history), simultaneous use of NMDA receptor antagonists (amantadine, ketamine, dextromethorphan), presence of factors that increase urine pH (drastic change in diet, e.g., switching to a vegetarian diet, abundant intake of alkaline gastric buffers), severe urinary tract infections, myocardial infarction (in history), heart failure functional class III-IV (according to NYHA classification), uncontrolled arterial hypertension, renal impairment, hepatic impairment.

This drug contains less than 1 mmol sodium (23 mg) per tablet, and can be considered sodium-free.

Effect on ability to drive vehicles and operate machinery

Moderate and severe dementia generally leads to a reduced ability to drive vehicles and operate machinery. Akatinol Memantine, in turn, also has a slight or moderate effect on the ability to drive vehicles and operate machinery, so patients should be warned to exercise special caution and refrain from driving vehicles.

Overdose

There are only limited data on overdose obtained during clinical studies and in the post-registration period.

Symptoms

Cases of relatively large overdose (intake of 200 mg and 105 mg/day for 3 days, respectively) were accompanied either only by symptoms of fatigue, weakness and/or diarrhea, or were not accompanied by any symptoms at all. In cases of overdose with a dose of less than 140 mg or an unknown dose, patients experienced symptoms of CNS involvement (confusion, lethargy, drowsiness, dizziness, agitation, aggressiveness, hallucinations, and gait disturbances) and/or gastrointestinal tract (vomiting and diarrhea).

In the most severe case of overdose, the patient survived after ingesting a total of 2000 mg of memantine, accompanied by CNS involvement (coma for 10 days, later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without irreversible consequences.

In another case of large overdose, the patient also survived and recovered. The patient took 400 mg of memantine orally. The patient developed CNS symptoms such as anxiety, psychosis, visual hallucinations, seizure readiness, drowsiness, stupor and loss of consciousness.

Treatment

In case of overdose, treatment should be symptomatic. There is no specific antidote for intoxication or overdose. If necessary, standard therapeutic measures aimed at eliminating the active substance from the body, such as gastric lavage, administration of activated charcoal (to prevent potential recirculation in the intestine and liver), urine acidification, forced diuresis, should be carried out. If signs and symptoms of general CNS hyperstimulation appear, symptomatic therapy should be administered with caution.

Drug Interactions

Given the pharmacological action and mechanism of action of memantine, the following interactions are possible.

The mechanism of action suggests an enhancement of the effects of levodopa, dopamine receptor agonists and anticholinergic drugs when used concomitantly with NMDA antagonists such as Memantine.

When used concomitantly with barbiturates or antipsychotics, the effect of the latter may be reduced.

Concomitant use of memantine with antispasmodics, dantrolene or baclofen may alter their effect and require dose adjustment.

Concomitant administration of memantine with amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both substances are chemically related NMDA antagonists. The same applies to ketamine and dextromethorphan. There is also one published report in the literature on the possible risk of combined use of memantine and phenytoin.

Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which use the same renal cation transport system as amantadine, may possibly interact with memantine, creating a potential risk of increased plasma concentrations.

There is a possibility of a decrease in the serum level of hydrochlorothiazide when taken concomitantly with memantine.

During the post-registration period, isolated cases of increased INR were recorded in patients simultaneously receiving treatment with warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is recommended in patients taking oral anticoagulants concomitantly.

In pharmacokinetic studies of a single dose in young healthy volunteers, no interactions of the active substance memantine with the active substances glibenclamide/metformin or donepezil were observed.

In a clinical study involving young healthy volunteers, no significant effect of memantine on the pharmacokinetics of galantamine was found.

Memantine does not inhibit the activity of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin monooxygenase, epoxide hydrolase and sulfation in vitro.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.