Memantine

Pharmacological properties

According to modern scientific data, disruption of glutamatergic neuromediation plays an important role in the symptoms and progression of neurodegenerative dementia, especially with the participation of nmda (n-methyl-d-aspartate) receptors.

Memantine is a voltage-dependent, medium affinity, non-competitive NMDA receptor antagonist. Memantine blocks the effects of glutamate, which in pathologically elevated concentrations can lead to neuronal dysfunction.

Pharmacokinetics Memantine is characterized by an absolute bioavailability of approximately 100%; time to reach T_max in blood plasma - 3–8 hours. No effect of food intake on the absorption of the drug was revealed.

A daily dose of 20 mg causes a stable concentration of memantine in blood plasma in the range of 70–150 ng / ml (0.5–1 μmol) with significant individual variations. When prescribing memantine in a daily dose of 5-30 mg, the ratio of the drug in cerebrospinal fluid and blood plasma is 0.52. Approximately 45% of memantine binds to plasma proteins.

In the human body, about 80% of memantine circulates unchanged, the main metabolites do not have NMDA antagonistic activity. The involvement of cytochrome P450 in in vitro metabolism was not detected.

Memantine is eliminated predominantly by the kidneys according to the curve of monoexponential dependence, T_½ - 60–100 hours. Total clearance - 170 ml / min / 1.73 m². The renal stage of memantine pharmacokinetics also includes tubular reabsorption.

The rate of renal elimination of memantine in an alkaline urine reaction may decrease by 7–9 times. Alkalization of urine can occur as a result of a change in diet, for example, when replacing a diet rich in meat dishes with a vegetarian one, or due to the frequent use of antacids.

Pharmacokinetics is linear in the dose range of 10–40 mg.

Pharmacodynamic and pharmacokinetic relationship: when using memantine at a dose of 20 mg / day, the concentration level in the cerebrospinal fluid corresponds to the Ki value (pressure constant) for memantine, which is 0.5 μmol in the frontal cortex of the human brain.

Indications

Mild to severe Alzheimers disease.

Application

Treatment should be started and carried out under the supervision of a physician. therapy should be started only if there is a guardian who will regularly monitor the patients intake of the drug.

Tablets must be taken once a day every day at the same time, with food or regardless of food.

Adults

The maximum daily dose is 20 mg. In order to reduce the risk of adverse reactions, the maintenance dose is determined by gradually increasing the dose by 5 mg per week for the first 3 weeks as follows:

• 1st week (1st – 7th day): 5 mg / day (½ tablets per day).
• 2nd week (8-14th day): 10 mg / day (1 tablet per day).
• 3rd week (15-21st day): 15 mg / day (1½ tablets per day).
• starting from the 4th week: 20 mg / day (2 tablets per day).

The recommended maintenance dose is 20 mg / day.

The duration of treatment is individually determined by the doctor who has experience in diagnosing and treating Alzheimers disease.

Elderly patients. Based on the results of clinical studies, the recommended dose for patients over the age of 65 is 20 mg / day (2 tablets of 10 mg once a day), as described above.

Impaired renal function. In patients with impaired renal function of mild degree (creatinine clearance of 50–80 ml / min), a dose reduction is not required. In patients with moderate renal impairment (creatinine clearance 30–49 ml / min), the daily dose should be reduced to 10 mg. The dose can be increased to 20 mg / day according to the standard scheme, if there are no negative reactions after at least 7 days of treatment.In patients with severe renal impairment (creatinine clearance 5–29 ml / min), the daily dose should be reduced to 10 mg.

Impaired liver function. For patients with mild or moderate hepatic impairment (Child Pugh A, B), dose adjustment is not required. The use of memantine in patients with severely impaired liver function is not recommended.

Contraindications

Hypersensitivity to the active substance or any component of the drug.

Side effects

During clinical trials, the overall incidence of side effects did not differ from that observed with placebo, and the side effects themselves were usually mild to moderate.

The adverse reactions listed in the table below during clinical trials and medical use are defined by frequency as: very often (≥1 / 10), often (≥1 / 100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (≥1 / 10,000 to 1/1000), very rarely (1/10 000), not determined (cannot be determined from the available data).

¹Hallucinations were predominantly observed in patients with severe Alzheimers disease.

²Separate reports for medical use.

Alzheimers disease is associated with depression, suicidal ideation and suicide. Such cases are known in the medical use of memantine.

special instructions

Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizures, and also to patients at risk of developing epilepsy.

Some factors causing an increase in urine pH may necessitate careful monitoring of the patient. They include a significant change in diet, for example, replacing a meat-rich diet with a vegetarian or frequent antacid intake. In addition, urine pH may increase with tubular renal acidosis or severe urinary tract infection caused by Proteus bacteria.

In the majority of clinical trials, patients who recently suffered myocardial infarction, as well as patients with decompensated congestive heart failure (grade III – IV according to NYHA classification), uncontrolled hypertension, were excluded from the participants. Consequently, only limited relevant data are available, and patients with such diseases must be carefully monitored.

During pregnancy and breastfeeding. There is no data on the effect of memantine during pregnancy. Experimental studies in animals indicate the possibility of slowing intrauterine growth at identical or slightly higher concentrations compared to those in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy unless absolutely necessary.

It is not known whether memantine passes into breast milk, which however can take place, given the lipophilic nature of the substance. When using memantine, breast-feeding should be discontinued.

Children. B