Memantine, 20 mg 30 pcs.

Disruption of glutamatergic neurotransmission, particularly NMDA receptor function, contributes to both the symptoms and progression of neurodegenerative dementia.

Memantine is a potential-dependent, moderately affinity-dependent, noncompetitive inhibitor of NMDA receptors. The drug modulates the pathological increase of glutamate, which can lead to neuronal dysfunction. It improves cognitive processes and increases daily activity.

Pharmacokinetics

Intake

After oral administration, memantine is quickly and completely absorbed from the gastrointestinal tract. Absolute bioavailability is about 100%. Maximum concentration (Cmax) in plasma is reached within 3-8 hours. Food intake does not affect the absorption of memantine.

Distribution

The daily dose of 20 mg produces a constant plasma concentration of memantine in the range 70-150 ng/mL (0.5-1 μmol) with marked individual variation. In daily doses of 5 to 30 mg, the average ratio of the drug content in cerebrospinal fluid to that in blood serum was 0.52. The volume of distribution is 10 l/kg. About 45% of memantine is bound to plasma proteins.

Metabolism

About 80% of memantine taken orally circulates unchanged. The major metabolites in humans are N-3,5-dimethylgludantane, a mixture of isomers
4- and 6-hydroxymemantine and l-nitroso-3,5-dimethyladamantane. None of these metabolites has NMDA-antagonistic activity.

In in vitro studies, no involvement of cytochrome P450 system isoenzymes in the metabolism of memantine was detected.

In an oral study of labeled 14C-memantine, more than 84% of the dose was excreted within 20 days, and more than 99% was excreted by the kidneys.

The excretion of memantine is monoexponential with a half-life (T½) of 60 to 100 hours. Total clearance is 170 ml/min/1.73 m2, with part of the total renal clearance achieved by tubular secretion.

There is also a process of tubular reabsorption in the kidneys, probably mediated by proteins involved in cation transport. The rate of renal clearance of memantine may decrease when urine is alkaline to pH 7-9. Alkalinization of the urine can be the result of dramatic changes in diet, such as switching to vegetarianism, or taking plenty of alkaline gastric buffers.

Linearity

Volunteer studies have demonstrated linear pharmacokinetics over a dose range of 10 to 40 mg.

The relationship between pharmacokinetics and pharmacodynamics

When using memantine at a dose of 20 mg daily, the cerebrospinal fluid content of the drug corresponds to the ki value (inhibition constant) of memantine, which is 0.5 μmol of the drug in the frontal lobe of the cerebral cortex.

Indications

Active ingredient

Composition

1 film-coated tablet, 20 mg contains:

Composition of the core of the tablet:

The active ingredient: memantine hydrochloride – 20.0 mg.

Excipients: siliconized microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate.

Particle coating composition: opadray II white (33G28435) (hypromellose, titanium dioxide, lactose monohydrate, triacetin, macrogol).

How to take, the dosage

Treatment should be started and administered under the supervision of a physician experienced in the diagnosis and treatment of dementia in Alzheimer’s disease. Therapy should only be initiated with a caregiver who will regularly monitor the patient’s medication intake. Diagnosis of the disease should be made in accordance with current guidelines. The tolerability and dosage of memantine should be reviewed on a regular basis, preferably within three months of starting treatment. Thereafter, the clinical benefit of memantine and patient tolerability should be reviewed on a regular basis in accordance with current clinical guidelines. Maintenance treatment can be continued indefinitely as long as the therapeutic benefit is favorable and as long as the patient tolerates memantine treatment well. If there is no evidence of therapeutic efficacy or if the patient is intolerant to treatment, discontinuation of memantine should be considered.

The drug should be taken orally once daily and always at the same time, regardless of meals.

To reduce the risk of adverse reactions, the initial dose is increased to a maintenance dose by titration at 5 mg per week for the first 3 weeks according to the following schedule:

Week 1 (days 1-7): 5 mg daily (½ tablet of 10 mg) for 7 days.

Week 2 (day 8-14): 10 mg daily (1 10 mg tablet) for 7 days.

Week 3 (day 15-21): 15 mg daily (1½ 10 mg tablets) for 7 days.

From week 4, 20 mg (1 20 mg tablet or 2 10 mg tablets) daily.

The maximum daily dose is 20 mg daily.

The recommended maintenance dose is 20 mg daily.

Special patient groups

Patients in the elderly

There is no need for dose adjustment in patients over 65 years of age.

Patients with impaired renal function

In patients with mild renal impairment (creatinine clearance 50-80 ml/min) no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance 30-49 ml/min) the daily dose is 10 mg. Further, in case of good tolerability of the drug at least for 7 days of treatment, the dose can be increased to 20 mg per day according to the standard scheme. In patients with severe renal insufficiency (creatinine clearance 5-29 ml/min) the daily dose is 10 mg.

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh grades A and B) no dose adjustment is required. In patients with severe hepatic impairment (Child-Pugh class C) the drug is contraindicated.

Interaction

Simultaneous use with levodopa drugs, dopamine receptor antagonists, m-cholinoblockers may increase their effect.

Concomitant use with barbiturates, neuroleptics may decrease their effect.

Concomitant use may change (increase or decrease) the effects of dantrolene and baclofen; therefore, the doses of the drugs should be adjusted individually.

Concomitant use with amantadine should be avoided because of the increased risk of psychosis. This risk is also common with ketamine and dektromethorphan. A case of a similar risk of interaction between memantine and phenytoin has been described. These drugs are chemically related NMDA receptor antagonists.

Possible increase in plasma concentrations of cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine when combined with memantine.

Possible decrease in concentrations of hydrochlorothiazide when concomitantly administered with memantine.

Possible increase in INR (international normalized ratio) in patients taking oral anticoagulants (warfarin). Despite the fact that a causal relationship has not been found, in patients concomitantly taking oral anticoagulants, it is recommended to monitor carefully the prothrombin time and INR.

There is a possibility of decreased serum concentrations of hydrochlorothiazide when used concomitantly with memantine or any combination containing hydrochlorothiazide. Memantine may increase the excretion of hydrochlorothiazide.

Simultaneous use with antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors requires close monitoring of patients.

There are no pharmacokinetic interactions of memantine with glibenclamide, metformin or donepezil.

There is no significant effect of memantine on the pharmacokinetics of galantamine.

Memantine does not inhibit the activity of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavinmonoxidase, epoxydehydrolase and sulfation isoenzymes in vitro.

Special Instructions

The optimal dose is reached gradually, increasing the dose every week.

In patients with a history of epilepsy, seizures or in patients with a predisposition to epilepsy, memantine should be used with caution.

The co-administration of memantine with an NMDA receptor antagonist such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine, so adverse reactions (mostly central nervous system related) may be more frequent and severe.

The presence of a number of factors that can increase urine pH in patients requires close medical monitoring. These include drastic changes in diet, such as switching from a meat diet to a vegetarian diet, or high intake of alkaline gastric buffer solutions. Renal tubular acidosis or severe urinary tract infections caused by Proteus spp. Conditions that increase urinary pH may reduce urinary excretion of memantine, resulting in increased plasma concentrations of memantine.

Patients with a history of myocardial infarction, decompensated chronic heart failure
(NYHA functional class III-IV) or uncontrolled arterial hypertension were excluded from most clinical trials. Therefore, there are limited data on the use of memantine in these patients, and memantine should be administered under close medical supervision.

The age of most people with Alzheimer’s disease is 65 years or older. In clinical trials of memantine, the average age of patients was about 76 years: more than 90% of patients were 65 years or older, 60% were 75 years or older, and 12% were over the age of 85. There were no clinically significant differences in most adverse events between patient groups ≥65 years and < 65 years.

Dose adjustment is not required in patients with mild to moderate renal impairment. Dose reduction is recommended in patients with severe renal impairment.

Dose adjustment is not required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).

The effect of the drug for medical use on the ability to drive vehicles, mechanisms

In patients with Alzheimer’s disease at the stage of moderate to severe dementia the ability to drive vehicles and operate complex mechanisms is usually impaired. In addition, memantine may cause changes in psychomotor reaction speed, so patients should refrain from driving or operating complex machinery.

Contraindications

Hypersensitivity to memantine or other drug components; lactose intolerance, lactase deficiency, glucose-galactose malabsorption; severe hepatic insufficiency (Child-Pugh class C); childhood and adolescence below 18 years (efficacy and safety not established); pregnancy and breast-feeding.

With caution

Patients with thyrotoxicosis, epilepsy, seizures (including history), myocardial infarction, heart failure, simultaneous use of NMDA-receptor antagonists (amantadine, ketamine, dextromethorphan); presence of factors that increase urine pH (sudden change of diet (change from meat to vegetarian diet), heavy intake of alkaline gastric buffers, severe urinary tract infections (caused by Proteus bacteria)), renal tubular acidosis, uncontrolled arterial hypertension, renal failure, mild to moderate hepatic insufficiency (grade A and B according to Child-Pugh classification).

Side effects

The incidence of side effects is classified according to clinical manifestations (according to the involvement of certain organ systems) and frequency of occurrence: Very common (≥ 1/10), common (≥ 1/100, < 1/10), infrequent (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000, including individual reports), frequency unknown (no data on the incidence of side effects currently available).

Infectious and parasitic diseases: infrequent – fungal infections.

Immune system disorders: often – hypersensitivity to the drug.

Psychiatric disorders: common – somnolence; infrequent – confusion, hallucinations (mainly observed in patients with Alzheimer’s disease at the stage of severe dementia); frequency unknown – psychotic reactions (single cases reported in the post-registration period).

Nervous system disorders: frequently – dizziness, impaired balance; infrequently – gait disturbance; very rarely – seizures.

Cardiovascular system disorders: frequently – arterial hypertension; infrequently – heart failure, venous thrombosis/thromboembolism.

Respiratory system, thorax and mediastinum disorders: frequently – dyspnea.

Gastrointestinal disorders: frequently – constipation; infrequently – nausea, vomiting; frequency unknown – pancreatitis (single cases reported in the post-registration period).

Liver and biliary tract disorders: frequently – increased biochemical parameters of liver function; frequency unknown – hepatitis.

General disorders and disorders at the site of administration: frequent – headache, infrequent – fatigue.

In Alzheimer’s disease, patients may experience depression, suicidal thoughts and suicide attempts. In clinical practice, these effects have been reported in patients taking memantine.

Postmarketing experience with the drug

The following are adverse events described in spontaneous reports during postmarketing use of memantine for which a causal association with the drug cannot be excluded agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura, acute renal failure, Stevens-Johnson syndrome.

Overdose

There are limited data on overdose from clinical trials and post-registration experience with memantine.

Symptoms: a relatively large overdose (200 mg once and 105 mg daily for 3 days) was manifested by fatigue, weakness and/or diarrhea, or no symptoms. In patients with an overdose of less than 140 mg or with an unknown dose, symptoms such as confusion, hypersomnia, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbance, vomiting, and diarrhea were observed.

The administration of 2000 mg of memantine was not fatal, but was accompanied by nervous system disturbances (coma for 10 days, then diplopia and agitation). After symptomatic treatment and plasmapheresis there was recovery without further complications.

In another reported case, the patient also recovered. After oral administration of 400 mg of memantine he had the following central nervous system disorders: anxiety, psychosis, visual hallucinations, decreased seizure threshold, somnolence, stupor, unconsciousness.

Treatment: gastric lavage, activated charcoal, urine acidification, forced diuresis, symptomatic therapy. There is no specific antidote. If signs and symptoms of general central nervous system hyperstimulation occur, symptomatic therapy should be used with caution.

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