Abixa film-coated tablets 10 mg blister No. 28

Instructions for Abixa film-coated tablets 10 mg blister No. 28

Composition

active ingredient: memantine;

1 tablet contains memantine hydrochloride 10 mg;

excipients: microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silicon dioxide, magnesium stearate;

shell: hypromellose, titanium dioxide (E 171), macrogol 400, iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets, pale yellow to yellow, oval in shape, with a break line and markings relative to it: “M” on the left and right on one side and “1” on the left and “0” on the right on the other.

The tablet can be divided into two halves.

Pharmacotherapeutic group

Psychoanaleptics. Other drugs for use in dementia. Memantine.

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.

Clinical trials

The pivotal monotherapy study in patients with moderate to severe Alzheimer's disease (MMSE score 3–14) included a total of 252 outpatients. The beneficial effect of memantine treatment is evident after 6 months of treatment compared to placebo (observed case analysis for clinician interview based on changes in CIBIC-plus (p = 0.025); ADCS-ADLsev (p = 0.003) and SIB (p = 0.002)). The pivotal monotherapy study of memantine in the treatment of mild to moderate Alzheimer's disease (MMSE total score at baseline 10 to 22) included 403 patients. Patients treated with memantine showed statistically significantly better results than patients treated with placebo on the primary endpoints ADAS-cog (p = 0.003) and CIBIS-plus (p = 0.004) at 24 weeks (LOCF). In another monotherapy study in mild to moderate Alzheimer's disease, a total of 470 patients (baseline MMSE total score 11–23) were randomized. In the prospectively defined primary analysis, statistical significance was not reached for the primary efficacy endpoint at 24 weeks.

A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total score < 20) from six phase III placebo-controlled 6-month studies (including monotherapy studies and studies in patients taking a stable dose of acetylcholinesterase inhibitors) showed a statistically significant effect of memantine treatment on cognitive, general and functional domains.

When a patient experienced concomitant deterioration in all three domains, the results demonstrated a statistically significant effect of memantine in preventing deterioration; patients in the placebo group experienced deterioration in all three domains twice as often as patients receiving memantine (21% vs. 11%, p < 0.0001).

Pharmacokinetics.

Absorption

The absolute bioavailability of memantine is approximately 100%, the time to peak plasma concentration (Tmax) 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 involvement in metabolism in vitro has not been demonstrated.

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

Elimination

Memantine is eliminated monoexponentially with a t1/2 of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cltot) is 170 ml/min/1.73 m2 and part of the total renal clearance is achieved by tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, which is probably mediated by a cationic transport system.

The renal elimination rate of memantine may be reduced by 7–9 times in alkaline urine. Alkalinization of urine may occur as a result of profound dietary changes, such as changing from a meat-rich diet to a vegetarian diet or as a result of intensive use of antacids.

Linearity

According to studies in volunteers, the pharmacokinetics of memantine are linear in the dose range of 10–40 mg.

At a dose of 20 mg of memantine per day, its 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 moderate 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

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 the 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 found.

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 (New York Heart Association grades 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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

There are no data on the effects of memantine during pregnancy. Experimental studies in animals indicate the possibility of intrauterine growth retardation at exposure levels of memantine 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.

It is not known whether memantine is excreted in breast milk, which is, however, possible given the lipophilicity of the substance. Women taking memantine should refrain from breastfeeding.

Fertility

No negative effect of memantine on male or female fertility was observed.

The ability to influence the reaction speed when driving or working with other mechanisms

Moderate to severe Alzheimer's disease usually causes impairment of the ability to drive and use machines. Furthermore, memantine has minor or moderate influence on the ability to drive and use machines, so outpatients should exercise caution when performing the above-mentioned operations.

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.

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 dosage by

5 mg per week for the first 3 weeks as follows:

Week 1 (days 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 the 4th week:

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 Alzheimer's disease. The tolerability and dosage of memantine should be assessed regularly, preferably within three 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 may be continued as long as the therapeutic effect remains favourable and the patient's tolerance of memantine is good. 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.

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 memantine in patients with severe hepatic impairment. The use of memantine in patients with severe hepatic impairment is not recommended.

Children

The drug is not used in children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose

Experience is limited.

Symptoms

Relatively large overdoses (200 mg and 105 mg per day for 3 days, respectively) were either associated with symptoms of fatigue, weakness and/or diarrhea, or were asymptomatic. Overdoses up to 140 mg or an unknown dose have been associated with symptoms of central nervous system disorders (confusion, lethargy, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disorders (vomiting and diarrhea).

In the most severe known case of overdose, a patient survived after oral administration of a total dose of 2000 mg of memantine and developed central nervous system disorders (coma for 10 days, later diplopia and agitation). The patient was treated symptomatically and underwent plasmapheresis. The patient recovered completely without any permanent sequelae.

In another case of a large overdose (400 mg memantine orally), the patient also survived and recovered. He experienced central nervous system disorders such as anxiety, psychosis, visual hallucinations, convulsive readiness, drowsiness, stupor, and unconsciousness.

Treatment

Treatment is symptomatic, there is no specific antidote. Standard clinical procedures should be used to remove the active substance from the body, such as gastric lavage, administration of activated charcoal, methods of acidifying the urine reaction, forced diuresis.

In case of excessive general stimulation of the central nervous system, symptomatic treatment measures should be used with caution.

Side effects

General safety profile data

In clinical trials of memantine in patients with mild to severe dementia (1,784 patients received Abixa and 1,595 received placebo), the overall incidence of adverse events was not different from that seen with placebo, and adverse events were usually mild to moderate in severity.

The most common adverse reactions, observed at a higher frequency in the group of patients taking Abixa than in 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%), and hypertension (4.1% vs. 2.8%).

The adverse reactions observed during clinical trials and medical use are listed in the table below, defined by frequency as: 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), unknown (cannot be determined from the available data).

1Hallucinations were mainly observed in patients with severe Alzheimer's disease.

2Separate 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

4 years.

Storage conditions

No special storage conditions required. Keep out of the reach of children.

Packaging

14 tablets in blisters, 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

H. Lundbeck A/S / H. Lundbeck A/S.

Location of the manufacturer and address of its place of business

Ottiliavej 9, 2500 Valby, Denmark.