Abixa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABIXA (ABIXA)

Composition:

Active substance:
memantine;

One tablet contains memantine hydrochloride 10 mg;

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

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

Pharmaceutical form.
Film-coated tablets.

Main physicochemical properties:
film-coated tablets of pale yellow to yellow colour, oval-shaped, with a score line and markings on either side: «M» on the left and right on one side, and «1» on the left and «0» on the right on the other side.

The tablet may be divided into two equal halves.

Pharmacotherapeutic group.
Psychoanaleptics. Other agents used in dementia. Memantine.

ATC code N06DX01.

Pharmacological Properties

Pharmacodynamics

In the manifestation of symptoms and progression of neurodegenerative dementia, impaired glutamatergic neurotransmission plays a key role, particularly involving NMDA (N-methyl-D-aspartate) receptors.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. Memantine modulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.

The main monotherapy study in patients with moderate to severe Alzheimer’s disease (Mini-Mental State Examination [MMSE] score of 3–14) included a total of 252 outpatients. A positive effect of memantine therapy was observed after 6 months of treatment compared to placebo (observed cases analysis for clinician interview based on CIBIC-plus scores [p = 0.025]; ADCS-ADLsev scale [p = 0.003]; and SIB scores [p = 0.002]).

The primary monotherapy trial of memantine in mild to moderate Alzheimer’s disease (baseline MMSE total score from 10 to 22) included 403 patients. Patients receiving memantine treatment showed statistically significant better outcomes than those receiving placebo for the primary endpoints on the ADAS-cog scale (p = 0.003), CIBIC-plus (p = 0.004) at week 24 (using LOCF). In another monotherapy study in patients with mild to moderate Alzheimer’s disease, a total of 470 patients were randomized (baseline MMSE total score 11–23). In the prospectively defined primary analysis, statistical significance was not achieved for the primary efficacy endpoint at week 24.

A meta-analysis of patients with moderate to severe Alzheimer’s disease (baseline MMSE total score < 20) from six phase III, 6-month, placebo-controlled studies (including both monotherapy trials and trials in patients receiving stable doses of acetylcholinesterase inhibitors) demonstrated a statistically significant beneficial effect of memantine treatment on cognitive, global, and functional domains.

When deterioration across all three domains was assessed, results showed a statistically significant effect of memantine in preventing such deterioration; patients in the placebo group experienced deterioration in all three domains twice as frequently as those receiving memantine (21% vs. 11%, p < 0.0001).

Pharmacokinetics

Absorption

Absolute bioavailability of memantine is approximately 100%. Time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food effect on absorption.

Distribution

A daily dose of 20 mg results in a steady-state plasma concentration of memantine ranging from 70 to 150 ng/mL (0.5–1 µmol), with considerable inter-individual variability. When daily doses of 5 to 30 mg are administered, the ratio of drug concentration in cerebrospinal fluid to serum is 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is protein-bound in plasma.

Biological Transformation

In humans, approximately 80% of memantine circulates as the parent compound; the main metabolites lack NMDA-antagonistic activity. In vitro studies have shown no involvement of the cytochrome P450 system in memantine metabolism.

In a study using oral administration of 14C-labeled memantine, on average 84% of the dose was eliminated within 20 days, with over 99% of the dose excreted via the kidneys.

Elimination

Memantine is eliminated in a monoexponential manner with a half-life (t1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m², and a significant portion of total renal clearance is achieved via tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, which may be mediated by a cationic transport system.

Renal elimination of memantine may be reduced by 7–9 fold under alkaline urinary pH conditions. Alkalinization of urine may occur as a result of significant dietary changes, such as switching from a meat-rich diet to a vegetarian diet, or due to intensive use of antacid gastric medications.

Linearity

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

Pharmacodynamic/Pharmacokinetic Relationship

At a daily dose of 20 mg, memantine concentrations in cerebrospinal fluid correspond to the ki (inhibition constant) of memantine, which is 0.5 µmol in the frontal cortex region of the human brain.

Clinical characteristics.

Indications.

Moderate to severe Alzheimer's disease.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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 apply to ketamine and dextromethorphan. One published report also indicated a potential risk of combining memantine with phenytoin.

The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when used concomitantly with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant administration of memantine with the muscle relaxants dantrolene or baclofen may modify their effects, possibly necessitating dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cation transport system as amantadine, may also potentially interact with memantine, leading to a potential risk of increased plasma levels of memantine.

Concomitant administration of memantine with hydrochlorothiazide (HCTZ) or any combination containing HCTZ may lead to decreased serum levels of HCTZ.

There have been reports of isolated cases of increased international normalized ratio (INR) in patients taking warfarin who were treated with memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly with memantine.

In pharmacokinetic studies in healthy volunteers, no significant interaction effects were observed between memantine and glimepiride/metformin, donepezil, or galantamine.

Memantine in vitro is not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase.

Special precautions for use.

Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizures, as well as patients with risk factors for developing epilepsy.

Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may occur more frequently or be more pronounced.

Certain factors that may increase urinary pH may necessitate careful patient monitoring. Such factors include significant dietary changes, for example switching from a meat-rich diet to a vegetarian diet, or intensive use of antacid gastric medications. In addition, urinary pH may increase in conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.

In most clinical trials, patients who had recently experienced myocardial infarction, patients with decompensated congestive heart failure (NYHA class III–IV), and those with uncontrolled arterial hypertension were excluded from participation. Therefore, only limited relevant data are available, and careful monitoring is required for patients with these conditions.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

There are no data on the effects of memantine when used during pregnancy. Animal studies indicate a possibility of delayed intrauterine growth at exposure levels equal to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy, except in cases where clearly and explicitly necessary.

It is unknown whether memantine is excreted in breast milk, although this is possible due to the lipophilic nature of the substance. Women taking memantine should avoid breastfeeding.

Fertility

No negative effects of memantine on fertility in men or women have been observed.

Ability to affect reaction speed when driving or operating machinery.

Moderate to severe Alzheimer's disease typically impairs the ability to drive a car and operate other machinery. Furthermore, memantine may have a slight or moderate influence on the ability to drive vehicles or operate machinery. Therefore, outpatients should exercise particular caution when performing the aforementioned activities.

Dosage and Administration

Treatment should be initiated and supervised by a physician. Therapy should only be initiated if a caregiver is available who will regularly monitor the patient’s intake of the medication.

The tablets should be taken once daily at the same time each day. The tablets may be taken with or without food.

Adults

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the maintenance dose should be established by gradually increasing the dosage by 5 mg per week over the first 3 weeks as follows:

Week 1 (days 1–7):
Take ½ tablet (5 mg once daily) for one week;

Week 2 (days 8–14):
Take 1 tablet (10 mg once daily) for one week;

Week 3 (days 15–21):
Take 1½ tablets (15 mg once daily) for one week;

Starting from week 4:
Take 2 tablets (20 mg once daily) every day.

The recommended maintenance dose is 20 mg daily.

The duration of treatment is determined individually by a physician experienced in the diagnosis and treatment of Alzheimer’s disease. Tolerance and dosage of memantine should be regularly evaluated, preferably within three months after initiation of treatment. Thereafter, the clinical effect of memantine and the patient’s response to treatment should be regularly assessed according to current clinical guidelines. Maintenance therapy may be continued as long as a favorable therapeutic effect and good tolerability are maintained. Discontinuation of memantine treatment should be considered if therapeutic benefit is lost or if tolerability deteriorates.

Elderly patients

Based on clinical trial data, the recommended dose for patients aged 65 years and older is 20 mg daily (2 tablets of 10 mg once daily), as described above.

Renal impairment

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), dose reduction is not 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 daily according to the standard titration schedule if no adverse reactions occur 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.

Hepatic impairment

For patients with mild to moderate hepatic impairment (Child Pugh A, B), dose adjustment is not required. There is no data available on the use of memantine in patients with severe hepatic impairment. Memantine is not recommended in patients with severe hepatic impairment.

Children

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

Overdose

Experience is limited.

Symptoms

Significant overdoses (200 mg and 105 mg daily for 3 days, respectively) were either associated with symptoms of increased fatigue, weakness, and/or diarrhea, or were asymptomatic. Following overdoses of up to 140 mg or with an unknown dose, symptoms of central nervous system disturbances (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal symptoms (vomiting, diarrhea) were observed.

In the most severe known case of overdose, a patient survived after oral ingestion of a total dose of 2000 mg of memantine and experienced central nervous system disturbances (coma lasting 10 days, followed by diplopia and agitation). The patient received symptomatic treatment and plasmapheresis and recovered fully without any permanent sequelae.

In another case of massive overdose (400 mg of memantine orally), the patient also survived and recovered. The patient experienced central nervous system disturbances such as restlessness, psychosis, visual hallucinations, seizure readiness, somnolence, stupor, and unconsciousness.

Treatment

Treatment is symptomatic; there is no specific antidote. Standard clinical procedures to remove the active substance from the body should be applied, such as gastric lavage, activated charcoal, urinary acidification, and forced diuresis.

In cases of excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Adverse Reactions

During clinical trials of memantine involving patients with mild to severe dementia (1784 patients received Abixa and 1595 received placebo), the overall incidence of adverse events was similar to that observed with placebo, and adverse events were generally mild to moderate in severity.

The most common adverse reactions observed more frequently in patients treated with 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%), somnolence (3.4% vs. 2.2%), and hypertension (4.1% vs. 2.8%).

The adverse reactions listed below, observed during clinical trials and post-marketing use, are classified by frequency as follows: 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), and not known (cannot be estimated from available data).

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

2Spontaneously reported cases during clinical use.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have been reported during clinical use of memantine.

Shelf life.
4 years.

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

Packaging.
14 tablets per blister pack, 2 blisters per cardboard box.

Prescription status.
Prescription only.

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

Manufacturer's address and place of business.
Ottiliavej 9, 2500 Valby, Denmark / Ottiliavej 9, 2500 Valby, Denmark.