Consumer medicine information

Ebixa

Memantine hydrochloride

BRAND INFORMATION

Brand name

Ebixa

Active ingredient

Memantine hydrochloride

Schedule

What is in this leaflet

This leaflet contains answers to some common questions about Ebixa.

It does not contain all the information that is known about Ebixa. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risk of you using this medicine against the benefits he/she expects it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Ebixa is used for

Ebixa is used to treat moderately severe to severe Alzheimer's disease (AD). AD can be described as a general decline in all areas of mental ability.

Ebixa belongs to a group of medicines called N-methyl-D-aspartate (NMDA) receptor antagonists. It is thought to work by protecting NMDA receptors in the brain against high levels of the chemical glutamate, which could be the cause of brain degeneration. NMDA receptors are involved in the transmission of nerve signals within the brain, e.g. in learning and memory.

Ebixa should improve your thinking capacity and your ability to remember.

Your doctor, however, may prescribe Ebixa for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you. This medicine is only available with a doctor's prescription.

Ebixa is not addictive.

Before you take it

When you must not take it

Do not take Ebixa if you are allergic to it or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, or rash, itching or hives on the skin.

Do not take Ebixa if you have a seizure disorder or any history of seizures (fits or epilepsy).

Do not take it after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well. The expiry date refers to the last day of the month.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if:

you have allergies to any other substances such as foods, preservatives or dyes.
you are pregnant or intend to become pregnant.

Ebixa is not recommended to be used during pregnancy. Your doctor will discuss the risks and benefits of using it if you are pregnant.

you are breast-feeding or planning to breast-feed.

It is not known whether Ebixa passes into breast milk. Due to the possibility that their baby might be affected, women taking Ebixa should not breast-feed.

you have, or have had, the following medical conditions:

a history of epileptic seizures or convulsions
kidney problems
severe bladder infection
severe liver problems
heart or blood vessel problems
high blood pressure.

you smoke.

Also tell your doctor if you have recently changed your diet or intend to change your diet substantially, for example if you wish to become a vegetarian. Your doctor may need to adjust the dose.

Tell your doctor if you are hypersensitive to memantine, the active substance in Ebixa.

Do not give Ebixa to a child or adolescent under 18 years old.

If you have not told your doctor about any of the above, tell them before you use Ebixa.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Ebixa may interfere with each other. These include:

medicines used to treat stomach cramps or spasms, or travel sickness (anticholinergics)
atropine, a medicine used in some eye drops
levodopa, bromocriptine, amantadine and other medicines for the treatment of Parkinson's disease
anticonvulsants and barbiturates, used to treat epilepsy or fits
ketamine, an anaesthetic agent
medicines used to treat certain mental and emotional conditions (psychoses or schizophrenia)
dantrolene and baclofen, used to treat leg cramps or to relax muscles
dextromethorphan, contained in cough, cold and flu medicines
quinidine and procainamide, used to treat irregular heart beat
nicotine, contained in patches or gums to treat smoking addiction
cimetidine and ranitidine, used to treat stomach ulcers or reflux
urinary alkalinisers, used to treat urinary tract infection
quinine, a medicine used to treat malaria
warfarin, used to prevent blood clots.

These medicines may be affected by Ebixa, or may affect how well it works. You may need to use different amounts of your medicines, or take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Ebixa.

How to take it

How much to take

The standard dose for this medicine is 20 mg per day.

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight and your response to the medicine.

Your doctor will start you on smaller doses which will be gradually increased for three weeks until the dose is reached where Ebixa works best for you.

Week 1 (5 mg per day)

Take half a 10 mg tablet (pale yellow to yellow).

Week 2 (10 mg per day)

Take one 10 mg tablet (pale yellow to yellow).

Week 3 (15 mg per day)

Take one and a half 10 mg tablets (pale yellow to yellow).

From week 4 onwards (20 mg per day)

Take two 10 mg tablets (pale yellow to yellow) or one 20 mg tablet (pink to grey-red).

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Ebixa may not work as well and your condition may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

Do not chew them.

When to take it

Take Ebixa as a single dose either in the morning or in the evening.

Take Ebixa with or without food.

How long to take it

Continue taking your medicine for as long as your doctor tells you to. Ebixa helps control your condition, but does not cure it. Your doctor will assess your treatment on a regular basis.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.

Do not take a double dose to make up for the dose you have missed.

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Ebixa.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include feeling dizzy, tired or having a headache. You may feel confused and see, feel or hear things that are not there. You could also have a seizure.

While you are taking it

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Ebixa.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking Ebixa, tell your doctor immediately.

Tell your doctor immediately if you are feeling depressed or have any suicidal thoughts. Alzheimer's disease has been associated with depression and thoughts of suicide. All mentions of suicide or violence by a patient must be taken seriously.

If you or someone you know demonstrates suicide-related behaviour while taking Ebixa, contact a health care provider immediately, or even go to the nearest hospital for treatment.

Things you must not do

Do not give the tablets to anyone else, even if they have the same condition as you.

Do not take Ebixa to treat any other complaints unless your doctor tells you to.

Do not stop taking Ebixa, or lower the dosage, without checking with your doctor

Things to be careful of

If you drive a motor vehicle or operate machinery, ask your doctor whether you should continue to do so. Your doctor will discuss with you whether your condition allows you to drive or operate machinery safely. Furthermore, Ebixa may change your reactivity which may make driving or using machinery inappropriate.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits he/she expects it will have for you.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ebixa. It helps most people with moderately severe to severe Alzheimer's disease, but it may have unwanted side effects in a few people.

Tell your doctor if you notice any of the following and they worry you:

tiredness, sleepiness, sleeplessness, or problems sleeping
dizziness or feeling off balance
diarrhoea, vomiting, or nausea
loss of appetite
feeling anxious
conjunctivitis.

These are mild side effects of the medicine.

Ebixa may cause inflammation of the liver and/or changes in liver function tests.

Tell your doctor as soon as possible if you notice any of the following:

swelling of hands, ankles or feet
headache
feeling confused
seeing, feeling or hearing things that are not there
having fixed, irrational ideas that are not shared by others.

These may be serious side effects of Ebixa. You may need urgent medical attention.

If you are an epileptic, Ebixa could increase the chance of a fit occurring.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

serious allergic reaction
(symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, or hives).

This is a very serious side effect. You may need urgent medical attention or hospitalisation.

This side effect is very rare.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep Ebixa tablets in the blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep the medicine in a cool dry place where the temperature stays below 30°C.

Do not store Ebixa or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking the tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Ebixa comes in two types of tablets:

Ebixa 10 mg film-coated tablets - oval, pale yellow to yellow, embossed with 'M' on both sides of the break line; on the other side, '1' and '0' left and right of the break line
Ebixa 20 mg film-coated tablets - oval, pink to grey-red, embossed with '20' on one side and 'MEM' on the other side

A box contains 56 tablets (Ebixa 10 mg) or 28 tablets (Ebixa 20 mg), respectively.

Ingredients

Active ingredient(s):

Ebixa 10 mg tablets - 10 mg memantine hydrochloride (equivalent to 8.31 mg memantine) per tablet
Ebixa 20 mg tablets - 20 mg memantine hydrochloride (equivalent to 16.62 mg memantine) per tablet

Inactive ingredients (10 mg tablets):

microcrystalline cellulose
croscarmellose sodium
hypromellose
iron oxide yellow
macrogol 400
magnesium stearate
colloidal anhydrous silica
titanium dioxide

Ebixa 10 mg tablets do not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Inactive ingredients (20 mg tablets):

microcrystalline cellulose
croscarmellose sodium
hypromellose
iron oxide red
iron oxide yellow
macrogol 400
magnesium stearate
colloidal anhydrous silica
titanium dioxide.

Ebixa 20 mg tablets do not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Note: Ebixa 20mg tablets are not registered for supply in NZ.

Manufacturer/Sponsor

Ebixa is supplied by H. Lundbeck A/S, Denmark.

Distributed in Australia by:

Lundbeck Australia Pty Ltd
1 Innovation Road
North Ryde NSW 2113
Ph: +61 2 8669 1000

Distributed in New Zealand by:

Healthcare Logistics
PO Box 62027
Mt Wellington, Auckland
Ph: +64 9 918 5100

This leaflet was prepared on
26 May 2020

Australian Registration Numbers:

Ebixa tablets

10 mg - AUST R 180400

20 mg - AUST R 156299

"Ebixa" is the registered trademark of H. Lundbeck A/S.

AU-NZ-628310.

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Ebixa

Active ingredient

Memantine hydrochloride

Schedule

1 Name of Medicine

Memantine hydrochloride.

2 Qualitative and Quantitative Composition

Film-coated tablets containing 10 mg memantine hydrochloride.
Film-coated tablets containing 20 mg memantine hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ebixa 10 mg tablets are pale yellow to yellow, oval shaped film-coated tablets with break line and engravings 'M' on both parts right and left of the break line and on the other side, '1' left and '0' right of the break line.
Ebixa 20 mg tablets are pink to grey-red oval biconvex film-coated tablets with '20' embossed on one side and 'MEM' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of the symptoms of moderately severe to severe Alzheimer's disease (see Section 5 Pharmacological Properties; Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Ebixa should be administered once a day and should be taken at the same time every day. Tablets should be taken with a little liquid, with or without food.
The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Adults.

The recommended maintenance dose is 20 mg per day. This is achieved by upward titration of 5 mg per week. The 10 mg tablet is required for titration as follows:
Dose titration.

Week 1 (day 1-7).

The patient should take 5 mg (½ x 10 mg tablet) per day.

Week 2 (day 8-14).

The patient should take 10 mg (1 x 10 mg tablet) per day.

Week 3 (day 15-21).

The patient should take 15 mg (1½ x 10 mg tablets) per day.
Maintenance dose from week 4. The recommended maintenance dose is 20 mg per day.

Children.

The use of Ebixa in children is not recommended.

Hepatic impairment.

In patients with mild or moderate hepatic impairment (Child-Pugh A and Child-Pugh B), no dosage adjustment is required. No data on the use of memantine in patients with severe hepatic impairment is available. Administration of Ebixa is not recommended in patients with severe hepatic impairment.

Renal impairment.

In patients with mildly impaired renal function (creatinine clearance 50-80 mL/min), no dosage adjustment is required.
In patients with moderate renal impairment (creatinine clearance 30-49 mL/min), the daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose can be increased up to 20 mg/day according to the standard titration scheme.
In patients with severe renal impairment (creatinine clearance 5-29 mL/min), the daily dose should be 10 mg per day.

4.3 Contraindications

Ebixa is contraindicated in patients with:
hypersensitivity to either the active ingredient or any of the excipients;
patients with a current seizure disorder or with any history of seizures.

4.4 Special Warnings and Precautions for Use

Risk of seizures.

Memantine is contraindicated in patients with epilepsy. Caution is recommended in patients with a former history of convulsions or patients with predisposing factors for epilepsy.

Patient care.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of dementia. Diagnosis should be made according to current guidelines. Therapy should usually be started only when a caregiver is available who will regularly monitor patient compliance. Treatment with memantine hydrochloride should only be continued where there is a therapeutic benefit to the patient. The clinical benefit should be reassessed on a regular basis.

Ocular toxicity.

Animal studies have reported adverse effects of memantine on the visual system. Dietary administration of memantine to rats for one year was associated with abnormal lysosomal storage in ganglion cells and retinal pigment cells at systemic exposures (plasma AUC) 10-fold anticipated clinical exposure at the recommended dose, while administration for 8 weeks was associated with lens opacity, increased corneal and lens capsular densities, and histological changes in cornea and lens at exposures (plasma AUC) of 20-fold clinical exposure. Oral administration of memantine to dogs with systemic exposures (plasma AUC) of 3-8-fold clinical exposure was associated with corneal clouding/opacity and baboons showed swollen lenticular fibres in the eyes following oral memantine for 3 months at less than clinical exposure.
Specific ophthalmological examinations including slit lamp examinations in a 6-month clinical study with memantine did not disclose any ocular changes in the double blind placebo controlled treatment period. In the following 6 months open label extension period 368 patients underwent eye examinations. At the end of open label treatment, the incidence of cataract (lens previously clear but unclear at end of open label treatment) was reported in 11 out of 197 patients (6%) treated with memantine for 12 months compared to 5 out of 171 patients (3%) who received placebo in the double blind period and then memantine for 6 months (p = 0.3059, Fisher's Exact Test).

Urinary pH.

Some factors that may raise urinary pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubular acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.

Use in renal impairment.

In patients with mildly impaired renal function (creatinine clearance 50-80 mL/min), no dosage adjustment is required. A reduction in dosage is advised for patients with moderate to severe renal impairment (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

In patients with mild or moderate hepatic impairment (Child-Pugh A and Child-Pugh B), no dosage adjustment is required. No data is available for patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration). Administration of Ebixa is not recommended in patients with severe hepatic impairment.

Cardiovascular disease.

In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV) and uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

Use in the elderly.

No dosage adjustment is required.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

NMDA antagonists.

Concomitant use of N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse drug reactions (mainly CNS-related) may be more frequent or more pronounced. There is a risk of pharmacotoxic psychosis when memantine and amantadine are used concomitantly. Both compounds are chemically related NMDA antagonists. The same may be true for ketamine and dextromethorphan.

Drugs affecting the central nervous system.

The mode of action suggests that the effects of L-dopa, dopaminergic agonists (e.g. bromocriptine), anticholinergics and amantadine on the central nervous system may be potentiated.
If barbiturates, neuroleptics, anticonvulsants, dantrolene or baclofen are being given simultaneously, their effect can be modified, possibly necessitating a dose adjustment.
These recommendations are mainly based on theoretical considerations.
In in vitro studies, interactions with reversible acetylcholinesterase inhibitors (donepezil, tacrine) were not seen. In single dose PK studies in young healthy subjects, no relevant drug-drug interaction of memantine with donepezil was observed. Similarly, no relevant effect of memantine on the pharmacokinetics of galantamine was observed in a clinical study in young healthy subjects.
In clinical trials, clinically relevant interactions with aspirin, tocopherol, paracetamol and chloral hydrate were not observed.

Glyburide/metformin.

In single dose PK studies in young healthy subjects, no relevant drug-drug interaction of memantine with glyburide/metformin was observed.

Hepatic enzymes.

Because of its low extent of metabolism by CYP450 isoenzymes, metabolic drug interactions appear unlikely. In vitro interaction investigations using human liver microsomes did not reveal interaction with markers of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A. The only reaction slightly affected by the addition of 10 micromolar memantine was methimazole oxidation (marker of Ziegler's enzyme, a flavin containing monooxygenase).

Highly protein bound drugs.

As memantine is bound to plasma proteins at only 42% to 54%, interactions with highly protein bound drugs (e.g. warfarin) would not be expected.

Warfarin.

In postmarketing experience, isolated cases with international normalised ratio (INR) increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants.

Drugs using the same renal cationic transport system.

In vitro studies to examine potential interactions at renal tubular secretion sites revealed a potential competition with drugs which are secreted via the same basic cation transporter. In rat proximal and distal tubules (in vitro), memantine inhibited renal tubular uptake of amantadine.
Drugs such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels.

Diuretics.

The potential interaction with hydrochlorothiazide/triamterene in humans was also studied. Elderly volunteers received hydrochlorothiazide/triamterene and/or memantine, and the pharmacokinetics of memantine was analysed under steady state conditions. AUC, C_max and T_max values were within the 80-125% bioequivalence limits compared to values obtained for memantine alone. Similarly, memantine had no significant effect on the kinetics of triamterene or its hydroxymetabolite. However, the rate and extent of hydrochlorothiazide bioavailability was reduced by memantine by about 20%. No clinically relevant impact on the pharmacokinetics of memantine or hydrochlorothiazide/triamterene was observed.

Atropine.

Serious interactions between atropine and memantine have been noted in a toxicity study in rats. The interaction with atropine occurred at very high doses of memantine under conditions not relevant to humans treated at therapeutic doses of memantine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not affected by oral administration of memantine to male and female rats prior to and during mating at doses associated with respective systemic exposures (plasma AUC) of twice and 4-fold anticipated clinical exposure at the recommended dose.
(Category B2)
There was no evidence of teratogenicity in rats following oral administration of memantine during the period of organogenesis at estimated exposures (plasma AUC) of up to 4-fold anticipated clinical exposure at the recommended dose. There was also no teratogenicity in rats following oral administration to males prior to and during mating and to females from prior to mating to late gestation or to weaning, with respective estimated systemic exposures (plasma AUC) of twice and 4-fold anticipated clinical exposure. There was no teratogenicity in rabbits following oral administration of memantine during the period of organogenesis at doses up to 25-fold the clinical dose, based on body surface area.
Oral administration of memantine to rats during late gestation and lactation was associated with increased post-implantation loss and transiently reduced neonatal bodyweight at estimated systemic exposures (plasma AUC) of 4-fold anticipated clinical exposure at the recommended dose. It is not known whether memantine is excreted in animal or human milk. Because of the potential for causing toxicity, memantine should be contraindicated in nursing women.

4.7 Effects on Ability to Drive and Use Machines

Moderately severe to severe Alzheimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, Ebixa may change reactivity and, therefore, outpatients should be warned to take special care when driving a vehicle or operating heavy machinery.

4.8 Adverse Effects (Undesirable Effects)

Table 1 gives an overview of the most frequent (≥ 2% for memantine) adverse events (irrespective of causal relationship) that were observed in the trial population with moderately severe to severe dementia.
The following adverse events were reported with memantine at a frequency between 1% and < 2% at an incidence greater than placebo in patients with moderately severe to severe AD: pain, abnormal crying, influenza-like symptoms, leg pain, syncope, dependent oedema, hypertonia (increased muscle tone), gastroenteritis, bradycardia, hyperuricaemia, hypertension, dehydration, dyspnoea, hypokalaemia, arthrosis, angina pectoris, purpura, rash, basal cell carcinoma, cerebrovascular disorder, phlebitis, deep thrombophlebitis, toothache and tooth caries. As in the above table, causality to memantine has not been established.
Adverse events reported with memantine at a frequency between 1% and 2% that occurred at a similar rate to or less than placebo were: weight decrease, oedema, coma, abdominal pain, cardiac arrest, increased ALT, AST and GGT, diabetes mellitus, aggressive reaction, apnoea, rhinitis, abrasion, micturition frequency and leucocytosis.

Treatment emergent adverse drug reactions.

Although no causal relationship to Ebixa treatment has been found, the following adverse events were reported in at least one patient, either from clinical trials or spontaneous reports. All of these events, which are not listed above, either occurred rarely (< 1%) or at an unknown incidence from data originating from spontaneous reports.
Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these events have been reported in patients treated with memantine.

Body as a whole - general disorders.

Fever, increased appetite, increased libido, asthenia, somnolence, tiredness.

Cardiovascular disorders.

Chest pain, hypotension, postural hypotension, rhythm and rate disturbance e.g. atrial fibrillation, QTc prolongation, ischaemic event and sudden death e.g. myocardial infarction. Cardiac failure: in placebo controlled clinical trials of memantine an increase in the incidence rate has been observed in non-serious cases; no difference was seen in fatal or serious cases. Causal relationship to memantine has not been ascertained.

Gastrointestinal system disorders.

Diverticulitis, dyspepsia, haemorrhoids, gastric ulcer, ileus, pancreatitis.

Hepatobiliary disorders.

Hepatitis, elevated liver function test.

Infections and infestations.

Fungal infections.

Metabolic and nutritional disorders.

Bilirubinaemia, aggravated diabetes mellitus, hypernatraemia, hyponatraemia.

Musculoskeletal disorders.

Muscle weakness, myalgia, skeletal pain.

Neurological disorders.

Aphasia, speech disorder, hyperkinesia, dyskinesia, dementia, partial epileptic seizure, convulsions, tremor, extrapyramidal disorder, transient ischaemic attack, vertigo, numbness, paraesthesia, mental status changes, balance disorders.

Platelet, bleeding and clotting disorders.

Embolism.

Psychiatric disorders.

Delusion, nervousness, stupor, excitation/mania, suicide attempt, psychotic reactions.

Renal and urinary disorders.

Acute renal failure, abnormal renal function, renal calculus.

Reproductive disorders.

Menstrual disorder.

Respiratory system disorders.

Atelectasis.

Red blood cell disorders.

Anaemia.

Skin and appendages disorders.

Dermatitis, skin disorder, skin ulceration, bullous eruption, pruritus, increased sweating.

Urinary system disorders.

Cystitis, pyuria, haematuria, urinary retention.

Vascular (extracardiac) disorders.

Cerebrovascular disorder, intracranial haemorrhage, venous thrombosis/thromboembolism (uncommon).

Vision disorders.

Cataract, abnormal vision, glaucoma.

Others.

Tooth disorder, inguinal hernia, sepsis.
The following immune system disorder adverse reaction has been found in clinical studies with Ebixa and since its introduction in the market, at an incidence classified as common (≥ 1/100 to < 1/10): drug hypersensitivity.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

In general, the main therapy for all overdoses is supportive and symptomatic care.

Symptoms.

In the event of accidental overdose, no life-threatening clinical signs and symptoms are expected. The toxic effects observed in early single-dose toxicity studies in animals were consistent with acute, high-dose NMDA receptor-blockage and included ataxia, tremor, prone position, bradypnoea, and amnesia.
In one case of suicidal overdose the patient survived the intake of up to 400 mg memantine showing central nervous effects (e.g. restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor and unconsciousness) which resolved without permanent sequelae.

Treatment.

In the event of overdose, treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at N-methyl-D-aspartate (NMDA) receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine is a rapid, strongly voltage-dependent, uncompetitive NMDA receptor antagonist. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg²⁺ ions and allow continuous influx of Ca²⁺ ions into cells and ultimately neuronal degeneration. Studies suggest that memantine binds more effectively than Mg²⁺ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca²⁺ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate.
In animal models of disturbances in glutamatergic transmission memantine has been shown both to improve learning and to inhibit neurodegeneration at doses achieving plasma levels similar to those seen in clinical use. This in turn may explain the effect of memantine on dementia of the Alzheimer type.
At later stages of dementia, a functional deficit in glutamatergic transmission occurs due to loss of neurones bearing NMDA receptors.
In humans, memantine has not been shown to slow or reverse the neurodegenerative processes of Alzheimer's disease.

Clinical trials.

Two clinical trials in a population of patients suffering from moderately severe to severe dementia showed a beneficial effect of memantine treatment in comparison to placebo over a treatment period of three and six months, respectively. This benefit was measured by the patient's cognitive function, functional capacities (activities of daily living) and by clinical global status. There were no consistent differences between sexes observed in these trials.

6 month study.

A pivotal 6-month multicentre, double-blind, randomised, placebo-controlled study conducted in a population of patients with moderately severe to severe Alzheimer's disease (MMSE 3-14) included a total of 252 outpatients of Asian American, African American and Caucasian background (33% male, 67% female, mean age 76 years). The dosing was 10 mg memantine b.i.d.
Outcomes included assessment of the cognitive domain (using the Severe Impairment Battery (SIB)), the global domain (using the Clinicians Interview-Based Impression of Change (CIBIC-Plus)) and the functional domain (using the modified Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL)).
The efficacy results described are from the ITT dataset (all randomised patients) with the LOCF method (last observation carried forward) as well as the OC (observed cases). Based on the OC analyses, the results of this study met the requirement of the European Union Guideline CPMP/EWP/553/95 for statistically significant improvements in the functional and global endpoints as primary evidence of clinically relevant symptomatic improvement in more advanced forms of Alzheimer's disease. An overview of the results in the most important domains of efficacy is displayed in Table 2.

Memantine was very well tolerated with similar frequency and type of adverse events observed with memantine compared with placebo.

3 month study.

A pivotal 3-month multicentre, double-blind, randomised, placebo-controlled study was conducted in Caucasian patients with moderately severe to severe Alzheimer's disease or vascular dementia (MMSE < 10). In this study a total of 79 nursing home residents (33% male, 67% female, mean age 74 years) had Alzheimer's disease. The dosing used was 10 mg memantine daily.
Outcomes included assessment of the cognitive domain (using the cognitive subscore of the rating scale for geriatric patients (BGP)), the global domain (using the Clinical Global Impression of Change (CGI-C)) and the functional domain (using the subscore care dependency of the BGP).
Despite the small sample size, the results in all of these three domains were statistically significant in favour of memantine (see Table 3). The efficacy results described are from the ITT dataset (all randomised patients) with the LOCF method (last observation carried forward) as well as OC (observed cases).

Memantine was well tolerated, with physicians rating tolerability as 'very good' in 71% of memantine and 69% of placebo treated patients. In the remaining patients, tolerability was assessed as 'good', with the exception of one memantine treated patient where it was assessed as 'moderate'.

5.2 Pharmacokinetic Properties

Absorption.

In humans, complete absorption of memantine with no first pass effect was demonstrated. The absolute bioavailability is approximately 100%. Peak plasma concentration is achieved between 5 and 8 hours. Food tended to slow the rate of memantine absorption but not the extent of absorption. The tablet and drop formulations are bioequivalent.

Distribution.

Daily doses of 20 mg in humans lead to steady state plasma concentrations ranging from 70 to 150 nanogram/mL (0.5-1 micromolar) with large interindividual variations. In healthy volunteers, the pharmacokinetics of memantine were linear over the dose range of 10 to 40 mg.
When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was obtained. The inhibition constant (k_i) of memantine at its site of action in human frontal cortex has been determined to be 0.5 micromolar. In subjects receiving a daily dose of 2 x 10 mg, steady state plasma levels were reached around day 11 and varied between 0.5 and 1.0 micromolar, which leads to CSF levels close to the k_i of memantine.
The volume of distribution is approximately 10 L/kg. Protein binding in humans varied from 42% to 54% and no relationship was observed between plasma memantine concentration and protein binding.

Metabolism.

In humans, memantine is excreted mainly (60-80%) in its unchanged form in urine. Human metabolites are 1-amino-3-hydroxymethyl-5-methyl-adamantane, 3-amino-1-hydroxy-5,7-dimethyl-adamantane and various secondary hydroxylated not yet definitively identified memantine-derivatives; phase II metabolism amounts for up to 10%. The known metabolites do not have any NMDA-antagonistic activity. In view of the minor degree of metabolism, variation with respect to polymorphic metabolism is not anticipated.
In vitro experiments have indicated that memantine is not metabolised by CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4.

Excretion.

Memantine is eliminated predominantly by the kidneys in a monoexponential manner with a terminal half-life of 60 to 100 h. In volunteers with normal kidney function, systemic clearance amounts to 170 mL/min.
In a study on the absorption, metabolism and excretion of orally administered ¹⁴C-memantine, a mean of 84% of the dose was recovered within 20 days, the majority being excreted unchanged renally.
Renal clearance has been shown to depend on the pH of the urine. Under alkaline conditions the renal clearance of unchanged memantine is markedly reduced compared to neutral or acidic urine conditions. This is presumably due to tubular reabsorption of memantine under alkaline conditions.

5.3 Preclinical Safety Data

Genotoxicity.

Memantine did not show any genotoxic potential in assays for gene mutation (bacterial and mammalian cells in vitro) or in clastogenicity assays (human lymphocytes in vitro and mouse bone marrow in vivo).

Carcinogenicity.

Long-term dietary administration of memantine to mice (2 years) and rats (2.5 years), with respective estimated systemic exposures of 9-fold (plasma levels) and 4-8-fold (plasma AUC) the anticipated clinical exposure at the recommended dose, did not reveal any carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ebixa 10 mg tablets contain the following excipients: microcrystalline cellulose, croscarmellose sodium, hypromellose, iron oxide yellow, macrogol 400, magnesium stearate, colloidal anhydrous silica and titanium dioxide.
Ebixa 20 mg tablets contain the following excipients: microcrystalline cellulose croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, macrogol 400, magnesium stearate, colloidal anhydrous silica and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Ebixa 10 mg tablets: Blister packs of 14 and 56 tablets.
Ebixa 20 mg tablets: Blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical name: 1-amino-3, 5-dimethyl-adamantane hydrochloride.
Molecular formula: C₁₂H₂₁N.HCl.
Molecular weight: 215.77.

Chemical structure.

Memantine hydrochloride is a colourless crystalline substance with a bitter taste. The solubility of memantine hydrochloride in water at room temperature is about 3.5%. No polymorphic forms have been detected.

CAS number.

19982-08-2 (free base); 4110-52-1 (hydrochloride salt).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

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Ebixa

Memantine hydrochloride

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Ebixa 10 mg Tablets

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