Consumer medicine information

Memanxa

Memantine hydrochloride

BRAND INFORMATION

Brand name

Memanxa

Active ingredient

Memantine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Memanxa.

What is in this leaflet

This leaflet answers some common questions about MEMANXA.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking MEMANXA against the benefits they expect it will have for you.

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

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

What MEMANXA is used for

MEMANXA is used to treat the symptoms of moderately severe to severe Alzheimer’s Disease (AD). AD can be described as a general decline in all areas of mental ability.

MEMANXA belongs to a group of medicines called N-methyl-D-aspartate (NMDA) receptor antagonists. It is thought to work by protecting NDMA 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, for example in learning and memory.

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

This medicine is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take MEMANXA if you are allergic to medicines containing memantine or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take MEMANXA if you have:

  • severe kidney problems
  • a seizure disorder or any history of seizures (fits or epilepsy).

Do not take this medicine if the expiry date (Exp.) printed on the pack has passed.

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

Do not give your medicine to children. The safety and effectiveness in children has not been established.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant. MEMANXA is not recommended for use during pregnancy. Your doctor will discuss the risks and benefits of taking this medicine while pregnant.

Tell your doctor if you are breastfeeding or wish to breastfeed. It is not known whether MEMANXA passes into breast milk. It is not recommended for women taking this medicine to breastfeed as it is possible their baby may be affected.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • a history of epileptic seizures or convulsions
  • kidney problems
  • severe bladder infection
  • liver problems
  • problems with the heart or blood vessels
  • high blood pressure.

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 smoke or are using nicotine patches or replacement therapy.

If you have not told your doctor about any of the above, tell them before you start taking MEMANXA.

Taking other medicines

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

Some medicines may be affected by MEMANXA, or may affect how well it works. These include:

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

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking MEMANXA.

How to take it

How much to take

The usual dose is 20 mg per day. Your doctor will tell you how many tablets you need to take each day and when to take them. This depends on your condition, your weight and your response to the medicine.

When you start taking MEMANXA, your doctor will start you at a low dose and gradually increase it until the dose that works for your condition is reached.

The usual starting dose is 5 mg (half a tablet) once a day for the first week.

In the second week this is increased to 10 mg (one tablet) once a day.

In the third week the dose is increased to 15 mg (one and a half tablets) once a day.

From the fourth week on, the recommended dose is 20 mg (two tablets) once a day.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take it

Swallow the tablets with a glass of water.

MEMANXA can be taken with or without food.

If you forget to take it

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

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

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.

How long to take it for

Keep taking MEMANXA for as long as your doctor recommends.

This medicine helps to control your condition, but it does not sure it.

Your doctor should assess your treatment on a regular basis.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much MEMANXA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much MEMANXA, you may feel dizziness, tired or have a headache. You may also feel confused and see, hear or feel things that are not there.

While you are taking it

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking MEMANXA.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking MEMANXA.

If you become pregnant while taking this medicine, tell your doctor immediately. If you are a woman of childbearing age, you should avoid becoming pregnant while taking it.

Visit your doctor regularly so they can check on your progress.

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

If you or some-one you know demonstrates suicide-related behaviour while taking this medicine, contact a health care provider immediately, or even got to the nearest hospital for treatment.

Things you must not do

Do not use this medicine to treat any other conditions unless your doctor tells you to.

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

Do not stop taking it or lower the dosage without checking with your doctor.

Things to be careful of

If you drive a motor vehicle or operate machinery you should ask your doctor whether it is safe to do so. Your doctor will discuss whether your condition allows you to drive and use machines safely.

MEMANXA may also change your reactivity, thus making you less able to drive and use machines.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MEMANXA.

Like all other medicines, it may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

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

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

These side effects are usually mild.

MEMANXA 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, hearing or feeling things that are not real
  • having fixed, irrational ideas that are not shared by others.

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

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 skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath).

This is a very serious side effect.

You may need urgent medical attention or hospitalisation. Allergic reactions are very rare.

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

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

After using it

Storage

Keep MEMANXA 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.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store this, or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

MEMANXA is an oval white scored tablet.

Each pack contains 56 tablets.

Ingredients

The active ingredient in MEMANXA is memantine hydrochloride. Each tablet contains 10 mg of memantine hydrochloride.

The tablets also contain:

  • microcrystalline cellulose
  • lactose monohydrate
  • magnesium stearate
  • hypromellose
  • macrogol 6000
  • titanium dioxide.

The tablets contains sugars as lactose. The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

Australian registration numbers:
MEMANXA - AUST R 152754

Date of preparation:
March 2023

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Memanxa

Active ingredient

Memantine hydrochloride

Schedule

S4

 

1 Name of Medicine

Memantine hydrochloride.

2 Qualitative and Quantitative Composition

Memanxa tablets contain 10 mg of memantine hydrochloride.

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Memanxa tablets are oval, white scored tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of the symptoms of moderately severe to severe Alzheimer's disease (see Section 5.1 Pharmacodynamic Properties; Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Memantine tablets 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.

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 tablet) per day.
Maintenance dose from week 4. The recommended maintenance dose is 20 mg per day.

Children.

The use of memantine tablets 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 memantine tablets 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

Memantine is contraindicated in patients with:
renal impairment (patients with a creatinine clearance less than or equal to 50 mL/minute);
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) tenfold anticipated clinical exposure at the recommended dose, while administration for eight 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 three to eightfold clinical exposure was associated with corneal clouding/opacity and baboons showed swollen lenticular fibres in the eyes following oral memantine for three months at less than clinical exposure.
Specific ophthalmological examinations including slit lamp examinations in a six months clinical study with memantine did not disclose any ocular changes in the double blind placebo controlled treatment period. In the following six month 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 six 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.

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 hepatic impairment.

In patients with mild or moderate hepatic function (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 memantine tablets is not recommended in patients with severe hepatic impairment.

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 the elderly.

No data available.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

N-methyl-D-aspartate 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.

Medicines 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, donepezil, 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 memantine 10 microM was methimazole oxidation (marker of Ziegler's enzyme, a flavin containing monooxygenase).

Highly protein bound medicines.

As memantine is bound to plasma proteins at only 42 to 54%, interactions with highly protein bound medicines (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.

Medicines 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, Cmax and Tmax values were within the 80 to 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 two and fourfold 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 fourfold 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 two and fourfold 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 postimplantation loss and transiently reduced neonatal bodyweight at estimated systemic exposures (plasma AUC) of fourfold 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 breastfeeding 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. Further, memantine 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 (greater than or equal to 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 Alzheimer's disease: pain, abnormal crying, influenza-like symptoms, leg pain, syncope, dependent oedema, cardiac failure, 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 Table 1, 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 memantine 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 postmarketing 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 disturbances, 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. Uncommon: hallucinations (mainly observed in patients with severe Alzheimer's disease).

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 memantine 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 memantine 400 mg 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 while 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 could be 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.

Six month study.

A six month multicentre, double blind, randomised, placebo controlled study has been performed in a population of patients suffering from moderately severe to severe Alzheimer's disease (MMSE 3 to 14). A total of 252 outpatients of Asian American, African American and Caucasian background were included (33% male, 67% female, mean age 76 years). The dosing was memantine 10 mg b.i.d (twice daily).
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.

Three month study.

A three month multicentre, double blind, randomised, placebo controlled study has been performed in Caucasian patients suffering from 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 memantine 10 mg 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 doctors 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 five and eight hours. Food tended to slow the rate of memantine absorption but not the extent of absorption.

Distribution.

Daily doses of 20 mg in humans lead to steady state plasma concentrations ranging from 70 to 150 nanogram/mL (0.5 to 1 microM) 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 (ki) of memantine at its site of action in the human frontal cortex has been determined to be 0.5 microM. 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 microM, which leads to CSF levels close to the ki 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 to 80%) in its unchanged form in urine. Human metabolites are 1-amino-3-hydroxymethyl-5- methyl-adamantane, 3-amino-1-hydroxy-5,7-dimethyladamantane 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, variations 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 hours. In volunteers with normal kidney function, systemic clearance amounts to 170 mL/minute.
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.

Reduced renal function.

In elderly volunteers with impaired renal function (creatinine clearance down to about 50 mL/minute), a significant correlation was observed between creatinine clearance and total renal clearance of memantine. Total renal clearance substantially exceeded renal clearance by filtration thus indicating that a significant part of renal clearance is due to tubular secretion processes.

Reduced hepatic function.

There are no pharmacokinetic data in patients with hepatic impairment.

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 ninefold (plasma levels) and four to eightfold (plasma AUC) the anticipated clinical exposure at the recommended dose, did not reveal any carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Memanxa tablets contain the following excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, hyprolose, macrogol 6000 and titanium dioxide.
The tablets are gluten free.

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 25°C.

6.5 Nature and Contents of Container

Memanxa 10 mg tablets are available in blister pack (PVC-PVDC/Al) and bottle (HDPE)* of 56.
*Bottles are not currently marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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.

Chemical structure.

The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyl-adamantane hydrochloride. Its structural formula is:
Molecular formula: C12H21N.HCl. Molecular weight: 215.77.

CAS number.

Cas No.: 4110-52-1.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine - Schedule 4.

Summary Table of Changes