Consumer medicine information

APO-Memantine

Memantine hydrochloride

BRAND INFORMATION

Brand name

APO-Memantine

Active ingredient

Memantine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Memantine.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about memantine. It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or diabetes educator.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits expected for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Memantine.

It contains the active ingredient, memantine (as memantine hydrochloride).

This medicine 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.

Ask your doctor if you have any questions about why it has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

How it works

Memantine 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.

This medicine should improve your thinking capacity and your ability to remember.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have a seizure disorder or a history of seizures (fits or epilepsy).
  • You are hypersensitive to, or have had an allergic reaction to, memantine or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • a history of convulsions or are at risk of epilepsy
  • kidney problems
  • severe bladder infection
  • liver problems
  • heart or blood vessel problems
  • high blood pressure.
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.
  3. You have recently changed your diet or intend to change your diet substantially, for example if you wish to become a vegetarian.
  4. If you are lactose intolerant, contact your doctor before taking this medicine. The 10mg strength tablet contains lactose.
  5. You are planning to have surgery or an anaesthetic.
  6. You are currently receiving or are planning to receive dental treatment.
  7. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with memantine. 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 or if you smoke
  • 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
  • anticoagulant medications such as warfarin, used to prevent blood clots.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with memantine.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

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 memantine works best for you.

  • Week 1 (5 mg per day):
    Take half a 10mg tablet (white).
  • Week 2 (10 mg per day):
    Take one 10mg tablet (white).
  • Week 3 (15 mg per day):
    Take one and a half 10mg tablet (white).
  • From week 4 onwards (20 mg per day):
    Take two 10mg tablets (white) or one 20mg tablet (pale red).

Do not stop taking your medicine or change your dosage without first checking with your doctor.

When to take it

Swallow the tablets with a full glass of water. Do not chew them.

It does not matter if you take it before, with or after food.

How to take it

Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

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.

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

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 for Australia) for advice. Alternatively, go to the Accident and Emergency Department at your nearest hospital.

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 this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Stop taking your medicine, or lower the dosage, without checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Your doctor will discuss with you whether your condition allows you to drive or operate machinery safely. Furthermore, memantine may change your reactivity which may make driving or using machinery inappropriate.

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 memantine, contact a health care provider immediately, or go to the nearest hospital for treatment.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking memantine or if you have any concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time, they are not.

Tell your doctor if you notice any of the following:

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

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

  • 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
  • depression or suicidal thoughts.

Other side effects not listed above may occur in some people.

Allergic reactions

If you think you are having an allergic reaction to memantine, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take them.

If you take the tablets out of their original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness 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 this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Memantine looks like

10 mg tablets:

White, peanut shaped, biconvex film coated tablet. Engraved "APO" bisect "APO" on one side, "MEM" bisect "10" on the other side.

They are packaged in a blister pack of 56 tablets

Also packaged in blister packs of 14, 30, 50, 100 tablets (not marketed).

Also packaged in bottles of 14, 30, 50, 56 & 1000 tablets (not marketed).

20 mg tablets:

Pale red, oval, biconvex, coated tablet. Engraved "MEM 20" on one side, "APO" on the other side.

They are packaged in a blister pack of 28 tablets

Ingredients

Each tablet contains 10 mg or 20mg of Memantine Hydrochloride, as the active ingredient.

The 10mg tablets also contain the following inactive ingredients:

  • Lactose monohydrate
  • Microcrystalline cellulose
  • Croscarmellose sodium
  • Magnesium stearate
  • Hypromellose
  • hyprolose
  • Macrogol 8000
  • Titanium dioxide.

The 20mg tablets also contain the following inactive ingredients:

  • Microcrystalline cellulose
  • Croscarmellose sodium
  • Methylcellulose
  • Magnesium stearate
  • Hypromellose
  • hyprolose
  • Macrogol 8000
  • Titanium dioxide
  • Iron oxide red
  • Iron oxide yellow.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

The 10mg tablets contains lactose.

Australian Registration Numbers

APO-Memantine 10 mg tablets blister pack:
AUST R 159582.

APO-Memantine 10 mg tablets bottles:
AUST R 159576.

APO-Memantine 20 mg tablets blister pack:
AUST R 207782.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are the registered trade marks of Apotex Inc.

This leaflet was last updated in: August 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

APO-Memantine

Active ingredient

Memantine hydrochloride

Schedule

S4

 

1 Name of Medicine

Memantine hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 10 mg or 20 mg memantine hydrochloride as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Memantine 10 mg tablets.

White, peanut shaped, biconvex film coated tablet. Engraved "APO" bisect "APO" on one side, "MEM" bisect "10" on the other side.

APO-Memantine 20 mg tablets.

Pale red, oval, biconvex, film coated tablet. Engraved "MEM 20" on one side, "APO" 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

APO-Memantine tablets are intended for oral administration.

Dosage.

Memantine tablets should be administered once a day and should be taken at the same time every day 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 guideline. 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 memantine 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 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: hypersensitivity to either the active ingredient or any of the excipients (see Section 6.1 List of Excipients); 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 to 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 months 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 are available for patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration). Administration of memantine 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.

Lactose intolerance.

The 10 mg tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not take this medicine.

Use in the elderly.

No data available.

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, 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 10 microM 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, Cmax and Tmax 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 postimplantation 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, 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 (≥ 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, tooth ache 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 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 incidence rate has been observed in nonserious 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 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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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 131126 (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 patients' 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 6 month multicenter, double blind, randomised, placebo controlled study conducted in a population of patients suffering from moderately severe to severe Alzheimer's Disease (MMSE 3-14). 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 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 3 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 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 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 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 (60-80%) 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 hours. 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 to 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

The 10 mg tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose, hyprolose, macrogol 8000, titanium dioxide.
The 20 mg tablet contains the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, methylcellulose, magnesium stearate, hypromellose, hyprolose, macrogol 8000, titanium dioxide, iron oxide red, iron oxide yellow.

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

APO-Memantine 10 mg tablets.

Blister pack (Clear PVC/PVDC/Aluminium) of 14, 30, 50, 56 and 100 tablets: AUST R 159582.
Bottle (white, round HDPE bottle with white child-resistant cap) of 14, 30, 50, 56 and 1000 tablets: AUST R 159576.

APO-Memantine 20 mg tablets.

Blister pack (Clear PVC/PVDC/Aluminium or PVC/Aclar film/Aluminium) of 28 tablets: AUST R 207782.
APO and APOTEX are the registered trade marks of Apotex Inc.
Not all strengths, pack types and/or pack sizes may be available.

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.


Chemical Name: 1-amino-3, 5-dimethyl-adamantane hydrochloride.
Molecular Formula: C12H21N.HCl.
Molecular Weight: 215.77.

CAS number.

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

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes