Consumer medicine information

APO-Galantamine MR Capsules

Galantamine

BRAND INFORMATION

Brand name

APO-Galantamine MR

Active ingredient

Galantamine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Galantamine MR Capsules.

SUMMARY CMI

APO-GALANTAMINE MR

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APO-GALANTAMINE MR?

APO-GALANTAMINE MR contains the active ingredient galantamine (as hydrobromide). APO-GALANTAMINE MR is used to treat mild to moderately severe dementia of the Alzheimer's type.

For more information, see Section 1. Why am I using APO-GALANTAMINE MR? in the full CMI.

2. What should I know before I use APO-GALANTAMINE MR?

Do not use if you have ever had an allergic reaction to galantamine hydrobromide or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APO-GALANTAMINE MR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-GALANTAMINE MR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-GALANTAMINE MR?

APO-GALANTAMINE MR modified release capsules should be taken once a day, preferably with food. Be sure to drink plenty of liquids during your treatments to keep yourself hydrated. The capsule must be swallowed whole. The contents should not be crushed or sprinkled on food.

More instructions can be found in Section 4. How do I use APO-GALANTAMINE MR? in the full CMI.

5. What should I know while using APO-GALANTAMINE MR?

Things you should do
  • Remind any doctor, dentist or pharmacist, surgeon, or anesthetist you visit that you are using APO-GALANTAMINE MR.
  • Always follow your doctor's instructions carefully.
  • Tell your doctor if you become pregnant while taking this medicine.
  • If you are about to start taking a new medicine, tell you doctor and pharmacist that you are taking APO-GALANTAMINE MR.
Things you should not do
  • Do not use APO-GALANTAMINE MR to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Driving or using machines
  • Alzheimer's disease may reduce your ability to drive or operate machinery.
  • APO-GALANTAMINE MR may cause dizziness or drowsiness in some people, especially during initial treatment.
  • Discuss with your doctor whether it is safe for you to drive or operate machinery.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your capsules in the pack until it is time to take them.
  • Keep it in a cool dry place where the temperature is below 25°C.

For more information, see Section 5. What should I know while using APO-GALANTAMINE MR? in the full CMI.

6. Are there any side effects?

Nausea, vomiting, diarrhea, stomach pain or discomfort, indigestion, difficulty swallowing, weakness, muscle cramps, numbness and tingling that begins in the lower extremities, leg camps, tingling in the hand or feet, ringing in the ears, runny or blocked nose, dehydration (sometimes severe), thirst, lack of fluids, hallucinations, mood changes such as agitation or aggressive feelings, feeling depressed or having thoughts of harming yourself, dizziness, light-headedness, slow, fast or irregular heartbeat, high blood pressure, yellowing of the skin and eyes, increased sweating, fever, trembling or shakiness, loss of appetite, weight loss, drowsiness, tiredness, weakness, feeling unwell, confusion, visual disturbances, trouble sleeping, headache, fits (seizures), pain or tightness in the chest, skin rashes or hives, swelling of the face, lips, tongue or other parts of the body wheezing or difficulty breathing, fainting.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-GALANTAMINE MR

Active ingredient(s): galantamine hydrobromide

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-GALANTAMINE MR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APO-GALANTAMINE MR.

Where to find information in this leaflet:

1. Why am I using APO-GALANTAMINE MR?
2. What should I know before I use APO-GALANTAMINE MR?
3. What if I am taking other medicines?
4. How do I use APO-GALANTAMINE MR?
5. What should I know while using APO-GALANTAMINE MR?
6. Are there any side effects?
7. Product details

1. Why am I using APO-GALANTAMINE MR?

APO-GALANTAMINE MR contains the active galantamine (as hydrobromide).

APO-GALANTAMINE MR is used to treat mild to moderately severe dementia of the Alzheimer's type.

The symptoms of Alzheimer's disease include confusion, memory loss or other changes in behaviour. As the disease progresses, patients find it more and more difficult to carry out their normal daily activities.

The symptoms of Alzheimer's disease are thought to be due to lack of acetylcholine, a substance which transmits messages between brain cells. APO-GALANTAMINE MR increases the amount of this substance to help improve or stabilise the symptoms and therefore slow the progress of Alzheimer's disease.

Your doctor may have prescribed APO-GALANTAMINE MR for another reason.

Ask your doctor if you have any questions about why APO-GALANTAMINE MR has been prescribed for you.

2. What should I know before I use APO-GALANTAMINE MR?

Warnings

Do not use APO-GALANTAMINE MR if:

  • you are allergic to galantamine hydrobromide 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; rash, itching or hives on the skin
    - Always check the ingredients to make sure you can use APO-GALANTAMINE MR.
  • severe liver and/or kidney disease.
  • the package is torn or shows signs of tampering.
  • the expiry date (EXP) printed on the pack has passed or if the tablets appear damaged in some way.

Check with your doctor if you have, or have had any of the following health problems:

  • liver and/or kidney disease
  • heart problems
  • stomach ulcers
  • brain disorders, such as Parkinson's disease, fits
  • problems controlling movements of the body or limbs (extrapyramidal disorder)
  • breathing disorders, such as asthma, pneumonia
  • recent gut or bladder surgery
  • difficulties in passing urine
  • attacks of sudden abdominal pain
  • low potassium levels in the blood – weakness, muscle cramps, numbness and tingling that begins in the lower extremities.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given APO-GALANTAMINE MR.

Your doctor will advise you whether or not to take APO-GALANTAMINE MR or if you need to adjust the dose or alter your treatment. Since there may be other related conditions that APO-GALANTAMINE MR is not intended to treat, you should verify with your doctor that you are taking it for the treatment of mild to moderate Alzheimer's disease.

Initial results from clinical trials in patients with mild cognitive impairment of various causes have shown a slightly higher mortality rate (higher death rate) in those taking APO-GALANTAMINE MR than those taking a placebo (a pill without an active ingredient which is commonly used in clinical trials as a reference for comparison). The reason for this difference is currently not known and may just be due to chance. There is no evidence of increased risk of death for those with mild to moderately severe Alzheimer's disease taking APO-GALANTAMINE MR.

Check with your doctor if you take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Surgery

Check with your doctor if you are planning to undergo surgery which will require anesthesia.

3. What if I am taking other medicines?

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

In particular, tell your doctor or pharmacist if you are taking any other the following:

  • anticholinergic medicines (used to prevent travel sickness, relieve stomach cramps, spasms or diarrhea)
  • cholinergic medicines (e.g. bethanecol and certain medicines used during surgery)
  • medicines used to treat Parkinson's disease
  • medicines for certain heart problems (such as digoxin, quinidine) or to help lower blood pressure (such as class of medicine called beta blockers)
  • medicines used for breathing problems
  • certain medicines used to treat fungal infections (such as ketoconazole) or bacterial infections (such as erythromycin)
  • certain medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • certain medicines used to treat depression obsessive compulsive disorder (OCD), panic disorder or anxiety (such as paroxetine fluoxetine, fluvoxamine).

These medicines may be affected by APO-GALANTAMINE MR or may affect how well it works. Your doctor or pharmacist can tell you what to do if you take any of these medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-GALANTAMINE MR.

4. How do I use APO-GALANTAMINE MR?

How much to take / use

APO-GALANTAMINE MR modified release capsules should be taken once a day, preferably with food. Be sure to drink plenty of liquids during your treatments to keep yourself hydrated. The capsule must be swallowed whole. The contents should not be crushed or sprinkled on food.

Adults

The dose of APO-GALANTAMINE MR is gradually increased to the most suitable dose. The necessary dosage steps should be determined by your doctor to suit your needs.

The following scheme is an example of how your doctor may increase your dose:

  • Start with 8 mg a day
  • After 4 weeks of treatment, raise the dose to 16 mg a day
  • After at least another 4 weeks of treatment, raise the dose to 24 mg a day.

For long-term treatment, up to 24 mg a day is usually suitable but your doctor will determine the dose that is best for you.

If treatment is discontinued for more than several days, tell your doctor.

Your doctor will need to restart your treatment at the lowest dose. This will minimize the chance of experiencing side effects.

Children

APO-GALANTAMINE MR is not recommended for children.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

When to take / use APO-GALANTAMINE MR

APO-GALANTAMINE MR modified release capsules should be used once daily in the morning, preferably with food.

If you forget to use APO-GALANTAMINE MR

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 it as soon as you remember, and then go back to taking it as you normally would.

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

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

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

If you use too much APO-GALANTAMINE MR

If you think that you have used too much APO-GALANTAMINE MR, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much APO-GALANTAMINE MR, you may experience vomiting or a feeling that you want to vomit, nausea, stomach cramps, excessive production of saliva, tears or sweat, dry mouth, loss of control of your bladder or bowels, a slow or fast heartbeat, low blood pressure, dizziness, light-headedness, muscle weakness or twitching, fits, breathing difficulties, chest pain, hallucinations or you may collapse.

5. What should I know while using APO-GALANTAMINE MR?

Things you should do

  • Always follow your doctor's instructions carefully.
  • Tell your doctor if you become pregnant while taking this medicine.
  • If you are about to start taking a new medicine, tell you doctor and pharmacist that you are taking APO-GALANTAMINE MR.

Remind any doctor, dentist or pharmacist you visit that you are using APO-GALANTAMINE MR. You should tell your surgeon or anaesthetist if you are having surgery.

Things you should not do

  • Do not use APO-GALANTAMINE MR to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-GALANTAMINE MR affects you.

  • Alzheimer's disease may reduce your ability to drive or operate machinery.
  • APO-GALANTAMINE MR may cause dizziness or drowsiness in some people, especially during initial treatment.
  • Discuss with your doctor whether it is safe for you to drive or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your capsules in the pack until it is time to take them.
  • Keep it in a cool dry place where the temperature is below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking APO-GALANTAMINE MR, or your medicine has passed its expiry date, ask your pharmacist what to do with any of the medicine which may be left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • nausea, vomiting or diarrhoea
  • stomach pain, discomfort. indigestion or difficulty swallowing
  • tiredness or weakness
  • muscle cramps, spasms or trembling
  • numbness and tingling or burning sensations
  • headache
  • ringing in the ears
  • blurred vision
  • dehydration (sometimes severe); thirst or lack of fluids
  • hallucinations (seeing, feeling or hearing things that are not there)
  • feeling depressed or having thoughts of harming yourself
  • low blood pressure – dizziness or light-headedness
  • high blood pressure
  • slow, fast or irregular heart beat
  • increased sweating
  • changes in taste
  • loss of appetite or weight loss
  • fainting or falling (sometimes resulting in injury)
  • problems controlling movements of the body or limbs (extrapyramidal disorder)
  • abnormal liver test results
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • yellowing of the skin and eyes, light coloured bowel motions, or dark coloured urine
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhea
  • fainting, especially if you have a slow or irregular heart beat
  • flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters
  • widespread severe rash with peeling skin which may be accompanied by fever, flu-like symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome Acute generalized exanthematous pustulosis)
  • fits (seizures)
  • pain or tightness in the chest
  • symptoms of stroke which can include collapsing, numbness or weakness of arms or legs, headache, dizziness and confusion, visual disturbances, difficulty swallowing, slurred speech and loss of speech.
  • symptoms of an allergic reaction including 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Always inform your doctor about any unwanted side effect that has occurred while taking this medicine as some of these effects may be due to the Alzheimer's disease.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What APO-GALANTAMINE MR contains

Active ingredient
(main ingredient)		Each capsule contains 8, 16 or 24 mg of galantamine (as hydrobromide) as the active ingredient.
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • hypromellose
  • ethylcellulose
  • magnesium stearate
  • titanium dioxide
  • gelatin

In addition, the 16 mg capsules contain

  • iron oxide red

In addition, the 24 mg capsules contain

  • indigo carmine
  • erythrosine
  • iron oxide red
  • iron oxide yellow.
Potential allergens
  • contains traces of galactose
  • May contain traces of sulfites

Do not take this medicine if you are allergic to any of these ingredients.

APO-Galantamine MR modified release capsule does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

What APO-GALANTAMINE MR looks like

APO-Galantamine MR modified release capsules are available in blister packs of 28 capsules:

  • 8 mg modified release capsules: White opaque capsules containing one round biconvex tablet (AUST R 182030).
  • 16 mg modified release capsules: Flesh opaque capsules containing two round biconvex tablets (AUST R 182041).
  • 24 mg modified release capsules: Orange opaque capsules containing three round biconvex tablets. (AUST R 182034).

* Not all strengths, pack types and/or pack sizes may be available.

Who distributes APO-GALANTAMINE MR

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

www.arrotex.com.au

This leaflet was prepared in January 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

APO-Galantamine MR

Active ingredient

Galantamine

Schedule

S4

 

1 Name of Medicine

Galantamine (as hydrobromide).

2 Qualitative and Quantitative Composition

Galantamine modified release capsules contain the active galantamine hydrobromide, equivalent to 8, 16, 24 mg galantamine base.

Excipients with known effect.

Contains traces of galactose.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Galantamine 8 mg modified release capsules.

Opaque white-white, size 2 hard gelatin capsules containing one round biconvex tablet.

APO-Galantamine 16 mg modified release capsules.

Opaque flesh-flesh, size 2 hard gelatin capsules containing two round biconvex tablets.

APO-Galantamine 24 mg modified release capsules.

Opaque orange-orange, size 2 hard gelatin capsules containing three round biconvex tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Galantamine is indicated for the treatment of mild to moderately severe dementia of the Alzheimer type.

4.2 Dose and Method of Administration

APO-Galantamine modified release capsules are intended for oral administration.
Galantamine modified release capsules should be administered once daily in the morning, preferably with food. Ensure adequate fluid intake during treatment. The contents should not be crushed and sprinkled on food. The dose of galantamine should be gradually increased to the maintenance dose to minimise side effects.

Dosage.

Starting dose.

The recommended starting dose is 8 mg a day for four weeks.

Maintenance dose.

The initial maintenance dose is 16 mg a day and patients should be maintained on this dose for at least 4 weeks.
An increase to the maximum recommended maintenance dose of 24 mg a day should be considered after appropriate assessment including evaluation of clinical benefit and tolerability.
There is no rebound effect after abrupt discontinuation of treatment, for example, prior to surgery.

Re-initiation of therapy.

If treatment is interrupted for longer than several days, treatment should be re-initiated with the lowest daily dose and gradually increased to the maximum tolerated dose to achieve the desired clinical effect. The incidence and severity of adverse events are generally related to the higher doses of galantamine. In patients cotreated with ketoconazole or potent inhibitors of cytochrome P450 2D6, dose reductions can be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hepatic impairment.

Plasma levels of galantamine may be increased in patients with moderate to severe hepatic impairment.
In patients with moderately impaired hepatic function, based on pharmacokinetic modelling, dosing should begin with 8 mg every other day for at least one week, preferably taken in the morning. Then dosage should be increased to 8 mg once daily for at least four weeks. In these patients, total daily doses should not exceed 16 mg a day.
In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of galantamine is contraindicated (see Section 4.3 Contraindications).
No dosage adjustment is required for patients with mild hepatic impairment.

Renal impairment.

Plasma levels of galantamine may be increased in patients with moderate to severe renal impairment.
For patients with a creatinine clearance greater than 9 mL/min, no dosage adjustment is required. In patients with severe renal impairment (creatinine clearance less than 9 mL/min), the use of galantamine is contraindicated (see Section 4.3 Contraindications).

4.3 Contraindications

Galantamine is contraindicated in patients with known hypersensitivity to galantamine hydrobromide or any excipients used in the formulation (see Section 6.1 List of Excipients).
Since no data are available on the use of galantamine in patients with severe hepatic impairment (Child-Pugh score greater than 9) or severe renal impairment (creatinine clearance less than 9 mL/min), galantamine is contraindicated in these populations.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

As with other cholinomimetics, galantamine should be given with caution in the following conditions:

Cardiovascular conditions.

Because of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate, including bradycardia and all types of atrioventricular node block (see Section 4.8 Adverse Effects (Undesirable Effects)). The potential for this action may be particularly important to patients with sick sinus syndrome or other supraventricular cardiac conduction disturbances or who concomitantly use medicines that significantly reduce heart rate (e.g. digoxin and beta-blockers) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Cholinomimetics should therefore be given with caution to patients in the immediate postmyocardial infarction period, who have new onset atrial fibrillation, who have second degree heart block or greater, who have unstable angina pectoris, uncorrected electrolyte disturbance (e.g. hyperkalaemia, hypokalaemia) or congestive cardiac failure, especially NYHA group III-IV. In clinical trials, use of galantamine has been associated with syncope and rarely with severe bradycardia.
There have been reports of QT prolongation in patients using therapeutic doses of galantamine and of torsades de pointes in association with overdose. Galantamine should therefore be used with caution in patients with prolongation of the QT interval, in patients treated with drugs affecting the QT interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gastrointestinal conditions.

Patients at increased risk of developing peptic ulcers (e.g. those with a history of ulcer disease or those predisposed to these conditions), including those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS), should be monitored for symptoms. However, clinical studies with galantamine showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. The use of galantamine is not recommended in patients with gastrointestinal obstruction or recovering from gastrointestinal surgery.

Neurological conditions.

Cholinomimetics are believed to have some potential to cause seizures. Convulsions have been reported with galantamine (see Section 4.8 Adverse Effects (Undesirable Effects)). Seizure activity may also be a manifestation of Alzheimer's disease. An increase in cholinergic tone may worsen Parkinsonian symptoms and symptoms related to extrapyramidal disorders (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing data).

Pulmonary conditions.

Because of their cholinomimetic actions, cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease. Similarly, caution should be exercised in treating patients with active pneumonia.

Genitourinary.

The use of galantamine is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.

Use in hepatic impairment.

Plasma levels of galantamine may be increased in patients with moderate to severe hepatic impairment. In patients with moderately impaired hepatic function, dosage should be adjusted (see Section 4.2 Dose and Method of Administration).
Since no data are available on the use of galantamine in patients with severe hepatic impairment, its use is contraindicated (see Section 4.3 Contraindications).

Use in renal impairment.

For patients with a creatinine clearance greater than 9 mL/min, no dosage adjustment is required. In patients with severe renal impairment (creatinine clearance less than 9 mL/min), the use of galantamine is contraindicated (see Section 4.3 Contraindications).

Use in other types of dementia.

The benefit of galantamine in patients with other types of dementia or other types of memory impairment has not been demonstrated. Galantamine is indicated for patients with mild to moderately severe dementia of the Alzheimer type.

Mortality in subjects with mild cognitive impairment.

Galantamine is not indicated for individuals with mild cognitive impairment (MCI), i.e. those who demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.
In two randomised placebo controlled trials of 2 years duration in subjects with mild cognitive impairment (MCI), a total of 14 deaths were initially recorded in the double blind period with 13 subjects randomised to galantamine (n = 1026) and 1 randomised to placebo (n = 1022). The relative risk (95% exact confidence interval) was 6.19 (2.17, 17.68). This dataset consists of the number of deaths originally recorded in the double blind period of the 2 studies and up to 30 days after stopping study medicine. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine and placebo deaths appeared to result from various vascular causes (myocardial infarction, stroke and sudden death).
Although the difference in initially recorded mortality between galantamine and placebo treated groups was significant, the results were highly discrepant with other studies of galantamine. Specifically, in these two MCI studies, the initially recorded mortality rate in subjects randomised to placebo was markedly lower than the rate in placebo treated patients in trials of galantamine in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the initially recorded mortality rate in MCI subjects randomised to galantamine was also lower than that observed in galantamine treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n = 6000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no subjects in the placebo group died after 6 months, a highly unexpected finding in this population. Because of this finding a retrieved drop out study was conducted to determine the mortality status of all subjects who participated in the two studies. Mortality status and cause of death where known were collected for subjects who had dropped out of the two studies and hence were not recorded in the initial analysis. Three additional deaths were identified as specified in the protocol; thus 14 deaths in subjects randomised to galantamine and 3 in placebo occurred during the double blind period within up to 30 days of stopping study medicine. The relative risk (95% exact confidence interval) was 4.08 (1.57, 10.57). Information on subsequent treatment or adverse events following dropout was not collected and therefore the data may be subjected to bias. On completion of this study with vital status recorded on greater than 98% of enrolled subjects, a total of 46 deaths were recorded on subjects randomised to placebo compared to 56 deaths recorded with galantamine. The relative risk (95% exact confidence interval) was 1.24 (0.84,1.83).
There is no evidence of an increased risk of mortality in the current approved indication of mild to moderately severe Alzheimer's disease.

Serious skin reactions.

Serious skin reactions (Stevens-Johnson syndrome and acute generalised exanthematous pustulosis) have been reported in patients receiving galantamine (see Section 4.8 Adverse Effects (Undesirable Effects)). It is recommended that patients be informed about the signs of serious skin reactions, and that use of galantamine be discontinued at the first appearance of skin rash.

Weight monitoring.

Patients with Alzheimer's disease lose weight. Treatment with cholinesterase inhibitors, including galantamine, has been associated with weight loss in these patients. During therapy, patient's weight should be monitored.

Use in the elderly.

No data available.

Paediatric use.

Use of galantamine in children is not recommended. No data on the use of galantamine in paediatric patients are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Because of its mechanism of action, galantamine should not be given concomitantly with other cholinomimetics. Galantamine antagonises the effect of anticholinergic medication. As expected with cholinomimetics, a pharmacodynamic interaction is possible with medicines that significantly reduce the heart rate (e.g. digoxin and beta-blockers). Caution should be taken with medicinal products that have potential to cause torsades de pointes. In such cases an ECG should be considered (also see Section 4.4 Special Warnings and Precautions for Use). Galantamine, as a cholinomimetic, is also likely to exaggerate succinylcholine type muscle relaxation during anaesthesia.

Pharmacokinetic interactions.

Inhibition of gastric acid secretion will not impair the absorption of galantamine.
Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine. This may explain why no major interactions were observed.

Other medicines affecting the metabolism of galantamine.

Formal medicine interaction studies showed an increase in galantamine bioavailability of about 40% during coadministration of paroxetine (a potent CYP2D6 inhibitor) and of 30% and 12% during coadministration with ketoconazole and erythromycin (both CYP3A4 inhibitors). Therefore, during initiation of treatment with potent inhibitors of CYP2D6 (e.g. quinidine, paroxetine, fluoxetine or fluvoxamine) or CYP3A4 (e.g. ketoconazole), patients may experience an increase incidence of cholinergic side effects, predominantly nausea and vomiting. Based on tolerability, a reduction of the galantamine maintenance dose can be considered.
Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, at a dose of 10 mg once daily for 2 days followed by 10 mg twice daily for 12 days had no effect on the pharmacokinetics of galantamine 16 mg once daily at steady state.

Effect of galantamine on the metabolism of other medicines.

Therapeutic dose of galantamine (12 mg twice daily) had no effect on the kinetics of digoxin and warfarin. Galantamine did not affect the increase prothrombin time induced by warfarin.
In vitro studies indicated that the inhibition potential of galantamine with respect to the major forms of human cytochrome P450 is very low and is not considered clinically relevant.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Galantamine had no effect on the fertility in rats at plasma AUC0-24h levels 5 times higher than those in humans at the maximum recommended dose.
(Category B1)
No studies are available on the use of galantamine in pregnant women. Galantamine should be used with caution during pregnancy and only if the potential benefit justifies the potential risk to the foetus.
Reproduction studies in pregnant rats and rabbits at respective exposure levels up to 5 and 3 times higher than that in humans at the maximum recommended dose (based on plasma AUC values), did not show any evidence of teratogenic potential. Minor skeletal abnormalities and decreased birthweight were seen at the highest doses in rats.
 It is not known whether galantamine is excreted in human breast milk and no studies have been performed in lactating women. Therefore, women taking galantamine should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. As with other cholinomimetics, galantamine may cause dizziness and somnolence, especially during the first weeks after initiation of treatment. This could affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Double-blind data - adverse reactions reported at ≥ 1% frequency.

The safety of galantamine was evaluated in 6502 subjects with mild to moderately severe dementia of the Alzheimer's type who participated in 8 placebo controlled, double blind clinical trials. The information presented in this section was derived from pooled data.
Adverse reactions reported by ≥ 1% of galantamine treated subjects in these trials are shown in Table 1.
In a randomised, double blind, placebo controlled clinical trial, the safety profile of once daily treatment with galantamine modified release capsules was similar in frequency and nature to that seen with tablets.
Nausea and vomiting, the most frequent adverse drug reactions, occurred mainly during titration periods, lasted less than a week in most cases and the majority of patients had one episode. Prescription of antiemetics and ensuring adequate fluid intake may be useful in these instances.

Double blind and open-label data - adverse reactions reported at < 1% frequency.

In addition to double-blind clinical trials, the safety of galantamine was evaluated in 1454 subjects with mild to moderately severe dementia of the Alzheimer's type who participated in 5 open-label clinical trials.
Additional adverse reactions not reported in Table 1 that occurred in < 1% of galantamine-treated subjects in the double-blind and 5 open-label clinical data sets are listed in Table 2.

Postmarketing data.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during postmarketing experience (Table 3). In each table, the frequencies are provided according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/ 1000 and < 1/100; Rare ≥ 1/10,000 and < 1/1000; Very rare < 1/10,000, including isolated reports.

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 and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the signs of a cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions. Increasing muscle weakness together with tracheal hypersecretions and bronchospasm, may lead to vital airway compromise.
There have been postmarketing reports of torsades de pointes, QT prolongation, bradycardia, ventricular tachycardia and brief loss of consciousness in association with inadvertent overdoses of galantamine. In one case where the dose was known, eight 4 mg tablets (32 mg total) were ingested on a single day. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalisations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalisation. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Treatment.

As in any case of overdose, general supportive measures should be used. In severe cases, anticholinergics, such as atropine, can be used as a general antidote for cholinomimetics, an initial dose of 0.5 to 1.0 mg given intravenously is recommended, with subsequent doses based on the clinical response.
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.

Galantamine is a cholinomimetic with a dual mechanism of action. Galantamine is a reversible inhibitor of the enzyme acetylcholinesterase, and enhances the intrinsic action of acetylcholine on nicotinic receptors.
The cognitive dysfunction (memory, attention, learning) in dementia of the Alzheimer type is related to the profound dysfunction of the cholinergic neurotransmission system in the brain. Galantamine, a tertiary alkaloid, enhances the efficacy of the physiologically available acetylcholine through a dual mechanism of action: acetylcholinesterase inhibition and nicotinic receptor modulation.
Galantamine is a selective, competitive and reversible inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. As a consequence, the breakdown of acetylcholine, released by the remaining healthy brain cells, is slowed down leaving more neurotransmitter available to support normal brain function.
In addition, galantamine enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor. Stimulation of nicotinic receptors has been associated with improved cognitive function and neuroprotection against amyloid induced neurotoxicity. Amyloid peptide is the major component of amyloid plaques, one of the hallmarks of Alzheimer's disease.
Modulation of the nicotinic receptor could also lead to enhanced neurotransmitter release, including the release of acetylcholine.
Animal studies have shown that galantamine effectively increases brain acetylcholine levels and enhances cognitive function, as inferred from its pharmacological mode of action.

Clinical trials.

At the time of registration, more than 2500 patients in Australia, Canada, Europe and USA had received galantamine in both controlled and uncontrolled clinical studies. The efficacy of galantamine in treating patients with the symptoms of mild to moderate Alzheimer's disease was assessed in three pivotal double blind, randomised, placebo controlled clinical trials of 5 months (GAL-USA-10) and 6 months duration (GAL-INT-1 and GAL-USA-1). GAL-INT-1 and GAL-USA-1 studied the effect of galantamine at maintenance doses of 24 mg/day (n = 428) and 32 mg/day (n = 429). GAL-USA-10 (n = 979) was conducted to evaluate the efficacy and tolerability of lower maintenance doses (16 mg/day and 24 mg/day) of galantamine with a slower dose escalation regimen. Galantamine was shown to be effective at 16, 24 and 32 mg/day in controlled clinical trials.
In the assessment of galantamine for the treatment of Alzheimer's disease, improvement of symptoms was assessed in three domains: cognition as measured by objective tests; activities of daily living; and an overall clinical response as measured by a global assessment. All three domains were assessed in each of the above pivotal clinical trials. In addition, a fourth domain of behavioural assessment was included in GAL-USA-10 and GAL-INT-2.
NINCDS-ADRDA criteria were used to select patients with probable Alzheimer's disease. Mild to moderate disease was defined as Mini Mental State Exam score of 11-24 with an ADAScog score > 12 at baseline. Other causes of dementia were excluded, and patients with psychiatric illness were excluded based on DSM-IV criteria.

Cognitive endpoint - ADAScog.

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAScog) was used to measure the ability of galantamine to improve cognitive performance. The ADAScog is an established scale, specifically designed to assess cognitive therapy in Alzheimer's disease. The ADAScog is a multi-item test battery that examines select aspects of cognitive performance including memory, orientation, attention, reasoning, language and praxis. The ADAScog scale extends from 0 to 70, higher scores indicating greater cognitive impairment. Elderly, normal patients may score as low as 0 or 1 unit, but individuals judged not to be demented can score higher. The mean score of patients entering each study was approximately 27 units. The ADAScog score is reported to deteriorate at a rate of about 8 to 11 units per year for untreated patients with Alzheimer's disease.
As shown in Figure 1, the cognitive performance of patients, who were treated with galantamine in GAL-INT-1 and GAL-USA-1, was statistically significantly better than that of patients who were given placebo (p < 0.001). The cognitive improvement was also statistically significant from as early as 3 weeks after the start of treatment.
The cognitive performance of patients treated with galantamine, at the end of the 6 month observation period, was still well above the baseline performance whereas patients treated with placebo deteriorated. The effect size compared to placebo increased over time and was greatest at the end of the double blind treatment period. Subanalysis revealed that patients treated with galantamine performed better than placebo treated patients in all clusters addressing specific cognitive domains contained in the ADAScog. This shows that the overall effect of treatment was not related to a specific domain of cognitive performance, but that galantamine improved all domains.
Treatment effect was present in all patient subgroups and the most pronounced effects were seen in patients in the more advanced stages of disease. There were no significant treatment by subgroup interactions for subpopulations of age, gender, race, baseline weight, APO-E genotype and smoking status. Statistically significant findings were consistent between trials and countries, and robust with respect to possible selective censoring due to premature discontinuation of missing data.
In Gal-USA-10, statistically significant reductions in cognitive impairment was observed for the 16 and 24 mg/day groups (p < 0.001) when compared to placebo after 5 months. The results for the 16 and 24 mg/day doses were similar at all time points (see Figure 2).

Global endpoint - CIBICplus.

The Clinician Interview Based Impression of Change with carer input (CIBICplus) was used to provide global clinical assessment. CIBICplus involves an independent, semistructured medical interview assessing all domains of cognition and activities of daily living. By its nature the CIBICplus is a crude and insensitive outcome measure, less responsive to medicine effects than psychometric tests alone. It was intentionally designed so that any statistically significant difference between two groups is evidence of a clinically relevant effect.
Figure 3 displays the percentage of patients who improved or did not deteriorate over the course of the trial according to CIBICplus. In both trials there were always more patients treated with galantamine found to have improved or not deteriorated compared to the placebo treated patients, and the differences were consistently statistically significant.
The results of the CIBICplus indicate that independent clinicians were able to discern a treatment effect and thus the result on the global test confirm the findings on the ADAScog and render it clinically relevant.

Functional endpoint - DAD.

The Disability Assessment in Dementia (DAD) was used to assess three categories of activities of daily living (ADL): the basic ADL's comprise dressing, hygiene, continence and eating; the instrumental ADL's consist of meal preparation, telephoning, housework, taking care of finance and correspondence and the ability to safely stay at home. The third category consists of one topic, leisure activities. The specific merit of the DAD is that it provides the possibility to assess different levels of performance; initiation, planning and organisation, and effective performance of the activity. The maximum score on the DAD is 46 and higher scores indicate less disability. This scale often fails to show improvements in activities of daily living, since once a patient loses the ability to perform a certain task, carers often remove the possibility for the patient to perform that activity again. Hence the test is not sensitive to improvements in function. However, maintaining function in a progressive disease can be considered a positive outcome that the scale is likely to document.
As expected, the functional endpoint (DAD) showed more variability within groups and showed less consistent treatment effects compared to the cognitive and global endpoints. In all trials patients treated with galantamine maintained functionality over the observation period. Significant differences between placebo and galantamine were seen in trials where significant placebo deterioration was present.
In GAL-USA-10, ADCS/ADL (Alzheimer's Disease Cooperative Study Activities Daily Living) inventory was used to measure the overall change in activities of daily living. At months 3 and 5 a significantly superior treatment effect was demonstrated in the groups receiving 16 and 24 mg/day of galantamine when compared to the placebo group.
The effect of galantamine on caregiver burden was evaluated in clinical studies. In GAL-INT-1, the average time required for patients care was less in the galantamine group as opposed to the placebo group at month 6. Patients treated with galantamine could also be left unsupervised for a longer period of time than the placebo group.

Clinically relevant response - overall benefit.

Figure 4 shows the results of a pooled analysis of the two pivotal studies in which different types of responders are assessed. A clinically relevant response was categorised either as: no decline on ADAScog; improvement of at least 4 points on the ADAScog; improvement on the CIBICplus; or improvement of at least 4 points on the ADAScog and no worsening on the CIBICplus and no worsening on the DAD.
There is a statistically significant difference for both doses of galantamine compared to placebo for all response categories.
In order to assess the overall efficacy of galantamine in the treatment of the symptoms of mild to moderate Alzheimer's disease, all three endpoints (cognitive, global and functional performance) must be considered to determine whether a clinically significant effect can be concluded.
Figure 4 shows the percentage of patients with a clinically significant response on a combination of scales: improvement of at least 4 points on the ADAScog and no worsening on the CIBICplus and no worsening on the DAD. In the placebo group, 5.5% of patients met the criterion whilst this percentage was 14.3% for patients treated with galantamine 24 mg daily, and 13.3% for patients treated with galantamine 32 mg daily. The difference between placebo and both galantamine treatment groups was statistically significant (p < 0.001).

Behavioural endpoint - NPI (neuropsychiatry inventory).

NPI was used as an additional outcome measure to evaluate behavioural disturbances in GAL-USA-10. The NPI covered 10 domains of behaviours seen in patients with Alzheimer's disease, which included delusions, hallucinations, agitation/ aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/ lability and aberrant motor behaviour. Caregivers were also given the opportunity to rate the amount of distress each behaviour caused them (the caregivers).
In comparison to the placebo group or the 8 mg/day group, galantamine showed a statistically significant (p ≤ 0.05) advantage in maintaining the total NPI score after 5 months of treatment at doses of 16 mg/day and 24 mg/day. Stabilised behaviour was observed in patients receiving 16 or 24 mg/day of galantamine.

Long-term safety and efficacy.

The long-term safety and efficacy of 24 mg galantamine (12 mg twice daily) in Alzheimer's disease patients who had completed GAL-USA-1 was evaluated during an additional six month open label extension. These patients had received either placebo, 24 mg or 32 mg of galantamine during the initial six month trial.
The extension study (GAL-USA-3) results support the findings of the 24 week pivotal trials in demonstrating the safety and efficacy of galantamine. Patients treated with galantamine 24 mg/day for the entire 12 month period maintained cognitive benefits during the second six months of treatment. They finished the extension trial with ADAScog scores no worse than they were at baseline. Although no placebo group was available for comparison in this study, the result is quite significant considering that literature suggests the average decline for Alzheimer's disease patients on the ADAScog over 12 months is eight to eleven points.
Patients who received placebo for the first 24 week period in GAL-USA-1 and were than given galantamine 24 mg daily in GAL-USA-3, did experience an improvement in their cognitive function according to ADAScog after 3 months treatment with galantamine. Although the ADAScog score at the end of the initial placebo phase had deteriorated by 2.2 points from baseline (i.e. at the start of GAL-USA-1), there was no further statistically significant change for this group during treatment with galantamine.
No rebound effect on cognitive performance was seen in patients abruptly withdrawn from galantamine treatment. Contrary to what would be expected from a purely symptomatic treatment, patients did not completely lose the treatment benefits during a six week observation period after cessation of galantamine treatment.
Gastrointestinal tolerability of galantamine improved during modified dosing, and no unexpected time dependent adverse events were apparent.

Galantamine modified release capsules.

The efficacy of galantamine modified release (MR) capsules was studied in a randomised, double blind, placebo and active controlled trial using a 4 week dose escalation, flexible dosing regimen of 16 or 24 mg/day for a treatment duration of 6 months. The three treatment groups in the study were galantamine modified release capsule, galantamine immediate release tablets and placebo.
NINCDS-ADRDA criteria were used to select patients with probable Alzheimer's disease. Mild to moderate disease was defined as Mini Mental State Exam score of 10 to 24 with an ADAScog/11 score ≥ 18 at screening.
In the protocol specified primary efficacy analysis for the two endpoints (ADAS-cog/11 and CIBIC-plus), at month 6, galantamine MR capsules showed a statistically significant improvement over placebo for ADAScog/11. A numerical trend in favour of galantamine modified release capsules was observed for the CIBICplus score, however neither galantamine MR capsules or galantamine IR tablets achieved the nominal statistical significance when compared to placebo. This may have been due to the over representation of subjects with a screening MMSE score > 22 in the placebo group. These patients contributed to the disproportionately high placebo response rate. In addition, galantamine MR was statistically significantly better than placebo in improving activities of daily living (ADCS-ADL), a key secondary efficacy measure. There were no clinically relevant differences in medicine compliance, including dose titration, dose reduction, discontinuation, and daily dose compliance.
Efficacy results were similar for galantamine modified release capsules and galantamine tablets, which served as an active control in this study.

5.2 Pharmacokinetic Properties

Galantamine has a low clearance (plasma clearance of approximately 300 mL/min) with a moderate volume of distribution (average Vdss of 175 L). The disposition of galantamine is biexponential, with a terminal half-life in the order of 7-8 hours.
After repeated oral dosing of the immediate release tablets (12 mg galantamine twice daily), mean trough and peak plasma concentrations fluctuated between 30 and 90 nanogram/mL. The pharmacokinetics of galantamine are linear in the dose range of 4-16 mg twice daily for the immediate release formulation.
Galantamine modified release capsules (24 mg once daily) are bioequivalent to the immediate release tablets (12 mg twice daily) with respect to AUC24h and Cmin at steady state. The Cmax value was about 24% lower than that of tablet. Galantamine pharmacokinetics of galantamine modified release capsules are dose proportional within the studied dose range of 8 mg to 24 mg in elderly and young age groups. The terminal half-life of galantamine modified release capsule is similar to that of immediate release tablet.
Data from clinical trials indicate that the plasma concentrations of galantamine (immediate release tablet) in patients with Alzheimer's disease are 30-40% higher than in healthy young subjects.

Absorption.

Immediate release tablets.

Absorption is rapid, with a Tmax of about 1 hour. The absolute bioavailability of galantamine is high, 88.5 ± 5.4%. The presence of food delays the rate of absorption (Tmax) and reduces peak concentration (Cmax) by about 25%, without affecting the extent of absorption (AUC).

Modified release capsules.

Well absorbed with Tmax value around 4.4 hours. Food has no significant effect on AUC of the modified release capsules. Cmax was increased by about 12% and Tmax increased by about 30 minutes when the capsule was given after food. However, these changes are unlikely to be clinically significant.
The mean pharmacokinetic parameters at steady state in 22 healthy adults following the 24 mg once daily modified release capsules and the 12 mg twice daily immediate release tablets are summarised in Table 4.

Distribution.

The plasma protein binding of galantamine is low: 17.7 + 0.8%. In whole blood, galantamine is mainly distributed to blood cells (52.7%) and plasma water (39%), whereas the fraction of galantamine bound to plasma proteins is only 8.4%. The blood to plasma concentration ratio of galantamine is 1.17.

Metabolism.

Major metabolic pathways were N-oxidation, N-demethylation, O-demethylation, glucuronidation and epimerisation. O-demethylation was far more important in extensive metabolisers of CYP2D6. The levels of excretion of total radioactivity in urine and faeces did not differ between poor and extensive metabolisers. In vitro studies confirmed that cytochrome P450 2D6 and 3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine.
In plasma from poor and extensive metabolisers, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity. In plasma from extensive metabolisers, the glucuronide of O-desmethylgalantamine was also present.
None of the active metabolites of galantamine (norgalantamine, O-desmethylgalantamine and O-desmethylnorgalantamine) could be detected in their unconjugated form in plasma from poor or extensive metabolisers after single dosing. Norgalantamine was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the galantamine levels.

Excretion.

Seven days after a single oral dose of 4 mg 3H-galantamine (solution), 90-97% of the radioactivity was recovered in urine and 2.2-6.3% in the faeces. After intravenous and oral solution administration, 18-22% of the dose was excreted as unchanged galantamine in the urine in 24 hours, with a renal clearance of about 65 mL/min, which represents 20-25% of the total plasma clearance.
The disposition of galantamine (8 mg immediate release tablet) was studied in young subjects with varying degrees of renal function. Elimination of galantamine decreased with decreasing creatinine clearance. Plasma concentrations of galantamine increased in subjects with impaired renal function by 38% in moderate (creatinine clearance between 52-104 mL/min) or 67% in severe renal impairment (creatinine clearance between 9-51 mL/min), compared to age and weight matched healthy subjects (creatinine clearance greater than or equal to 121 mL/min). A population pharmacokinetic analysis and simulations indicate that no dose adjustments are needed in Alzheimer patients with renal impairment provided that the creatinine clearance is at least 9 mL/min.
The pharmacokinetics of galantamine in subjects with mild hepatic impairment (Child-Pugh score of 5-6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7-9), AUC and half-life of galantamine (4 mg immediate release tablet) were increased by about 30%.

5.3 Preclinical Safety Data

Genotoxicity.

Galantamine was not mutagenic in bacterial reverse mutation tests in Salmonella typhimurium and Escherichia coli or in a mammalian gene mutation test in vitro. Galantamine did not induce chromosome aberrations in Chinese hamster ovary cells in vitro or in the micronucleus test in mice in vivo.

Carcinogenicity.

Galantamine showed no medicine related increase in tumour incidences in transgenic tumour suppressor gene p53 deficient mice at plasma AUC0-24h levels slightly greater than those in humans after the maximum recommended dose. There was also no increase in tumour incidences in a 24 month carcinogenicity study in Charles River CD1 mice at plasma AUC0-24h levels 1 to 2 times those in humans at the maximum recommended dose.
In a 24 month carcinogenicity study in Wistar rats, dose related increases in the incidences of endometrial (adeno) carcinomas and sarcomas of the genital tract were observed in females. At the no-effect level of 2.5 mg/kg/day, systemic exposure (plasma AUC0-24h) was slightly greater than that in humans at the maximum therapeutic dose. The mechanism of tumour development has not been clearly established, but may be related to decreased prolactin levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, hypromellose, ethylcellulose, magnesium stearate, gelatin, titanium dioxide, iron oxide red (16 and 24 mg capsules only), indigo carmine (24 mg capsules only), erythrosine (24 mg capsules only), iron oxide yellow (24 mg capsules only).

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-Galantamine 8 mg modified release capsules.

Blister Pack PVC/PE/PVDC/Aluminium of 28 capsules (AUST R 182030).

APO-Galantamine 16 mg modified release capsules.

Blister Pack PVC/PE/PVDC/Aluminium of 28 capsules (AUST R 182041).

APO-Galantamine 24 mg modified release capsules.

Blister Pack PVC/PE/PVDC/Aluminium of 28 capsules (AUST R 182034).
APO and APOTEX are registered trade marks of Apotex Inc.
Not all strengths 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

Galantamine hydrobromide is a white to almost white powder with a solubility in water at 25°C of 3.69 g/100 mL. It is slightly soluble in methanol and very slightly soluble in ethanol and acetonitrile. The pKa is 8.2 with a pH of 5.2. Galantamine hydrobromide contains three chiral centres and is presented as a single enantiomer.

Chemical structure.


Chemical name: (4aS, 6R, 8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11- methyl-6Hbenzofuro [3a,3,2-ef][2]benzazepin-6-ol hydrobromide.
Molecular Formula: C17H21NO3.HBr.
MW: 368.27.

CAS number.

1953-04-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes