Consumer medicine information

Exelon Patch

Rivastigmine

BRAND INFORMATION

Brand name

Exelon Patch

Active ingredient

Rivastigmine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Exelon Patch.

What is in this leaflet

This leaflet answers some common questions about Exelon Patch.

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

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

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au Those updates may contain important information about the medicine and its use of which you should be aware.

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

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

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

What Exelon Patch is used for

Exelon Patch contains rivastigmine as the active substance. Rivastigmine belongs to a class of substances called cholinesterase inhibitors and is used to treat a condition called Alzheimer's disease.

In patients with Alzheimer's dementia, certain nerve cells die in the brain, resulting in low levels of the neurotransmitter: acetylcholine (a substance that allows nerve cells to communicate with each other). This causes changes in the brain and problems with memory, thinking and behaviour. These problems gradually become worse with time.

Exelon Patch works by preventing the breakdown of a chemical in the brain called acetylcholine. This chemical is needed to help keep the brain working properly.

Rivastigmine helps to reduce the symptoms of Alzheimer's disease, to slow down the mental decline that happens in people with this condition, and helps to improve the patient's ability to cope with everyday activities. It does not cure the condition.

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

Exelon Patch is only available with a doctor's prescription. It is not addictive.

There is not enough information to recommend this medicine for children.

Before you apply Exelon Patch

When you must not use it

Do not apply Exelon Patch if you have had an allergic reaction to any of the following:

  • rivastigmine, the active ingredient in Exelon Patch
  • any of the other ingredients of Exelon Patch listed at the end of this leaflet.
  • other related "carbamate" medicines (if you are unsure about these, ask your doctor or pharmacist)

Symptoms of an allergic reaction may include wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash or hives on the skin.

Do not apply Exelon Patch if you have a severe liver disorder. There is no information on the use of this medicine in people with severe liver problems.

Do not apply Exelon Patch if you have had a skin reaction which has spread beyond the patch size, if there was a more intense local reaction (such as blisters, increasing skin inflammation, swelling) and if it did not improve within 48 hours after removal of the transdermal patch.

Do not apply Exelon Patch after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Do not use Exelon Patch in children. It is not known how Exelon Patch will affect children.

If you are not sure whether you should start using Exelon Patch, talk to your doctor or pharmacist.

Before you start to use it

Tell your doctor if you have any of the following conditions:

  • a problem with your heart
  • a history of stomach ulcer
  • problems with your lungs such as asthma or obstructive pulmonary disease
  • emphysema
  • difficulty passing urine (water)
  • seizures (fits)
  • problems with your kidneys or liver
  • problems with your stomach such as nausea (feeling sick) and vomiting (being sick)
  • if you have a low body weight (less than 50 kg)

If you have any of the above conditions your doctor may want to take special precautions while you are taking this medicine.

Tell your doctor if you are pregnant or breast-feeding.

It is not known whether using Exelon Patch during pregnancy or while breast-feeding could affect your baby.

Breast-feeding is not recommended while you are using this medicine. It is not known whether the active ingredient passes into breast milk and could affect your baby.

Tell your doctor if you smoke. Nicotine can affect the amount of Exelon Patch that is in your body. A sudden change in your usual smoking habit can also change the effects of Exelon Patch.

Taking other medicines

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

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

  • cholinergic medicines (e.g. bethanechol, medicines used during surgery)
  • anticholinergic medicines (e.g. medicines for stomach cramps, medicines for travel sickness, many medicines used to treat mental illness)
  • metoclopramide (a medicine used to relieve or prevent nausea and vomiting). There may be additive effects such as stiff limbs and trembling hands.
  • beta-blockers (medicines used to treat hypertension, angina and other heart conditions). There may be additive effects such as a slow heartbeat that may result in fainting or loss of consciousness.
  • non-steroidal anti-inflammatory drugs (NSAIDs), which are medicines used to treat arthritis and other painful conditions such as muscle strains, back pain, menstrual cramps and migraine

You may need to take different amounts of your medicines or to take different medicines while you are using Exelon Patch. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start using this medicine.

How to use Exelon Patch

Follow all directions given to you by your doctor and pharmacist carefully. These instructions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How to apply Exelon Patch

Every 24 hours, gently remove any existing Exelon patch before putting on a new one. See "How to remove Exelon Patch".

Having multiple patches on your body could expose you to an excessive amount of this medicine which could be potentially dangerous.

Apply your new patch to a different area of skin.

Before you apply Exelon Patch, make sure that your skin is:

  • clean, dry and hairless
  • free of any powder, oil, moisturiser, or lotion (that could keep the patch from sticking to your skin properly)
  • free of cuts, rashes and/or irritations.

Apply ONE patch only per day to ONLY ONE of the following locations on your body:

  • upper arm, left or right side, or
  • chest, left or right side, or
  • upper back, left or right side, or
  • lower back, left or right side.

A leaflet in the carton contains diagrams showing these locations. When changing your patch, you must remove the previous day's patch before you apply your new patch to a different area of skin (for example on the right side of your body one day, then on the left side the next day). Do not apply a new patch to that same area for at least one week.

How to remove Exelon Patch

Gently pull at one edge of the Exelon Patch to remove it completely from the skin.

If any adhesive residue is left on your skin, gently soak the area with warm water and mild soap, or use baby oil to remove it. Do not use alcohol or other dissolving liquids (nail polish remover or other solvents).

Wash your hands with soap and water after removing the patch.

In case of contact with eyes or if the eyes become red after handling the patch, rinse them immediately with plenty of water and seek medical advice if symptoms do not resolve.

How much to use

Your doctor will tell you which Exelon Patch is more suitable for you. Treatment usually starts with one Exelon Patch 5 daily. After about four weeks of treatment the usual daily dose is Exelon Patch 10. If well tolerated, your doctor may increase the dose to Exelon Patch 15.

During the course of the treatment your doctor may adjust the dose to suit your individual needs.

Do not wear more than one Exelon Patch at a time.

If for any reason you stop using Exelon Patch for more than three days, tell your doctor before you start taking Exelon Patch again. Your doctor will restart you at the lowest dose to help prevent side effects such as nausea and vomiting.

How to use it

Read the "How to use" leaflet carefully. A "How to use" leaflet is enclosed in Exelon Patch cartons. This leaflet contains pictures and instructions showing how to apply the patch properly.

How long to use it

Apply a new patch every day. Exelon Patch should be replaced with a new one after 24 hours.

Apply the new patch at about the same time each day. Change your patch at the same time each day to obtain the best effect from your medicine. It will also help you remember when to take it.

Continue using Exelon Patch for as long as your doctor tells you to.

This medicine helps to slow the progression of Alzheimer's disease but does not cure it. Your treatment can be continued for as long as it benefits your condition. Your doctor can give you more information.

Do not stop using Exelon Patch or change your dose without talking with your doctor.

Switching from Exelon Capsules to Exelon Patch

Your doctor will have advised you on switching from Exelon Capsules.

NEVER take Exelon Capsules when using Exelon Patch.

If you forget to use it

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

Otherwise, apply a new patch as soon as you remember, and then go back to your usual schedule.

Do not apply two Exelon Patches to make up for the one you missed. This may increase the chance of you getting an unwanted side effect.

Tell your doctor if you have not applied your Exelon Patch for more than three days. Do not apply the next patch before you have talked to your doctor. Your doctor will restart you at the lowest dose to help prevent side effects such as nausea and vomiting.

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

If your Exelon Patch falls off

If your Exelon Patch falls off, apply a new patch to the same site for the rest of the 24 hours. Replace this patch the next day at the same time as usual.

Do not re-apply the used patch. Applying a new patch ensures that your body keeps getting the medicine it needs.

If you use too much (overdose)

If you think that you or anyone else may have accidentally applied more than one Exelon Patch at a time or swallowed a patch, immediately telephone your doctor or the Poisons Information Centre (telephone number 13 11 26), or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

Keep the telephone numbers for these places handy.

Because of the way this medicine is used, an intentional overdose is unlikely.

Applying more than one patch or swallowing a patch may cause

  • nausea (feeling sick)
  • vomiting
  • diarrhoea
  • high or low blood pressure
  • fainting
  • salivation
  • sweating
  • increasing muscle weakness
  • hallucinations (hearing or seeing things that are not there)
  • unusually slow heart beat
  • breathing difficulties
  • convulsions.

While you are using Exelon Patch

Things you must do

Be sure to keep all of your doctor's appointments so your progress can be checked. You and your caregiver can help to produce the maximum benefit from your treatment by keeping in close contact with your doctor.

Tell your doctor if you smoke. Nicotine can affect the amount of Exelon that is in your body. A sudden change in your usual smoking habit can also change the effects of Exelon.

Make sure you or your caregiver tells your doctor if you experience considerable nausea, vomiting or diarrhoea with loss of appetite and weight loss. You may become dehydrated (losing too much fluid) if vomiting or diarrhoea are prolonged.

Talk to your doctor right away if you have skin inflammation, blisters or swelling of the skin that are increasing and spreading.

If you become pregnant while taking Exelon Patch, tell your doctor. There is not enough information to recommend the use of this medicine during pregnancy. Your doctor can discuss with you the risks and benefits involved.

If you are going to have surgery, tell your doctor and anaesthetist that you are using Exelon Patch. Exelon Patch may affect some medicines you receive during surgery.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Exelon Patch.

Tell any other doctor, dentist or pharmacist who treats you that you are using Exelon Patch.

Things you must not do

Avoid placing the patch where it might be rubbed off by tight clothing.

Do not give this medicine to anyone else even if their condition seems similar to yours.

Do not use Exelon Patch to treat any other complaints unless your doctor tells you to.

Do not expose the patch to any external heat sources (excessive sunlight, saunas, and solariums) for long periods of time.

Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. Exelon Patch may cause dizziness and somnolence, mainly at the start of treatment or when increasing the dose. Therefore, you should wait to know what effects the drug may cause before engaging in such activities. If you feel dizzy or drowsy, do not drive, use machines or perform any other tasks that require your attention.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Exelon Patch, even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them. Ask your doctor or pharmacist to answer any questions you may have.

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

  • nausea (feeling sick) or vomiting
  • diarrhoea
  • dehydration (losing too much fluid)
  • loss of appetite
  • anorexia
  • anxiety
  • indigestion, abdominal pain or discomfort
  • weight loss
  • dizziness or a spinning feeling
  • headache
  • unusual fatigue/tiredness, weakness or sleepiness, feeling generally unwell
  • inability to adequately retain urine (urinary incontinence)
  • redness, itching, irritation, swelling at the application site
  • increased sweating
  • difficulty sleeping
  • confusion
  • mood changes such as feeling aggression, anxious, nervousness, depressed (sad mood)
  • unusual high level of activity (hyperactivity)
  • hallucinations (hearing or seeing things that are not there)
  • loss of control of your bladder or bowels (incontinence).

The above side effects usually happen at the start of treatment when the dose is being increased. They are not usually serious and may gradually disappear as your body gets used to the medicine.

Women are more likely than men to get some side effects (e.g. nausea, vomiting, loss of appetite, weight loss).

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

  • signs of allergy such as rash or hives on the skin; swelling of the face, lips, tongue or other parts of the body; wheezing or difficulty breathing
  • chest pain
  • stroke (loss of coordination, difficulty in speaking and signs of brain disorder)
  • unusually fast, slow or irregular heart beat
  • raised blood pressure
  • unusual thinking (e.g. feeling a fixed, irrational idea not shared by others, or feeling strong suspiciousness)
  • severe dizziness, fainting or fits (seizures)
  • severe confusion
  • blood in the stools or when vomiting gastric ulcer and gastrointestinal haemorrhage)
  • severe pain in the abdomen, often with nausea and vomiting (inflammation of the pancreas)
  • signs of a urinary tract infection such as frequent urge to urinate or pain on urination
  • fits or convulsions
  • signs of a liver disorder (yellow skin, yellowing of the whites of eyes, abnormal darkening of the urine or unexplained nausea, vomiting, tiredness and loss of appetite)
  • skin inflammation, blisters or swelling of the skin that are increasing and spreading
  • stiff limbs, trembling hands (extrapyramidal symptoms)

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet. Some of the side effects can only be found when your doctor does tests from time to time to check your progress.

After using Exelon Patch

Storage

  • Keep your medicine in the original container (sachet) until it is time to use it.
  • Store it in a cool, dry place at room temperature (below 25°C).
  • Do not store Exelon patch or any other medicine in the bathroom or near a sink
  • Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines. Exelon Patch will keep well if it is kept cool and dry.

Keep the medicine 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

After the patch has been removed, fold the patch in half with the adhesive sides on the inside and press them together. Place the folded used patch in its original sachet. Discard safely out of reach and sight of children. Wash your hands with soap and water after removing the patch.

If your doctor tells you to stop using Exelon Patch or if they have passed their expiry date, ask your pharmacist what to do with any medicine you have left over.

Product description

What it looks like

Exelon Patch is available in two strengths, in packs of 30 sachets.

  • Patch 5: the outside of the backing layer is beige and labelled with "AMCX" and "Exelon® Patch 5 (rivastigmine)"
  • Patch 10: the outside of the backing layer is beige and labelled with "BHDI" and "Exelon® Patch 10 (rivastigmine)"
  • Patch 15: the outside of the backing layer is beige and labelled with "CNFU" and "Exelon® Patch 15 (rivastigmine)"

Ingredients

Each Exelon Patch 5, Patch 10 or Patch 15 contains respectively 9 mg, 18 mg or 27mg of the active ingredient (rivastigmine). They also contain:

  • Dl-alpha-tocopherol
  • Acrylates copolymer
  • Silicone oil (dimethicone 12500)
  • Adhesive matrix (Durotak 387-2353 and Bio PSA Q7-4302)

Sponsor

Exelon is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Web site: www.novartis.com.au

® = Registered Trademark

This leaflet was prepared in December 2019.

Australian Registration Numbers:
Exelon Patch 5: AUST R 133422
Exelon Patch 10: AUST R 133428
Exelon Patch 15: AUST R 222604

(exp161219c) based on PI (exp161219i)

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Exelon Patch

Active ingredient

Rivastigmine

Schedule

S4

 

1 Name of Medicine

Rivastigmine.

6.7 Physicochemical Properties

Chemical name.

3-[(1S)-1-(dimethylamino)ethyl]phenyl ethyl(methyl)carbamate.

Molecular formula.

C14H22N2O2.

Molecular weight.

250.34.
Rivastigmine is a viscous, clear colourless to yellow to very slightly brown liquid.

Chemical structure.


CAS number.

123441-03-2.

2 Qualitative and Quantitative Composition

Exelon Patches are available in three strengths.
Exelon Patch 5: each patch of 5 cm2 contains 9 mg rivastigmine.
Exelon Patch 10: each patch of 10 cm2 contains 18 mg rivastigmine.
Exelon Patch 15: each patch of 15 cm2 contains 27 mg rivastigmine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Exelon Patch is a thin, matrix-type transdermal patch consisting of three layers one of which contains rivastigmine.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pathological changes in Alzheimer's disease involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are known to be involved in attention, learning, memory and other cognitive processes. Rivastigmine, a brain selective, pseudo-irreversible inhibitor of the enzymes acetyl- and butyrylcholinesterase, is thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Data from animal studies indicate that rivastigmine selectively increases the availability of acetylcholine in the cortex and hippocampus. Thus, Exelon may have an ameliorative effect on cholinergic mediated cognitive deficits associated with Alzheimer's disease. In addition, there is some evidence that cholinesterase inhibition could slow the formation of amyloidogenic β-amyloid precursor protein (APP) fragments, and thus of amyloid plaques, which are one of the main pathological features of Alzheimer's disease.
Rivastigmine interacts with its target enzyme by forming a covalently bound complex that temporarily inactivates the enzyme. In healthy young men, an oral 3.0 mg dose decreases acetylcholinesterase (AChE) activity in cerebrospinal fluid (CSF) by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. Butyrylcholinesterase (BuChE) activity in CSF was transiently inhibited and was no longer different from baseline after 3.6 hours in healthy young volunteers. In patients with Alzheimer's disease, inhibition of acetylcholinesterase in CSF by rivastigmine is dose dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of BuChE activity in the CSF of 18 patients with Alzheimer's disease was similar to that of AChE, with a change from baseline of more than 60% after 6 mg rivastigmine twice daily. The effect of rivastigmine on AChE and BuChE activity in CSF (a reduction from baseline of 33% and 45%, respectively) was sustained in 11 patients after administration of rivastigmine at a mean dose of 8.6 mg/day for 12 months. Statistically significant correlations were found between the degree of inhibition by rivastigmine of AChE and BuChE in the CSF and changes on a compound measure of cognitive performance, the Computerised Neuropsychological Test Battery (CNTB), in 18 patients with Alzheimer's disease treated with daily doses of rivastigmine for a duration of at least 3 consecutive days. However, only BuChE inhibition in CSF was significantly and consistently correlated with improvements in speed, attention and memory related subtests of the CNTB. The clinical significance of the inhibitory effect of rivastigmine on BuChE in patients with Alzheimer's disease is unknown.

Clinical trials.

Mild to moderate Alzheimer's dementia.

Study 2320 - 24-week placebo controlled study.

The efficacy of Exelon patches in patients with Alzheimer's dementia has been demonstrated in a 24 week double blind core study and its open label extension phase. Patients involved in this study had an MMSE (mini-mental state examination) score of 10-20. Efficacy was established by the use of independent, domain specific assessment tools which were applied at regular intervals during the 24 week treatment period. These include the ADAS-Cog (a performance based measure of cognition) and the ADCS-CGIC (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the ADCS-ADL (a caregiver rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities related to finances). The 24 week results for the three assessment tools are summarised in Table 6. Patch 5 was intended as the initiating dose for patients not currently being treated with oral formulations. No specific 24 week results for the three assessment tools were collected during the study and its extension phase for Patch 5.
The results for clinically relevant responders from the 24 week study are provided in Table 7. Clinically relevant improvement was defined a priori as at least 4 point improvement on the ADAS-cog, no worsening on the ADCS-CGIC and no worsening on the ADCS-ADL.

Effects on the ADAS-Cog.

Figure 1 illustrates the time course for the change from baseline in ADAS-Cog scores by treatment group over the 24 week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the Exelon treated patients, compared to the patients on placebo, was 1.6 units for the Exelon Patch 9.5 mg/24 hours and Exelon capsule 6 mg BID groups. The difference between each of these groups and placebo was statistically significant.

Effects on the ADCS-CGIC.

Figure 2 is a histogram of the distribution of patients' scores on the ADCS-CGIC for all 3 treatment groups. At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the Exelon treated groups with the patients on placebo was 0.3 units. The difference between each of these groups and placebo was statistically significant.

Moderate to severe Alzheimer's dementia.

Study 2340.

This study was a randomized double blind clinical investigation in patients with Alzheimer's disease Mini-Mental State Examination (MMSE) score ≥ 10 and ≤ 24. The mean age of patients participating in this trial was 76 years with a range of 53-87 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 97%, Black 2%, Asian 0.5%, and other races 1%. Approximately 27% of the patients were taking memantine throughout the entire duration of the study. Alzheimer's disease patients who received 24 to 48 weeks open label treatment with Exelon Patch 10 cm2 and who demonstrated functional and cognitive decline were randomized into treatment with either Exelon Patch 10 cm2 or Exelon Patch 15 cm2 in a 48 week double blind treatment phase.
The ability of the Exelon Patch 15 cm2 to improve overall function versus that provided by Exelon Patch 10 cm2 was assessed by the instrumental subscale of the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-IADL). The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver based ADCS-ADL scale. The ADCS-IADL assesses activities such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests. A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.
The ability of the Exelon Patch 15 cm2 to improve cognitive performance over that provided by the Exelon Patch 10 cm 2 was assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog).
Study 2340 was designed to compare the efficacy of Exelon Patch 10 cm2 versus that of Exelon Patch 15 cm2 during the 48 week double blind treatment phase as assessed by the coprimary outcome variables of the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-Instrumental ADL) at 48 weeks and the Alzheimer's disease assessment scale-cognitive (ADAS-cog) subscale at 48 weeks. The statistical analysis required showing significant superiority for the 15 cm2 patch over the 10 cm2 patch in both these endpoints to demonstrate efficacy.
Out of a total of 1584 patients enrolled in the initial open label phase of the study, 567 patients showed functional and cognitive decline and were randomized into the 48 week double blind treatment phase of the study. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of > 2 points from the previous visit or a decrease of ≥ 3 points from baseline. The percentage of patients with decline was lower than expected, and the planned sample size (432 patients in each group during the DB phase) was not met. Two hundred eighty seven (287) patients entered the 10 cm2 Exelon Patch treatment group and 280 patients entered the 15 cm2 Exelon Patch treatment group.
The study failed to show efficacy in that in one of two coprimary endpoints at week 48 - the difference between the treatment groups at week 48 was statistically significant for the ADCS-Instrumental ADL score, but it was not for the ADAS-Cog scores.
Figure 3 illustrates the time course for the mean change from double blind baseline in ADCS-IADL scores for each treatment group over the course of the 48 week treatment phase of the study.
Decline in the mean ADCS Instrumental ADL score from the double blind baseline for the intent to treat-last observation carried forward (ITT-LOCF) analysis showed the 15 cm2 dose was statistically significantly superior to the 10 cm2 dose at weeks 16, 24, 32 and 48 (primary endpoint).
Figure 4 illustrates the time course for the mean change from double blind baseline in ADAS-Cog scores for both treatment groups over the 48 week treatment phase. The between treatment group difference for Exelon Patch 15 cm2 versus Exelon Patch 10 cm2 was nominally statistically significant at week 24 (p = 0.027), but not at week 48 (p = 0.227), which was the primary endpoint, nor any other time point.

Secondary efficacy measures.

In the DB phase, functional decline was defined by either at least 1 point decrease in the ADCS-Instrumental ADL score in a visit and confirmed by the following visit/ assessment or at least 2 points decrease from DB randomization baseline, and was still at least 1 point less at the subsequent confirmation visit. For time to functional decline in ADCS-Instrumental ADL in the DB phase the p-value of the log rank test for treatment comparison was not significant (p = 0.186).
For Trail Making Test (parts A and B) in the DB phase the between treatment group LSM differences were not statistically significant for the LOCF (week 48 part A p = 0.473; part B p = 0.881).
In both the NPI-10 and NPI-D scales, the between dose treatment group differences were not statistically significant.

Subgroup analysis of moderate to severe Alzheimer's dementia patients in study 2340.

A post hoc subgroup analysis of moderate to severe Alzheimer's dementia patients initial baseline MMSE score of 0-20 was undertaken. Although the subset population was quite large (91% of the original study patients), efficacy post hoc analyses of study D2340 moderate to severe subjects were not formally powered to show statistically significant differences between the two active dose groups (Exelon Patch 15 cm2 N = 237, Exelon Patch 10 cm2 N = 249). This analysis showed similar results to the main study. The subgroup analysis of those patients with an MMSE ≥ 3 and ≤ 12 was likewise similar.

Severe Alzheimer's dementia.

Study US44 - 24 week controlled study.

The efficacy of Exelon Patch in patients with severe dementia of the Alzheimer's type has been demonstrated in a 24 week double blind study (8 weeks titration, 16 weeks maintenance on 15 cm2 patch) and its 24 week open label extension phase (20 weeks of 15 cm2 treatment). Patients involved in the controlled study had at baseline an MMSE score of 3-12 (~ 50% of patients had MMSE scores of < 10).
The mean age of patients was 77.0 years (range 51-96 years). Approximately 64.4% of patients were women and 35.6% of patients were men. The racial composition of the population was 87.3% Caucasian, and approximately 1.3% Oriental and 4.2% other. The study was designed to compare the efficacy of Exelon Patch 15 versus Exelon Patch 5 during a 24 week double blind phase in severe Alzheimer's disease. See Table 8.

Efficacy measures.

Efficacy was established by the use of independent, domain specific assessment tools. These include the Severe Impairment Battery (SIB), the Alzheimer's Disease Cooperative Study Activity of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) and the ADCS-CGIC. The SIB is a 40 item scale with a range of possible scores from 0 to 100, with higher scores reflecting higher levels of cognitive function. The ADCS-ADL-SIV is a caregiver based scale consisting of 19 items designed to assess the patient's performance of both basic and instrumental activities of daily living, which had been used in several studies in moderate to severe Alzheimer's dementia. The total score ranges from 0-54, with higher scores indicating better function. The ADCS-CGIC is a comprehensive global assessment of the patient by the physician incorporating caregiver input.

Study results.

The week 24 results for the two primary assessment tools are summarized in Table 9.
See Figures 5 and 6.

Secondary efficacy measures.

Results from the MFAS-LOCF analysis of the ADCS-CGIC showed significant benefit with regards to global functioning (mental/ cognitive state, behavior, and functioning) at all timepoints for patients treated with Exelon Patch 15 compared to patients who received Exelon Patch 5.
The NPI-12 scores are used to distinguish frequency and severity of psychiatric behavioural changes. Changes in NPI-12 scores from baseline and the between group difference in these changes at all timepoints were not statistically significant.

5.2 Pharmacokinetic Properties

Absorption.

Absorption of rivastigmine from Exelon transdermal patches is slow. After the first dose, detectable plasma concentrations are observed after a lag time of 0.5-1 hour. Concentrations then rise slowly and typically after 8 hours reach levels close to maximum, although maximum values (Cmax) are often reached at later times (10-16 hours).
As with Exelon Patch 5 and 10, rivastigmine plasma concentrations following Exelon Patch 15 increased slowly, reaching Tmax at approximately 8 h post-application (see Figures 7 and 8). The mean (SD) Cmax following administration of Exelon Patch 15 at steady-state in AD patients (study D2331) was 14.1 (6.3) nanogram/mL compared to 2.7 (1.2) nanogram/mL and 7.9 (2.9) nanogram/mL for Exelon Patches 5 and 10, respectively (see Table 10); whereas mean (SD) AUC24h was 233 (83.2) nanogram.h/mL compared to 46.3 (17.2) and 127 (41.4) nanogram.h/mL, respectively (see Table 10).
After the peak, plasma concentrations slowly decrease over the remainder of the 24 hour period of application. With multiple dosing (such as at steady-state), after the previous patch is replaced with a new one, plasma concentrations initially decrease slowly for about 40 min on average, until absorption from the newly applied patch becomes faster than the elimination, and plasma levels begin to rise again to reach a new peak at approximately 8 hours. At steady-state, trough levels are approximately 50% of peak levels, in contrast to oral dosing, with which concentrations fall to virtually zero between doses (see Figures 7 and 8). Although less pronounced than with the oral formulation, exposure to rivastigmine (Cmax and AUC) increased over-proportionally by a factor of 2.6 when escalating from Exelon Patch 5 to Exelon Patch 10, and by a factor of 4.9 when escalating from Exelon Patch 5 to Patch 15. Results from study 2331 showed the fluctuation index (FI), a measure of the relative difference between peak and trough concentrations ((Cmax - Cmin)/Cavg), was 0.58 for Exelon Patch 5, 0.77 for Exelon Patch 10, and 0.72 for Exelon Patch 15, thus demonstrating a much smaller fluctuation between trough and peak concentrations than for the oral formulation (FI = 3.96 (6 mg/day) and 4.15 (12 mg/day)).
The release rate of rivastigmine from Exelon Patch 15 is 13.3 mg/24 h as determined in AD patients at steady-state (study D2331) compared to 4.6 and 9.5 mg/24 h for Exelon Patch 5 and 10, respectively.
The dose of rivastigmine released from the transdermal patch over 24 hours (mg/24 h) cannot be directly equated to the amount (mg) of rivastigmine contained in a capsule with respect to plasma concentration produced over 24 hours.
In a single dose study directly comparing the patch versus oral administration, the intersubject variability in rivastigmine pharmacokinetic parameters (normalised to dose/kg bodyweight) was 43% (Cmax) and 49% (AUC0-24h) after the patch versus 74% and 103%, respectively, after the oral capsule. Similarly, intersubject variability in rivastigmine pharmacokinetic parameters was lower after the patch than after the oral capsule in a steady-state study in Alzheimer's dementia patients given repeated doses. The interpatient variability was at most 45% (Cmax) and 43% (AUC0-24h) after the patch, while 71% and 73%, respectively, after the oral form.
A relationship between drug exposure at steady-state (rivastigmine and metabolite NAP226-90) and bodyweight was observed in Alzheimer's dementia patients. Compared to a patient with a bodyweight of 65 kg, the rivastigmine steady-state concentrations in a patient with a bodyweight of 35 kg would be approximately doubled, while for a patient with a bodyweight of 100 kg the concentrations would be approximately halved. The effect of bodyweight on drug exposure suggests that special attention should be given to patients with very low bodyweight during up titration. Rivastigmine was well released from the transdermal system over a 24 hour dermal application with approximately 50% of the drug load being released from the system.
Exposure (AUC) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest or upper arm. There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer's disease, except that with patch treatment plasma levels on the second day were higher than on the first.

Distribution.

Rivastigmine is weakly bound to plasma proteins (approximately 40%). The apparent volume of distribution of rivastigmine is in the range of 1.8-2.7 L/kg. Rivastigmine distributes equally between blood and plasma with a blood to plasma partition ratio of 0.9 at concentrations ranging from 1-400 nanogram/mL.

Metabolism.

Rivastigmine is rapidly and extensively metabolised with an apparent elimination half-life in plasma of approximately 3.4 hours after patch removal. Elimination was absorption rate limited, which explains the longer t1/2 after patch (3.4 h) versus oral or i.v. administrations (1.4 to 1.7 h). Metabolism is primarily via cholinesterase mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (< 10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 litres/h after a 0.2 mg intravenous dose and decreased to 70 litres/h after a 2.7 mg intravenous dose, which is consistent with the nonlinear, over proportional pharmacokinetics of rivastigmine due to saturation of its elimination.
The metabolite to parent AUC ratio was around 0.7 after patch versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first-pass) metabolism.

Excretion.

Unchanged rivastigmine is not found in the urine. Renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (> 90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces.

Pharmacokinetics in the elderly.

Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with Exelon transdermal patches.

Pharmacokinetics in renal impairment.

Following a single 3 mg dose, mean oral clearance of rivastigmine is 64% lower in moderately impaired renal patients (n = 8, GFR 10 - 50 mL/min) than in healthy subjects (n = 10, GFR 60 mL/min); CL/F = 1.7 L/min (cv = 45%) and 4.8 L/min (cv = 80%), respectively. In severely impaired renal patients (n = 8, GFR < 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n = 10, GFR 60 mL/minute); CL/F = 6.9 L/min and 4.8 L/min, respectively. For unexplained reasons, the severely impaired renal patients had a higher clearance of rivastigmine than moderately impaired patients. However, dosage adjustment may not be necessary in renally impaired patients as the dose of the drug is individually titrated to tolerability (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Use in patients with renal or hepatic impairment).

Pharmacokinetics in hepatic impairment.

Following a single 3 mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n = 10, biopsy proven) than in healthy subjects (n = 10). After multiple 6 mg twice daily oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n = 7, Child-Pugh score 5-6) and moderate (n = 3, Child-Pugh score 7-9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n = 10). Dosage adjustment is not necessary in hepatically impaired patients as the dose of drug is individually titrated to tolerability (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Use in patients with renal or hepatic impairment).

Special populations.

Gender and race.

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Exelon, but a population pharmacokinetic analysis indicates that gender (n = 277 males and 348 females) and race (n = 575 white, 34 black, 4 Asian and 12 other) did not affect the clearance of Exelon.

Nicotine use.

Population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% (n = 75 smokers and 549 non-smokers).

5.3 Preclinical Safety Data

Genotoxicity.

Rivastigmine was not genotoxic in tests for gene mutation in bacteria and primary DNA damage in mammalian cells in vitro. In tests for chromosomal damage in vitro, a small increase in the number of cells carrying chromosomal aberrations occurred at very high concentrations. However, there was no evidence of clastogenicity in the more relevant in vivo test in mice.

Carcinogenicity.

No evidence of carcinogenicity was found in oral and topical studies in mice, or in an oral study in rats, at the maximum tolerated dose of rivastigmine. However, achieved systemic exposures to rivastigmine and the phenolic metabolite NAP226-90 in animals were lower than in humans treated with Exelon transdermal patches at the maximum recommended dose.

Dermal toxicity.

There was no evidence of phototoxicity in guinea pigs exposed to UV-A radiation following a 30 minute application of a rivastigmine patch.

4 Clinical Particulars

4.1 Therapeutic Indications

Exelon is indicated for the treatment of patients with mild, moderate and severe dementia of the Alzheimer's type.

4.3 Contraindications

The use of Exelon is contraindicated in patients with:
Known hypersensitivity to rivastigmine, to the excipients of the formulation, or to other carbamate derivatives.
Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine transdermal patch (see Section 4.4 Special Warnings and Precautions for Use, Application site and skin reactions).
Severe liver impairment since it has not been studied in this population.

4.4 Special Warnings and Precautions for Use

The incidence and severity of adverse reactions generally increase with increasing doses, particularly when the dose is increased. If treatment is interrupted for more than three days, it should be re-initiated with Exelon Patch 5 (see Section 4.2 Dose and Method of Administration).

Medication misuse and dosing errors resulting in an overdose.

The previous day's patch must be removed before applying a new one.
Medication misuse and dosing errors with Exelon patches have resulted in serious adverse reactions; some cases have required hospitalisation, and rarely led to death (see Section 4.9 Overdose). The majority of medication misuse and dosing errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time. Patients and their caregivers must be instructed on important administration instructions for Exelon Patch (see Section 4.2 Dose and Method of Administration).

Gastrointestinal disorders.

The incidence and severity of adverse reactions generally increase with increasing doses, particularly at dose changes. Caregivers should be advised that nausea and vomiting are associated with the use of the drug along with possible anorexia and weight loss.

Nausea and vomiting.

Gastrointestinal disorders such as nausea, vomiting and diarrhoea may occur when initiating treatment and/or increasing the dose. They may respond to a dose reduction. In other cases, use of Exelon patches has been discontinued. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with IV fluids and dose reduction or discontinuation if recognized and treated promptly. Dehydration can be associated with serious outcomes (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the controlled clinical trial [study 2320], 7% of patients treated with the Exelon Patch 9.5 mg/24 hours developed nausea, as compared to 23% of patients who received the Exelon capsule at doses up to 6 mg BID and 5% of those who received placebo. In the same clinical trial, 6% of patients treated with Exelon Patch 9.5 mg/24 hours developed vomiting, as compared with 17% of patients who received the Exelon capsule at doses up to 6 mg BID and 3% of those who received placebo. The proportion of patients who discontinued treatment due to vomiting was 0% of the patients who received the Exelon Patch 9.5 mg/24 hours as well as 2% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo. Vomiting was severe in 0% of patients who received the Exelon Patch 9.5 mg/24 hours and 1% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo.

Anorexia.

Patients with Alzheimer's disease may lose weight whilst taking cholinesterase inhibitors, including rivastigmine.
In the controlled clinical trial in patients with mild to moderate Alzheimer's dementia [study 2320], 3% of the patients treated with the Exelon Patch 9.5 mg/24 hours were recorded as developing decreased appetite or anorexia, as compared with 9% of patients who received the Exelon capsule at doses up to 6 mg BID and 2% of those who received placebo.

Diarrhoea.

In the controlled clinical trial in patients with mild to moderate Alzheimer's dementia [study 2320], 6% of the patients treated with the Exelon Patch 9.5 mg/24 hours developed diarrhoea, as compared with 5% of patients who received the Exelon capsule at doses up to 6 mg BID and 3% of those who received placebo.

Weight loss.

Patients with Alzheimer's disease may lose weight whilst taking rivastigmine. The patient's weight should be monitored during therapy with Exelon patches.
Patients with bodyweight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse reactions. Carefully titrate and monitor these patients for adverse reactions (e.g. excessive nausea or vomiting) and consider reducing the dose if such adverse reactions develop (see Section 4.2 Dose and Method of Administration).
In the controlled clinical trial in patients with mild to moderate Alzheimer's dementia (study 2320), the proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with the Exelon Patch 9.5 mg/24 hours, 11% of patients who received the Exelon capsule at doses up to 6 mg BID and 6% of those who received placebo. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting and the diarrhoea associated with the drug.

Anaesthesia.

Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine type relaxation during anaesthesia.

Application site and skin reactions.

Skin application site reactions may occur with Exelon Patch and are usually mild or moderate in intensity (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions are not in themselves an indication of sensitisation. However, use of rivastigmine patch may lead to allergic contact dermatitis.
Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued (see Section 4.3 Contraindications).
In patients who develop application site reactions suggestive of allergic contact dermatitis to Exelon Patch and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.
There have been isolated post-marketing reports of patients experiencing allergic dermatitis (disseminated) when administered rivastigmine irrespective of the route of administration (oral, transdermal). In these cases, treatment should be discontinued (see Section 4.3 Contraindications). Patients and caregivers should be instructed accordingly.

Extrapyramidal symptoms.

Like other cholinomimetics, rivastigmine may induce or exacerbate extrapyramidal symptoms. In patients with Parkinson's disease who were treated with rivastigmine capsules, worsening of parkinsonian symptoms, especially tremor has been observed. Such adverse events may also occur with Exelon patches.

Use in patients with cardiovascular conditions.

As with other cholinergic substances care must be taken when prescribing Exelon transdermal patches to patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see Section 4.8 Adverse Effects (Undesirable Effects)). Drugs that increase cholinergic activity may have vagotonic effects on heart rate (e.g. bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions.

Use in patients with active gastric or duodenal ulcers or patients predisposed to these conditions.

Because of their pharmacological action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients with active gastric or duodenal ulcers or predisposed to these conditions should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing gastric or duodenal ulcers, e.g. those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of Exelon have shown no significant increase relative to placebo in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Use in patients predisposed to urinary obstruction.

Cholinomimetics may induce or exacerbate urinary obstruction. Although this has not been observed with Exelon, caution is recommended in such cases.

Use in patients predisposed to seizures.

Cholinomimetics may induce or exacerbate seizures. However, seizure activity also may be a manifestation of Alzheimer's disease. Although this has not been observed with Exelon, caution is recommended in such cases.

Use in patients with pulmonary conditions.

As with other cholinomimetics, Exelon should be used with caution in patients with a history of asthma or obstructive pulmonary disease. There is evidence from animal studies that rivastigmine may potentiate bronchoconstriction.

Use in patients with low bodyweight.

A relationship between drug exposure at steady-state (rivastigmine and metabolite NAP226-90) and bodyweight was observed in Alzheimer's dementia patients. Compared to a patient with a bodyweight of 65 kg, the rivastigmine steady-state concentrations in a patient with a bodyweight of 35 kg would be approximately doubled, while for a patient with a bodyweight of 100 kg the concentrations would be approximately halved. The effect of bodyweight on drug exposure suggests that special attention should be given to patients with very low bodyweight during up-titration.

Patients with bodyweight below 50 kg.

Caution should be exercised in titrating patients with bodyweight below 50 kg as these patients may experience more adverse reactions. Carefully titrate and monitor these patients for adverse reactions (e.g. excessive nausea and vomiting) and consider reducing the dose if such adverse reactions develop. See Section 4.2 Dose and Method of Administration.

Use in hepatic impairment.

No study was conducted with the Exelon transdermal patches in subjects with hepatic impairment. Patients with clinically significant hepatic impairment might experience more adverse reactions (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in hepatic impairment). Dosing recommendations to titrate according to individual tolerability should be closely followed. Particular caution should be exercised in titrating these patients above Exelon Patch 10. Exelon Patches are contraindicated in patients with severe liver impairment since they have not been studied in this population (see Section 4.3 Contraindications).

Use in renal impairment.

No study was conducted with the Exelon transdermal patches in subjects with renal impairment. However, due to increased exposure in renal impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in renal impairment).

Use in the elderly.

See Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly.

Paediatric use.

There is no experience with the use of Exelon in children. Exelon is not recommended for use in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The patient group to be treated frequently takes additional medications. Therefore, physicians should carefully evaluate any concomitant drug administration in this patient group.

Anticipated interactions resulting in a concomitant use not recommended.

Metoclopramide.

Considering the possibility of an additive extrapyramidal effect the concomitant use of metoclopramide and rivastigmine is not recommended.

Medicines acting on cholinergic system.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs due to possible additive effect. Rivastigmine might also interfere with the activity of anticholinergic medications (e.g. oxybutynin, tolterodine).

Succinylcholine-type muscle relaxants.

A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.
Exelon transdermal patches should not be used with any other acetylcholinesterase inhibitors.

Observed interactions to be considered.

Beta-blockers.

Additive effects leading to bradycardia (which may result in syncope) have been reported with the combined use of various beta-blockers (including atenolol) and rivastigmine. Cardioselective beta-blockers are expected to be associated with the greatest risk, but reports have also been received in patients using other beta-blockers.

Interaction with nicotine.

Population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% (n = 75 smokers and 549 nonsmokers).
Rivastigmine is metabolised mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic interactions with drugs metabolised by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6.
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in single dose studies in healthy volunteers. The elevation of prothrombin time induced by warfarin was not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.
Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.
Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n = 77), antidiabetics (n = 21), antihypertensives (n = 72), calcium channel blockers (n = 75), antianginals (n = 35), nonsteroidal anti-inflammatory drugs (n = 79), oestrogens (n = 70), salicylate analgesics (n = 177) and antihistamines (n = 15). In addition, in clinical trials, no increased risk of clinically relevant untoward effects was observed in patients treated concomitantly with rivastigmine and these agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral rivastigmine, at doses which achieved systemic drug exposures below the therapeutic value, had no effect on fertility in rats. Specific dermal studies have not been conducted. The effects of rivastigmine on human fertility are not known.
(Category B2)
Oral rivastigmine was not teratogenic in rats and rabbits at doses producing maternal toxicity, but systemic drug exposures in these studies were below the maximum therapeutic value. No specific dermal studies have been performed. The safety of Exelon transdermal patches in human pregnancy has not been established.
Rivastigmine and its metabolites are excreted into the milk of lactating rats and rabbits. It is not known whether excretion into human milk occurs, and patients using Exelon transdermal patches should not breastfeed.

4.8 Adverse Effects (Undesirable Effects)

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.
In general, adverse events are mild to moderate and usually resolve without therapeutic intervention. Incidence and severity of adverse events generally increase with higher doses.

Adverse events reported in controlled trials.

Table 1 lists treatment emergent signs and symptoms that were reported in at least 2% of patients with mild to moderate Alzheimer's dementia in placebo controlled trials and for which the rate of occurrence was greater for patients treated with Exelon transdermal patches than for those treated with placebo. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.
In this clinical trial, Patch 5 was intended as the initiating dose for patients not currently being treated with oral formulations. Adverse events were collected per target dose group. It is expected that some of the adverse events reported in Table 1 may occur with Patch 5.

Information from clinical trials in patients with severe Alzheimer's dementia treated with Exelon Patch 15.

The following adverse drug reactions (from sponsor's review) were reported in patients with severe Alzheimer's dementia treated with Exelon Patch 15. See Table 2.
Table 3 details adverse events which were thought to be related to Exelon Patch by the reporting investigator for DUS44 using the cut off of 2%.
Table 4 shows the adverse events (≥ 2% in Exelon Patch groups) from the 48 week double blind clinical trial observed in subpopulation of patients with moderate to severe Alzheimer's dementia treated with Exelon Patch 15.

Application site reactions (skin irritation).

In the 24 week double-blind study [study 2320], the most commonly observed symptoms (skin irritation rating scale) with Exelon Patch 10 were very slight (21.8%), mild (12.5%) or moderate (6.5%) erythema or very slight (11.9%), mild (7.3%) or moderate (5.0%) pruritus. The most commonly observed severe symptoms with Exelon Patch 10 were pruritus (1.7%) and erythema (1.1%). Most skin reactions were limited to the application site and resulted in discontinuation in only 2.4% of the patients in the Exelon 9.5 mg/24 h transdermal patch group. In clinical trials in a Chinese population and a Japanese population discontinuations for skin reactions in the groups receiving Exelon Patch were 4.9% and 8.4%, respectively.
The overall incidence of adverse events in patients treated with Exelon Patch 10 was lower than the rate in patients who received Exelon capsule treatment.
In the 48-week active controlled clinical trial [study 2340], cases of skin irritation were captured as patient or caregiver reported adverse events. The most commonly reported skin irritation events during the first 24 weeks of the double blind period for Exelon Patch 15 group and Exelon Patch 10 group, respectively were application site erythema (5.7% vs. 4.6%) and application site pruritus (3.6% vs. 2.8%). The percentages decreased in both Exelon Patch 15 and Exelon Patch 10 treatment groups over time (> 24 weeks): application site erythema (0.8% vs. 1.6%) and application site pruritus (0.4% vs. 1.2%), respectively. Application site pruritus led to discontinuation in 1.1% of the patients from each of the treatment groups during the total 48 week double blind treatment phase. Application site reactions were mostly mild or moderate in severity and were rated as severe in less than 2% of patients.
In the 24-week double-blind, double-dummy, controlled clinical trial in patients with severe Alzheimer's disease [study US44], cases of skin irritation were captured as adverse events. The most commonly reported skin irritation events for Exelon Patch 15 and Exelon Patch 5, respectively were application site erythema (13.2% vs. 11.7%), application site dermatitis (7.6% vs. 9.2%) and application site pruritus (3.7% vs. 2.2%). Application site erythema led to discontinuation in only 0.8% of the patients in 15 cm2 group and in 0.6% of patients in 5 cm2 group. Application site erythema in both groups was mostly mild or moderate in severity.
See Section 4.4 Special Warnings and Precautions for Use, Application site and skin reactions.
A direct comparison of the rate of skin irritation events reported in each of these studies cannot be made due to the difference in data collection methods employed.

Adverse drug reactions reported in controlled trials.

The overall incidence of adverse events (AEs) in patients treated with Exelon Patch 10 was lower than the rate in patients who received 3 to 12 mg/day Exelon capsule treatment (50.5% with Exelon Patch 10 vs 63.3% with Exelon capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse events, including nausea and vomiting, were the most common adverse events in patients who received active treatment, and occurred at a substantially lower rate in the Exelon Patch 10 group compared to the rivastigmine capsule group (7.2% vs 23.1% for nausea and 6.2% vs 17.0% for vomiting; 5.0% and 3.3% of patients on placebo reported nausea and vomiting, respectively).
Adverse reactions in Table 5 are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Additional adverse drug reactions from post-marketing spontaneous reports.

Additional adverse drug reactions have been identified based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Rarely reported.

Hypertension, application site hypersensitivity, pruritus, erythema, urticaria, blister, dermatitis allergic.

Very rarely reported.

Tachycardia, atrioventricular block, atrial fibrillation, pancreatitis, seizure.

Frequency not known.

Hepatitis, restlessness, sick sinus syndrome, abnormal liver function tests, allergic dermatitis (disseminated), extrapyramidal symptoms in patients with Alzheimer's dementia, tremor, nightmares.

Additional adverse drug reactions which have been reported with rivastigmine capsules or oral solution.

Very rare.

Severe vomiting associated with oesophageal rupture.

Rare.

Angina pectoris, myocardial infarction, duodenal ulcers.

Common.

Confusion.

4.2 Dose and Method of Administration

Dosage.

Initial dose and dose titration to the effective dose.

Treatment is started with Exelon Patch 5 once a day.
Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been well tolerated. For mild and moderate Alzheimer's disease patients continue the recommended effective dose of Exelon Patch 10 for as long as therapeutic benefit persists. Moderate patients can then be increased to the maximum recommended dose of Exelon Patch 15. For patients with severe Alzheimer's disease, after titration up Exelon Patch 15 may be used. Doses higher than Exelon Patch 15 confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse events.

Maintenance dose.

Mild Alzheimer's disease.

The effective dosage is Exelon Patch 10 administered once per day; replace with a new patch every 24 hours.

Moderate Alzheimer's disease.

After 4 weeks on Patch 5, if tolerated increase to Patch 10. The effective dosage is Exelon Patch 10 for as long as therapeutic benefit persists but (after a minimum of 4 weeks) this may be increased to Exelon Patch 15 administered once per day; replace with a new patch every 24 hours.

Severe Alzheimer's disease.

After a minimum 4 weeks on Patch 5 if tolerated increase to Patch 10. If this is tolerated for a further 4 weeks then Exelon Patch 15 administered once per day; replace with a new patch every 24 hours.

Method of administration.

Rivastigmine transdermal patches should be applied once a day to clean, dry, hairless, intact healthy skin on the upper or lower back, upper arm or chest, in a place which will not be rubbed by tight clothing. The patch should be replaced by a new one after 24 hours.
The patch should not be used with any other acetylcholinesterase inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Important administration instructions (patients and caregivers should be instructed).

The previous day's patch must be removed before applying a new one.
The patch should be replaced by a new one after 24 hours. Only one patch should be worn at a time (see Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose).
The patch should not be applied to skin that is red, irritated or cut. It is recommended to change the application site daily to avoid potential irritation, although consecutive patches can be applied to the same general anatomic site (e.g. another spot on the upper back).
The patch should be pressed down firmly for at least 30 seconds using the palm of the hand until the edges stick well.
If the patch falls off, a new one should be applied to the same site for the rest of the 24 hours, then it should be replaced at the same time as usual the next day.
The patch can be used in everyday situations, including bathing and during hot weather.
The patch should not be exposed to any external heat sources (e.g. excessive sunlight, saunas, solarium) for long periods of time.
The patch should not be cut into pieces.
Wash your hands with soap and water after removing the patch. In case of contact with eyes or if the eyes become red after handling the patch, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.

Interruption of treatment.

Treatment should be temporarily interrupted if gastrointestinal adverse effects are observed until these adverse effects resolve. Patch treatment can be resumed at the same dose if treatment is not interrupted for more than three days. Otherwise treatment should be re-initiated with Exelon Patch 5.
If adverse effects persist on re-initiation of therapy, the dose should be temporarily reduced to the previous well-tolerated dose.

Switching from capsules or oral solution.

Based on comparative exposure between oral and transdermal rivastigmine, patients treated with Exelon capsules or Exelon oral solution can be switched directly to Exelon transdermal patches:
A patient on a total daily oral rivastigmine dose of 3 mg can be switched to Exelon Patch 5.
A patient on a total daily oral rivastigmine dose of 6 mg can be switched to Exelon Patch 5.
A patient on a stable and well tolerated total daily oral rivastigmine dose of 9 mg can be switched to Exelon Patch 10. If the daily oral dose of 9 mg has not been stable and well tolerated, a switch to Exelon Patch 5 is recommended.
A patient on a total daily oral rivastigmine dose of 12 mg can be switched to Exelon Patch 10.
After switching to Exelon Patch, please see instructions for dose titration to the effective dose (see Section 4.2 Dose and Method of Administration, Dosage). It is recommended to apply the first patch on the day following the last oral dose.

Dosage adjustment.

Patients with renal or hepatic impairment.

Due to anticipated increased exposure in renal impairment and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed. Patients with clinically significant hepatic impairment may experience more dose dependent adverse reactions (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in renal impairment, Pharmacokinetics in hepatic impairment).

Patients with low bodyweight.

The effect of bodyweight on drug exposure suggests that special attention should be given to patients with very low bodyweight during up-titration (see Section 4.4 Special Warnings and Precautions for Use, Use in patients with low bodyweight). Exercise caution when up-titrating patients below 50 kg bodyweight as these patients may experience more adverse reactions. Carefully titrate and monitor these patients for adverse reactions (e.g. excessive nausea or vomiting) and consider reducing the dose if such adverse reactions develop.

4.7 Effects on Ability to Drive and Use Machines

Alzheimer's disease dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. Rivastigmine may induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. Therefore, the ability of Alzheimer's patients to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.9 Overdose

Symptoms.

Most cases of accidental overdosage have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued Exelon treatment. Where symptoms have occurred, they have included severe nausea, vomiting, diarrhoea, abdominal pain, dizziness, tremor, headache, somnolence, bradycardia, confusional state, hyperhidrosis, hypertension, hallucinations and malaise. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when coadministered with quaternary anticholinergics such as glycopyrrolate. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur.
Overdose with Exelon patches resulting from misuse/ medication errors (application of multiple patches at a time) has been reported in the postmarketing setting and rarely in clinical trials. Fatal outcome has been rarely reported with rivastigmine overdose. Symptoms of overdose and outcome vary from patient to patient and the severity of the outcome is not predictably related to the amount of the overdose.

Treatment.

As rivastigmine has a plasma half-life of about 1 hour and duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that, in cases of asymptomatic overdoses, no further dose of Exelon should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse events should be given as necessary.
Due to the short half-life of Exelon, dialysis (haemodialysis, peritoneal dialysis or haemofiltration) would not be clinically indicated in the event of an overdose.
In massive overdoses, atropine can be used. An initial intravenous dose of 0.03 mg/kg atropine sulphate is recommended, with subsequent doses based upon clinical response. Use of hyoscine as an antidote is not recommended.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

dl-alpha-tocopherol, dimeticone 12500, Durotak 387-2353 (ARPING no: 2261), Bio-PSA 7-4302, silicone adhesive (ARPING no: 12567), and acrylates copolymer.

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. Keep the patch in the sachet until use. Do not freeze. Keep out of the reach of children.

6.5 Nature and Contents of Container

Three strengths of Exelon patches are available, providing the following in vivo release rates (see Table 11).
The outside of the backing layer is beige and labelled. Each patch strength is labelled as follows.
Exelon Patch 5 with "AMCX" and "Exelon Patch 5 (rivastigmine)".
Exelon Patch 10 with "BHDI" and "Exelon Patch 10 (rivastigmine)".
Exelon Patch 15 with "CNFU" and "Exelon Patch 15 (rivastigmine)".
The Exelon patches are individually sealed in child resistant sachets made of a paper/ polyester/ aluminium/ polyacrylonitrile or paper/ polyethylene terephthalate/ polyethylene/ aluminium/ polyamide multi-laminated material.
The sachets are packed into cartons of 7 or 30 patches.

6.6 Special Precautions for Disposal

Used patches should be folded, with the adhesive surfaces pressed together, and discarded safely and out of the reach and sight of children.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes