Anticholinesterases

Rivastigmine

Exelon 4.6 mg/24 h transdermal patch: Each transdermal patch releases 4.6 mg of rivastigmine per 24 hours. Each transdermal patch of 5 cm2 contains 9 mg of rivastigmine. Exelon 9.5 mg/24 h transdermal patch: Each transdermal patch releases 9.5 mg of rivastigmine per 24 hours. Each transdermal patch of 10 cm2 contains 18 mg of rivastigmine.

Transdermal patch Exelon 4.6 mg/24 h transdermal patch: Each transdermal patch is a thin, matrix-type transdermal patch consisting of three layers. The outside of the backing layer is beige and labelled with “Exelon”, “4.6 mg/24 h” and “AMCX”. Exelon 9.5 mg/24 h transdermal patch: Each transdermal patch is a thin, matrix-type transdermal patch consisting of three layers. The outside of the backing layer is beige and labelled with “Exelon”, “9.5 mg/24 h” and “BHDI”.

Symptomatic treatment of mild to moderately severe Alzheimer's dementia.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made according to current guidelines. Similar to any treatment initiated in patients with dementia, therapy with rivastigmine should only be started if a caregiver is available to regularly administer and monitor the treatment.

Posology

Initial dose Treatment is started with 4.6 mg/24 h.

After a minimum of four weeks of treatment and if well tolerated according to the treating physician, this dose should be increased to 9.5 mg/24 h, which is the recommended effective dose

Maintenance dose

9.5 mg/24 h is the recommended daily maintenance dose which can be continued for as long as the patient is deriving therapeutic benefit. Treatment should be temporarily interrupted if gastrointestinal adverse reactions are observed until these adverse reactions resolve. Transdermal patch treatment can be resumed at the same dose if treatment is not interrupted for more than several days. Otherwise treatment should be re-initiated with 4.6 mg/24 h.

Switching from capsules or oral solution to transdermal patches

Based on comparable exposure between oral and transdermal rivastigmine, patients treated with Exelon capsules or oral solution can be switched to Exelon transdermal patches as follows:

• A patient on a dose of 3 mg/day oral rivastigmine can be switched to 4.6 mg/24 h transdermal patches.

• A patient on a dose of 6 mg/day oral rivastigmine can be switched to 4.6 mg/24 h transdermal patches.

• A patient on a stable and well tolerated dose of 9 mg/day oral rivastigmine can be switched to 9.5 mg/24 h transdermal patches. If the oral dose of 9 mg/day has not been stable and well tolerated, a switch to 4.6 mg/24 h transdermal patches is recommended.

• A patient on a dose of 12 mg/day oral rivastigmine can be switched to 9.5 mg/24 h transdermal patches.

After switching to 4.6 mg/24 h transdermal patches, provided these are well tolerated after a minimum of four weeks of treatment, the dose of 4.6 mg/24 h should be increased to 9.5 mg/24 h, which is the recommended effective dose.

It is recommended to apply the first transdermal patch on the day following the last oral dose.

Method of administration

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. It is not recommended to apply the transdermal patch to the thigh or to the abdomen due to decreased bioavailability of rivastigmine observed when the transdermal patch is applied to these areas of the body.

The transdermal patch should not be applied to skin that is red, irritated or cut. Reapplication to the exact same skin location within 14 days should be avoided to minimise the potential risk of skin irritation.

The transdermal patch should be pressed down firmly until the edges stick well. It can be used in everyday situations, including bathing and during hot weather.

The transdermal patch should be replaced by a new one after 24 hours. Only one transdermal patch should be worn at a time. Patients and caregivers should be instructed accordingly.

Renal impairment: No dose adjustment is necessary for patients with renal impairment.

Children and adolescents (age below 18 years): Rivastigmine is not recommended for use in children and adolescents.

Children and adolescents (age below 18 years): Rivastigmine is not recommended for use in children and adolescents.

Hypersensitivity to the active substance, to other carbamate derivatives or to any of the excipients used in the formulation.

The incidence and severity of adverse reactions generally increase with increasing doses, particularly at dose changes. If treatment is interrupted for more than several days, it should be re-initiated with 4.6 mg/24 h.

Gastrointestinal disorders such as nausea and vomiting are dose-related, and may occur when initiating treatment and/or increasing the dose.

Patients with Alzheimer's disease may lose weight whilst taking cholinesterase inhibitors, including rivastigmine. The patient's weight should be monitored during therapy with Exelon transdermal patches.

Care must be taken when prescribing Exelon transdermal patches:

• to patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block)

• to patients with active gastric or duodenal ulcers or patients predisposed to these conditions because rivastigmine may cause increased gastric secretions

• to patients predisposed to urinary obstruction and seizures because cholinomimetics may induce or exacerbate these diseases.

• to patients with a history of asthma or obstructive pulmonary disease.

Rivastigmine may exacerbate or induce extrapyramidal symptoms.

Contact with the eyes should be avoided after handling Exelon transdermal patches.

Special populations:

• Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions.

• Hepatic impairment: Patients with clinically significant hepatic impairment might experience more adverse reactions

No specific interaction studies have been conducted with Exelon transdermal patches.

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

No pharmacokinetic interaction was observed between oral rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of oral rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and oral rivastigmine.

Concomitant administration of rivastigmine with commonly prescribed medicinal products, such as antacids, antiemetics, antidiabetics, centrally acting antihypertensives, beta blockers, calcium channel blockers, inotropic agents, antianginals, non-steroidal anti-inflammatory agents, oestrogens, analgesics, benzodiazepines and antihistamines, was not associated with an alteration in the kinetics of rivastigmine or an increased risk of clinically relevant untoward effects.

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

The overall incidence of adverse events (AEs) in patients treated with Exelon 9.5 mg/24 h transdermal patches was lower than the rate in patients who received 3 to 12 mg/day Exelon capsule treatment (50.5% with Exelon 9.5 mg/24 h transdermal patches vs 63.3% with Exelon capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse reactions, including nausea and vomiting, were the most common adverse reactions in patients who received active treatment, and occurred at a substantially lower rate in the Exelon 9.5 mg/24 h transdermal patch group compared to the Exelon 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).

Table 1 displays the adverse reactions (events reasonably believed to be causally related to the medicinal product) reported in 291 patients with Alzheimer's dementia treated in a specific 24-week double-blind, placebo and active-controlled clinical study with Exelon transdermal patches at target dose of 9.5 mg/24 h (4.6 mg/24 h titrated to 9.5 mg/24 h).

Adverse reactions 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).

Table 1

When doses higher than 9.5 mg/24 h were used in the above-mentioned study, dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure were observed more frequently than with 9.5 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 9.5 mg/24 h transdermal patches than with placebo.

The following adverse reactions have only been observed with Exelon capsules and oral solution and not in clinical studies with Exelon 9.5 mg/24 h transdermal patches: Dizziness (very common); agitation, somnolence, malaise, tremor, confusion, sweating increased (common); insomnia, accidental fall, elevated liver function tests (uncommon); seizures, duodenal ulcers, angina pectoris (rare); cardiac arrhythmia (e.g. atrio-ventricular block, atrial fibrillation and tachycardia), hypertension, pancreatitis, gastrointestinal haemorrhage, hallucination (very rare); and some cases of severe vomiting were associated with oesophageal rupture (unknown).

Skin irritation

In clinical trials, skin reactions were measured at each visit using a skin irritation rating scale that rated the degree of erythema, oedema, scaling, fissures, pruritus and pain/stinging/burning at the application site. The most commonly observed symptom was erythema which disappeared within 24 hours in the vast majority of patients. In a 24-week double-blind study, the most commonly observed symptoms (skin irritation rating scale) with Exelon 9.5 mg/24 h transdermal patches 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 9.5 mg/24 h transdermal patches 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.

Novartis

(POM)

11 August 2009