Exelon Patch

Rivastigmine.

Each transdermal patch releases 4.6 mg of rivastigmine per 24 hours. Each transdermal patch of 5 cm² contains 9 mg of rivastigmine.
Each transdermal patch releases 9.5 mg of rivastigmine per 24 hours. Each transdermal patch of 10 cm² contains 18 mg of rivastigmine.
Each transdermal patch releases 13.3 mg of rivastigmine per 24 hours. Each transdermal patch of 15 cm² contains 27 mg of rivastigmine.
Excipients/Inactive Ingredients: Exelon 4.6 mg/24 h transdermal patch and Exelon 9.5 mg/24 h transdermal patch: Vitamin E, poly butylmethacrylate, methyl-methacrylate, acrylic copolymer, silicone oil (Ph. Eur.). Pharmaceutical formulations may vary between countries.
Exelon 13.3 mg/24 h transdermal patch: Drug product matrix: acrylic pressure sensitive adhesive, poly(butylmethacrylate, methylmethacrylate), tocopherol (all-rac-α), Vitamin E.
Adhesive matrix: silicone pressure sensitive adhesive (contains ethyl acetate), silicone oil 12,500 cSt, Dimethicone, tocopherol (all-rac-α), Vitamin E.
Print Ink: Beige print ink (contains ethyl acetate, ethanol, 1-methoxypropan-2-ol, resin, pigments), Hardener for print ink (contains ethanol, organic polymers/resins (without chlorine)).

Pharmacotherapeutic Group: Psychoanaleptics, anticholinesterases. ATC Code: N06DA03.
Pharmacology: Pharmacodynamics: Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in 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. In patients with Alzheimer's disease, inhibition of AChE in CSF by oral rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer's disease patients by oral rivastigmine was similar to the inhibition of AChE activity.
Clinical studies in Alzheimer's dementia: The efficacy of Exelon transdermal patches in patients with Alzheimer's dementia has been demonstrated in a 24-week double-blind, placebo-controlled core study and its open-label extension phase and in a 48-week double-blind comparator study.
24-week placebo-controlled study: Patients involved in this study had a 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 (Alzheimer's Disease Assessment Scale-Cognitive subscale, a performance-based measure of cognition) and the ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change, a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living, a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores eg, 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 1. (See Table 1.)

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The results for clinically relevant responders from the 24-week study are provided in Table 2. 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. (See Table 2.)

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Similar results were observed with Exelon Patch 10 in separately conducted controlled studies in Chinese and Japanese patients with mild to moderately severe Alzheimer's dementia.
As suggested by compartmental modelling, 9.5 mg/24 h transdermal patches exhibited exposure similar to that provided by an oral dose of 12 mg/day.
48-week active comparator-controlled study: Patients involved in the active comparator controlled study had an initial baseline MMSE score of 10-24. The study was designed to compare the efficacy of the 13.3 mg/24 h transdermal patch against the 9.5 mg/24 h transdermal patch during a 48-week double-blind treatment phase in Alzheimer's disease patients who demonstrated functional and cognitive decline after an initial 24-48 week open-label treatment phase while on a maintenance dose of 9.5 mg/24 hrs transdermal patch. 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. Efficacy was established by the use of ADAS-Cog (Alzheimer's Disease Assessment Scale - Cognitive subscale, a performance-based measure of cognition) and the ADCS-IADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) assessing instrumental activities which include maintaining finances, meal preparation, shopping, ability to orient oneself to surroundings, ability to be left unattended. The 48-week results for the two assessment tools are summarised in Table 3.

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The European Medicines Agency has waived the obligation to submit the results of studies with Exelon in all subsets of the paediatric population in the treatment of Alzheimer's dementia (see Dosage & Administration).
Pharmacokinetics: 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. C_max is reached after 10-16 hours. 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 transdermal patch is replaced with a new one, plasma concentrations initially decrease slowly for about 40 minutes on average, until absorption from the newly applied transdermal patch becomes faster than 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 administration, with which concentrations fall off to virtually zero between doses. Although less pronounced than with the oral formulation, exposure to rivastigmine (C_max and AUC) increased over-proportionally by a factor of 2.6 and 4.9 when escalating from 4.6 mg/24 h to 9.5 mg/24 h and to 13.3 mg/24 h, respectively. The fluctuation index (FI), a measure of the relative difference between peak and trough concentrations [(C_max-C_min)/C_avg], was 0.58 for Exelon 4.6 mg/24 h transdermal patches, 0.77 for Exelon 9.5 mg/24 h transdermal patches and 0.72 for Exelon 13.3 mg/24 h transdermal patches, 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 dose of rivastigmine released from the transdermal patch over 24 hrs (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.
The single-dose inter-subject variability in rivastigmine pharmacokinetic parameters (normalised to dose/kg body weight) was 43% (C_max) and 49% (AUC_0-24h) after transdermal administration versus 74% and 103%, respectively, after the oral form. The inter-patient variability in a steady-state study in Alzheimer's dementia was at most 45% (C_max) and 43% (AUC_0-24h) after use of the transdermal patch and 71% and 73%, respectively, after administration of the oral form.
A relationship between active substance exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer's dementia patients. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved. The effect of bodyweight on active substance exposure suggests special attention to patients with very low body weight during up-titration (see Dosage & Administration).
Exposure (AUC_∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm and approximately 20-30% lower when applied to the abdomen or thigh.
There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer's disease, except that with plasma levels were higher on the second day of transdermal patch therapy than on the first.
Distribution: Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brain barrier and has an apparent volume of distribution in the range of 1.8-2.7 l/kg.
Biotransformation: Rivastigmine is rapidly and extensively metabolised with an apparent elimination half-life in plasma of approximately 3.4 hrs after removal of the transdermal patch. Elimination was absorption rate limited (flip-flop kinetics), which explains the longer t_½ after patch (3.4 h) versus oral or intravenous administrations (1.4-1.7 h). Metabolism is primarily via cholinesterase-mediated hydrolysis to the metabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on in vitro studies, no pharmacokinetic drug interactions are expected with drugs metabolized by the following cytochrome isoenzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. 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 non-linear, over-proportional pharmacokinetics of rivastigmine due to saturation of its elimination.
The metabolite-to-parent AUC_∞ ratio was around 0.7 after patch administration versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal compared to oral treatment. Less NAP226-90 is formed following patch application of the transdermal patch, presumably because of the lack of presystemic (hepatic first-pass) metabolism, in contrast to oral administration.
Elimination: Unchanged rivastigmine is found in trace amounts in the urine; renal excretion of the metabolites is the major route of elimination after transdermal patch administration. 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 feces.
Elderly population: Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with Exelon transdermal patches.
Hepatic Impairment: No study was conducted with the Exelon transdermal patches in subjects with hepatic impairment. After oral administration, the C_max of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects. Following a single 3-mg oral dose or multiple 6-mg twice a day oral doses, the mean oral clearance of rivastigmine was approximately 60-65% lower in mild (n=7, Child-Pugh score 5-6) and moderate (n=3, Child-Pugh score 7-9) hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). These pharmacokinetic changes had no effect on either the incidence or severity of adverse effects (see Dosage & Administration and Precautions).
Renal Impairment: No study was conducted with the Exelon transdermal patches in subjects with renal impairment. Based on population analysis, creatinine clearance did not show any clear effect on steady-state concentrations of rivastigmine or its metabolite. No dosage adjustment is necessary in patients with renal impairment (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Oral and topical repeated-dose toxicity studies in mice, rats, rabbits, dogs and minipigs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. Oral and topical dosing in animal studies was limited due to the sensitivity of the animal models used.
Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose exceeding 10⁴ times the foreseen clinical exposure. The in vivo micronucleus test was negative.
No evidence of carcinogenicity was found in oral and topical studies in mice and in an oral study in rats at the maximum tolerated dose. The exposure to rivastigmine and its metabolites was approximately equivalent to human exposure with highest doses of rivastigmine capsules and transdermal patches.
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. Specific dermal studies in pregnant animals have not been conducted.
Rivastigmine transdermal patches were not phototoxic. In some other dermal toxicity studies, a mild irritant effect on the skin of laboratory animals, including controls, was observed. This may indicate a potential for Exelon transdermal patches to induce mild erythema in patients. When administered to rabbit eyes in primary eye irritation studies, rivastigmine caused reddening and swelling of the conjunctiva, corneal opacities and miosis which persisted for 7 days. Therefore, the patient/caregiver should avoid contact with the eyes after handling of the patch (see Precautions).

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. (See Table 4.)

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Initial dose: Treatment is started with 4.6 mg/24 h.
Maintenance dose: After a minimum of four weeks of treatment and if well tolerated according to the treating physician, the dose of 4.6 mg/24 h should be increased to 9.5 mg/24 h, the daily recommended effective dose, which should be continued for as long as the patient continues to demonstrate therapeutic benefit.
Dose escalation: 9.5 mg/24 h is the recommended daily effective dose which should be continued for as long as the patient continues to demonstrate therapeutic benefit. If well tolerated and only after a minimum of six months of treatment at 9.5 mg/24 h, the treating physician may consider increasing the dose to 13.3 mg/24 h in patients who have demonstrated a meaningful cognitive deterioration (e.g. decrease in the MMSE) and/or functional decline (based on physician judgement) while on the recommended daily effective dose of 9.5 mg/24 h (see Pharmacology: Pharmacodynamics under Actions).
The clinical benefit of rivastigmine should be reassessed on a regular basis. Discontinuation should also be considered when evidence of a therapeutic effect at the optimal dose is no longer present.
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 three 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 (see Pharmacology: Pharmacokinetics under Actions), 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.
Special populations: Paediatric population: There is no relevant use of Exelon in the paediatric population in the treatment of Alzheimer's disease.
Patients with body weight below 50 kg: Particular caution should be exercised in titrating patients with body weight 50 kg above the recommended effective dose of 9.5 mg/24 h (see Precautions). They may experience more adverse reactions and may be more likely to discontinue due to adverse reactions.
Hepatic impairment: No dose adjustment is necessary for patients with hepatic impairment. However, due to increased exposure in these populations as observed with the oral forms, dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant hepatic impairment might experience more adverse reactions. Patients with severe hepatic impairment have not been studied (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Renal impairment: No dose adjustment is necessary for patients with renal impairment. However, due to increased exposure in these populations as observed with the oral forms, dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal impairment might experience more adverse reactions (see Pharmacology: Pharmacokinetics under Actions and Precautions).
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.
Patients and caregivers should be instructed on important administration instructions: The previous day's patch must be removed before applying a new one every day (see Overdosage).
The patch should be replaced by a new one after 24 hours. Only one patch should be worn at a time (see Overdosage).
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 for the rest of the day, 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 (eg, excessive sunlight, saunas, solarium) for long periods of time.
The patch should not be cut into pieces.
Wash the 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.

Symptoms: Most cases of accidental overdosage of oral rivastigmine have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and 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 and convulsion. Muscle weakness is a possibility and may result in death if respiratory muscles are involved. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Overdose with Exelon transdermal patch resulting from misuse/dosing errors (application of multiple patches at a time) has been reported in the post-marketing setting and rarely in clinical trials. Fatal outcome has been rarely reported with rivastigmine overdose and relationship to rivastigmine was unclear. Symptoms of overdosage 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 3.4 hours and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose all Exelon transdermal patches should be removed immediately and no further patch should be applied 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.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulfate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in Description.
Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine patch (see Precations).

The incidence and severity of adverse reactions generally increase with increasing doses, particularly at dose changes. If treatment is interrupted for more than three days, it should be re-initiated with 4.6 mg/24 h.
Misuse of the medicinal product and dosing errors resulting in overdose: Misuse of the medicinal product and dosing errors with Exelon transdermal patch have resulted in serious adverse reactions; some cases have required hospitalisation, and rarely led to death (see Overdosage). Most cases of misuse of the medicinal product and dosing errors have involved not removing the old patch when putting on a new one and the use of multiple patches at the same time. Patients and their caregivers must be instructed on important administration instructions for Exelon transdermal patch (see Dosage & Administration).
Gastrointestinal disorders: Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur when initiating treatment and/or increasing the dose (see Adverse Reactions). These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes.
Weight loss: 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.
Other adverse reactions: 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 Adverse Reactions); to patients with active gastric or duodenal ulcers or patients predisposed to these conditions because rivastigmine may cause increased gastric secretions (see Adverse Reactions); 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.
Skin application site reactions: Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in intensity. Patients and caregivers should be instructed accordingly.
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 Contraindications).
Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine patch and who still require rivastigmine treatment should only be switched to oral rivastigmine 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 rare 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 Contraindications).
Other warnings and precautions: Rivastigmine may exacerbate or induce extrapyramidal symptoms.
Contact with the eyes should be avoided after handling Exelon transdermal patches (see Pharmacology: Toxicology under Actions). Hands should be washed 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.
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 (see Dosage & Administration). Carefully titrate and monitor these patients for adverse reactions (e.g. excessive nausea or vomiting) and consider reducing the maintenance dose to the 4.6 mg/24 h transdermal patch if such adverse reactions develop.
Hepatic impairment: Patients with clinically significant hepatic impairment might experience more adverse reactions (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration). Consider using the 4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.
Renal impairment: Patients with clinically significant renal impairment might experience more adverse reactions (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration). Consider using the 4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.
Effects on ability to drive or and use machines: Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machines. Furthermore, rivastigmine may induce syncope or delirium. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.

Women of child-bearing potential: There is no information available on the effects of rivastigmine in women of child-bearing potential.
Pregnancy: In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans. In animal studies, rivastigmine was not teratogenic. However, the safety of Exelon in human pregnancy has not been established, and it should only be given to pregnant women if the potential benefit outweighs the potential risk for the foetus.
Breast-feeding: In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
Fertility: In male and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive performance of either the parent generation or the offspring of the parents (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). There is no information available on the effects of rivastigmine on human fertility.

Summary of the safety srofile: Application site skin reactions (usually mild to moderate application site erythema), are the most frequent adverse reactions observed with the use of Exelon transdermal patch. The next most common adverse reactions are gastrointestinal in nature including nausea and vomiting.
Adverse reactions in Table 5 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Tabulated list of adverse reactions: Table 5 displays the adverse reactions reported in 854 patients with Alzheimer's dementia treated in randomised, double-blind, placebo and active-controlled clinical studies with Exelon transdermal patches for a duration of 24-48 weeks and from post-marketing data. (See Table 5.)

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Description of selected adverse reactions: When doses higher than 13.3 mg/24 h were used in the above-mentioned placebo-controlled study, insomnia and cardiac failure were observed more frequently than with 13.3 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 13.3 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 transdermal patches: somnolence, malaise, tremor, confusion, sweating increased (common); duodenal ulcers, angina pectoris (rare); gastrointestinal haemorrhage (very rare); and some cases of severe vomiting were associated with oesophageal rupture (not known).
Skin irritation: In double-blind controlled clinical trials, application site reactions were mostly mild to moderate in severity. The incidence of application site skin reactions leading to discontinuation was observed in ≤2.3% of Exelon Patch patients. This number was 4.9% and 8.4% in the Chinese population and Japanese population, respectively.
Cases of skin irritation were captured separately on an investigator-rated skin irritation scale. Skin irritation, when observed, was mostly slight or mild in severity and was rated as severe in ≤2.2% of Exelon Patch patients, in a double-blind controlled study and in ≤3.7% of Exelon Patch patients in a double-blind controlled study in Japanese patients. See Precautions-Application site reactions and skin reactions.

No specific interaction studies have been performed with the Exelon transermal patches.
Anticipated interactions resulting in a concomitant use not recommended.
Metoclopramide: Considering the possibility of an additive extra-pyramidal effect the concomitant use of metoclopramide and rivastigmine is not recommended.
Drugs 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: As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia.
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: A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% in patients with Alzheimer's dementia (n=75 smokers and 549 non-smokers) following rivastigmine oral capsule doses of up to 12 mg/day.
Interactions with commonly used concomitant drugs: 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, 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.

Incompatibilities: To prevent interference with the adhesive properties of the transdermal patch, no cream, lotion or powder should be applied to the skin area where the medicinal product is to be applied.
Special precautions for disposal: Used transdermal patches should be folded in half, with the adhesive side inwards, placed in the original sachet and discarded safely and out of the reach and sight of children. Any used or unused transdermal patches should be disposed of in accordance with local requirements or returned to the pharmacy.
Where to apply the Exelon transdermal patch: Before applying the Exelon Patch, make sure that the skin is clean, dry and hairless, free of any powder, oil, moisturiser or lotion that could keep the patch from sticking to the skin properly, free of cuts, rashes and/or irritations.
Carefully remove any existing patch before putting a new one. Having multiple patches on the body could expose the patient to an excessive amount of rivastigmine which could be potentially dangerous.
Apply one patch per day to only one of the possible locations: Left or right upper arm, left or right upper chest (avoid breast), left or right upper back, left or right lower back.
Every 24 hours, take off the previous patch before putting one new patch on to only one of the following possible locations.
When changing the patch, the patient must remove the previous day's patch before applying the new one to a different location of the skin each time. Do not apply new patch to the same skin area twice within 14 days.
How to apply the Exelon transdermal patch: Exelon patches are thin, opaque, plastic patches that stick to the skin. Each patch is sealed in a sachet that protects it until it is used. Do not open the sachet or remove a patch until just before application.
Carefully remove the existing patch before putting on a new one.
For patients starting treatment for the first time and for patients restarting Exelon after treatment interruption: Each patch is sealed in its own protective sachet. The patient should only open the sachet when it is ready to administer. Cut the sachet along the dotted line with scissors and remove the patch from the sachet.
A protective liner covers the sticky side of the patch. Peel off one side of the protective liner and do not touch the sticky part of the patch with the fingers.
Put the sticky side of the patch on the upper or lower back, upper arm or chest and then peel off the second side of the protective liner.
Then press the patch firmly in place for at least 30 seconds using the palm of the hand to make sure that the edges stick well.
The patient may write the date on the patch of when it is administered with a thin ball point pen.
The patch should be worn continuously until it is time to replace it with a new one. The patient may experiment with different locations when applying a new patch to find ones that are most comfortable and where clothing will not rub on the patch.
How to remove the Exelon transdermal patch: Gently pull at one edge of the Exelon Patch to remove it completely from the skin.
In case the adhesive residue is left over the skin, gently soak the area with warm water and mild soap or use baby oil to remove it. Alcohol or other dissolving liquids (nail polish remover or other solvents) should not be used.
Wash 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.
Wearing Exelon transdermal patch when you are bathing, swimming, or in the sun: Bathing, swimming or showering should not affect the patch. Make sure that the patch does not loosen during these activities.
Do not expose the patch to any external heat sources (e.g. excessive sunlight, saunas, solarium) for long periods of time.
What to do if a patch falls off: If the patch falls off, a new patch should be applied for the rest of the day, then replace the patch next day at the same time as usual.

Special precautions for storage: Keep the transdermal patch in the sachet until use.

Neurodegenerative Disease Drugs

N06DA03 - rivastigmine ; Belongs to the class of anticholinesterases. Used in the management of dementia.

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