Exelon Patch 4.600 mg

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs. 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 as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Rivastigmine is mainly metabolised through hydrolysis by esterases. No in vivo studies have investigated the effects of EXELON on the clearance of drugs metabolised by CYP450. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolised by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. Thus, no pharmacokinetics interactions are anticipated with other drugs metabolized by these enzymes.

Rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other drugs (see Actions and Clinical Pharmacology, Pharmacokinetics, Metabolism).

Studies to assess the potential of EXELON administered orally for interaction with digoxin, warfarin, diazepam or fluoxetine were limited to short term, single-dose studies in young healthy volunteers. No significant effects on the pharmacokinetics of these drugs or on the metabolism of rivastigmine were observed. Similar studies in elderly patients were not done.

In controlled clinical trials with EXELON capsules few patients received neuroleptics, antidepressants or anticonvulsants, there is thus limited information concerning the interaction of EXELON with these drugs.

Drugs which induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Formal pharmacokinetic studies to assess the potential for drug interaction with other medications commonly taken by the elderly were not done. Population-pharmacokinetic analyses of a subset (n=359; 6-12 mg/day) of patients with Alzheimer’s disease in controlled clinical trials do not suggest that the oral administration of EXELON with some commonly prescribed medications is associated with an alteration in the kinetics of rivastigmine, or an increased risk of clinically relevant untoward effects. However, the number of patients who received concomitant medications chronically was as follows: anilides (e.g. acetaminophen) (10%), antacids (12%), antianginals (6%), antihistamines (2%), antihypertensives (12%), benzodiazepines (<1%), β-blockers (7%), calcium channel blockers (12%), digitalis glycosides (5%), nonsteroidal anti-inflammatory drugs (13%), oral hypoglycemics (3%), and salicylic acid and derivatives (28%).

Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

No specific interaction studies have been conducted with EXELON PATCH (rivastigmine).

EXELON PATCH 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 that will not be rubbed by tight clothing. Application of the patch to other areas, such as the abdomen and thighs, has been shown to decrease the bioavailability of rivastigmine and cause more skin irritation (see Actions and Clinical Pharmacology, Pharmacokinetics and Adverse Reactions, Skin Irritation). The patch should not be applied to skin that is red, irritated, or cut. It is recommended to change the application spot daily to avoid potential irritation, although consecutive patches can be applied to the same anatomic site (e.g., another spot on the same upper arm). The same skin location should not be used within 14 days.

The patch should be pressed down firmly, by applying pressure with the hand over the entire patch for about 10 seconds, making sure that the edges stick well. It can be used in everyday situations, including bathing and during hot weather, however, it should be checked to ensure it has remained well adhered. Showering and washing the EXELON PATCH site is possible without loss of adherence. To ensure proper adherence, the patch should not be applied to wet or damp skin.

The patch should be replaced with a new one after 24 hours. Only one patch should be worn at a time. Patients and caregivers should be instructed accordingly (see Information for the Patient).

The missed dose should be taken immediately or at the next scheduled dose. Doses should not be doubled. If therapy has been interrupted for a few days, treatment should be reinitiated with EXELON PATCH 5.

Patients treated with EXELON capsules or oral solution may be switched to EXELON PATCH as follows:

• A patient who is on a dose of <3 mg BID (<6 mg/day) oral rivastigmine can be switched to EXELON PATCH 5.

  
  

• A patient who is on a dose of 3 to 6 mg BID (6 to 12 mg/day) oral rivastigmine may be directly switched to EXELON PATCH 10.

  
  

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

To prevent interference with the adhesive properties of the patch, the patch should not be applied to a skin area where cream, lotion or powder has recently been applied.

Hepatic Impairment: EXELON PATCH has not been studied in hepatic impairment. Patients with clinically significant hepatic impairment may experience more adverse events. Caution should be used when titrating hepatically impaired patients (see Action and Clinical Pharmacology).

Treatment is started with EXELON PATCH 5 once a day.

If EXELON PATCH 5 is well tolerated, the dose should be increased to EXELON PATCH 10 after a minimum of four weeks of treatment.

EXELON PATCH 10 is the maximum recommended daily maintenance dose which can be continued for as long as a therapeutic benefit for the patient exists. Higher doses confer no appreciable additional benefit, and are associated with significant increases in the incidence of adverse events (see Adverse Reactions).

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 a few days. Otherwise, treatment should be reinitiated with EXELON PATCH 5.

If adverse effects persist on reinitiation of therapy, the dose should be temporarily reduced to EXELON PATCH 5.

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

Infrequent: benign prostatic hyperplasia.

Infrequent: cataract, glaucoma, vision blurred.

Frequent: fall. Infrequent: hip fracture, subdural hematoma.

In clinical trials, skin reactions were measured at each visit using a skin irritation rating scale that rated the degree of erythema, edema, 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. During a 24-week double-blind study, symptoms or signs (skin irritation scale) of skin irritation were mainly erythema or pruritus and were mostly slight or mild in severity. Skin irritation rated as severe was observed on at least one occasion in ≤2.2% of EXELON PATCH patients, versus ≤1.0% of placebo patch. Most skin reactions were limited to the application site and resulted in discontinuation in only 2.4% of the patients on EXELON PATCH 10.

In one crossover trial in 40 healthy volunteers, the application of the patch to the abdomen or outer thigh was more likely to result in skin irritation (mild to moderate erythema), whereas application to the upper arm and chest was less likely to cause skin irritation when compared to application to the upper back (see also Actions and Clinical Pharmacology, Absorption, for effect of application site on plasma concentrations).

Voluntary reports of adverse events temporally associated with EXELON capsules that have been received since market introduction that may or may not be causally related to the drug include the following:

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In the single controlled clinical trial with the EXELON PATCH, 1190 patients were treated with EXELON PATCH 20, EXELON PATCH 10, EXELON capsule and placebo. The overall incidence of adverse events in patients treated with EXELON PATCH 10 (rivastigmine) was lower than the rate in patients who received EXELON PATCH 20 and EXELON capsule treatment. Nausea and vomiting were the most common adverse events in patients who received active treatment, and occurred at similar rates in both EXELON PATCH 20 and capsule groups. The rates of both these events were substantially lower in the EXELON PATCH 10 group compared to the EXELON PATCH 20 and EXELON capsule groups.

Infrequent: dyspnea, bronchospasm, chronic obstructive pulmonary disease.

Infrequent: application site dermatitis, application site irritation, peripheral edema, chest pain, application site eczema, hyperpyrexia, malaise.

Infrequent: angina pectoris, coronary artery disease, cardiac failure, bradycardia, atrial fibrillation, syncope, electrocardiogram QT prolonged, supraventricular extrasystoles, myocardial infarction, tachycardia, arrhythmia, atrioventricular block.

Overall, 11% of patients treated with EXELON PATCH 10, 10% of patients treated with EXELON PATCH 20, 9% of patients treated with EXELON capsule, compared to 6% of patients treated with placebo discontinued from the EXELON PATCH controlled clinical trial, due to adverse events. During the titration phase the incidence of discontinuations due to adverse events was 3.6% for placebo, 6.8% for EXELON capsule, 9.6% for EXELON PATCH 10, and 7.3% for EXELON PATCH 20. During the maintenance phase, 2.5% of patients who received placebo, 2.0% of patients who received EXELON capsule, 1.2% of patients who received EXELON PATCH 10, and 3.8% of patients who received EXELON PATCH 20 withdrew due to adverse events.

The most frequent adverse events leading to discontinuation from this study, defined as those occurring in at least 1% of patients receiving EXELON PATCH 20 or EXELON PATCH 10 and more frequent than those receiving placebo, were nausea, vomiting, anorexia, weight decreased, asthenia, application site pruritus, cerebrovascular accident, dizziness, syncope, agitation, anxiety, delirium, erythema and pruritus. Only nausea and vomiting resulted in discontinuation of >1% of patients in an EXELON PATCH treatment group (nausea-EXELON PATCH 20 2% vs placebo 1%; vomiting-EXELON PATCH 20 2% vs placebo <1%). All other adverse events leading to discontinuation occurred in 1% of patients treated with EXELON PATCH and <1% of patients who received placebo.

Infrequent: tinnitus.

Frequent: dehydration. Infrequent: blood amylase increased, blood creatine phosphokinase increased, hyperlipidemia, hypokalemia, hyponatremia, lipase increased.

Stevens-Johnson syndrome.

Frequent: tremor. Infrequent: migraine, parkinsonism, epilepsy, cerebrovascular accident, cerebral hemorrhage, cerebellar hemorrhage, transient ischemic attack.

Frequent: urinary incontinence. Infrequent: pollakiuria, hematuria, nocturia, renal failure.

Frequent: pruritus. Infrequent: erythema, eczema, dermatitis, rash erythematous, skin ulcer, hyperhidrosis.

Infrequent: arthralgia, muscle spasms, myalgia.

Frequent: nasopharyngitis, pneumonia. Infrequent: diverticulitis.

Infrequent: cholecystitis.

Infrequent: hypotension.

The following additional adverse events have been observed in clinical trials with EXELON capsules: confusion (frequent), abnormal liver function tests (infrequent), duodenal ulcers (infrequent), seizures (frequent) and hypertension (frequent).

Severe vomiting with esophageal rupture, pancreatitis (see Warnings and Precautions, Gastrointestinal, Pancreatic).

EXELON PATCH has been administered to 1071 patients with Alzheimer’s disease during clinical trials worldwide. Of these, 869 patients have been treated for at least 3 months, 706 patients have been treated for at least 6 months, 212 patients have been treated for 1 year.

Treatment-emergent signs and symptoms that occurred during 1 controlled and 4 open-label trials in North America, Europe, Latin America, Asia and Japan were recorded as adverse events by the clinical investigators using terminology of their own choosing.

To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using MedDRA dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 1071 patients from these trials who experienced that event while receiving EXELON PATCH. All patch doses are pooled. In general, adverse event rates with the patch were dose-related.

All adverse events occurring in at least 1 patient (approximately 0.1%) are included, except for those already listed elsewhere in labeling, too general to be informative, or relatively minor events.

Events are classified by system organ class and listed using the following definitions: Frequent—those occurring in at least 1/100 patients; Infrequent—those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to EXELON PATCH treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Frequent: anemia.

Infrequent: delusion, delirium, hallucinations.

Adverse Events (≥2% in EXELON PATCH groups, and occurring with a rate greater than placebo) of the 24-Week Clinical Trial Conducted with EXELON PATCH in Patients with Alzheimer’s Disease

In the pivotal clinical trial involving mild to moderate Alzheimer’s disease patients treated with EXELON PATCH cerebrovascular accident occurred in 1.0% of patients treated with EXELON PATCH 20, 0.7% of patients treated with EXELON PATCH 10 and 0.3% of patients treated with placebo. The events were fatal in the EXELON PATCH 10 and placebo groups. A lower frequency of cerebrovascular accident was observed in the controlled clinical trials involving patients with mild to moderate Alzheimer’s disease who were treated with EXELON capsules.

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with EXELON PATCH.

No data are available in children. Therefore, the use of EXELON PATCH is not recommended in children under 18 years of age.

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterised by severe nausea, vomiting, diarrhea, hypertension, hallucinations, salivation, sweating, 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 cholinomimetics when co-administered 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.

In a documented case of a 46 mg overdose with EXELON capsules, a 69 year old female patient experienced vomiting, incontinence, hypertension, psychomotor retardation and loss of consciousness. The patient was managed conservatively with only supportive measures and fully recovered within 24 hours.

Dose-related signs of toxicity in animals included lacrimation, excessive salivation, vomiting, decreased locomotor activity, ataxia, twitches/flutters, tremors and clonic convulsions.

There are currently no data on overdose with EXELON PATCH.

As rivastigmine has a plasma half-life of about 3.4 hours after patch administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the patch should be immediately removed and no further patch should be applied for the next 24 hours.

In overdoses accompanied by severe nausea and vomiting, the use of antiemetics should be considered.

Symptomatic treatment for other adverse events should also be given as necessary.

Tertiary anticholinergics such as atropine may be used as an antidote for EXELON overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1 to 2 mg IV with subsequent doses based upon clinical response.

Due to the short plasma elimination half-life of rivastigmine after patch administration, dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be clinically indicated in the event of an overdose.

Each patch of 5 cm² contains: 9 mg rivastigmine base, with in vivo release rate of 4.6 mg/24 hours. The outside of the backing layer is beige and labeled with “^PrEXELON* PATCH 5 (rivastigmine) 4.6 mg/24 h” and “AMCX”. Nonmedicinal ingredients: acrylic copolymer, poly(butylmethacrylate, methyl-methacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil and vitamin E. Cartons of 30. Each patch is individually sealed in a separate pouch.

Each patch of 10 cm² contains: 18 mg rivastigmine base, with in vivo release rate of 9.5 mg/24 hours. The outside of the backing layer is beige and labeled with “^PrEXELON* PATCH 10 (rivastigmine) 9.5 mg/24 h” and “BHDI”. Nonmedicinal ingredients: acrylic copolymer, poly(butylmethacrylate, methyl-methacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil and vitamin E. Cartons of 30. Each patch is individually sealed in a separate pouch.

Use in elderly patients with serious comorbid disease has not been studied in large phase III-IV clinical studies. The use of EXELON in Alzheimer’s disease patients with chronic illnesses common among the geriatric population, should be considered after careful risk/benefit assessment and dose escalation in this patient population should proceed with caution.

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

Treatment with EXELON PATCH at higher than recommended doses is associated with significant gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, anorexia/decreased appetite and weight loss (see Adverse Reactions). Due to the risk of gastrointestinal adverse reactions treatment should always be started with EXELON PATCH 5. A dose increase to EXELON PATCH 10, the maximum recommended maintenance dose, should only occur after a minimum of 4 weeks of treatment with EXELON PATCH 5 and if well tolerated. If treatment is interrupted for longer than a few days, treatment should be reinitiated with EXELON PATCH 5 to reduce the possibility of severe vomiting and its potentially serious sequelae (e.g., there have been very rare postmarketing reports of severe vomiting with esophageal rupture following oral administration) (see Dosage and Administration).

Caregivers should be advised of the high incidence of nausea and vomiting associated with the use of the EXELON PATCH at higher than recommended doses along with the possibility of anorexia and weight loss. Caregivers should be encouraged to monitor for these adverse events and inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than a few days, the next dose should not be administered until they have discussed this with the physician.

In the controlled clinical trial, 3% of the patients treated with the EXELON PATCH 10 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.

No study was conducted with EXELON PATCH in subjects with hepatic impairment (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions). Patients with clinically significant hepatic impairment might experience more adverse events.

EXELON PATCH (rivastigmine) as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

The effect of genetic polymorphism of butyrylcholinesterase enzyme on rivastigmine metabolism is unknown.

Like other cholinomimetic drugs, EXELON PATCH should be used with care in patients with a history of asthma or obstructive pulmonary disease. No experience is available in treating patients with these conditions.

The safety and effectiveness of EXELON in any illness occurring in pediatric patients have not been established.

The safety of EXELON in pregnant women has not been established. EXELON PATCH should not be used in women of childbearing potential unless, in the opinion of the physician, the potential benefit to the patient justifies the potential risk to the fetus.

In the pivotal clinical trial involving AD patients treated with the EXELON PATCH, acute pancreatitis was reported as an adverse event for one patient treated with EXELON capsule (0.3%) during double-blind treatment and one patient treated with EXELON PATCH (0.2%) during open label treatment. Cases of pancreatitis have been reported during postmarketing experience with EXELON capsules shortly after initial use as well as after several months or years of use.

Patients experiencing persistent and unexplained upper abdominal pain, that may or may not be accompanied by vomiting and confusion, should promptly seek medical attention.

No study was conducted with the EXELON PATCH in subjects with renal impairment (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions).

Cholinesterase inhibitors as well as Alzheimer’s disease can be associated with significant weight loss. Where weight loss may be of clinical concern, body weight should be monitored.

In the controlled clinical trial, 3% of the patients treated with EXELON PATCH 10 had a decreased weight, as compared with 5% of patients who received the EXELON capsule at doses up to 6 mg BID and 1% of those who received placebo. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% (5.4% males and 9.6% females) of those treated with EXELON PATCH 10 compared with 11% of patients (9.9% males and 11.4% females) who received the EXELON capsule at doses up to 6 mg BID and 6% (5.0% males and 6.5% females) of those who received placebo.

Laboratory values were not systematically evaluated during the controlled clinical trial with EXELON PATCH after screening.

Modest elevations in serum amylase and lipase in a clinical trial with EXELON capsules in patients with dementia associated with Parkinson’s disease were seen more frequently with EXELON capsule-treatment than in patients receiving placebo. These elevations were not associated with clinical consequences.

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with EXELON PATCH.

Although not reported in clinical trials of EXELON, cholinomimetics may cause bladder spasms.

The incidence and severity of adverse events generally increases with increasing dose, particularly at dose changes. If treatment is interrupted for more than a few days, it should be reinitiated with EXELON PATCH 5 (rivastigmine).

As with other cholinergic substances care must be taken when prescribing EXELON PATCH:

• To patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see Cardiovascular).

  
  

• To patients with active gastric or duodenal ulcers or patients predisposed to these conditions because gastric acid secretions may be increased (see Gastrointestinal).

  
  

• To patients predisposed to urinary obstruction and seizures because cholinomimetics may induce or exacerbate these diseases (see Neurologic).

  
  

• To patients with a history of asthma or obstructive pulmonary disease (see Respiratory).

  
  

EXELON PATCH has not been studied in patients with severe Alzheimer’s disease, non-Alzheimer dementias or individuals with dementia associated with Parkinson’s disease. The efficacy and safety of EXELON PATCH in these patient populations is unknown.

Contact with the eyes should be avoided after handling EXELON PATCH.

Patients with body weight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse events. Particular caution should be exercised when titrating these patients to the maintenance dose.

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer’s disease. The risk/benefit of EXELON PATCH treatment for patients with a history of seizure disorder must therefore be carefully evaluated.

Patients diagnosed with probable vascular dementia, according to NINDS-AIREN criteria, were randomized to double-blind treatment with EXELON capsules (3-12 mg/day, N=363) or placebo (N=344) for 6 months in a controlled clinical trial. The NINDS-AIREN criteria are designed to identify patients with dementia that appears to be due primarily to vascular causes, and to exclude patients with Alzheimer’s disease. Overall, EXELON was not shown to be an effective treatment for patients with vascular dementia in this study.

The study also showed that the overall rate of occurrence of treatment emergent adverse events was lower in vascular dementia patients than what was observed previously in Alzheimer’s disease patients. However, rates of serious adverse events were generally greater for vascular dementia patients compared to mild to moderate Alzheimer’s disease patients for both EXELON and placebo groups, and may relate to the greater number of co-morbid medical conditions in the vascular dementia population.

In vascular dementia patients, higher rates of all-cause mortality (2.2% on EXELON vs 1.2% on placebo) and certain cardiovascular and cerebrovascular adverse events such as, angina pectoris, myocardial infarction, coronary artery disease, hypertension, dysarthria and cerebrovascular accident were observed in patients who were treated with EXELON compared to those who received placebo. The majority of deaths in patients taking either EXELON or placebo resulted from either cardiovascular or cerebrovascular disorders or respiratory failures.

Gastrointestinal disorders such as nausea and vomiting may occur when initiating treatment and/or increasing the dose. Patients may respond to a dose reduction. In other cases, use of EXELON PATCH has been discontinued.

In the controlled clinical trial, 7% of patients treated with the EXELON PATCH 10 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 10 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 10 as compared to 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 10 and 1% of patients who received the EXELON capsule at doses up to 6 mg BID and 0% of those who received placebo. In this study, patients treated with a higher dose of the patch (EXELON PATCH 20) experienced nausea and vomiting at higher frequencies than patients treated with EXELON PATCH 10 (see Adverse Reactions; Dosage and Administration).

Alzheimer’s disease 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, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.

Like other cholinomimetics, rivastigmine may exacerbate extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson’s disease who were treated with EXELON capsules. Such adverse events may also occur with EXELON PATCH.

In the EXELON PATCH controlled clinical trial 1.4% of patients treated with EXELON PATCH 10 and 0.3% of patients treated with placebo experienced extrapyramidal symptoms including tremor, bradykinesia, dyskinesia and rigidity. Most patients who experienced extrapyramidal symptoms were treated concomitantly with antipsychotics.

It is not known whether rivastigmine is excreted into human milk, and therefore EXELON PATCH should not be used in nursing mothers. ¹⁴CRivastigmine was excreted into the milk of pregnant rats after a single oral dose. In rats given rivastigmine orally, concentrations of rivastigmine plus metabolites were approximately two times higher in milk than in plasma.

In the controlled clinical trial, 6% of the patients treated with the EXELON PATCH 10 developed diarrhea, 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.

Because of their pharmacological action, cholinomimetics 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. In clinical trials patients with serious cardiovascular disease were excluded. Caution should therefore be exercised in treating patients with active coronary artery disease or congestive heart failure. Syncopal episodes have been reported in association with the use of EXELON capsules and EXELON PATCH. It is recommended that EXELON PATCH not be used in patients with cardiac conduction abnormalities (except for right bundle branch block) including “sick sinus syndrome” and those with unexplained syncopal episodes.

No study was conducted with EXELON PATCH in subjects with hepatic impairment. After oral administration of EXELON capsules 1-3 mg, 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.

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with EXELON PATCH.

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.

Absorption of rivastigmine from EXELON PATCH (rivastigmine) transdermal systems 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 (C_max) are often reached at later times (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 patch is replaced with a new one, plasma concentrations initially decrease slowly for about 40 minutes 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 off to virtually zero between doses (see Figure 1 and Figure 2). Although less pronounced than with the oral formulation, the pharmacokinetics of rivastigmine is non-linear, with exposure (C_max and AUC) increasing over-proportionally by a factor of 2.6 when escalating from EXELON PATCH 5 to EXELON PATCH 10. The fluctuation index (FI), i.e., a measure of the relative difference between peak and trough concentrations [(C_max-C_min)/C_avg)], was 0.58 for EXELON PATCH 5 and 0.77 for EXELON PATCH 10, thus demonstrating a much smaller fluctuation between trough and peak concentrations than for the oral formulation (FI=3.96 to 6.24); therefore providing a more continuous delivery of rivastigmine with the patch. As determined by compartmental modeling, EXELON PATCH 10 exhibited exposure approximately the same as that provided by an oral dose of about 6 mg twice daily (i.e., 12 mg/day).

Pathological changes in Dementia of the Alzheimer type involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. A decrease in the function of these cholinergic pathways has been proposed to account for some of the clinical manifestations of dementia. Rivastigmine, a reversible cholinesterase inhibitor of the carbamate-type, is thought to enhance cholinergic neurotransmission by slowing the degradation of acetylcholine released by cholinergic neurons through the inhibition of acetylcholinesterase. If this proposed mechanism of action is correct, rivastigmine’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.

There is no evidence that rivastigmine alters the course of the underlying dementing process.

Unchanged rivastigmine is found in trace amounts 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 feces.

No study was conducted with EXELON PATCH in subjects with renal impairment. After oral administration of EXELON capsules 1-3 mg, C_max and AUC of rivastigmine were more than twice as high in Alzheimer’s disease patients with moderate renal impairment compared with healthy subjects; however there were no changes in C_max and AUC of rivastigmine in Alzheimer’s disease patients with severe renal impairment.

Rivastigmine is rapidly and extensively metabolized with an apparent elimination half-life in plasma of approximately 3.4 hours after patch removal. Elimination was absorption rate limited (flip-flop kinetics), which explains the longer t_½ after patch (3.4 hours) versus oral or i.v. administrations (1.4 to 1.7 hours). 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.

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.

In a single dose study directly comparing the patch (10 cm²) versus oral (3 mg) administration, the inter-subject variability in rivastigmine pharmacokinetic parameters (normalized to dose/kg bodyweight) was 43% (C_max) and 49% (AUC_0-24h) after the patch versus 74% and 103%, respectively, after the oral capsule. Similarly, inter-subject variability in rivastigmine pharmacokinetic parameters was lower after the patch than after the oral capsule in a steady-state study in Alzheimer’s disease patients given repeated doses. The inter-patient variability was at most 45% (C_max) and 43% (AUC_0-24h) 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 disease 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 drug exposure suggests special attention to patients with very low body weight during up-titration (see Dosage and Administration).

Rivastigmine was well released from the transdermal system over a 24-hour dermal application with approximately 50% of the drug load 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. Two other sites (abdomen and thigh) could be used if none of the three other sites is available, but the practitioner should keep in mind that the rivastigmine plasma exposure associated with these sites was approximately 20-30% lower (see Adverse Reactions, Skin Irritation, for effect of application site on skin irritation).

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease.

No data are available in children.

Rivastigmine inhibits acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. In patients with Alzheimer’s disease significant dose-dependent inhibition of AChE and BuChE activity were noted in cerebrospinal fluid, with comparable maximum mean inhibition (62%). In plasma, significant inhibition of BuChE activity is generally observed from 1.5 hours post-dose up to 8 hours post-dose, with a maximum observed inhibition of 51% at 5 mg b.i.d. Rivastigmine may therefore inhibit the butyrylcholinesterase mediated metabolism of other drugs (see Drug Interactions, Overview).