Exelon
FDA Label NDC 54868-6070

Exelon Patch (rivastigmine transdermal system) is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

Exelon Patch (rivastigmine transdermal system) is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease.

The dementia of Parkinson’s disease is purportedly characterized by impairments in executive function, memory retrieval, and attention in patients with an established diagnosis of Parkinson’s disease. The diagnosis of dementia of Parkinson’s disease can be made reliably in patients in whom a progressive dementia syndrome occurs (without the necessity to document the specific deficits described above) at least 2 years after a diagnosis of Parkinson’s disease has been made, and in whom other causes of dementia have been ruled out.

Treatment is started with Exelon Patch 4.6 mg/24 hours.

After a minimum of four weeks of treatment and if well tolerated, this dose should be increased to Exelon Patch 9.5 mg/24 hours, which is the recommended effective dose.

Dose increases should occur only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been well tolerated. The maximum recommended dose is 9.5 mg/24 hours. Higher doses confer no appreciable additional benefit, and are associated with significant increase in the incidence of adverse events [see Adverse Reactions (6)].

If adverse effects (e.g., nausea, vomiting, diarrhea, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several days and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose and titrated as described above [also see Warnings and Precautions (5)].

Patients treated with Exelon capsules or oral solution may be switched to Exelon Patch as follows:

A patient who is on a total daily dose of less than 6 mg of oral rivastigmine can be switched to Exelon Patch 4.6 mg/24 hours.

A patient who is on a total daily dose of 6-12 mg of oral rivastigmine may be directly switched to Exelon Patch 9.5 mg/24 hours.

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

Exelon Patch should be applied once a day to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing. The upper or lower back is recommended as the site of application because the patch is less likely to be removed by the patient; however, when sites on the back are not accessible the patch can be applied to the upper arm or chest. The patch should not be applied to skin that is red, irritated, or cut. It is recommended that the site of patch application be changed daily to avoid potential irritation, although consecutive patches can be applied to the same anatomic site (e.g., another spot on the upper back).

The patch should be pressed down firmly until the edges stick well. The patch can be used in situations that include bathing and hot weather.

The patch should be replaced with a new one every 24 hours. Do not apply a new patch to that same spot for at least 14 days. Patients and caregivers should be instructed accordingly [see Patient Counseling Information (17)].

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.

2.1.6.1 Hepatic Impairment

Dosage adjustment is not necessary in hepatically impaired patients, as the dose of drug is individually titrated to tolerability.

2.1.6.2 Renal Impairment

No dose adjustment is necessary for patients with renal impairment.

2.1.6.3 Low Body Weight

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 in titrating these patients above the recommended maintenance dose of Exelon Patch 9.5 mg/24 hours.

      See Dosage and Administration (2.1).

      Patch.

Each patch is a thin, matrix-type transdermal system consisting of three layers when worn by the patient. A fourth layer, the release liner, covers the adhesive layer prior to use and is removed at the time the system is applied to the skin.

The outside of the backing layer is beige and labeled for each dose as follows:

      - “EXELON^® PATCH “4.6 mg/24 hours” and “AMCX”

      - “EXELON^® PATCH “9.5 mg/24 hours” and “BHDI”

Table 1 summarizes the available strengths and quantity of rivastigmine provided in each patch:

• Each 5 cm² patch contains 9 mg rivastigmine base, with
  in vivo release rate of 4.6 mg/24 hours.
  
• Each 10 cm² patch contains 18 mg rivastigmine base, with in vivo release rate of 9.5 mg/24 hours.

      For a full list of excipients, see Description (11).

Exelon Patch (rivastigmine transdermal system) is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation [see Description (11)].

At higher than recommended doses, Exelon Patch (rivastigmine transdermal system) use is associated with significant gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, anorexia/decreased appetite and weight loss. For this reason, patients administered Exelon Patch should always be started at a dose of 4.6 mg/24 hours and titrated to the maintenance dose of 9.5 mg/24 hours. If treatment is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose [see Dosage and Administration (2)] to reduce the possibility of severe vomiting and its potentially serious sequelae (e.g., there has been one post-marketing report of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment with a 4.5-mg dose of an oral formulation after 8 weeks of treatment interruption).

At higher than recommended doses, caregivers should be advised of the high incidence of nausea and vomiting associated with the use of Exelon Patch 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 several days, the next dose should not be administered until they have discussed this with the physician.

In the controlled clinical trial, 7% of patients treated with 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 on account of vomiting was 0% of the patients who received 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 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.

In the same clinical trial, 21% of patients treated with the higher dose of Exelon Patch 17.4 mg/24 hours developed nausea, 19% developed vomiting, and the proportion of these patients who discontinued treatment on account of vomiting was 2%. Vomiting was severe in 1% of patients treated with Exelon Patch 17.4 mg/24 hours.

In the controlled clinical trial, the proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with 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.

In the same clinical trial, 12% of those treated with 17.4 mg/24 hours had weight loss equal to or greater than 7% of their baseline weight. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.

In the controlled clinical trial, 6% of patients treated with Exelon Patch 9.5 mg/24 hours developed diarrhea, as compared with 5% of patients who received the Exelon capsule at doses up to 6 mg BID, 10% of those treated with 17.4 mg/24 hours and 3% of those who received placebo.

In the controlled clinical trial, 3% of patients treated with 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, 9% of those treated with Exelon Patch 17.4 mg/24 hours and 2% of those who received placebo.

Because of their pharmacological action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely 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 have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Exelon, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

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. In clinical trials, Exelon was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or ECG abnormalities.

Although this was not observed in clinical trials of Exelon, drugs that increase cholinergic activity may cause urinary obstruction.

Drugs that increase cholinergic activity are believed to have some potential for causing seizures. However, seizure activity also may be a manifestation of Alzheimer's disease.

Like other cholinomimetics, rivastigmine may exacerbate or induce 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.

Like other drugs that increase cholinergic activity, Exelon should be used with care in patients with a history of asthma or obstructive pulmonary disease.

Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse events that are detrimental to these functions. Thus, the ability to continue driving or operating machinery should be routinely evaluated by the treating physician.

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 in titrating these patients above the recommended maintenance dose of the Exelon Patch 9.5 mg/24 hours.

Significant gastrointestinal adverse reactions including nausea, vomiting, anorexia, and weight loss have been reported with the Exelon Patch at higher than recommended doses [see Warnings and Precautions (5.1)].

In the single controlled clinical trial of Exelon Patch [see Clinical Studies (14)], which randomized a total of 1195 patients, the proportions of patients in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups who discontinued treatment due to adverse events were 9.6%, 8.6%, 8.1%, and 5.0%, respectively.

The most common adverse events in the Exelon Patch-treated groups that led to treatment discontinuation in this study were nausea and vomiting. The proportions of patients who discontinued treatment due to nausea were 0.7%, 1.7%, 1.7%, and 1.3% in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 1.7%, 2.0%, and 0.3% in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively.

The most commonly observed adverse events seen in patients administered Exelon Patch in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours group and at a frequency at least as high as in the placebo group are largely predicted by the cholinergic effects of Exelon. These are nausea, vomiting, and diarrhea. All these events were more common at the higher Exelon Patch dose of 17.4 mg/24 hours than at a dose of 9.5 mg/24 hours.

The following table lists treatment-emergent adverse events that were seen at an incidence of ≥2% in either Exelon Patch-treated group in the controlled clinical trial and for which the rate of occurrence was greater for patients treated with that dose of Exelon Patch than for those treated with placebo. The prescriber should be aware that these frequencies 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 frequencies 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 non-drug factors to the adverse event incidences in the population studied.

The vast majority of patients participating in the controlled clinical trial had either no observed skin irritation or mild to moderate skin reactions. The incidence of severe reactions was very low regardless of administered dosage.

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, and 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 the 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.

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 1/1,000 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.

Blood and Lymphatic System Disorders: Frequent: Anemia.

Cardiac Disorders: Infrequent: Angina pectoris, cardiac failure, bradycardia, atrial fibrillation, supraventricular extrasystoles, myocardial infarction, tachycardia, arrhythmia, atrioventricular block.

Ear and Labyrinth Disorders: Infrequent: Tinnitus.

Eye Disorders: Infrequent: Cataract, glaucoma, vision blurred.

Gastrointestinal System: Frequent: Constipation, gastritis. Infrequent: Gastroesophageal reflux disease, hematochezia, peptic ulcer, hematemesis, pancreatitis, salivary hypersecretion.

General Disorders and Administration Site Conditions: Infrequent: Application site dermatitis, application site irritation, peripheral edema, chest pain, application site eczema, hyperpyrexia.

Hepatobiliary Disorders: Infrequent: Cholecystitis.

Infections and Infestations: Frequent: Nasopharyngitis, pneumonia. Infrequent: Diverticulitis.

Injury, Poisoning and Procedural Complications: Frequent: Fall. Infrequent: Hip fracture, subdural hematoma.

Investigations: Infrequent: Blood creatine phosphokinase increased, lipase increased, blood amylase increased, electrocardiogram QT prolonged.

Metabolic and Nutritional Disorders: Frequent: Dehydration Infrequent: Hyperlipidemia, hypokalemia, hyponatremia.

Musculoskeletal and Connective Tissue Disorders: Infrequent: Arthralgia, muscle spasms, myalgia.

Nervous System Disorders: Frequent: Tremor. Infrequent: Migraine, parkinsonism, epilepsy.

Psychiatric Disorders: Infrequent: Delusion.

Renal and Urinary Disorders: Frequent: Urinary incontinence. Infrequent: Pollakiuria, hematuria, nocturia, renal failure.

Reproductive System and Breast Disorders: Infrequent: Benign prostatic hyperplasia.

Respiratory, Thoracic, and Mediastinal Disorders: Infrequent: Dyspnea, bronchospasm, chronic obstructive pulmonary disease.

Skin and Subcutaneous Tissue Disorders: Frequent: Pruritus. Infrequent: Erythema, eczema, dermatitis, rash erythematous, skin ulcer.

Vascular Disorders: Infrequent: Hypotension.

No specific interaction studies have been conducted with Exelon Patch (rivastigmine transdermal system).

Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in-vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19.

No pharmacokinetic interaction was observed between rivastigmine taken orally 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 rivastigmine.

Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.

Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), ß-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15).

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and might interfere with the activity of anticholinergic medications. A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Exelon Patch should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. No dermal reproduction studies in animals have been conducted. Oral reproduction studies conducted in pregnant rats at doses up to 2.3 mg base/kg/day and in pregnant rabbits at doses up to 2.3 mg base/kg/day revealed no evidence of teratogenicity. Studies in rats showed slightly decreased fetal/pup weights, usually at doses causing some maternal toxicity.

Milk transfer studies in animals have not been conducted with dermal rivastigmine. In rats given rivastigmine orally, concentrations of rivastigmine plus metabolites were approximately two times higher in milk than in plasma. It is not known whether rivastigmine is excreted in human breast milk. Exelon Patch (rivastigmine transdermal system) has no indication for use in nursing mothers.

There are no adequate and well-controlled trials documenting the safety and efficacy of Exelon in any illness occurring in children.

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

No pharmacokinetic study was conducted with Exelon Patch in subjects with 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 BID 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.

No study was conducted with Exelon Patch in subjects with 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 greater than or equal to 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 less than 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR greater than or equal to 60 mL/min); 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.

Rivastigmine exposure is higher in subjects with low body weight. 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. This suggests special attention should be given to patients with very low body weight during up-titration [see Dosage and Administration (2)].

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 administered orally. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Exelon Patch.

Population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% (n=75 Smokers and 549 Nonsmokers). No dose adjustment is necessary as the dose of the drug is individually titrated to tolerability.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized.

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.

As in any case of overdose, general supportive measures should be utilized. 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 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.

In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. In a documented case of an oral 46-mg overdose with Exelon, the patient experienced vomiting, incontinence, hypertension, psychomotor retardation, and loss of consciousness. The patient fully recovered within 24 hours and conservative management was all that was required for treatment.

There are currently no data on overdose with Exelon Patch (rivastigmine transdermal system).

Exelon Patch (rivastigmine transdermal system) is a reversible cholinesterase inhibitor and is known chemically as (S)- 3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate. It has an empirical formula of C₁₄H₂₂N₂O₂ as the base and a molecular weight of 250.34 (as the base). Rivastigmine is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate.

The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27.

Exelon Patch is for transdermal administration. The patch comprises a four-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner. The release liner is removed and discarded prior to use. See Figure 1 for a detailed illustration.