Probrain

Probrain uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Probrain reviews

1 INDICATIONS AND USAGE

Probrain PATCH is an acetylcholinesterase inhibitor indicated for treatment of:

• Mild, moderate, and severe dementia of the Alzheimer’s type. (1.1)
  

• Mild to moderate dementia associated with Parkinson’s disease (PDD). (1.2)

1.1 Alzheimer’s Disease

Probrain PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.

1.2 Parkinson’s Disease Dementia

Probrain PATCH is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease (PDD).

2 DOSAGE AND ADMINISTRATION

• Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours.
• Initial Dose: Initiate treatment with 4.6 mg/24 hours Probrain PATCH. (2.1)
• Dose Titration (2.1):
  

  After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.

• Mild to Moderate Alzheimer’s Disease and Parkinson’s Disease Dementia: Probrain PATCH 9.5 mg/24 hours or 13.3 mg/24 hours once daily. (2.1)
• Severe Alzheimer’s Disease: Probrain PATCH 13.3 mg/24 hours once daily. (2.1)
• For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours. (2.1)
• Consider dose adjustments in patients with (2.2):
  • Mild to moderate hepatic impairment (8.6)
  • Low (<50 kg) body weight (8.7)

2.1 Recommended Dosing

Initial Dose

Initiate treatment with one 4.6 mg/24 hours Probrain PATCH applied to the skin once daily .

Dose Titration

Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been tolerated. For mild to moderate AD and PDD patients, continue the effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists. Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose. For patients with severe AD, 13.3 mg/24 hours is the effective dose. Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions .

Mild to Moderate Alzheimer’s Disease and Mild to Moderate Parkinson’s Disease Dementia

The effective dosage of Probrain PATCH is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Severe Alzheimer’s Disease

The effective dosage of Probrain PATCH in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Interruption of Treatment

If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength Probrain PATCH. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours Probrain PATCH and titrate as described above.

2.2 Dosing in Specific Populations

Dosing Modifications in Patients with Hepatic Impairment

Consider using the 4.6 mg/24 hours Probrain PATCH as both the initial and maintenance dose in patients with mild to moderate (Child-Pugh score 7 to 9) hepatic impairment .

Dosing Modifications in Patients with Low Body Weight

Carefully titrate and monitor patients with low body weight (<50 kg) for toxicities (e.g., excessive nausea, vomiting) and consider reducing the maintenance dose to the 4.6 mg/24 hours Probrain PATCH if such toxicities develop.

2.3 Switching to Probrain PATCH from Probrain Capsules or Probrain Oral Solution

Patients treated with Probrain Capsules or Oral Solution may be switched to Probrain PATCH as follows:

• A patient who is on a total daily dose of <6 mg of oral Probrain can be switched to the 4.6 mg/24 hours Probrain PATCH.
  

• A patient who is on a total daily dose of 6 mg to 12 mg of oral Probrain can be switched to the 9.5 mg/24 hours Probrain PATCH.

Instruct patients or caregivers to apply the first patch on the day following the last oral dose.

2.4 Important Administration Instructions

Probrain PATCH is for transdermal use on intact skin.

(a) Do not use the patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

(b) Apply the Probrain PATCH once a day

• Press down firmly for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing.
• Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient. If sites on the back are not accessible, apply the patch to the upper arm or chest.
• Do not apply to a skin area where cream, lotion, or powder has recently been applied.

(c) Do not apply to skin that is red, irritated, or cut.

(d) Replace the Probrain PATCH with a new patch every 24 hours. Instruct patients to only wear 1 patch at a time (remove the previous day’s patch before applying a new patch) . If a patch falls off or if a dose is missed, apply a new patch immediately and then replace this patch the following day at the usual application time.

(e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days. Do not apply a new patch to the same location for at least 14 days.

(f) May wear the patch during bathing and in hot weather. But avoid long exposure to external heat sources (excessive sunlight, saunas, solariums).

(g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children.

(h) 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.

3 DOSAGE FORMS AND STRENGTHS

Probrain PATCH is available in 3 strengths. Each patch has a beige backing layer labeled as either:

• Probrain ^® PATCH 4.6 mg/24 hours, AMCX
  

• Probrain ^® PATCH 9.5 mg/24 hours, BHDI
• Probrain ^® PATCH 13.3 mg/24 hours, CNFU

Patch: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours (3)

4 CONTRAINDICATIONS

Probrain PATCH is contraindicated in patients with:

• known hypersensitivity to Probrain, other carbamate derivatives, or other components of the formulation .
• previous history of application site reactions with Probrain transdermal patch suggestive of allergic contact dermatitis .

Isolated cases of generalized skin reactions have been described in postmarketing experience .

• Known hypersensitivity to Probrain, other carbamate derivatives, or other components of the formulation. (4)
• History of application site reactions with Probrain transdermal patch suggestive of allergic contact dermatitis. (4, 6.2)

5 WARNINGS AND PRECAUTIONS

• Hospitalization and, rarely, death have been reported due to application of multiple patches at same time. Ensure patients or caregivers receive instruction on proper dosing and administration.
  

• Gastrointestinal adverse reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. (5.2)
• Application site reactions may occur with the patch form of Probrain. Discontinue treatment if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal. (5.3)

5.1 Medication Errors Resulting in Overdose

Medication errors with Probrain PATCH have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time.

Instruct patients and their caregivers on important administration instructions for Probrain PATCH .

5.2 Gastrointestinal Adverse Reactions

Probrain PATCH can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. The incidence and severity of these reactions are dose-related . For this reason, initiate treatment with Probrain PATCH at a dose of 4.6 mg/24 hours and titrate to a dose of 9.5 mg/24 hours and then to a dose of 13.3 mg/24 hours, if appropriate .

If treatment is interrupted for more than 3 days because of intolerance, reinitiate Probrain PATCH with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae. A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of Probrain without retitration after 8 weeks of treatment interruption.

Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.

5.3 Skin Reactions

Skin application site reactions may occur with Probrain PATCH These reactions are not in themselves an indication of sensitization. However, use of Probrain 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, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued .

In patients who develop application site reactions to Probrain PATCH suggestive of allergic contact dermatitis and who still require Probrain, treatment should be switched to oral Probrain only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to Probrain by exposure to Probrain patch may not be able to take Probrain in any form.

There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered Probrain irrespective of the route of administration (oral or transdermal). In these cases, treatment should be discontinued . Patients and caregivers should be instructed accordingly.

5.4 Other Adverse Reactions from Increased Cholinergic Activity

Neurologic Effects

Extrapyramidal Symptoms: Cholinomimetics, including Probrain, 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 Probrain Capsules.

Seizures: 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.

Peptic Ulcers/Gastrointestinal Bleeding

Cholinesterase inhibitors, including Probrain, may increase gastric acid secretion due to increased cholinergic activity. Monitor patients using Probrain PATCH 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. Clinical studies of Probrain have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Use with Anesthesia

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

Cardiac Conduction Effects

Because Probrain increases cholinergic activity, use of the Probrain PATCH may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, Probrain was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or electrocardiogram (ECG) abnormalities.

Genitourinary Effects

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

Pulmonary Effects

Drugs that increase cholinergic activity, including Probrain PATCH, should be used with care in patients with a history of asthma or obstructive pulmonary disease.

5.5 Impairment in Driving or Use of Machinery

Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of Probrain may also result in adverse reactions that are detrimental to these functions. During treatment with Probrain PATCH, routinely evaluate the patient's ability to continue driving or operating machinery.

6 ADVERSE REACTIONS

The following adverse reactions are described below and elsewhere in the labeling:

• Gastrointestinal Adverse Reactions
• Skin Reactions
• Other Adverse Reactions from Increased Cholinergic Activity

Most common adverse reactions (>5% and higher than with placebo): Nausea, vomiting, and diarrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Probrain PATCH has been administered to 4516 patients with Alzheimer’s disease during clinical trials worldwide. Of these, 3005 patients have been treated for at least 26 weeks, 1771 patients have been treated for at least 52 weeks, 974 patients have been treated for at least 78 weeks and 24 patients have been treated for at least 104 weeks.

Mild to Moderate Alzheimer’s Disease

24-Week International Placebo-Controlled Trial (Study 1)

Most Common Adverse Reactions

The most common adverse reactions in patients administered Probrain PATCH in Study 1 , defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours Probrain PATCH arm and at a frequency at higher than in the placebo group, were nausea, vomiting, and diarrhea. These reactions were dose-related, with each being more common in patients using the unapproved 17.4 mg/24 hours Probrain PATCH than in those using the 9.5 mg/24 hours Probrain PATCH.

Discontinuation Rates

In Study 1, which randomized a total of 1195 patients, the proportions of patients in the Probrain PATCH 9.5 mg/24 hours, Probrain Capsules 6 mg twice daily, and placebo groups who discontinued treatment due to adverse events were 10%, 8%, and 5%, respectively.

The most common adverse reactions in the Probrain 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%, and 1.3% in the Probrain PATCH 9.5 mg/24 hours, Probrain Capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2.0%, and 0.3% in the Probrain PATCH 9.5 mg/24 hours, Probrain Capsules 6 mg twice daily, and placebo groups, respectively.

Adverse Reactions Observed at an Incidence of ≥2%

Table 1 lists adverse reactions seen at an incidence of ≥2% in either Probrain PATCH-treated group in Study 1, and for which the rate of occurrence was greater for patients treated with that dose of Probrain PATCH than for those treated with placebo. The unapproved 17.4 mg/24 hours Probrain PATCH arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours Probrain PATCH.

48-Week International Active Comparator-Controlled Trial (Study 2)

Most Common Adverse Reactions

In Study 2 of the commonly observed adverse reactions (≥3% in any treatment group) the most frequent event in the Probrain PATCH 13.3 mg/24 hours group was nausea, followed by vomiting, fall, weight decreased, application site erythema, decreased appetite, diarrhea and urinary tract infection (Table 3). The percentage of patients with these events was higher in the Probrain PATCH 13.3 mg/24 hours group than in the Probrain PATCH 9.5 mg/24 hours group. Patients with nausea, vomiting, diarrhea and decreased appetite experienced these reactions more often during the first 4 weeks of the double-blind treatment phase. These reactions decreased over time in each treatment group. Weight decreased was reported to have increased over time in each treatment group.

Discontinuation Rates

Table 2 displays the most common adverse reactions leading to discontinuation during the 48-week, double-blind treatment phase in Study 2.

Most Common Adverse Reactions ≥3%

Other adverse reactions of interest which occurred less frequently, but which were observed in a markedly higher percentage of patients in the Probrain PATCH 13.3 mg/24 hours group than in the Probrain PATCH 9.5 mg/24 hours group in Study 2, included dizziness and upper abdominal pain. The percentage of patients with these reactions decreased over time in each treatment group (Table 3). The adverse reaction severity profile was generally similar for both the Probrain PATCH 13.3 mg/24 hours and 9.5 mg/24 hours groups.

Severe Alzheimer’s Disease

24-Week US Controlled Trial (Study 3)

Most Commonly Observed Adverse Reactions

The most common adverse reactions in patients administered Probrain PATCH in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 13.3 mg/24 hours Probrain PATCH arm and at a frequency higher than in the 4.6 mg/24 hours Probrain PATCH were application site erythema, fall, insomnia, vomiting, diarrhea, weight decreased, and nausea (Table 4). Patients in the lower dose group reported more events of agitation, urinary tract infection, and hallucinations than patients in the higher dose group.

Discontinuation Rates

In Study 3 , the proportions of patients in the Probrain PATCH 13.3 mg/24 hours (n=355) and Probrain PATCH 4.6 mg/24 hours (n=359), who discontinued treatment due to adverse reactions were 21% and 14%, respectively.

The most frequent adverse reaction leading to discontinuation in the 13.3 mg/24 hours treatment group versus the 4.6 mg/24 hours treatment group was agitation (2.8% versus 2.2%), followed by vomiting (2.5% and 1.1%), nausea (1.7% and 1.1%), decreased appetite (1.7% and 0%), aggression (1.1% and 0.3%), fall (1.1% and 0.3%) and syncope (1.1% and 0.3%). Otherwise, all AEs leading to discontinuation were reported in <1% of patients.

Most Commonly Observed Adverse Reactions ≥5%

Other adverse reactions of interest which were observed in a higher percentage of patients in the Probrain PATCH 13.3 mg/24 hours group than in the Probrain PATCH 4.6 mg/24 hours group, included application site erythema, fall, insomnia, vomiting, diarrhea, weight decreased, and nausea (Table 4). Overall, the majority of patients in this study experienced adverse reactions that were mild (30.7%) or moderate (32.1%) in severity. Slightly more patients in the 4.6 mg/24 hours patch group reported mild events than in the 13.3 mg/24 hours patch group, while the numbers of patients reporting moderate events were comparable between groups. Severe adverse reactions were reported at a slightly higher percentage at the higher dose (12.4%) than at the lower dose (10%) treatment groups. With the exception of severe adverse reactions of agitation (13.3 mg: 1.1%; 4.6 mg: 1.4%), fall (13.3 mg: 1.1%) and urinary tract infection (4.6 mg: 1.1%), all adverse reactions reported as severe occurred in less than 1% of patients in either treatment group.

Application Site Reactions

Application site skin reactions leading to discontinuation were observed in ≤2.3% of Probrain 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 Probrain PATCH patients in a double-blind controlled study and in ≤3.7% of Probrain PATCH patients in a double-blind controlled study in Japanese patients.

Parkinson’s Disease Dementia

76-week International Open-Label Trial (Study 4)

Probrain PATCH has been administered to 288 patients with mild to moderate Parkinson’s Disease Dementia in a single, 76-week, open-label, active-comparator safety study. Of these, 256 have been treated for at least 12 weeks, 232 for at least 24 weeks, and 196 for at least 52 weeks.

Treatment with Probrain PATCH was initiated at 4.6 mg/24 hours and if tolerated the dose was increased after 4 weeks to 9.5 mg/24 hours. Probrain Capsule (target maintenance dose of 12 mg/day) served as the active comparator and was administered to 294 patients. Adverse reactions are presented in Table 5.

Additional adverse reactions observed during the 76-week prospective, open-label study in patients with dementia associated with Parkinson’s disease treated with Probrain PATCH: Frequent (those occurring in at least 1/100 patients): dehydration, weight decreased, aggression, hallucination visual.

In patients with dementia associated with Parkinson’s disease the following adverse drug reactions have only been observed in clinical trials with Probrain Capsules: Frequent: nausea, vomiting, decreased appetite, restlessness, worsening of Parkinson’s disease, bradycardia, diarrhea, dyspepsia, salivary hypersecretion, sweating increased; Infrequent (those occurring between 1/100 to 1/1000 patients): dystonia, atrial fibrillation, atrioventricular block.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Probrain Capsules, Probrain Oral Solution, or Probrain Patch. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders: Tachycardia.

Hepatobiliary Disorders: Abnormal liver function tests, hepatitis.

Nervous System Disorders: Parkinson’s disease (worsening), seizure, tremor.

Psychiatric Disorders: nightmares.

Skin and Subcutaneous Tissue Disorders: Allergic dermatitis, application site hypersensitivity, blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria.

Vascular Disorders: Hypertension.

7 DRUG INTERACTIONS

Concomitant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended.

7.1 Metoclopramide

Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and Probrain PATCH is not recommended.

7.2 Cholinomimetic and Anticholinergic Medications

Probrain PATCH may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications. Concomitant use of Probrain PATCH with medications having these pharmacologic effects is not recommended unless deemed clinically necessary .

7.3 Beta-blockers

Additive bradycardic effects resulting in syncope may occur when Probrain is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use is not recommended when signs of bradycardia including syncope are present.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. No dermal reproduction studies in animals have been conducted.

Oral reproduction studies conducted in pregnant rats and rabbits revealed no evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Probrain and its metabolites are excreted in rat milk following oral administration of Probrain; levels of Probrain plus metabolites in rat milk are approximately 2 times that in maternal plasma. It is not known whether Probrain is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Probrain PATCH, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. The use of Probrain PATCH in pediatric patients is not recommended.

8.5 Geriatric Use

Of the total number of patients in clinical studies of Probrain PATCH, 88% were 65 years and over, while 55% were 75 years. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Increased exposure to Probrain was observed in patients with mild or moderate hepatic impairment with oral Probrain. Patients with mild or moderate hepatic impairment may be able to only tolerate lower doses . No data are available on the use of Probrain in patients with severe hepatic impairment.

8.7 Low or High Body Weight

Because Probrain blood levels vary with weight, careful titration and monitoring should be performed in patients with low or high body weights .

10 OVERDOSAGE

Overdose with Probrain PATCH has been reported in the postmarketing setting . Overdoses have occurred from application of more than one patch at one time and not removing the previous day’s patch before applying a new patch. The symptoms reported in these overdose cases are similar to those seen in cases of overdose associated with Probrain oral formulations.

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 Probrain 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, 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. Additional symptoms associated with Probrain overdose are diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, confusional state, hyperhidrosis, hypertension, hallucinations and malaise. Due to the short plasma elimination half-life of Probrain 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. A fatal outcome has rarely been reported with Probrain overdose.

11 DESCRIPTION

Probrain PATCH (rivastigmine transdermal system) contains Probrain, a reversible cholinesterase inhibitor 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). Probrain 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.

Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system.

Exposure (AUC_∞) to Probrain (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 3 other sites is available, but the practitioner should be aware that the Probrain plasma exposure associated with these sites was approximately 20% to 30% lower.

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

The pharmacokinetic profile of Probrain transdermal patches was comparable in patients with Alzheimer’s disease and in patients with dementia associated with Parkinson’s disease.

Distribution

Probrain is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg.

Metabolism

Probrain is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. 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 Probrain metabolism.

The metabolite-to-parent AUC_∞ ratio was about 0.7 after Probrain PATCH application 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. Based on in vitro studies, no unique metabolic routes were detected in human skin.

Elimination

Renal excretion of the metabolites is the major route of elimination. Unchanged Probrain is found in trace amounts in the urine. 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. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1 to 2.8 L/hr.

Age

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

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Probrain PATCH. A population pharmacokinetic analysis of oral Probrain indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, 4 Asian, and 12 Other) affected clearance of the drug. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Probrain PATCH.

Body Weight

A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Probrain exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the Probrain 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 .

Renal Impairment

No study was conducted with Probrain PATCH in subjects with renal impairment. Based on population analysis, creatinine clearance did not show any clear effect on steady state concentrations of Probrain or its metabolite.

Hepatic Impairment

No pharmacokinetic study was conducted with Probrain PATCH in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of Probrain was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg twice a day oral dosing, the mean clearance of Probrain was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10) .

Smoking

Following oral Probrain administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of Probrain by 23% (n=75 smokers and 549 nonsmokers).

Drug Interaction Studies

No specific interaction studies have been conducted with Probrain PATCH. Information presented below is from studies with oral Probrain.

Effect of Probrain on the Metabolism of Other Drugs

Probrain 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, CYP2C19, or CYP2B6.

No pharmacokinetic interaction was observed between Probrain 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 Probrain.

Effect of Other Drugs on the Metabolism of Probrain

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

Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of Probrain taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), beta-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).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In oral carcinogenicity studies conducted at doses up to 1.1 mg base/kg/day in rats and 1.6 mg base/kg/day in mice, Probrain was not carcinogenic.

In a dermal carcinogenicity study conducted at doses up to 0.75 mg base/kg/day in mice, Probrain was not carcinogenic. The mean Probrain plasma exposure (AUC) at this dose was less than that in humans at the maximum recommended human dose (13.3 mg/24 hours).

Mutagenesis

Probrain was clastogenic in in vitro chromosomal aberration assays in mammalian cells in the presence, but not the absence, of metabolic activation. Probrain was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro HGPRT assay, and in an in vivo mouse micronucleus test.

Impairment of Fertility

No fertility or reproduction studies of dermal Probrain have been conducted in animals. Probrain had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg base/kg/day.

14 CLINICAL STUDIES

The effectiveness of the Probrain PATCH in dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease was based on the results of 3 controlled trials of Probrain PATCH in patients with Alzheimer’s disease (Studies 1, 2, and 3) ; 3 controlled trials of oral Probrain in patients with dementia of the Alzheimer’s type; and 1 controlled trial of oral Probrain in patients with dementia associated with Parkinson’s disease. See the prescribing information for oral Probrain for details of the four studies of oral Probrain.

Mild to Moderate Alzheimer’s Disease

International 24-Week Study of Probrain PATCH in Dementia of the Alzheimer’s Type (Study 1)

This study was a randomized double-blind, double dummy clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score ≥10 and ≤20] (Study 1). The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years. Approximately 67% of patients were women, and 33% were men. The racial distribution was Caucasian 75%, Black 1%, Asian 9%, and other races 15%.

The effectiveness of the Probrain PATCH was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect.

The ability of the Probrain PATCH to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients. The ADAS-Cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language, and praxis. The ADAS-Cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The ability of the Probrain PATCH to produce an overall clinical effect was assessed using the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of the Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus) and is also scored as a 7-point categorical rating; scores range from 1, indicating “markedly improved,” to 4, indicating “no change,” to 7, indicating “marked worsening.”

In Study 1, 1195 patients were randomized to 1 of the following 4 treatments: Probrain PATCH 9.5 mg/24 hours, Probrain PATCH 17.4 mg/24 hours, Probrain Capsules in a dose of 6 mg twice daily, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the EXELON-treated patients compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the Probrain PATCH 9.5 mg/24 hours, Probrain PATCH 17.4 mg/24 hours, and Probrain Capsule 6 mg twice daily groups, respectively. The difference between each of these groups and placebo was statistically significant. Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation.

Figure 4 presents the distribution of patients’ scores on the ADCS-CGIC for all 4 treatment groups. At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the EXELON-treated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant.

International 48-Week Study of Probrain PATCH in Dementia of the Alzheimer’s Type (Study 2)

This study was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score ≥10 and ≤24] (Study 2). The mean age of patients participating in this trial was 76 years with a range of 50 to 85 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 97%, Black 2%, Asian 0.5%, and other races 1%. Approximately 27% of the patients were taking memantine throughout the entire duration of the study.

Alzheimer’s disease patients who received 24 to 48 weeks open-label treatment with Probrain PATCH 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either Probrain PATCH 9.5 mg/24 hours or Probrain PATCH 13.3 mg/24 hours in a 48-week, double-blind treatment phase. 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.

Study 2 was designed to compare the efficacy of Probrain PATCH 13.3 mg/ 24 hours versus that of Probrain PATCH 9.5 mg/24 hours during the 48-week, double-blind treatment phase.

The ability of the Probrain PATCH 13.3 mg/24 hours to improve cognitive performance over that provided by the Probrain PATCH 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) .

The ability of the Probrain PATCH 13.3 mg/24 hours to improve overall function versus that provided by Probrain PATCH 9.5 mg/24 hours was assessed by the instrumental subscale of the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-IADL). The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale. The ADCS-IADL assesses activities such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests. A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.

Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study. Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours Probrain PATCH treatment group and 280 patients entered the 13.3 mg/24 hours Probrain PATCH treatment group.

Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study. Decline in the mean ADCS-IADL score from the double-blind baseline for the Intent to Treat–Last Observation Carried Forward (ITT-LOCF) analysis was less at each timepoint in the 13.3 mg/24 hour Probrain PATCH treatment group than in the 9.5 mg/24 hours Probrain PATCH treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint).

Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase. The between-treatment group difference for Probrain PATCH 13.3 mg/24 hours versus Probrain PATCH 9.5 mg/24 hours was nominally statistically significant at week 24 (p=0.027), but not at week 48 (p=0.227), which was the primary endpoint.

Severe Alzheimer’s Disease

24-Week United States Study with Probrain PATCH in Severe Alzheimer’s Disease (Study 3)

This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score ≥3 and ≤12]. The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged >75 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 87%, Black 7%, Asian 1%, and other races 5%. Patients on a stable dose of memantine were permitted to enter the study. Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study.

The study was designed to compare the efficacy of Probrain PATCH 13.3 mg/ 24 hours versus that of Probrain PATCH 4.6 mg/24 hours during the 24-week double-blind treatment phase.

The ability of the 13.3 mg/24 hours Probrain PATCH to improve cognitive performance versus that provided by the 4.6 mg/24 hours Probrain PATCH was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.

The ability of the 13.3 mg/ 24 hours Probrain PATCH to improve overall function versus that provided by the 4.6 mg/24 hours Probrain PATCH was assessed with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment.

In this study, 716 patients were randomized into one of the following treatments: Probrain PATCH 13.3 mg/24 hours or Probrain PATCH 4.6 mg/24 hours in a 1:1 ratio. This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase. In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.

Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours Probrain PATCH treatment group than in the 4.6 mg/24 hours Probrain PATCH treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean ADCS-ADL-SIV score from baseline for the MFAS-LOCF analysis was less at each timepoint in the 13.3 mg/24 hours Probrain PATCH treatment group than in the 4.6 mg/24 hours Probrain PATCH treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing the Study Figure 5 Time Course of the Change from Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6 Time Course of the Change from Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2 Figure 7 Time Course of the Change from Baseline in SIB Score for Patients Observed at Each Time Point (Modified full analysis set – LOCF) Figure 8 Time Course of the Change from Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified full analysis set – LOCF)

16 HOW SUPPLIED/STORAGE AND HANDLING

Probrain PATCH: 4.6 mg/24 hours

Each patch of 5 cm² contains 9 mg Probrain base with in vivo release rate of 4.6 mg/24 hours.

Carton of 30………………………NDC 0078-0501-15

Probrain PATCH: 9.5 mg/24 hours

Each patch of 10 cm² contains 18 mg Probrain base with in vivo release rate of 9.5 mg/24 hours.

Carton of 30………………………..NDC 0078-0502-15

Probrain PATCH: 13.3 mg/24 hours

Each patch of 15 cm² contains 27 mg Probrain base with in vivo release rate of 13.3 mg/24 hours.

Carton of 30………………………NDC 0078-0503-15

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep Probrain PATCH in the individual sealed pouch until use. Each pouch contains 1 patch. Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Importance of Correct Usage

Inform patients or caregivers of the importance of applying the correct dose on the correct part of the body. They should be instructed to rotate the application site in order to minimize skin irritation. The same site should not be used within 14 days. The previous day’s patch must be removed before applying a new patch to a different skin location. Probrain PATCH should be replaced every 24 hours and the time of day should be consistent. It may be helpful for this to be part of a daily routine, such as the daily bath or shower. Only 1 patch should be worn at a time.

Instruct patients or caregivers to avoid exposure of the patch to external heat sources (excessive sunlight, saunas, solariums) for long periods of time.

Instruct patients who have missed a dose to apply a new patch immediately. They may apply the next patch at the usual time the next day. Instruct patients to not apply 2 patches to make up for 1 missed.

Inform the patient or caregiver to contact the physician for retitration instructions if treatment has been interrupted.

Discarding Used Patches

Instruct patients or caregivers to fold the patch in half after use, return the used patch to its original pouch, and discard it out of the reach and sight of children and pets. They should also be informed that drug still remains in the patch after 24-hour usage. They should be instructed to avoid eye contact and to wash their hands after handling the patch. In case of accidental contact with the eyes, or if their eyes become red after handling the patch, they should be instructed to rinse immediately with plenty of water and to seek medical advice if symptoms do not resolve.

Gastrointestinal Adverse Reactions

Inform patients or caregivers of the potential gastrointestinal adverse reactions such as nausea, vomiting, and diarrhea, including the possibility of dehydration due to these symptoms. Explain that Probrain PATCH may affect the patient’s appetite and/or the patient’s weight. Patients and caregivers should be instructed to look for these adverse reactions, in particular when treatment is initiated or the dose is increased. Instruct patients and caregivers to inform a physician if these adverse reactions persist.

Skin Reactions

Inform patients or caregivers about the potential for allergic contact dermatitis reactions to occur. Patients or caregivers should be instructed to inform a physician if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal.

Concomitant Use of Drugs with Cholinergic Action

Inform patients or caregivers that while wearing Probrain PATCH, patients should not be taking Probrain Capsules or Probrain Oral Solution or other drugs with cholinergic effects.

T2016-92

November 2016

Patient Information

Probrain (ECS-‘el-on) Patch

(rivastigmine transdermal system)

Probrain Patch is for skin use only.

What is Probrain Patch?

Probrain Patch is a prescription medicine used to treat:

• Mild, moderate, and severe memory problems (dementia) associated with Alzheimer’s disease.
  

• Mild to moderate memory problems (dementia) associated with Parkinson’s disease.

Based on clinical trials conducted over 6 to 12 months Probrain Patch was shown to help with cognition which includes (memory, understanding communication, reasoning) and with doing daily tasks. Probrain Patch does not work the same in all people. Some people treated with Probrain Patch may:

• Seem much better
• Get better in small ways or stay the same
• Get worse but slower than expected
• Not change and then get worse as expected

Some patients will not benefit from treatment with Probrain Patch. Probrain Patch does not cure Alzheimer’s disease. All patients with Alzheimer’s disease get worse over time.

Probrain Patch comes as a transdermal system that delivers Probrain (the medicine in Probrain Patch) through the skin.

It is not known if Probrain Patch is safe or effective in children under 18 years of age.

Who should not use Probrain Patch?

Do not use Probrain Patch if you:

• are allergic to Probrain, carbamate derivatives, or any of the ingredients in Probrain Patch. See the end of this leaflet for a complete list of ingredients in Probrain Patch.
• have had a skin reaction that:
  • spread beyond the Probrain Patch size
  • had blisters, increased skin redness, or swelling
  • did not get better within 48 hours after you removed the Probrain Patch

Ask your healthcare provider if you are not sure if you should use Probrain Patch.

What should I tell my healthcare provider before using Probrain Patch ?

Before you use Probrain Patch, tell your healthcare provider if you:

• have or have had a stomach ulcer
  

• are planning to have surgery
  

• have or have had problems with your heart
  

• have problems passing urine
  

• have or have had seizures
  

• have problems with movement (tremors)
  

• have asthma or breathing problems
  

• have a loss of appetite or are losing weight
  

• have had a skin reaction to Probrain (the medicine in Probrain Patch) in the past
  

• have any other medical conditions
  

• are pregnant or plan to become pregnant. It is not known if the medicine in Probrain Patch will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
  

• are breastfeeding or plan to breastfeed. It is not known if the medicine in Probrain Patch passes into your breast milk. You and your healthcare provider should decide if you will use Probrain Patch or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take:

• a medicine used to treat inflammation [nonsteroidal anti-inflammatory drugs (NSAIDs)]
  

• other medicines used to treat Alzheimer’s or Parkinson’s disease
  

• an anticholinergic medicine, such as an allergy or cold medicine, a medicine to treat bladder or bowel spasms, or certain asthma medicines, or certain medicines to prevent motion or travel sickness
• metoclopramide, a drug given to relieve symptoms of nausea, gastroesophageal reflux disease(GERD), or nausea and vomiting after surgery or chemotherapy treatment
• If you are undergoing surgery while using Probrain Patch, inform your doctor because Probrain Patch may exaggerate the effects of anesthesia, or the effects of a beta-blocker, a type of medicine given for high blood pressure, heart disease, and other medical conditions

Ask your healthcare provider if you are not sure if your medicine is one listed above.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I use Probrain Patch?

• Use Probrain Patch exactly as your healthcare provider tells you to use it.
  

• Probrain Patch comes in 3 different dosage strengths.
  

• Your healthcare provider may change your dose as needed.
  

• Wear only 1 Probrain Patch at a time.
  

• Probrain Patch is for skin use only.
  

• Only apply Probrain Patch to healthy skin that is clean, dry, hairless, and free of redness, irritation, burns or cuts.
  

• Avoid applying Probrain Patch to areas on your body that will be rubbed against tight clothing.
  

• Do not apply Probrain Patch to skin that has cream, lotion, or powder on it.
  

• Change your Probrain Patch every 24 hours at the same time of day. You may write the date and time you put on the Probrain Patch with a ballpoint pen before applying the patch to help you remember when to remove it.
  

• Change your application site every day to avoid skin irritation. You can use the same area, but do not use the exact same spot for at least 14 days after your last application.
  

• Check to see if the Probrain Patch has become loose when you are bathing, swimming, or showering.
  

• Probrain Patch is designed to deliver medication during the time it is worn. If your Probrain Patch falls off before its usual replacement time, put on a new Probrain Patch right away. Replace the new patch the next day at the same time as usual. Do not use overlays, bandages, or tape to secure an Probrain Patch that has become loose or try to reapply an Probrain Patch that has fallen off.
  

• If you miss a dose or forget to change your Probrain Patch apply your next Probrain Patch as soon as you remember. Do not apply 2 Probrain Patches to make up for the missed dose.
  

• If you miss more than 3 doses of applying Probrain Patch, call your healthcare provider before putting on a new Probrain Patch. You may need to restart Probrain Patch at a lower dose.
  

• Always remove the old Probrain Patch from the previous day before you apply a new one.
  

• Having more than 1 Probrain Patch on your body at the same time can cause you to get too much medicine. If you accidentally use more than 1 Probrain Patch at a time, call your healthcare provider right away. If you are unable to reach your healthcare provider, call your local Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.

What should I avoid while using Probrain Patch ?

• Do not touch your eyes after you touch the Probrain Patch. In case of accidental contact with your eyes or if your eyes become red after handling the patch, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.
  

• Probrain Patch can cause drowsiness, dizziness, weakness, or fainting. Do not drive, operate heavy machinery, or do other dangerous activities until you know how Probrain Patch affects you.
  

• Avoid exposure to heat sources such as excessive sunlight, saunas, or sunrooms for long periods of time.

What are the possible side effects of Probrain Patch ?

Probrain Patch may cause serious side effects, including:

• Medication overdose. Hospitalization and rarely death may happen when people accidently wear more than 1 patch at the same time. It is important that the old Probrain Patch be removed before you apply a new one. Do not wear more than 1 Probrain Patch at a time.
• Stomach or bowel (intestinal) problems, including:
  • nausea
  • vomiting
  • diarrhea
  • dehydration
  • loss of appetite
  • weight loss
  • bleeding in your stomach (ulcers)
• Skin reactions. Some people have had a serious skin reaction called allergic contact dermatitis (ACD) when using Probrain Patch. Stop using Probrain Patch and call your healthcare provider right away if you experience reactions that spread beyond the patch size, are intense in nature and do not improve within 48 hours after the patch is removed. Symptoms of ACD may be intense and include:
  • itching, redness, swelling, warmth or tenderness of the skin
  • peeling or blistering of the skin that may ooze, drain or crust over
• heart problems
• seizures
• problems with movement (tremors)

The most common side effects of Probrain Patch include:

• depression
  

• headache
  

• anxiety
  

• dizziness
  

• stomach pain
  

• urinary tract infections
  

• muscle weakness
  

• tiredness
  

• trouble sleeping

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Probrain Patch. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How should I store Probrain Patch ?

• Store Probrain Patch between 68^oF to 77^oF (20^oC to 25^oC).
  

• Keep Probrain Patch in the sealed pouch until ready to use.

Keep Probrain Patch and all medicines out of the reach of children.

General information about the safe and effective use of Probrain Patch .

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Probrain Patch for a condition for which it was not prescribed. Do not give Probrain Patch to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Probrain Patch. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Probrain Patch that is written for health professionals.

For more information, go to www. EXELONPATCH.com or call 1-888-669-6682.

What are the ingredients of Probrain Patch ?

Active ingredient: Probrain

Excipients include: acrylic copolymer, poly (butylmethacrylate, methylmethacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E

T2016-93

November 2016

Figure AApply one patch to ONLY ONE of the following possible sites each day Cut the pouch along the dotted line and remove the patch. A protective liner covers the adhesive 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. Press the patch firmly in place with the hand to make sure that the edges stick well. Figure F Figure G Figure H

Instructions for Use

Probrain (ECS-‘el-on) Patch

(rivastigmine transdermal system)

You will need the following supplies :

Probrain Patch is supplied in cartons containing 30 patches

Figure A

• Probrain Patch is a thin, beige, plastic patch that sticks to the skin. Each Probrain Patch is sealed in a pouch that protects it until you are ready to put it on.
• Only 1 Probrain Patch should be worn at a time. Do not apply more than 1 Probrain Patch at a time to the body.
• Do not open the pouch or remove the Probrain Patch until you are ready to apply it.

Using Probrain Patch:

Step 1. Choose an area to apply the Probrain Patch.

• Instructions for Caregivers: Apply Probrain Patch to the upper or lower back if it is likely that the patient will remove it. If this is not a concern, the Probrain Patch can be applied instead to the upper arm or chest. Do not apply the Probrain Patch to areas where it can be rubbed off by tight clothing or belts.
• Only apply the Probrain Patch to healthy skin that is clean, dry, hairless, and free of redness, irritation, burns or cuts.

Figure B

The diagram represents areas on the body where Probrain Patch may be applied. Only 1 patch should be worn at a time. Do not apply multiple patches to the body.

Step 2. Remove the Probrain Patch from the pouch.

Carefully cut the pouch along the dotted line to open and remove the Probrain Patch. Save the pouch for later use.

Figure C

• Do not cut or fold the Probrain Patch itself.

Step 3. Remove 1 side of the adhesive liner.

• A protective liner covers the sticky (adhesive) side of the Probrain Patch. Peel off 1 side of the protective cover. Do not touch the sticky part of the Probrain Patch with your fingers.

Figure D

Step 4. Apply the Probrain Patch to your skin.

• Apply the sticky (adhesive) side of the Probrain Patch to your chosen area of skin and then peel off the other side of the protective cover.

Figure E

• Press down on the Probrain Patch firmly for 30 seconds to make sure that the edges stick to your skin.

Figure F

Step 5: Wash your hands with soap and water right away.

Note:

• If your Probrain Patch falls off, select a new area, and repeat Steps 2 to 5 to apply a new Probrain Patch.
• Be sure to replace the new Probrain Patch the next day at the same time as usual.

Removing your Probrain Patch:

Step 6. Remove the Probrain Patch from the skin.

• Gently pull on 1 edge of the Probrain Patch to remove it from your skin.

Figure G

Throwing away the used Probrain Patch:

Step 7. Throw away the used Probrain Patch.

• Fold the used Probrain Patch in half (with the sticky sides together) and put it back into the pouch that you saved.

Figure H

• Throw away the used Probrain Patch safely and out of the reach of children and pets.
• Some medicine stays in the patch for 24 hours after you use it and should be folded together (sticky side together) and safely thrown away. Do not try to re-use Probrain Patches.

Step 8: Wash your hands with soap and water right away.

• After you remove the Probrain Patch, if any adhesive remains on your skin, you can use soap and water or an oil-based substance (such as baby oil) to remove the adhesive. Alcohol or other dissolving liquids (such as nail polish remover) should not be used.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

©Novartis

T2015-29

February 2015

Probrain pharmaceutical active ingredients containing related brand and generic drugs:

• Rivastigmine

Probrain available forms, composition, doses:

• Tablets; Oral; Rivastigmine 1.5 mg
• Tablets; Oral; Rivastigmine 3 mg

Probrain destination | category:

• Human:
• Neurodegenerative disease drugs
• Parasympathomemetic (cholinergic) agents

Probrain Anatomical Therapeutic Chemical codes:

• N06DA03 - Rivastigmine

Probrain pharmaceutical companies:

• Alpes Chemie
• Royal Pharma

References

1. Dailymed."EXELON (RIVASTIGMINE) PATCH, EXTENDED RELEASE [NOVARTIS PHARMACEUTICALS CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."RIVASTIGMINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "rivastigmine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Probrain after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Probrain not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology