Probrain

Each patch of 5 cm² contains Rivastigmine base 9 mg, in vivo release rate of 4.6 mg/24 hrs.

Each patch of 10 cm² contains Rivastigmine base 18 mg, in vivo release rate of 9.5 mg/24 hrs.

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

Each patch is a thin, matrix-type transdermal patch consisting of 3 layers. The outside of the backing layer is beige and labelled for each patch dose as follows: "Probrain 5" and "AMCX", "Probrain 10" and "BHDI", or "Probrain 15" and "CNFU".

It also contains the following excipients: Vitamin E, poly butylmethacrylate, methyl-methacrylate, acrylic copolymer, silicone oil.

Alzheimer’s Disease

Probrain transdermal system 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.

Parkinson’s Disease Dementia

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

Probrain patch is used to treat dementia (memory loss) associated with mild, moderate, or severe Alzheimer's disease, or mild to moderate dementia associated with Parkinson's disease. Probrain will not cure these diseases and it will not stop these diseases from getting worse. However, Probrain can improve thinking ability in some patients with these diseases.

In Alzheimer's disease, many chemical changes take place in the brain. One of the earliest and biggest changes is that there is a decrease in a chemical called acetylcholine (ACh). ACh helps the brain to work properly. Probrain is an acetylcholinesterase inhibitor. It slows the breakdown of ACh, so it can build up and have a greater effect. However, as Alzheimer's disease gets worse, there will be less and less ACh, so Probrain may not work as well.

Probrain is available only with your doctor's prescription.

Dosing In Alzheimer's Disease

Probrain should be taken with meals in divided doses in the morning and evening.

The recommended dosage of Probrain

Oral Solution and Capsules in Alzheimer's disease is 6 mg to 12 mg per day, administered twice a day (daily doses of 3 mg to 6 mg twice a day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial.

Initial Dose

Initiate treatment with the 1.5 mg twice a day with Probrain.

Dose Titration

After a minimum of 2 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).

Dosing In Parkinson's Disease Dementia

Probrain should be taken with meals in divided doses in the morning and evening.

The dosage of Probrain shown to be effective in the single controlled clinical trial conducted in dementia associated with Parkinson's disease is 3 mg to 12 mg per day, administered twice a day (daily doses of 1.5 mg to 6 mg twice a day).

Initial Dose

Initiate treatment with the 1.5 mg twice a day with Probrain.

Dose Titration

After a minimum of 4 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).

Interruption Of Treatment

If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level.

If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower dose of Probrain. If dosing is interrupted for more than 3 days, treatment should be restarted with 1.5 mg twice a day and titrated as described above.

Dosing In Specific Populations

Dosing Modifications in Patients with Renal Impairment

Patients with moderate and severe renal impairment may be able to only tolerate lower doses.

Dosing Modifications in Patients with Hepatic Impairment

Patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 9) 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.

Dosing Modifications in Patients with Low Body Weight

Carefully titrate and monitor patients with low body weight (less than 50 kg) for toxicities (e.g., excessive nausea, vomiting), and consider reducing the dose if such toxicities develop.

Important Administration Instructions

Caregivers should be instructed in the correct procedure for administering Probrain

Oral Solution. In addition, they should be directed to the Instruction Sheet (included with the product) describing how the solution is to be administered. Caregivers should direct questions about the administration of the solution to either their physician or pharmacist.

Patients should be instructed to remove the oral dosing syringe provided in its protective case, and using the provided syringe, withdraw the prescribed amount of Probrain

Oral Solution from the container. Each dose of Probrain

Oral Solution may be swallowed directly from the syringe or first mixed with a small glass of water, cold fruit juice, or soda. Patients should be instructed to stir and drink the mixture.

Probrain

Oral Solution and Probrain Capsules may be interchanged at equal doses.

How supplied

Dosage Forms And Strengths

Probrain Capsules

Capsules, containing Probrain tartrate equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of Probrain base, are available as follows:

1.5 mg capsule – yellow, “Probrain 1,5 mg” is printed in red on the body of the capsule.

3 mg capsule – orange, “Probrain 3 mg” is printed in red on the body of the capsule.

4.5 mg capsule – red, “Probrain 4,5 mg” is printed in white on the body of the capsule.

6 mg capsule – orange and red, “Probrain 6 mg” is printed in red on the body of the capsule.

Probrain

Oral Solution

Oral Solution is a clear yellow, solution containing Probrain tartrate equivalent to 2 mg/mL of Probrain base. For a full list of excipients, see DESCRIPTION.

Storage And Handling

Probrain Capsules

Probrain (Probrain tartrate) Capsules equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of Probrain base are available as follows:

1.5 mg capsule – yellow, “Probrain 1,5 mg” is printed in red on the body of the capsule.

Bottles of 60 NDC 0078-0323-44

Bottles of 500 NDC 0078-0323-08

Unit Dose (blister pack) Box of 100 (strips of 10) NDC 0078-0323-06

3 mg capsule – orange, “Probrain 3 mg” is printed in red on the body of the capsule.

Bottles of 60 NDC 0078-0324-44

Bottles of 500 NDC 0078-0324-08

Unit Dose (blister pack) Box of 100 (strips of 10) NDC 0078-0324-06

4.5 mg capsule – red, “Probrain 4,5 mg” is printed in white on the body of the capsule.

Bottles of 60 NDC 0078-0325-44

Bottles of 500 NDC 0078-0325-08

Unit Dose (blister pack) Box of 100 (strips of 10) NDC 0078-0325-06

6 mg capsule – orange and red, “Probrain 6 mg” is printed in red on the body of the capsule.

Bottles of 60 NDC 0078-0326-44

Bottles of 500 NDC 0078-0326-08

Unit Dose (blister pack) Box of 100 (strips of 10) NDC 0078-0326-06

Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Store in a tight container.

Probrain

Oral Solution

Probrain (Probrain tartrate)

Oral Solution

Bottles of 120 mL NDC 0078-0339-31

Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Store in an upright position and protect from freezing.

When Probrain

Oral Solution is combined with cold fruit juice or soda, the mixture is stable at room temperature for up to 4 hours.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Oct 2013

See also:
What is the most important information I should know about Probrain?

Before taking Probrain, tell your doctor if you have a heart rhythm disorder such as "sick sinus syndrome" (slow heartbeats), an enlarged prostate, urination problems, asthma, obstructive pulmonary disease, or a seizure disorder such as epilepsy.

Stop using Probrain and call your doctor at once if the medicine causes you to have stomach pain, nausea and vomiting, and loss of appetite.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

It is important to use Probrain regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

If you stop taking Probrain for any reason, do not restart the medication without talking to your doctor first. You may need to restart treatment with a lower dose.

If you need to have any type of surgery, tell the surgeon ahead of time that you are taking Probrain.

Probrain can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Use Probrain solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Probrain solution. Talk to your pharmacist if you have questions about this information.
• Take Probrain solution by mouth with the morning and evening meals, unless your doctor tells you otherwise.
• Use the syringe that comes with the medicine to measure your dose. Hold the bottle upright. Insert the tip of the syringe into the opening of the white stopper. Hold the syringe and pull the plunger up to the level that equals the dose prescribed by your doctor. Move the plunger up and down a few times to push out the large bubbles. Pull the plunger again to the level that equals your prescribed dose. Do not worry about small bubbles in the syringe. Remove the syringe from the bottle.
• You may swallow Probrain solution directly from the syringe. It may also be mixed with a small glass of water, cold fruit juice, or soda. Do NOT mix with other liquids. If you mix Probrain solution, be sure to stir well and drink the entire mixture right away. Medicine that is mixed with cold fruit juice or soda may be stored at room temperature for up to 4 hours.
• After using the syringe, rinse it by putting the open end of the syringe into a glass of water. Pull the plunger out to draw in water and push the plunger in to remove the water. Repeat this several times. Let the syringe air dry and then put it back into its case. Close the bottle tightly.
• Take Probrain solution on a regular schedule to get the most benefit from it.
• Taking Probrain solution at the same time each day will help you remember to take it.
• Continue to take Probrain solution even if you feel well. Do not miss any doses.
• If you miss a dose of Probrain solution, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. Contact your doctor if you miss several doses of Probrain solution. Your doctor may need to restart your medicine at a lower dose to avoid side effects.

Ask your health care provider any questions you may have about how to use Probrain solution.

Use: Labeled Indications

Alzheimer dementia:

Oral: Treatment of mild to moderate dementia of the Alzheimer type.

Transdermal: Treatment of mild, moderate, and severe dementia of the Alzheimer type.

Parkinson disease dementia: Treatment of mild to moderate dementia associated with Parkinson disease.

Off Label Uses

Dementia with Lewy bodies

Therapeutic options for the management of behavioral symptoms associated with Lewy body dementia are limited. Cholinesterase inhibitors are recommended for treatment of neuropsychiatric symptoms associated with Lewy body dementia by the Dementia with Lewy Bodies Consortium (McKeith 2005); however, Probrain is the only cholinesterase inhibitor with placebo-controlled data supporting its use. Although limited to fewer than 200 patients, initial data indicate Probrain provides statistically significant early improvement in clinical and cognitive assessments in patients with dementia with Lewy bodies and no deterioration with long-term therapy.

See also:
What other drugs will affect Probrain?

No specific interaction studies have been conducted with the Probrain.

Anticipated interactions resulting in a concomitant use not recommended.

Metoclopramide: Considering the possibility of an additive extra-pyramidal effect the concomitant use of metoclopramide and Probrain is not recommended.

Drugs Acting on Cholinergic System: In view of its pharmacodynamic effects, Probrain should not be given concomitantly with other cholinomimetic drugs due to possible additive effect.

Probrain might also interfere with the activity of anticholinergic medications (eg, oxybutynin, tolterodine).

Succinylcholine-type Muscle Relaxants: As a cholinesterase inhibitor, Probrain may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Observed interactions to be considered.

Beta-blockers: Additive effects leading to bradycardia (which may result in syncope) have been reported with the combined use of various β-blockers (including atenolol) and Probrain. Cardioselective β-blockers are expected to be associated with the greatest risk, but reports have also been received in patients using other β-blockers.

Interaction with Nicotine: A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of Probrain by 23% in patients with Alzheimer’s dementia (n=75 smokers and 549 non-smokers) following Probrain oral capsule doses of up to 12 mg/day.

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

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

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

See also:
What are the possible side effects of Probrain?

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

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 transdermal system 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 transdermal system in Study 1, defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours Probrain transdermal system 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 transdermal system than in those using the 9.5 mg/24 hours Probrain transdermal system.

Discontinuation Rates

In Study 1, which randomized a total of 1195 patients, the proportions of patients in the Probrain transdermal system 9.5 mg/24 hours, Probrain tartrate 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 transdermal system-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 transdermal system 9.5 mg/24 hours, Probrain tartrate 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 transdermal system 9.5 mg/24 hours, Probrain tartrate 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 transdermal system-treated group in Study 1 and for which the rate of occurrence was greater for patients treated with that dose of Probrain transdermal system than for those treated with placebo. The unapproved 17.4 mg/24 hours Probrain transdermal system arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours Probrain transdermal system.

*Vomiting was severe in 0% of patients who received Probrain transdermal system 9.5 mg/24 hours, 1% of patients who received Probrain transdermal system 17.4 mg/24 hours, 1% of patients who received the Probrain tartrate capsule at doses up to 6 mg twice daily, and 0% of those who received placebo.

**Weight Decreased as presented in Table 1 is based upon clinical observations and/or adverse events reported by patients or caregivers. Body weight was also monitored at prespecified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with Probrain transdermal system 9.5 mg/24 hours, 12% of those treated with Probrain transdermal system 17.4 mg/24 hours, 11% of patients who received the Probrain tartrate capsule at doses up to 6 mg twice daily and 6% of those who received placebo. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.

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 transdermal system 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 transdermal system 13.3 mg/24 hours group than in the Probrain transdermal system 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 transdermal system 13.3 mg/24 hours group than in the Probrain transdermal system 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 transdermal system 13.3 mg/24 hours and 9.5 mg/24 hours groups.

*Decreased Weight as presented in Table 3 is based upon clinical observations and/or adverse events reported by patients or caregivers. Body weight was monitored as a vital sign at pre-specified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 15.2% of those treated with Probrain transdermal system 9.5 mg/24 hours and 18.6% of those treated with Probrain transdermal system 13.3 mg/24 hours during the 48-week double-blind treatment period.

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 transdermal system in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 13.3 mg/24 hours Probrain transdermal system arm and at a frequency higher than in the 4.6 mg/24 hours Probrain transdermal system 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 transdermal system 13.3 mg/24 hours (n=355) and Probrain transdermal system 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 transdermal system 13.3 mg/24 hours group than in the Probrain transdermal system 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 transdermal system 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 transdermal system patients in a double-blind controlled study and in ≤3.7% of Probrain transdermal system patients in a double-blind controlled study in Japanese patients.

Parkinson’s Disease Dementia

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

Probrain transdermal system 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 transdermal system 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 tartrate 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 transdermal system: 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 tartrate 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Probrain. 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.