Exelon - instructions for use, dose, side effects, contraindications

Excipients: D,L-α-tocopherol 0.03 mg / 0.06 mg, methyl methacrylate and butyl methacrylate copolymer 6.00 mg / 12.00 mg, acrylic acid copolymer 14.97 mg / 29.94 mg;

adhesive layer: silicone copolymer 14.84 mg / 29.67 mg, dimethicone (silicone oil 12,500 cSt) 0.15 mg / 0.30 mg, D,L-α-tocopherol 0.015 mg / 0.03 mg;

polymer films: polyethylene terephthalate substrate, 23 microns: 5 cm², 10 cm²; protective fluoropolymer polyethylene terephthalate film, 75 microns: 10.13 cm², 20.25 cm².

Description:

Transdermal therapeutic system with a beige substrate, double adhesive layer and rectangular protective film overlapped, with indentations, round. On the substrate TTS overprint: "AIHS" for a dosage of 4.6 mg / 24 h, "BHDI" for a dosage of 9.5 mg / 24 h.

Pharmacotherapeutic group:cholinesterase inhibitor

ATX: & nbsp

N.06.D.A Cholinesterase inhibitors

N.06.D.A.03 Rivastigmine

Pharmacodynamics:Rivastigmine, being a selective inhibitor of carbamate type acetyl- and butyrylcholinesterase, slows down the destruction of acetylcholine produced by functionally preserved neurons and improves synaptic transmission. The drug selectively increases the content of acetylcholine in the cerebral cortex and hippocampus, and thus contributes to the improvement of the cholinergic neural transmission. Rivastigmine has a positive effect in reducing the cognitive function associated with a deficiency of acetylcholine in dementia associated with Alzheimer's disease. In addition, there is evidence that the inhibition of cholinesterases can slow the formation of fragments of the beta-amyloid protein precursor, the accumulation of which leads to the formation of amyloid plaques, which are one of the main pathological signs of Alzheimer's disease. Rivastigmine interacts with the target enzyme to form a covalent bond, which leads to a temporary inactivation of the enzyme.
In young healthy men, when rivastigmine is administered orally at a dose of 3 mg, the activity of acetylcholinesterase in the cerebrospinal fluid (CSF) decreases by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, the enzyme activity returns to its original after about 9 hours. Inhibition of butyrylcholinesterase in CSF also has a reversible character, the enzyme activity is restored to the baseline level after 3.6 hours.
In patients with Alzheimer's disease, rivastigmine inhibition of acetylcholinesterase activity in CSF is dose-dependent in the dose range studied up to 6 mg twice a day (maximum dose). Inhibition of butyrylcholinesterase activity in CSF in 14 patients with Alzheimer's disease who took rivastigmine orally, was similar to the inhibition of acetylcholinesterase activity. A dose of 6 mg twice a day causes a decrease in enzyme activity by more than 60% compared to the initial one. This effect of the drug persisted for 12 months of therapy (the maximum period studied).
A statistically significant correlation was found between the extent to which rivastigmine inhibited both enzymes in CSF and changes in cognitive function in patients with Alzheimer's disease; wherein,it is the inhibition of butyrylcholinesterase in CSF that significantly and stably correlates with the improvement of memory test results, attention and reaction speed.
The use of the transdermal therapeutic system (TTC) of Excelon in patients with mild to moderate dementia in Alzheimer's disease (10-20 points in the Mental State Examination (MMSE), MiniMental State Examination (MMSE) and severe dementia of the Alzheimer's type leads to a significant improvement of cognitive functions (attention, memory, speech, etc.), functional status and activity in everyday life compared with placebo.

Pharmacokinetics:

Absorption

Absorption of rivastigmine from TTC Exelon®, is slow. After applying the first dose of the drug, the time to reach the concentration of rivastigmine determined was 0.5-1 h. The maximum concentration (C_mOh) in plasma is reached after 10-16 hours. After reaching C_max the concentration in the blood plasma slowly decreases in the remaining 24-hour period of application of the TTC Excelon®.

The equilibrium concentration of rivastigmine in the blood plasma after replacement of the used TTC Excelon® the new slowly decreases on average for about 40 minutes, While the absorption of the active substance from the newly glued TTC Excelon® does not begin to prevail over elimination. After that, the plasma concentration of rivastigmine begins to slowly rise and again reaches a maximum in about 8 hours. In the equilibrium state, the lowest concentration is approximately 50% of the maximum, as opposed to oral administration, in which the concentration in the plasma is virtually zero between the doses of the next dose. Similar temporal characteristics of the plasma concentration of rivastigmine were observed with the use of the TTC Excelon®, in the dose range from 4.6 mg / 24 hours to 13.3 mg / 24 hours. Despite the fact that the exposure (C_mOh and the area under the "concentration-time" curve (AUC)) Rivastigmine is obviously less than with oral administration, its increase is directly proportional to the increase in the dosage of the TTC Excelon®.

With increasing dosage from TTC Excelon® from 4.6 mg / 24 hours to 9.5 mg / 24 hours there was an increase in C_mOh and AUC rivastigmine in 2,6 times, with an increase to 13.3 mg / 24 hours - 4.9 times.

The relative difference between the maximum and minimum concentrations of rivastigmine (vibration index, IR) ((C_max -C_min)/C_avg)) when applying TTC Excelon® was 0.58 for a dosage of 4.6 mg / 24 h, 0.77 for a dosage of 9.5 mg / 24 h, 0.72 for a dosage of 13.3 mg / 24 h, which is significantly less than with oral administration from 3.96 for a dosage of 6 mg / day and 4.15 for a dosage of 12 mg / day).

The amount of rivastigmine released within 24 hours from the TTC Excelon® (dose in mg for 24 hours) is not equivalent to oral administration of the same dose of rivastigmine in capsules (the evaluation was carried out on the exposure of rivastigmine in blood plasma for 24 hours).

Exelon® TTC 9.5 mg / 24 h is equivalent to the use of capsules for ingestion of Excelon® inside at a dose of 6 mg twice a day (12 mg per day).

In direct comparison of the application of 1 dose of TTC Excelon® and capsules for ingestion intra-subject variability C_max and AUC_0-24_x rivastigmine was 43% and 49% for TTC Excelone® and 74% and 103% for capsules, respectively. With multiple application and achievement of an equilibrium state, the interpopulation variability of C_mOh and AUC_0-24_x rivastigmine in patients c dementia in Alzheimer's disease was also significantly lower for TTC Excelon® compared with oral capsules: 45% and 43% for the transdermal therapeutic system and 71% and 73% for the capsules, respectively.

In patients with dementia of the Alzheimer's type, a clear relationship between body weight and the equilibrium concentration of rivastigmine and metabolite NAP266-90). In patients with dementia of the Alzheimer's type and a body weight of 35 kg, the equilibrium concentration of rivastigmine increased approximately 2-fold compared to patients with a body weight of 65 kg; while for patients with a body weight of 100 kg, a decrease in the equilibrium concentration was approximately halved. The effect of body weight on the exposure of rivastigmine is particularly important for patients with very low body weight with increasing doses of the drug.

Rivastigmine was well released from the TTC Excelon® during the 24-hour period of application - on the skin (about 50% of the drug content). Highest score AUC∞ rivastigmine and metabolite NAP266-90 It was noted when applying the TTC Excelon® on the upper half of the back, chest or shoulder, AUC∞ decreased by approximately 20-30% when glued to the abdominal and hip areas.

There was no significant cumulation of rivastigmine or metabolite NAP226-90 in blood plasma in patients with dementia in Alzheimer's disease. Except that the plasma concentration of rivastigmine in the second application of TTC Excelon® was higher than the first day.

Distribution

Rivastigmine weakly binds to blood plasma proteins (about 40%), easily penetrates the blood-brain barrier.The apparent volume of distribution is 1.8-2.7 l / kg.

Metabolism

Rivastigmine is rapidly and largely metabolized with a half-life of plasma (T_1/2) about 3.4 hours after removal of the transdermal therapeutic system. Elimination was limited to the degree of absorption of rivastigmine (flip-flop kinetics), which explains the increase in T_1/2 after the use of TTC Excelon® (3-4 h) compared with oral or intravenous administration (1.4 and 1.7 h respectively) of the drug. The metabolism of rivastigmine occurs mainly by hydrolysis with cholinesterase with the formation of a decarbamylated metabolite (NAP226-90), which the in vitro demonstrated a minimal ability to inhibit acetylcholinesterase (<10%). Based on the data obtained in in vitro studies, it is not expected to interact with drugs metabolized by the following isoenzymes of the cytochrome system: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6. According to the data obtained in experimental studies, the main isoenzymes of cytochrome P450 are minimally involved in the metabolism of rivastigmine. Rivastigmine's total plasma clearance is about 130 l / h after intravenous injection at a dose of 0.2 mg and is reduced to 70l / h after intravenous administration of 2.7 mg, which is consistent with the nonlinear, inversely proportional character of the pharmacokinetics of rivastigmine due to its elimination as it saturates.

Ratio AUC metabolite to the starting material was 0.7 for the transdermal therapeutic system against 3.5 when using capsules for oral administration, indicating a lower rate of metabolism after the cutaneous application. The formation of less metabolite NAP226-90 is due to the lack of pre-systemic metabolism (the effect of "first passage" through the liver).

Excretion

Rivastigmine is excreted mainly by kidneys in the form of metabolites; in an unchanged form in the urine is almost not detected. After 24 hours after taking more than 90% of the dose is withdrawn. With feces less than 1% of the dose is excreted.

Pharmacokinetics in elderly patients

In elderly patients with Alzheimer's disease when applying TTC Excelon® There were no changes in rivastigmine exposure associated with age.

Pharmacokinetics in patients with impaired hepatic function

Study of the application of TTC Excelon®, in patients with impaired liver function was not performed.In patients with impaired liver function of mild to moderate severity after oral administration of rivastigmine, an increase in C_mOhby about 60% and AUC more than 2 times compared with healthy volunteers. When 3 mg of rivastigmine was taken once or twice after taking the drug 6 mg twice daily, rivastigmine clearance was approximately 60-65% less in patients with impaired liver function of mild and moderate severity compared with healthy patients. These pharmacokinetic features do not affect the incidence and severity of adverse events.

Pharmacokinetics in patients with impaired renal function

Study of the application of TTC Excelon® in patients with impaired renal function was not performed. Based on the population analysis, there was no clear effect of creatinine clearance on the equilibrium concentrations of rivastigmine or its metabolite in blood plasma. In patients with impaired renal function, dose adjustment is not required.

Indications:- Weak or moderately demented Alzheimer's type dementia.
- Severe dementia of the Alzheimer's type.

Contraindications:Hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients in the formulation.
Contact history of allergic dermatitis, caused by the use of the drug Excelon® TTC.
Age to 18 years.

Carefully:Rivastigmine should be used with caution in patients with sinus node weakness syndrome or conduction disorders (sinoatrial block, atrioventricular block).
Cholinergic stimulation can result in:
- to increase the secretion of hydrochloric acid in the stomach, so caution should be exercised when using rivastigmine in patients with gastric ulcer and duodenal ulcer in the acute stage or in patients predisposed to these conditions;
- to develop or worsen obstruction of the urinary tract and convulsive syndrome, therefore caution should be exercised when using rivastigmine in patients predisposed to these conditions.
Rivastigmine should be used with caution in patients with bronchial asthma or obstructive airways disease in the history.

Pregnancy and lactation:Pregnancy
In studies in animals rivastigmine penetrated through the placenta. There is no data on the ability of rivastigmine to penetrate the human hematoplacental barrier. Experimental data showed that rivastigmine does not have teratogenic properties. In studies in animals, there was an increase in the duration of the gestational period. Safety of Excelon® when pregnancy in humans has not been established to date, so the drug can be used in pregnancy only in those cases when the expected benefit of treatment exceeds the potential risk to the fetus.
Breast-feeding
In studies rivastigmine and its metabolites were excreted with the milk of lactating animals. It is not known whether rivastigmine in breast milk, so during the use of the drug should abandon breast-feeding.
Fertility
There is no evidence of the effect of rivastigmine on women of reproductive age.
There is no evidence of the effect of rivastigmine on fertility in humans. In studies in animals, there was no negative effect on the fertility of males and females, both parents and offspring.

Dosing and Administration:The drug should only be administered under the supervision of a doctor who has experience in treating patients with dementia and under the supervision of caregivers. Patients and caregivers should be instructed about the specific uses of the drug by competent medical personnel
The amount of contained and released rivastigmine, depending on the dosage of TTC Excelon®, is presented in Table 1.
Table 1.

TTC Exelon®	amount of the rivastigmine	The amount of rivastigmine released in vivo within 24 hours
TTC Exelon® 4.6 mg / 24 h	9 mg	4.6 mg
TTC Exelon® 9.5 mg / 24 h	18 mg	9.5 mg
TTC Excelon® 13.3 mg / 24 h	27 mg	13.3 mg

Weak or moderately expressed dementia of the Alzheimer's type.
Initial dose and selection of the recommended effective dose:
Treatment with the drug should begin with the use of TTC Exelon® 4.6 mg / 24 h 1 time per day. After 4 weeks of treatment, at least with good tolerability, the dose should be increased to the recommended effective dose by applying TTC Expresson® 9.5 mg / 24 h, which can be used as long as the therapeutic effect remains. Dose build-up:
For long-term treatment, with therapeutic effectiveness in the patient, the use of TTC Excelone® 9.5 mg / 24 hours is recommended. With good tolerability of the drug and at least 6 months after treatment with Excel® 9.5 mg / 24 h, the attending physician if it is necessary to achieve an additional therapeutic effect, may increase the dose to 13.3 mg / 24 h in patients who, despite the use of TTC Expresson® 9.5 mg / 24 h, there is a significant impairment of cognitive functions (eg, worsening of the results of CCHR) and / or worsening of the functional status (based on a subjective assessment of the doctor).
Severe dementia of the Alzheimer's type
Initial dose and selection of the recommended effective dose:
Treatment with the drug should begin with the use of TTC Exelon® 4.6 mg / 24 h 1 time per day. The dose of the drug should be firstly increased to 9.5 mg / 24 hours, and then to the effective dose of 13.3 mg / 24 hours. Each dose increase is possible only after 4 weeks of treatment at least and with good tolerability of the previous dose.
A dose greater than 13.3 mg / 24 hours does not have a significant benefit, but increases the incidence of side effects.
Interruption of treatment:
It should be regularly evaluated the clinical effect of therapy with the drug Exselon® TTC. In the absence of a clinical effect of therapy with the use of optimal doses of TTC Excelon, therapy should be discontinued.
It is necessary to temporarily stop therapy with the drug in case of undesirable phenomena on the part of the digestive system and / or worsen existing extrapyramidal symptoms (including tremor) prior to their resolution. If the break in the use of the drug was no more than three days, you can resume the use of the drug in the same dose. In the case of a longer period of cancellation, treatment should be resumed from the initial dose (Excelon® TTC 4.6 mg / 24 h).
Patients treated with rivastigmine in the form of capsules or oral solution may switch to treatment with TTC Excelon®, as follows:
- In patients who received oral rivastigmine at a dose of less than or equal to 6 mg per day, treatment should begin with the use of TTC Excelon® 4.6 mg / 24 h.
- In patients receiving oral therapy rivastigmine in a stable and well tolerated dose of 9 mg per day, treatment can begin immediately with the use of TTC Exelon® 9.5 mg / 24 h.But if oral therapy has not been stable and well tolerated, the transition to a transdermal form is recommended starting at a dose of 4.6 mg / 24 hours.
- In patients who received oral therapy with rivastigmine at a dose of 12 mg per day, treatment can begin immediately with the use of TTC Exelon® 9.5 mg / 24 h.
After 4 weeks of treatment, at a minimum, with good tolerability, the dose of TTS Excelone® 4.6 mg / 24 h should be increased to the recommended effective dose by applying TTC Exelon 9.5 mg / 24 h.
Treatment of TTC Excelon® is recommended starting the day after the last oral dose of rivastigmine.
Patients weighing less than 50 kg
Patients with a body weight of less than 50 kg experienced more frequent development of adverse events (AEs) and cancellation of therapy due to the occurrence of AEs, so with increasing doses in this group of patients, special care should be taken, the dose should be carefully titrated and monitored for AEs , excessive nausea or vomiting), and also consider the possibility of reducing the dose of the drug by applying TTC Excelon® 4.6 mg / 24 hours in the case of the development of such AEs. Particular care should be taken when titrating the dose above the recommended effective dose of Excel® 9.5 mg / 24 h.
Patients with hepatic impairment
Correction of the dosing regimen of TTC Excelon® is not required.
However, due to the increased exposure of rivastigmine observed with rivastigmine intake in patients with mild to moderate hepatic impairment, it is recommended that the dose of rivastigmine be carefully titrated in accordance with individual tolerability in patients in this category.
The study of the use of TTC Excelon® in patients with severe impairment of liver function was not performed. Special care should be taken when titrating the dose in patients of this category (see sections "Special instructions", "Pharmacological properties").
Patients with clinically expressed impairments of liver function may experience a more frequent development of dose-related adverse events, and therefore patients in this category should consider the possibility of using TTC Excelon® 4.6 mg / 24 h as the initial and maximum dose.
Patients with impaired renal function
Correction of the dosing regimen of TTC Excelon® is not required.
However, due to the increased exposure of rivastigmine, observed with rivastigmine intake, in patients with mild and moderate renal dysfunction,It is recommended to carefully titrate the dose of rivastigmine in accordance with individual tolerability in patients of this category. Patients with clinically manifested renal dysfunction may experience a more frequent development of dose-related adverse events, which is why patients of this category should consider the possibility of using TTC Excelon® 4.6 mg / 24 h as the initial and maximum dose.
Use in children
The use of rivastigmine in children has not been studied, so children should not use the drug.
INSTRUCTIONS FOR USE
ATTENTION!!!
- Each subsequent transdermal therapeutic system (TCS) of Excelon® should be glued only after removal of the previous one.
- Only one TTC Excelon® can be used at a time.
- TTC Exelon® can not be cut or divided into parts, or damaged in any way.
- It should be pressed firmly with the palm of the TTC Exelon® at the attachment point for at least 30 seconds.
Place of attachment of TTC Exelon®
- TTC Exelon® is glued on a clean, dry, undamaged skin with a minimal hairline.
- Do not use creams, lotions, oils, powder and other skin care products in the area of attachment to avoid peeling.
- TTC Exelon® can not be applied to reddened, rashy, irritated or damaged skin.
- It is necessary to paste only one TTC Exelon® per day only on one of the body parts:
- Left or right shoulder;
- The upper part of the chest on the left or right (should not be glued to the area of the breast);
- Upper back to the left or right;
- Lower back to the left or right.
Every 24 hours, the previous TTC Excelon® should be removed before one new TTC Excelon® is applied to one of the body parts shown below.
To avoid skin irritation, every subsequent TTC Excelon® should be glued to another area of the skin (within the same anatomical area). For example, if you attached the TTC Exelon® to the waist area on the right, next time you place the system on the left. To minimize the risk of skin irritation, the TTS can be glued to the same skin area only at intervals of two weeks.
TTC Exelon® is a thin, opaque, plastic patch for gluing to the skin. Do not remove the Excelon® TTC from the sealed bag and do not remove the previous Excel® TTC unless you plan to glue a new one.
The drug should be used immediately after removal from the sealed packet.
- Carefully remove the previous Excel® TTC.
- If you start treatment with the drug for the first time or resume treatment with the drug after a break, please follow the instructions for attaching the TTC Exelon®, starting with the following figure.
- The preparation is removed from the sealed packet immediately before use.
- To remove the Excelon® TTC, cut the package in the dotted line or groove.
- The adhesive side of the TTC Exelon® is covered with a protective film.
- Carefully remove the protective film on one side, protecting the adhesive side of the TTC Excelon® without touching the adhesive surface.
- Immediately after removing the protective film, apply the TTC Excelon® to the skin of the upper or lower half of the back, shoulder or chest.
- After attaching the transdermal therapeutic system to the skin, remove the upper protective layer from the other side of the TTS.
- It should be pressed firmly with the palm of the TTC Exelon® at the attachment point for at least 30 seconds. It must be ensured that the system fits snugly against the skin, especially around the edges.
If necessary, after gluing, you can write on the transdermal therapeutic system with a thin ballpoint pen the date of attachment (for example, the day of the week).
TTC Exelon® should be worn constantly and replaced with a new one after 24 hours. Attaching a transdermal therapeutic system to different areas of the skin allows choosing the most convenient areas of the body where the system will not come into contact with closely fitting clothing.
How to remove TTC Excelon®
- Gently bending one of the corners, slowly and carefully remove the transdermal therapeutic system.
- If there are residues of glue on your skin, lightly moisten this area with warm water and a mild soap solution or use baby oil to remove any glue residues. Do not use alcohol or other liquid solvents (nail polish remover or other solvents).
- Wash hands thoroughly with soap and water after attaching or removing TTC Exelon®. In case of eye contact or eye redness after attaching or removing TTC Excelon®, immediately flush eyes with plenty of water and seek medical attention if symptoms persist.
How to recycle used TTC Exelon®
- Bend the used transdermal therapeutic system in half and connect the adhesive pieces to each other.
- Place the used TTC Excelon® in the package. A package with a used transdermal therapeutic system should be thrown out of reach of children. After disposal, wash your hands with soap and water.
Conditions for wearing TTC Exelon® (water procedures, long stay near heat sources)
- TTC Exelon® does not come off during water procedures (shower, bath, pool). - During water procedures, you need to make sure that the system is snug against the skin, especially around the edges.
- Patients using Excelon® TTC should not be kept near any external heat sources (excessive sun radiation, saunas, solariums) for a long time.
What to do if the TTC Exelon® has become unstuck
If the TTC Exelon® has come unstuck it must be replaced by a new transdermal therapeutic system before the end of the day. The next day, as usual, the new TTC Excelon® should be attached.
When and for how long should I apply TTC Exelon®
To maximize the effectiveness of drug treatment, a new TTS should be applied every day, preferably at the same time.
If more than one Excelon® TTC is used simultaneously
You should immediately remove the weight of the TTS from your skin and inform your doctor about what happened. You may need medical attention. In some cases, an overdose of nausea, vomiting, diarrhea, increased blood pressure, hallucinations. Also, bradycardia and / or fainting may occur.
If you forgot to paste the next TTS at the usual time, you should paste it immediately. The application of the next TTS is possible the next day at the usual time. Do not paste two TTCs to compensate for the missed dose.

Side effects:The overall incidence of ATS in the context of TTC Excelon 9.5 / 24h (50.5%) was lower compared to oral therapy using capsules at a daily dose of 3-12 mg (63.3%) (for comparison, in the group placebo - this indicator was 46.0%).
The incidence and severity of AEs tend to increase with increasing doses, especially immediately after a dose change. If the interruption in the use of the drug is more than three days, the treatment should resume from the initial dose (Excelon® TTC 4.6 mg / 24 h).
The most frequent adverse events were skin reactions at the site of adhesion (usually erythema of mild to moderate severity).Next on the frequency were AEs from the digestive system: nausea (7.2%) and vomiting (6.2%) were noted significantly less with the use of TTC Exelon® 9.5 mg / 24 h compared with the capsules for oral administration, 23, 1% and 17.0%, respectively (in the placebo group, the same indices were 5.0% and 3.3%).
The incidence of adverse reactions in patients with Alzheimer's dementia who received TTC Excelon® (all dosages) was evaluated as follows: "very often" - ≥ 1/10, "often" - ≥ 1/100, <1/10, "infrequently "- ≥ 1/1000, <1/100, rarely ≥ 1/10000, <1/1000, very rarely <1/10000, unwanted reactions are separately presented with a precisely not fixed frequency.
In patients with mild to moderate dementia of the Alzheimer's type who received Exelon® TTC, the following AEs were observed:
Infectious and parasitic diseases: often - urinary tract infections.
Disorders from the metabolism and nutrition: often - anorexia, decreased appetite; infrequently - dehydration.
Disorders of the psyche: often - anxiety, depression, delirium, arousal; infrequently, aggression; frequency is not known - anxiety, hallucinations.
Impaired nervous system: often - headache, fainting, dizziness; infrequently - psychomotor hyperactivity; very rarely extrapyramidal disorders; frequency is not known - worsening symptoms of Parkinson's disease, convulsions, tremor.
Heart Disease: infrequently bradycardia; frequency is not known - tachycardia, atrioventricular block, atrial fibrillation, sinus node weakness syndrome.
Vascular disorders: frequency is not known - increased blood pressure.
Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain; infrequently - a stomach ulcer; frequency is not known - pancreatitis.
Disorders from the liver and bile ducts: the frequency is not known-hepatitis, an increase in the biochemical parameters of liver function.
Disturbances from the skin and subcutaneous tissues: often - a rash; The frequency is not known-judder, erythema, urticaria, blistering, allergic dermatitis, common allergic dermatitis.
Disorders from the kidneys and urinary tract: often - incontinence.
General disorders and disorders in the place of attachment of TTS: often - skin reactions at the place of gluing (erythema, pruritus, edema, dermatitis, irritation, etc.), fatigue, asthenia, fever, weight loss; rarely - accidental falls.
In patients with severe dementia of the Alzheimer's type, who received therapy with the drug Excelon® TTC, with a frequency of more than 2%, the following AEs were observed:
Infectious and parasitic diseases: often - urinary tract infections.
Disorders from the metabolism and nutrition: often - a decrease in appetite.
Disorders of the psyche: very often - arousal; often - insomnia, anxiety, depression, hallucinations.
Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea.
General disorders and disorders in the place of attachment of TTS: very often erythema in the place of gluing; often - accidental falls, weight loss.
In the clinical study, when the drug was used at doses above 13.3 mg / 24 h, the following AEs were noted more often than in the Excelon® TTS groups of 13.3 mg / 24 h and placebo: insomnia, heart failure (possibly associated with an increase in dose). The frequency of these AEs against the background of TTC Excelone therapy was 13.3 mg / 24 h similar to that of the placebo group.
The following adverse reactions were observed only in the treatment of dementia with capsules or Exselon® oral solution and were not documented in clinical trials using the TTC Excelon®:
Often - drowsiness, malaise, tremor, confusion, increased sweating;
Rarely - duodenal ulcer, stenocardia, myocardial infarction;
Very rarely - gastrointestinal bleeding;
The frequency is not known - severe vomiting, leading to rupture of the esophagus.
Reactions in the place of attachment of TTC Exelon® (skin irritation)
In clinical trials using the TTC Excelon®, the reactions at the site of TTS adhesion were mostly mild or moderate in most cases. The termination of treatment with the drug due to the development of the reaction at the TTC Excelon® attachment site was noted in ≤ 2.3% of cases, while in Chinese and Japanese patients, the discontinuation rate was 4.9% and 8.4%, respectively.
In the clinical study, when applying TTC Excelon 9.5 mg / 24 h, very light (21.8%), light (12.5%), mild (6.5%) redness of the skin, itching very light (11.9%) %), mild (7.3%) and moderate (5.0%) degree.Against the backdrop of therapy with Excel® 9.5 mg / 24 h, pruritus and severe erythema were observed in 1.7% and 1.1% of patients, respectively. Most of the skin reactions developed only in the field of gluing the TTS. When using TTC Exelon® 9.5 mg / 24 h, discontinuation of treatment with the drug due to the development of dermatological reactions was noted only in 2.4% of cases.
In the clinical trial of TTC Excelon® 9.5 mg / 24 h and TTC Excelon® 13.3 mg / 24 h, adverse reactions (erythema, pruritus) at the site of drug adherence were observed mainly in the first 24 weeks of use. The termination of treatment with the drug due to the development of pruritus was observed in 1.1% of patients. In most cases, the reactions at the site of TTS adhesion were mild or moderate, severe adverse reactions were observed in less than 2% of patients.
In the clinical trial of TTC Excelon® 13.3 mg / 24 h and TTC Excelon® 4.6 mg / 24 h, undesirable reactions at the place of adhesion were most frequently observed with erythema (13.2% and 11.7%, respectively) and skin itching (3.7% and 2.2%, respectively) at the TTC Excell® bonding site; discontinuation of treatment in the group of application of TTC Excelon ® 13.3 mg / 24 h and in the group of application of TTC Excelon ® 4.6 mg / 24 h due to the appearance of erythema was noted only in 0.8% and 0.6% of patients, respectively.In most cases of erythema, the place of adhesion of TTC Excelon® was weakly or moderately expressed in both groups.

Overdose:Symptoms. Accidental overdose of the drug for oral administration in most cases was not accompanied by any clinical manifestations; almost all patients continued treatment with rivastigmine. In case of an overdose, nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, drowsiness, bradycardia, confusion, increased sweating, increased blood pressure, hallucinations and general malaise were noted. An overdose of cholinesterase inhibitors can lead to a cholinergic crisis with the development of symptoms such as severe nausea, vomiting, excessive salivation, increased sweating, bradycardia, lowering blood pressure, respiratory depression and seizures. Perhaps the development of muscle weakness, which can lead to a lethal outcome with the involvement of respiratory muscles. Given the vagotonic effect of cholinesterase inhibitors on the heart rate (heart rate), bradycardia and / or syncope can not be ruled out.
In the course of post-marketing use of the preparation, and in rare cases during clinical trials, application / dosing errors were reported with the use of TTC Excelon®, due to the overlapping of several Excel® TTCs simultaneously (the next TTS was used without removing the previous one). Patients and caregivers should be instructed about the specific features of the drug.
When an overdose of the drug, there were rare cases of deaths, but the association with the use of the drug remains unclear. Symptoms and outcome varied in different patients. There was no clear connection between the dose taken and the severity of the outcome.
Treatment. Since the half-life of rivastigmine from the blood plasma is about 3.4 hours, and the duration of inhibition of acetylcholinesterase is about 9 hours, in the case of an asymptomatic overdose, immediate removal of all TTS is recommended, the TTC Excelon® should not be used within the next 24 hours. If an overdose is accompanied by severe nausea and vomiting, consider the use of anti-emetics.If other undesirable phenomena occur, if necessary, appropriate symptomatic treatment is performed.
If a significant overdose can be applied atropine, the initial dose of which is 0.03 mg / kg intravenously; the subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.

Interaction:Special study of the interaction of TTC Excelon® with other drugs has not been conducted.
Rivastigmine is metabolized predominantly by hydrolysis with the participation of esterases. The metabolism of rivastigmine with the participation of the main isoenzymes of cytochrome P450 occurs to a minimal extent. Thus, the pharmacokinetic interaction of rivastigmine with other drugs metabolized with the participation of these enzymes seems unlikely.
Nevertheless, rivastigmine can have an inhibitory effect on the metabolism of other substances mediated by the activity of butyrylcholinesterase.
Unsupported interaction
Metoclopramide
Given the possibility of the emergence of the combined effect of drugs on the extrapyramidal system,simultaneous use of metoclopramide and rivastigmine is not recommended.
Drugs affecting the cholinergic system
Given the pharmacodynamic characteristics of rivastigmine, simultaneous use of it with other cholinomimetics should be avoided in connection with the possibility of developing their combined effect. Rivastigmine can affect the effect of cholinergic blockers (eg, oxybutynin, tolterodine).
Salts of suxamethonium
When conducting anesthesia rivastigmine, being an inhibitor of cholinesterase, can enhance the effects of depolarizing muscle relaxants (eg suxamethonium salts).
Interactions that should be taken into account
Beta-blockers
With the simultaneous use of rivastigmine with various beta-blockers (including atenolol), a synergistic interaction was noted that led to the development of a bradycardia, which, in turn, can cause syncopal conditions. Despite the fact that simultaneous use with cardioselective beta-blockers is associated with the greatest risk of development of such effects, AE data were also observed in patients receiving other drugs of this group.
Interaction with nicotine
Increased absorption of rivastigmine by 23% when administered orally (in the form of capsules in a dose of up to 12 mg / day) in patients taking nicotine.
Interaction with the most commonly used drugs
In healthy volunteers, there was no pharmacokinetic interaction between rivastigmine for oral administration and digoxin, warfarin, diazepam, or fluoxetine. The increase in prothrombin time caused by warfarin with rivastigmine for oral administration did not change. With the simultaneous use of rivastigmine for oral administration and digoxin, there was no adverse effect on intracardiac conductivity.
The simultaneous use of rivastigmine with such commonly used drugs as antacids, antiemetics, hypoglycemic drugs, central antihypertensives, blockers of "slow" calcium channels, drugs that have a positive inotropic effect, antianginal agents, estrogens, analgesics, including non-steroidal anti-inflammatory drugs, benzodiazepines and antihistamines,It was not accompanied by any changes in the kinetics of rivastigmine or an increased risk of clinically significant adverse events.

Special instructions:Patients should avoid contact with the eyes immediately after attaching or removing the TTS. Wash hands thoroughly with soap and water after attaching or removing TTS. In case of eye contact or eye redness after attaching or removing TTS, immediately flush eyes with plenty of water and seek medical attention if symptoms persist.
Disorders from the gastrointestinal tract
The frequency of development and severity of side effects usually increases with an increase in the dose of rivastigmine, especially during the period of dose change. If the break in the use of the drug Excelon® TTC was more than three days, the treatment should resume from the initial dose (Excelon® TTC 4.6 mg / 24 h).
The severity of such dose-dependent gastrointestinal (GI) adverse events as nausea, vomiting and diarrhea observed at the start of treatment or with an increase in the dose of the drug may decrease with a decrease in the dose of rivastigmine, in the absence of an effect, the TTC Excelon® therapy should be discontinued. Data of AEs are more common in women.Patients who developed signs of dehydration, due to prolonged diarrhea or vomiting, are advised to intravenously administer the fluid and reduce the dose or discontinue rivastigmine therapy, because of the possible risk of developing serious complications.
Weight loss
Since in patients with Alzheimer's disease with cholinesterase inhibitor therapy, including rivastigmine, there may be a decrease in body weight, during the treatment of TTC Excelon®, it is necessary to control the weight of patients.
Other undesirable phenomena associated with increased cholinergic system activity
As with other cholinomimetics, caution should be exercised when using the Excelon® TTC in patients with sinus syndrome weakness or conduction disorders (sinoatrial block, atrioventricular block); In patients with bronchial asthma or obstructive airway disease in history.
Cholinergic stimulation can result in:
- to increase the secretion of hydrochloric acid in the stomach, so caution should be exercised in using the Excelon® TTC in patients with gastric ulcer and duodenal ulcer in the acute stage or in patients predisposed to these conditions;
- to the development or aggravation of urinary tract obstruction and convulsive syndrome, therefore caution should be exercised when prescribing rivastigmine to patients who are predisposed to these conditions.
Like other holinomimetics, when rivastigmine is used, an increase in the severity of extrapyramidal disorders may occur.
Reactions in the place of attachment of TTC Excelon® and skin reactions
Skin reactions that occur with the use of the drug Excelon® TTS, usually of mild or moderate severity. These reactions are an indicator of the patient's sensitization to rivastigmine. Nevertheless, against the background of the use of the drug Exselon ® TTS, allergic contact dermatitis may occur.
Allergic contact dermatitis should be suspected if a skin reaction occurs outside the size of the TTS at the site of TTS attachment, or skin reactions at the attachment site have reached a marked intensity (eg, increased erythema, edema, papules, vesicles), and if the severity of the skin reactions does not significantly decrease within 48 hours after removal of the TTS.In these cases, treatment with the drug should be discontinued (see section "Contraindications").
If patients develop a reaction at the place of attachment of a TTS similar to contact allergic dermatitis against the backdrop of the use of the drug Excelon® TTS, if there is a need to continue therapy with rivastigmine, the patient under the supervision of medical personnel and after receiving a negative result in allergological testing is recommended to switch to dosage forms rivastigmine for oral administration. Some patients sensitized to rivastigmine due to the use of Excelon® TTC can not apply rivastigmine in other dosage forms.
During the post-marketing use of the drug, data were obtained on the development of common allergic dermatitis in some patients with rivastigmine, regardless of the route of administration (either inward or transdermally). In these cases, the drug should be completely discarded (see Contraindications section). Patients and caregivers should be informed of the possibility of developing appropriate skin reactions while using rivastigmine.
Use in special patient groups
Use in elderly patients
In clinical studies of the drug Exselon® TTS, the age of 88% of patients was 65 years or more, and the age of 55% of patients is more than 75 years. In general, there were no differences in the safety and efficacy of the drug depending on the age. Nevertheless, one can not exclude an individual's higher sensitivity to the effects of the drug in older patients.
Patients with hepatic impairment
When rivastigmine was taken orally, patients with mild to moderate hepatic dysfunction had an increased exposure to rivastigmine, which might require a dose reduction in accordance with individual tolerability in patients in this category. The study of the use of rivastigmine in patients with impaired hepatic function was not carried out.
Patients with impaired renal function
When rivastigmine was taken orally, patients with mild to moderate renal dysfunction had an increased exposure to rivastigmine, which might require a reduction in dose in accordance with individual tolerability in patients in this category.
Patients with low or high body weight
Due to the presence of a link between body weight and rivastigmine exposure, the dose should be carefully titrated and the status of patients with low or high body weight should be monitored.

Effect on the ability to drive transp. cf. and fur:Dementia of the Alzheimer's type can cause a gradual deterioration in the ability to drive vehicles or jeopardize the possibility of using them. In patients treated with rivastigmine, dizziness and drowsiness may develop, especially at the onset of treatment or with a change in the dose of the drug. Rivastigmine may cause fainting or delirium. The ability of a patient with dementia receiving drug treatment, drive vehicles and / or work with mechanisms should be regularly evaluated by the attending physician.

Form release / dosage:The transdermal therapeutic system is 4.6 mg / 24 h or 9.5 mg / 24 h.

Packaging:One transdermal therapeutic system, 4.6 mg / 24 hours or 9.5 mg / 24 hours, in a multilayer laminate package (paper coated with a polyethylene terephthalate film, aluminum foil and a polyacrylonitrile copolymer). By 3, 7, 30 packs together with instructions for use in a cardboard pack.

Storage conditions:In a dry place at a temperature of no higher than 25 ° C.
The drug should be stored out of the reach of children.

Shelf life:2 years.
The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007020/08

Date of registration:02.09.2008

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

NOVARTIS PHARMA, GmbH Germany

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp01.11.2015