Plaster of dementia. Exelon® transdermal therapeutic system

1 transdermal therapeutic system (patch, TTS) may include in dosages: 9 mg (4.6 mg / day); 18 mg (9.5 mg/day); or 27 mg (13.3 mg/day).

Additionally: copolymer of acrylic acid, D,L-α-tocopherol, copolymer of butyl methacrylate and methyl methacrylate.

Adhesive layer: D,L-α-tocopherol, , silicone copolymer.

Release form

Novartis Pharma manufactures Exelon in the form of a transdermal therapeutic system (patch) with a contact adhesive surface of 5 cm2 for 9 mg; 10 cm2 for 18 mg; 15 cm2 for 27 mg.

pharmachologic effect

Anticholinesterase

Pharmacodynamics and pharmacokinetics

Exelon drug with active ingredient rivastigmine is cholinesterase inhibitor , namely selectively suppresses in the brain acetylcholinesterase And butyrylcholinesterase carbamate type, thereby slowing down the destruction processes acetylcholine secreted by functionally intact neurons and, contributing to the improvement synaptic transmission . in the hippocampus and cerebral cortex rivastigmine selectively increases the content acetylcholine , which leads to an increase in the quality of cholinergic transmission of nerve impulses. The drug has a positive effect on patients with an observed decrease cognitive functions caused by deficiency acetylcholine , including manifestations And Alzheimer's .

In addition to these effects, there is evidence that data suppression cholinesterase can lead to inhibition of the formation of the protein parts of the precursor amyloid beta responsible for education , which are the primary pathological manifestation . effects rivastigmina develop through interaction with enzyme -target, followed by the formation of a covalent bond, leading to temporary deactivation of the corresponding .

At the appointment of 3 mg rivastigmina healthy young men, during the first hour and a half in their cerebrospinal fluid (CSF) observed a decrease in activity acetylcholinesterase by about 40%. Approximately 9 hours after fixation of the maximum inhibitory effect rivastigmina , activity acetylcholinesterase returns to original values. CSF suppression process butyrylcholinesterase is also reversible with a return to baseline enzyme levels after 3.6 hours.

In case of application rivastigmina patients with Alzheimer's disease dose-dependent (in the dosage daily range up to 12 mg) inhibition is noted acetylcholinesterase in the CSF, and butyrylcholinesterase , the level of which is reduced by about 60% when using rivastigmina in a daily dose of 12 mg. This efficacy of the drug was maintained throughout the studied period of its use, which is 12 months.

During 12 months of therapy rivastigmine a statistically significant relationship was proved between the indices of its inhibition in the CSF of both enzymes and positive changes in cognitive functions sick, suffering Alzheimer's disease . Conducted studies significantly associated improvement in test results attention , memory And speed of reaction specifically with inhibition in the CSF butyrylcholinesterase .

Prescribing the Exelon patch to patients with mild/moderate manifestations dementia at Alzheimer's disease (MMSE - 10-20 points) compared to placebo led to a significant improvement in their cognitive functionality (including speech improvement , attention And memory ), increasing functional status, as well as increasing daily activity.

TTS Exelon is characterized by slow absorption of the active ingredient rivastigmina . Determination time rivastigmina c, after using the first dose of the patch, was 30-60 minutes. TCmax fluctuated within 10-16 hours, after which the serum content of the drug gradually decreased over 24 hours.

After changing the used patch to a new one, a slow decrease in Css was observed for about 40 minutes. rivastigmina , until the predominance of the processes of absorption of the active ingredient of fresh TTS over the elimination of this drug. In the next 8 hours, the plasma content rivastigmina slowly rises and reaches its maximum again. Least Concentration rivastigmina in the equilibrium state was about 50% of the maximum, in contrast to the oral forms of this drug, with the use of the next dose of which the plasma concentration of the active ingredient was practically equal to zero. Similar time parameters of plasma content rivastigmina were noted when using the Exelon patch in the dosage daily range of 4.6-13.3 mg.

Compared to oral administration rivastigmina its exposure (AUC and Cmax) when using the patch is obviously less, but the increase in these values ​​is proportional to the increase in the dose of TTS Exelon. In the case of an increase in daily dosages of TTS from 4.6 mg to 9.5 mg AUC rivastigmina increased by 2.6 times, and with an increase in the daily dose to 13.3 mg by 4.9 times.

Relative differences in parameters (oscillation index, IR) Cmax and Cmin rivastigmina when using patches with different dosages, respectively, were 0.58 for a daily dose of 4.6 mg; 0.77 for a daily dose of 9.5 mg and 0.72 for a daily dose of 13.3 mg, which is significantly lower than when taking oral forms of the drug, where the IC was 3.96 for a daily dose of 6 mg and 4.15 for a daily dose doses of 12 mg.

Mass fraction rivastigmina , which is released over 24 hours from Exelon TTS, does not correspond to that when taken orally at a similar dose of this drug (as measured by plasma exposure rivastigmina within 24 hours). Use of the daily dosage of Exelon 9.5 mg patch is equivalent to oral daily dose rivastigmina 12 mg.

In a head-to-head comparison of single-dose patch versus oral capsule use, interpopulation variability in daily Cmax and AUC rivastigmina were 43% and 49% for the patch and 74% and 103% for the capsules, respectively. In case of repeated use of Exelon for treatment dementia at Alzheimer's disease and achievement of the equilibrium state by the drug, the observed interpopulation variability of daily Cmax and AUC rivastigmina was also significantly lower for the patch compared to oral capsules and equaled 45% and 43%, respectively, versus 71% and 73%.

In patients weighing 65 kg with Alzheimer's disease css rivastigmina approximately doubled compared with patients with a body weight of 35 kg and, on the contrary, decreased by 2 times with a weight of 100 kg for patients. Effect of patient weight on exposure rivastigmina in the case of increasing dosages of Exelon, it is especially significant for patients with very low body weight.

Throughout the day rivastigmine quite well released from the Exelon patch, penetrating into the skin by about 50% of the full dosage. Highest AUC∞ rivastigmina like the product of it , – NAP 266-90 was fixed with a patch on the shoulder, upper chest or back. If it is impossible to use TTC on these areas of the body, it is allowed to stick a patch on the thigh and abdomen, adjusted for a decrease in the AUC dose by about 20-30%.

Significant plasma cumulation most rivastigmina , like his , was not observed, however, with repeated use, the serum content rivastigmina more than in the first 24 hours.

Binding rivastigmina with plasma proteins is at the level of 40%. The drug easily penetrates GEB . Apparent Vd values ​​vary between 1.8-2.7 l / kg

metabolic transformations rivastigmina significant and fast with T1 / 2 from plasma, which is approximately 3.4 hours after removing the patch. Degree of elimination rivastigmina was limited by the level of its absorption, which explains the increase in T1 / 2 after using the patch (3.4 hours) compared with oral administration of the drug or its intravenous administration (respectively 1.4 and 1.7 hours). main metabolic pathway rivastigmina is his hydrolysis by cholinesterase with the release of a decarbamylated metabolic product - NAP 226-90 demonstrating in vitro minimal (less than 10%) ability to inhibit acetylcholinesterase .

According to experimental studies and in vitro testing of the drug, the system cytochrome P450 takes minimal part in metabolism rivastigmina . cumulative serum clearance rivastigmina equals approximately 130 l / h, with an intravenous injection of the drug at a dose of 0.2 mg, decreases to 70 l / h with an intravenous injection of 2.7 mg rivastigmina and is consistent with the inversely proportional, non-linear nature of the parameters of its pharmacokinetics, due to the excretion of the drug as it saturates the body.

The AUC∞ ratio of the NAP 226-90-metabolite to the original substance was 0.7 for the patch at 3.5 for the capsules, which gives the right to note the reduced intensity of metabolic transformation processes during the cutaneous use of Exelon. Allotment of less NAP 226-90-metabolite dictated by the absence of processes of presystemic metabolism ("first pass" through the liver).

breeding rivastigmina mainly carried out by the kidneys in the form of products of its metabolism. In unchanged form, the drug is practically not detected in the urine. After 24 hours, virtually 90% of the dose used is excreted by the kidneys, less than 1% of the drug is excreted by the intestines.

In elderly patients suffering from Alzheimer's disease , the use of TTS Exelon did not lead to changes in bioavailability rivastigmina due to aging.

At liver pathologies /kidney study of the features of the use of the Exelon patch has not been conducted.

It is known that after oral administration rivastigmina patients with mild to moderate , there was an increase in Cmax of the drug by 60%, and its AUC by more than 100%, compared with patients without hepatic pathologies.

In patients with Alzheimer's disease and parallel moderately pronounced noted an increase in Cmax and AUC more than twice, compared with patients without renal pathologies. However, when severe impairment of renal function no changes were made to these parameters.

Indications for use

The appointment of TTC Exelon is indicated for the treatment of mild or moderate and mild or moderate dementia at .

Contraindications

The appointment of the Exelon patch is absolutely contraindicated for:

• personal hypersensitivity To rivastigmina and / or other components of drugs, as well as to other derivatives carbamate ;
• pregnancy;
• previously diagnosed (history) contact allergic , which developed against the background of the use of the patch;
• breastfeeding ;
• under the age of 18 years.

With special care, TTS Exelon should be used for:

• organic sinus node dysfunction or conduction disorders (including And sinoatrial blockade );
• during the period of exacerbation or predisposition of the patient to the formation gastrointestinal ulcers ;
• propensity to develop convulsive syndrome And urinary tract obstruction ;
• or frequent obstructive diseases of the respiratory tract observed in the past.

Side effects

The cumulative incidence of negative effects when using the Exelon patch was 50.5%, which is slightly less compared to the frequency of similar events observed when taking the capsules - 63.3% (in the receiving group placebo this indicator was equal to 46%).

Most often, when using a daily dose of a patch of 9.5 mg, adverse side effects were noted from gastrointestinal tract , expressed as a percentage in the readings of 7.2% - nausea ; 6,2% – vomit , with identical negative manifestations when taking capsules, respectively, 23.1% and 17.0% (in the group receiving placebo these indicators were equal to 5.0% and 3.3%). The remaining side effects of the drug met me often.

Urinary system:

• infectious pathology .

Nervous system:

• fainting;
• feeling of anxiety;
• delirium ;
• extrapyramidal disorders (very rarely).

Metabolism:

The cardiovascular system:

• violations ;
• bradycardia .

Digestive system:

• soreness in the abdomen;
• nausea, vomiting;
• ulcerative lesions of the gastrointestinal tract (occasionally).

Skin covers:

• skin rash ;
• erythema ;
• irritation;
• inflammation in the area of ​​application.

Others:

• increased fatigue;
• temperature increase ;
• asthenia ;
• weight loss.

In conducted clinical studies, when using a patch with a daily dosage of more than 9.5 mg, the following negative effects were observed much more often than when using TTC with a daily dose of 9.5 mg and in the group placebo : , , excitation, decrease , , heart failure . Presumably this is due to the increase in dosages. rivastigmina , since the frequency of similar adverse events in the group using the Exelon patch at a daily dose of 9.5 mg and the group placebo was almost identical.

From the side skin The most common manifestations were: erythema at the site of application, usually disappearing within 24 hours. In clinical studies, the use of Exelon TTC at a daily dose of 9.5 mg resulted in mild (21.8%), moderate (12.5%) and severe (6.5%) redness (erythema ) of the skin, as well as to mild (11.9%), moderate (7.3%) and severe (5%) .

When treated using a daily dosage of Exelon patch 9.5 mg, the appearance itching And erythema observed in 1.7% and 1.1% of patients, respectively. The vast majority of skin negative phenomena occurred exclusively in the area of ​​application. Interruption of therapy due to the development of skin manifestations was noted only in 2.4% of cases.

Plaster Exelon, instructions for use

The instructions for use of Exelon allow the use of the patch only under the supervision of medical personnel with clinical experience in conducting therapy. dementia of the Alzheimer's type .

The mass part contained in the patch and released from it in 24 hours rivastigmina corresponds to: 9 mg: 4.6 mg; 18 mg: 9.5 mg; 27 mg: 13.3 mg.

For maximum effectiveness of therapy, sticking the patch should be carried out at the same time of the day, after removing the used dosage form. In case of missing a constant time for gluing the TTS, it is necessary to replace the patch as soon as possible.

Treatment with Exelon TTS should begin with a 4.6 mg daily release patch.

If the dose is well tolerated by the patient rivastigmina , after 4 weeks of therapy, you can increase the daily dose to 9.5 mg, which is the recommended maintenance dosage in the presence of adequate therapeutic efficacy.

In some cases, it may be necessary to increase the dosage of Exelon TTS to a maximum daily dose of 13.3 mg, but not earlier than after 6 months.

Each subsequent increase in dosage is possible only with a good personal response to the previous dose. If the tolerability of the drug worsens with an increase in its dose, it is necessary to return to the last well-tolerated dosage.

Temporary cessation of therapy is required by situations that occur with the development of negative effects from gastrointestinal tract and/or worsening of observed extrapyramidal symptoms (including ), up to their full resolution.

In the event of a break in treatment of several days, further therapy should be started with a daily dose of 4.6 mg, in order to reduce the risk of resumption of adverse events (in particular severe vomiting ).

The transfer of patients who have previously received oral forms of Exelon to the use of TTS is possible while maintaining the following dosage proportions. When taken orally rivastigmina at a daily dose up to and including 6 mg, patch therapy can be continued at a daily release dose of 4.6 mg. With previous oral daily intake of 6-12 mg rivastigmina subsequent treatment with TTS can immediately begin with a daily dose of 9.5 mg. The transfer of the patient from oral forms of the drug to the patch is recommended to be carried out on the next day after the internal administration of the last dose of Exelon.

At liver pathologies /kidney adjustment of the dosage regimen is not required, however, the recommended maintenance dose of Exelon TTC for such patients is a daily dose of 4.6 mg.

Using the Exelon patch

The procedure for gluing the first and subsequent Exelon plasters should be carried out using clean, dry and intact areas of the skin , with a minimum amount (if possible) of hairline. The use of any cosmetic or medicinal products on this area of ​​\u200b\u200bthe skin is not recommended. When damage or hyperemia presumably chosen for gluing the patch skin area, it is prohibited to install TTC Exelon on it.

One patch is designed to be used for only 24 hours, after which it must be replaced with a similar one.

The recommended range of application areas for TTS Exelon includes: shoulder parts , top (right or left) chest (avoid sticking on mammary gland ), bottom or top (right or left) plot back . To reduce the risk of possible irritation and/or skin manifestations it is recommended to alternate the areas of application of the patch (optimally, on one part of the body, the patch should be used for no more than 14 days).

Before applying a new TTS, the previous patch must be completely removed.

Proper use of the patch involves first removing it from the package, for which you should cut the package along the line drawn on it. After that, it is necessary to remove from the patch protective film , while not touching its adhesive surface, apply TTS on a pre-selected skin surface and remove the opposite protective layer from the surface of the patch. Using the palms of your hands, firmly press the patch to the skin and hold in this state for at least 30 seconds, making sure solid fit TTS , especially around the edges.

You can write on the patch the exact time and date of its imposition (with a thin pen). TTS should be worn on the body without removing it for 24 hours.

After a day, it is necessary to replace the used patch with a new one, for which you should carefully bend the corner of the TTS and pull it until the patch is completely removed. Next, you need to wipe off the remaining glue, using for this warm soapy water (do not use alcohol or other solvents ).

The used TTC must be disposed of by folding it in half, connecting the adhesive parts, placing it in a sealed bag and further destroying it or throwing it out of the reach of children.

Any contact with patch surfaces requires subsequent thorough hand washing (in order to prevent the ingredients of the patch from getting into the eyes).

When in contact with water, a properly glued Exelon patch with tight-fitting edges does not peel off, which is important for water hygiene procedures (shower, bath). Unintended removal of TTS can be facilitated by a long stay of the patient near a heat source.

In case of accidental detachment of the patch, a new one should be attached in its place, and at the usual time of the next day, replaced with the next one.

If you accidentally use two or more TTCs at the same time, you should remove them all and seek the advice of a doctor.

Overdose

Unintentional overdose of oral forms rivastigmina , as a rule, was not accompanied by clinically significant adverse events requiring discontinuation of treatment. In general, the symptoms of an overdose were manifested nausea /vomiting , increase , and sometimes . Pay attention to vagotonic exelon effect on heart rate , it is possible to allow the development fainting and/or bradycardia . There is information about the simultaneous oral administration of 46 mg rivastigmina , after which conservative treatment was prescribed, which led to a complete recovery of the patient after 24 hours.

There are no reliable data on cases of overdose when using the Exelon patch, which led to any negative consequences.

Possible treatment for asymptomatic overdose should be to discontinue Exelon for the next 24 hours due to plasma T1/2 rivastigmina , which is 3.4 hours and the duration of inhibition acetylcholinesterase for 9 hours. In case of manifestations severe nausea followed by vomiting , it is necessary to consider the appointment antiemetics . Other possible negative effects require treatment appropriate to the observed symptoms. In severe cases, you can prescribe in / in the introduction at the initial dosage of 0.03 mg / kg, further administration Atropine carried out if necessary and in doses corresponding to the clinical effect produced. Not recommended for use as .

Interaction

Specialized studies of the interaction of the drug Exelon in the form of a patch with other therapeutic agents have not been carried out.

Due to the fact that metabolic transformations rivastigmina predominantly take place with the participation esterase through hydrolysis and with minimal system influence cytochrome P450 , its pharmacokinetic interactions with other drugs, the metabolism of which depends on the system cytochrome P450 , is unbelievable.

When conducting research rivastigmina with the participation of healthy volunteers, its pharmacokinetic interaction with , Digoxin , And Warfarin . Intake-induced enhancement prothrombin time when used in parallel rivastigmina , remained unchanged. Combined reception rivastigmina c did not lead to adverse effects of this combination on intracardiac conduction .

Joint appointment rivastigmina with oral hypoglycemic drugs, antacids , antianginal agents, antihistamines , antiemetics means, , hypotensive centrally acting drugs (including NSAIDs ), beta-blockers , benzodiazepines , calcium channel blockers and drugs with a positive inotropic effect, was not accompanied by significant changes in pharmacokinetic parameters rivastigmina or an increased risk of serious adverse effects.

In view of the influence rivastigmina on cholinergic structures, its simultaneous use with cholinomimetic drugs .

In case of parallel assignment anticholinergic drugs it is necessary to take into account the multidirectional effects of these drugs with the action of Exelon.

If during therapy with Exelon there is a need for , it should be remembered that the effects rivastigmina aimed at inhibiting cholinestrase , which may lead to an increase in depolarizing muscle relaxants .

Terms of sale

Acquisition of the Exelon patch requires a prescription.

Storage conditions

TTS Exelon can be stored at a maximum ambient temperature of 25 °C, away from children.

Best before date

The patch can be stored for 24 months from the date stamped on the secondary packaging.

special instructions

When increasing dosages rivastigmina a possible increase in the incidence of side effects and their severity should be taken into account.

The severity of negative phenomena rivastigmina from the side gastrointestinal tract , including manifestations nausea /vomiting , most often noted at the beginning of therapy and at the time of increasing dosages, may decrease with a decrease in the dose of Exelon.

In the event of a forced, for several days, interruption in treatment with Exelon, the return to the use of the patch should begin with the appointment of its minimum daily dose of 4.6 mg.

During treatment with Exelon in patients with Alzheimer's disease , there is a possibility reducing their weight , in connection with which it is necessary to constantly monitor this physical parameter.

During pregnancy (and lactation)

According to experimental data teratogenic properties rivastigmina not installed. The drug does not affect the observed , but may lead to an increase in the period gestation . Comprehensive data on the safety of using the Exelon patch for treatment pregnant women currently does not exist, and therefore its use is contraindicated. Application of Exelon pregnant women allowed in exceptional cases, with many times the benefit of such treatment for the expectant mother in comparison with the possible risk of negative effects on the fetus.

Possibility of penetration rivastigmina V breastfeeding mother's milk it is not known what is the reason for refraining from treatment or refusing to .

Mild to moderate dementia of the Alzheimer's type. Severe dementia of the Alzheimer's type.

Contraindications Exelon transdermal therapeutic system 4.6mg/24h

Hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients that make up the drug. Contact allergic dermatitis in history, which arose against the background of the use of TTS Exelon. Age up to 18 years.

Dosage and administration Exelon transdermal therapeutic system 4.6 mg/24h

Therapy with the drug should be carried out only under the supervision of a physician experienced in the treatment of patients with dementia and under the supervision of persons caring for patients. Patients and their carers should be instructed on the specifics of the use of the drug by competent medical professionals. The amount of contained and released rivastigmine, depending on the dosage of TTS Exelon, is presented below. TTS Exelon 4.6mg/24h - the amount of rivastigmine contained 9mg; the amount of rivastigmine released in vivo within 24 hours is 4.6 mg. TTC Exelon 9.5mg/24h - the amount of rivastigmine contained 18mg; the amount of rivastigmine released in vivo within 24 hours is 9.5 mg. TTC Exelon 13.3 mg/24h - the amount of rivastigmine contained 27 mg; the amount of rivastigmine released in vivo within 24 hours is 13.3 mg. Mild to moderate 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 TTS Exelon 4.6 mg / 24 hours 1 time per day. After 4 weeks of treatment, at least, with good tolerance, the dose of the drug should be increased to the recommended effective dose by using Exelon TTC 9.5 mg / 24 hours, which can be used as long as the therapeutic effect is maintained. Dose escalation: For long-term treatment, in the presence of therapeutic efficacy in the patient, the use of TTC Exelon 9.5 mg / 24 hours is recommended. If the drug is well tolerated and after at least 6 months of treatment with TTS Exelon 9.5 mg / 24 hours, the attending physician, if necessary, to achieve an additional therapeutic effect, can increase the dose to 13.3 mg / 24 hours in patients who, despite the use of TTS Exelon 9 ,5 mg/24h, there is a significant impairment of cognitive functions (for example, worsening of the results of the KShOPS) and / or deterioration in the functional status (based on the subjective assessment of the physician). 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 TTS Exelon 4.6 mg / 24 hours 1 time per day. The dose of the drug should be sequentially increased first to 9.5 mg / 24 hours, and then to an effective dose of 13.3 mg / 24 hours. Each increase in dose is possible only after 4 weeks of treatment at least and with good tolerance of the previous dose. Doses above 13.3 mg/24h do not provide significant benefit but increase the incidence of side effects. Interruption of treatment: the clinical effect of drug therapy should be regularly assessed. In the absence of a clinical effect of therapy with the use of optimal doses of TTS Exelon, therapy with the drug should be discontinued. It is necessary to temporarily stop drug therapy in case of adverse events from the digestive system and / or worsening of existing extrapyramidal symptoms (including tremor) until they resolve. If the break in the use of the drug was no more than three days, you can resume the use of the drug at the same dose. In case of a longer withdrawal period, treatment should be resumed from the initial dose (Exelon TTC 4.6 mg/24 h). Patients treated with rivastigmine in the form of capsules or oral solution can switch to treatment with TTC Exelon, as follows: in patients receiving oral therapy with rivastigmine at a dose less than or equal to 6 mg per day, treatment should begin with TTC Exelon 4.6 mg /24h In patients receiving oral therapy with rivastigmine at a stable and well-tolerated dose of 9 mg per day, treatment can be started immediately with the use of TTS Exelon 9.5 mg / 24 hours. But if oral therapy has not been stable and well tolerated, it is recommended to start switching to a transdermal form with a dose of 4.6 mg / 24 hours. In patients receiving oral therapy with rivastigmine at a dose of 12 mg per day, treatment can be started immediately with the use of TTS Exelon 9.5 mg / 24 hours. After 4 weeks of treatment, at least, if well tolerated, the dose of TTC Exelon 4.6 mg / 24 hours should be increased to the recommended effective dose by using TTC Exelon 9.5 mg / 24 hours. Treatment with TTS Exelon is recommended to start the day after the last oral dose of rivastigmine. Patients weighing less than 50 kg: in patients weighing less than 50 kg, there was a more frequent development of adverse events (AEs) and discontinuation of therapy due to the occurrence of AEs, therefore, when increasing the dose in this group of patients, special care should be taken, the dose should be carefully titrated and monitored for the development of AEs (for example, excessive nausea or vomiting), and also consider the possibility of reducing the dose of the drug by using TTC Exelon 4.6 mg / 24h in the event of the development of such AEs. Particular care should be taken when titrating a dose above the recommended effective dose of TTC Exelon 9.5 mg/24 hours. Patients with impaired liver function: correction of the dosing regimen of TTS Exelon is not required. However, due to the increased exposure to rivastigmine observed with oral rivastigmine in patients with mild to moderate hepatic impairment, it is recommended that the dose of rivastigmine be carefully titrated according to individual tolerability in this category of patients. The study of the use of TTC Exelon in patients with severely impaired liver function has not been conducted. Special care should be taken when titrating the dose in this category of patients. In patients with clinically pronounced liver dysfunction, there may be a more frequent development of dose-dependent adverse events, and therefore, in patients of this category, the possibility of using TTC Exelon 4.6 mg / 24 hours as the initial and maximum dose should be considered. Patients with impaired renal function: correction of the dosing regimen of TTC Exelon is not required. However, due to the increased exposure of rivastigmine observed when taking rivastigmine orally in patients with mild to moderate renal impairment, it is recommended that the dose of rivastigmine be carefully titrated according to individual tolerability in this category of patients. Patients with clinically pronounced impaired renal function may experience a more frequent development of dose-dependent adverse events, and therefore, in patients of this category, the possibility of using TTC Exelon 4.6 mg / 24 hours as the initial and maximum dose should be considered. Use in children: The use of rivastigmine in children has not been studied, therefore, the use of the drug in children is not recommended. Instructions for the use of TTS. Each subsequent transdermal therapeutic system (TTS) Exelon should be glued only after the removal of the previous one. Only one Exelon TTC can be used at a time. TTC Exelon must not be cut or divided into parts, or damaged in any way. Press firmly with the palm of the TTC Exelon at the attachment site for at least 30 seconds. Place of attachment of TTS Exelon: TTS Exelon is glued to clean, dry, intact skin with minimal hairline. Do not use creams, lotions, oils, powders and other skin care products in the area where the drug is attached to avoid peeling off. TTC Exelon should not be applied to reddened, rashed, irritated or damaged skin. Only one Exelon TTC per day should be applied to only one of the areas of the body shown: left or right shoulder; upper chest left or right (do not stick on the breast area); upper back left or right; lower back left or right. To avoid skin irritation, each subsequent Exelon TTS should be glued to a different area of ​​​​the skin (possibly within the same anatomical region). For example, if you attached the TTS Exelon to the lumbar region on the right, then next time place the system on the left. To minimize the risk of skin irritation, TTC may only be applied to the same area of ​​the skin at intervals of two weeks. How to apply TTC Exelon: TTC Exelon is a thin, opaque, plastic patch to be applied to the skin. Do not remove TTC Exelon from the sealed package and do not remove the previous TTC Exelon unless you plan to stick a new one. The drug should be used immediately after removal from the sealed package. Carefully remove the previous Exelon TTC. If you are starting treatment with the drug for the first time or resuming treatment with the drug after a break, please follow the instructions for attaching Exelon TTC, starting with the following figure below. The drug is removed from the sealed package immediately before use. To remove the Exelon TTC, cut the bag along the dotted line or groove. The adhesive side of TTS Exelon is covered with a protective film. It is necessary to carefully remove the protective film on one side, protecting the adhesive side of TTC Exelon, without touching the adhesive surface. Immediately after removing the protective film, stick Exelon TTC on 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 top protective layer from the other side of the TTS. Press firmly with the palm of the TTC Exelon at the attachment site for at least 30 seconds. You need to make sure that the system fits snugly against the skin, especially around the edges. If necessary, after gluing, you can write the date of affixing (eg day of the week) on the transdermal therapy system with a fine ballpoint pen. TTS Exelon must be worn constantly and replaced with a new one after 24 hours. Attaching the transdermal therapeutic system to different areas of the skin allows you to choose the most comfortable areas of the body where the system will not come into contact with tight-fitting clothing. How to remove Exelon TTS: Carefully fold back one of the corners and slowly and carefully remove the transdermal therapeutic system. If there is adhesive residue on your skin, lightly dampen the area with warm water and a mild soapy solution or use baby oil to remove adhesive residue. 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 Exelon TTS. In case of eye contact or redness of the eyes after applying or removing Exelon TTC, immediately flush eyes with plenty of water and, if symptoms persist, seek medical attention. How to dispose of used Exelon TTS: Fold the used transdermal therapy system in half and attach the adhesive parts together. Place the used Exelon TTC in the bag. The bag with the used transdermal therapeutic system should be discarded out of the reach of children. After disposing of the drug, wash your hands with soap and water. Conditions for wearing TTS Exelon (water procedures, prolonged stay near heat sources): TTS Exelon does not peel off during water procedures (shower, bath, pool). - During water procedures, it is necessary to make sure that the system fits snugly against the skin, especially around the edges. Patients using TTS Exelon should not be near any external heat sources (excessive solar radiation, saunas, solariums) for a long time. What to do if Exelon TTC has peeled off: If Exelon TTC has peeled off, it must be replaced with a new transdermal therapeutic system before the end of the day. The next day, you should attach a new Exelon TTC as usual. When and for how long should Exelon TTC be used: for maximum effectiveness of the drug treatment, a new TTC should be applied every day, preferably at the same time. When using more than one Exelon TTS at the same time: you should immediately remove all TTS from your skin and inform your doctor about what happened. You may need medical attention. In some cases, with an overdose, nausea, vomiting, diarrhea, increased blood pressure, hallucinations were noted. Bradycardia and/or syncope may also occur. If you forgot to stick another TTC at the usual time, you should stick it immediately. The application of the next TTC is possible the next day at the usual time. Do not stick two TTCs to make up for a missed dose.

Despite the high development of modern technologies, including in the field of medicine, there are still such terrible and almost incurable ailments as Alzheimer's disease. The neurodegenerative disease was first described in 1907 by the German psychiatrist Alois Alzheimer, from which it got its name.

However, there are drugs such as the Exelon patch that can quite successfully slow down the development of pathology.

Description of the drug

Alzheimer's disease is a pathology of the nervous system one of the most common forms of dementia. In other words, this disease is called "senile dementia" and in most cases it begins to develop in older people over the age of 50, although there are earlier cases of diagnosing the disease.

A drug called TTC "Exelon" is found both in injectable form and in tablet form, as well as in the form of patches. Compared to other forms of release, the patch has a much lower number of unwanted side effects, and during studies it was noted that this form has a lower incidence of negative effects.

The Exelon patch is a kind of transdermal therapeutic system (TTS). The main active ingredient of the drug is called rivastigmine. The patch is due to it that inhibits the enzyme cholinesterase inside the patient's brain cells. While wearing the patch, the medicinal component gradually penetrates the body and there is a temporary blocking of the enzymes butyrylcholinesterase and acetylcholinesterase due to their selective suppression.

The active substance of the drug functions in the body for about 9 hours, and then the enzymes begin to return to their original levels. In pharmacies, you can buy patches that contain 9, 18 and 27 milligrams of the main component. The patch has a rounded shape, white, with a beige backing. The area of ​​the main contact surface is about five square cm. The excipients of the drug include alpha-tocopherol, methyl methacrylate, butyl methacrylate, acrylic copolymer, silicone copolymer and silicone oil, which are directly on the adhesive layers of the patches.

Pharmacological properties

Rivastigmine is the main drug ingredient and is a selective cholinesterase inhibitor in the human brain. The substance allows you to slow down the processes of destruction of acetylcholine, produced by functionally preserved neurons, and, in addition, it allows you to improve the processes responsible for synaptic transmission.

The use of the drug helps to increase the level of acetylcholine inside the hippocampus and cerebral cortex, due to which there is an improvement in cholinergic transmission. Due to the fact that for the most part dementia and cognitive decline in case of illness are usually associated with a lack of acetylcholine, it turns out that the drug helps to normalize the functioning of the human nervous system. In addition, there is information that the drug reduces the synthesis of beta-amyloid, and this, in turn, prevents the appearance of harmful amyloid plaques, which are one of the main signs of the development of pathology.

Indications and contraindications for use

Despite the fact that the use of a drug in modern medicine is far from uncommon, indications for its use are still quite rare. These include:

• mild dementia associated with the disease;
• moderately severe dementia;
• the presence of functional or cognitive disorders.

The drug is used in the form of a patch both in the early stages of the development of the disease, and in the direct presence of the disease.

Prescribes the use of the drug "Exelon" exclusively by the attending physician after a thorough examination of the patient. It is impossible to make a decision on the use of this drug on your own. It must be borne in mind that only the attending physician can advise the use of the Exelon patch. Instructions for its use should also contain all the detailed recommendations on the correct use of the drug.

In most cases, therapy begins with the lowest dosage, about 4.6 milligrams per day. Only if the use of the drug after a few weeks has not caused any deterioration in the work of the patient's body, has a good effect and no harmful, undesirable effects have been diagnosed, then the dosage is usually increased. In cases where the use of the drug gives an unambiguously positive result on the body, the duration of therapy may be several months or more.

Sometimes the use of the patch is replaced with injections, similar tablets or other medications. If therapy for certain reasons needs to be interrupted, then it is resumed, again starting with a small dosage of the active component of the drug.

Contraindications to the use of the Exelon patch are as follows:

Possible complications and side effects

Most medical reviews indicate that complications and possible negative side effects in people undergoing treatment with Exelon appear quite rarely, especially when using patches in the form of a drug. However, exceptions are always possible and there is a certain list of disorders that may well manifest themselves with regular use of the drug. These include:

When the first signs of the development of a complication or side effect appear, you should definitely consult on this issue with your doctor. It is likely that the medicine may not help certain people due to the specifics of the body, or it may be necessary to change the dosage of therapy.

The instructions for use of the drug say that certain cases of overdose are recorded very rarely and basically do not pose any danger. In addition, after the end of the use of the drug, the body returns to its normal state after one or two days. Typical symptoms of an overdose include nausea, mild hallucinations, increased blood pressure, and, in very rare cases, fainting or even bradycardia.

Medication cost

The price of the Exleon patch is formed from several factors, such as dosage, manufacturer, and others. Sometimes in some cases, the drug is prescribed free of charge, by prescription of the attending physician, if a diagnosed Alzheimer's disease is present.

In general, the cost of one package of Exelon medicine containing 30 patches is approximately 3,500 to 4,200 rubles. In most cases, this should be enough for exactly one month of therapy.

Means analogues

Since, due to the fact that the drug is not suitable for all patients due to the presence of contraindications and side effects, the attending physician may advise you to choose a more suitable and no less effective analogue of the substance.

In most cases, patients diagnosed with Alzheimer's disease are prescribed a drug called Alzenorm. However, it is worth paying attention to the fact that most modern analogues are available in tablet form, in the form of injections or capsules, and this, of course, may not be suitable for all people. Sometimes situations are possible when the use of a patch as a medicine is the best option.

Despite scientific advances in the field of medicine, not all diseases that affect the nervous system can be treated.

There are a number of neurological diseases in which it is possible to only slightly alleviate the patient's condition and restrain the development of destructive processes occurring in the body. One of these complex neurological abnormalities is.

Since this disease cannot be completely cured, the drugs used by modern medicine act only as a deterrent, slightly slowing down the development of the disease. Exelon Patch can also be included in this group of funds.

What are the benefits of the patch?

Many people who are forced to constantly take medications in tablets or injections suffer from problems with the digestive tract. This is not surprising, since many of the active ingredients that make up medications irritate the gastric mucosa and adversely affect the digestive system as a whole.

In such cases, the use of a patch is the best way out. The necessary substances enter the body without affecting the stomach and intestines.

Composition and form of release

Exelon is an oval-shaped white patch with a beige backing. The surface area of ​​the drug can vary, it depends on the amount of active ingredient. The transdermal system can be an area of:

• 5 cm (contains 9 mg of the drug);
• 10 cm (at a dosage of 18 mg);
• 15 cm (for an amount of substance 27 mg).

The main component of the patch is rivastigmine. This active substance has a beneficial effect on the state of the nervous system and is actively used to treat diseases associated with.

When the patient uses the patch, the medicinal composition enters the body gradually, in small doses, which allows the active substances to be well absorbed and the risk of overdose is eliminated.

The active component of the transsystem is rivastigmine, in addition, the patch contains additional components (L-tocopherol, acrylic acid copolymer, methyl methacrylate and butyl methacrylate).

The adhesive surface consists of a silicone copolymer, L-tocopherol and dimethicone. This composition allows the therapeutic agent to remain on the skin even after contact with water.

Mechanism of action and effectiveness

The transdermal system works as follows: after it is fixed on the body, rivastigmine begins to gradually penetrate into the body.

The active substance has a beneficial effect on the state of the nervous system. As a result of the use of the tool, the following positive changes are noted:

• the state of the cerebral cortex improves due to the normalization of the processes of production of the necessary substances;
• destructive processes slow down;
• prevents the development of amyloid plaques.

Due to this effect, persistent improvements in memory and speech are noticeable in patients, the ability to concentrate is observed, and the intensity of the behavioral manifestations of the disease decreases. Excitability, tearfulness and forgetfulness disappear, thanks to which the patient is able to maintain an adequate state for a long time.

Indications and contraindications for use

The main indication for the use of the Exelon patch is Alzheimer's disease in mild or moderate form. Also, the drug can be used for various genesis.

It is forbidden to use the remedy in the following cases:

• with hypersensitivity to the components of the drug (rivastigmine and other carbamate derivatives);
• in case of allergic reactions on the skin, which may occur as a result of the use of the patch;
• under the age of 18.

Instructions for use

The application of the patch does not cause difficulties, it should be used as follows:

• wash your hands with soap, if possible, treating them with an antiseptic solution;
• examine the patch for integrity, if damage is present on the surface, it is not recommended to use the product;
• remove the protective film and attach the patch to the area of ​​​​the body with minimal hairline;
• fix the tool by pressing it with the palm of your hand to the selected area of ​​​​the body for 30-60 seconds;
• wash your hands again.

Remember that the transdermal system should be on the skin for a day, then it must be removed. In addition, the sticker cannot be cut into pieces, nor can a new Exelon be attached to the skin until the previous one has been removed.

Before using the product, wash your hands thoroughly, and if the substance gets into your eyes, immediately rinse them with plenty of water.

Dosage of the active ingredient

Rivastigmine formula

The starting dose of rivastigmine is 9 mg per day. If the patient normally tolerates the effects of the drug for a month, then the dosage can be gradually increased in accordance with the recommendations of a specialist.

With severe violations, it is allowed to increase the dose to 13.3 mg per day, but this should be done gradually. Substances come to this volume gradually, before that it is necessary to observe a dosage of 9.5 mg for at least six months.

However, it should be remembered that with increasing doses, the risk of side effects also increases.

Special instructions and patients

There are a number of cases where there is no direct prohibition on the use of the patch, but the effect of the drug on the body is not fully understood.

So, it is necessary to take precautions when using Exelon for the following categories of patients:

• in the presence of bronchial asthma and other respiratory diseases;
• during pregnancy and lactation (if the patch is used in the postpartum period, breastfeeding must be abandoned for the duration of treatment);
• persons suffering from diseases of the genitourinary system;
• in the presence of peptic ulcers of the stomach and intestines;
• in cases where the patient suffers from kidney and liver diseases.

In such situations, at the slightest deterioration in the condition, you should immediately stop using the medication and consult your doctor.

Side effects

The use of a medicinal product can lead to side effects. They appear as follows:

• the patient is ill or depressed;
• cerebral circulation is disturbed;
• develops;
• appear and ;
• nausea, vomiting, pain and indigestion occur for no apparent reason.

As a "local" reaction, you can designate the appearance of swelling, itching, burning or redness in the area of ​​\u200b\u200bthe skin where the patch was attached.

Read this leaflet carefully before you start taking/using this medicine.
Save the instructions, they may be needed again.
If you have any questions, please contact your doctor.
This medicine has been prescribed for you personally and should not be shared with others as it may harm them even if they have the same symptoms as you.

REGISTRATION NUMBER: LSR-007020/08-200315

TRADENAME: Exelon®

INTERNATIONAL NON-PROPRIETARY NAME (MHH): rivastigmine

PHARMACEUTICAL FORM: transdermal therapeutic system

COMPOUND
1 transdermal therapeutic system (TTS) contains: active substance- rivastigmine 9.00 mg (contained in TTS 4.6 mg/24 h, 5 cm 2), 18.00 mg (contained in TTS 9.5 mg/24 h, 10 cm 2) or 27.00 mg (contained in TTS 9.5 mg/24 h, 10 cm 2) in TTC 13.3 mg / 24 h, 15 cm 2); Excipients: D,L-α-tocopherol 0.03 mg, 0.06 mg, 0.09 mg, methyl methacrylate and butyl methacrylate copolymer 6.00 mg, 12.00 mg, 18.00 mg, acrylic acid copolymer 14.97 mg, 29 .94 mg, 44.91 mg; adhesive layer: silicone copolymer 14.84 mg, 29.67 mg, 44.505 mg, dimethicone (silicone oil 12.500 cSt) 0.15 mg, 0.30 mg, 0.45 mg, D,L-α-tocopherol 0.015 mg, 0.03 mg, 0.045 mg; polymer films: PET substrate, 23 µm: 5 cm 2 10 cm 2 , 15 cm 2 ; protective fluoropolymer polyethylene terephthalate film, 75 µm: 10.13 cm 2 , 20.25 cm 2 , 29.16 cm 2 .

DESCRIPTION:
Transdermal therapy system with beige backing, double adhesive layer and rectangular protective film overlapped, recessed, round. Overprinted on the TTS substrate: "AMCX" for a dosage of 4.6 mg/24 h, "BHDI" for a dosage of 9.5 mg/24 h, "CNFU" for a dosage of 13.3 mg/24 h.

PHARMACOTHERAPEUTIC GROUP: cholinesterase inhibitor

ATH CODE: N06DA03

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
Rivastigmine, being a selective inhibitor of carbamate-type acetylcholinesterase and butyrylcholinesterase, slows down the destruction of acetylcholine produced by functionally intact neurons and improves synaptic transmission. The drug selectively increases the content of acetylcholine in the cerebral cortex and hippocampus, and thus improves cholinergic nerve transmission. Rivastigmine has a positive effect on cognitive decline associated with acetylcholine deficiency in dementia associated with Alzheimer's disease. In addition, there is evidence that inhibition of cholinesterases can slow down the formation of beta-amyloid precursor protein fragments, 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 temporary inactivation of the enzyme.
In young healthy men, oral rivastigmine 3 mg reduces acetylcholinesterase activity in the cerebrospinal fluid (CSF) by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, the activity of the enzyme returns to its original value after about 9 hours. Inhibition of butyrylcholinesterase in the CSF is also reversible, the activity of the enzyme is restored to its original level after 3.6 hours.
In patients with Alzheimer's disease, rivastigmine's inhibition of acetylcholinesterase activity in the CSF is dose-dependent over the studied dose range up to 6 mg twice daily (maximum dose). Inhibition of CSF butyrylcholinesterase activity in 14 Alzheimer's patients treated with oral rivastigmine was similar to inhibition of acetylcholinesterase activity. A dose of 6 mg 2 times a day causes a decrease in enzyme activity by more than 60% compared with the original. This effect of the drug persisted for 12 months of therapy (the maximum period studied).
A statistically significant correlation was shown between the degree of rivastigmine inhibition of both enzymes in the CSF and changes in cognitive function in patients with Alzheimer's disease; at the same time, it is the inhibition of butyrylcholinesterase in the CSF that significantly and stably correlates with the improvement in the results of tests of memory, attention, and speed of reaction.
The use of the transdermal therapeutic system (TTS) Exelon® in patients with mild and moderate dementia in Alzheimer's disease (10-20 points on the Mini Mental State Examination (MMSE) and severe dementia of the Alzheimer's type leads to 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 the first dose of the drug, the time to reach a detectable concentration of rivastigmine was 0.5-1 hour. The maximum concentration (Cmax) in plasma is reached after 10-16 hours. After reaching Cmax, the plasma concentration slowly decreases in the remaining 24-hour period of using TTC Exelon®.
The equilibrium concentration of rivastigmine in plasma after replacing the used Exelon® TTC with a new one slowly decreases on average over a period of approximately 40 minutes, until the absorption of the active substance from the newly glued Exelon® TTC begins to prevail over elimination. After that, the plasma concentration of rivastigmine begins to rise slowly and again reaches a maximum after approximately 8 hours. At steady state, the lowest concentration is approximately 50% of the maximum, in contrast to oral administration, in which the plasma concentration is virtually zero between doses of the next dose. Similar temporal characteristics of the plasma concentration of rivastigmine were observed with the use of TTC Exelon®, in the dose range from 4.6 mg / 24 hours to 13.3 mg / 24 hours. Despite the fact that the exposure (Cmax and area under the concentration-time curve (AUC)) of rivastigmine is obviously less than with oral administration, its increase is directly proportional to the increase in the dosage of TTC Exelon®.
With an increase in the dosage from TTC Exelon® from 4.6 mg / 24 h to 9.5 mg / 24 h, an increase in Cmax and AUC of rivastigmine by 2.6 times was noted, with an increase to 13.3 mg / 24 h - by 4.9 times.
The relative difference between the maximum and minimum concentrations of rivastigmine (oscillation index, IC) ((Cmax - Cmin) / Cavg)) when using TTS Exelon® 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 (IC of 3.96 for a dosage of 6 mg / day and 4.15 for a dosage of 12 mg / day).
The amount of rivastigmine released in 24 hours from Exelon® TTS (dose in mg per 24 hours) is not equivalent to oral administration of the same dose of rivastigmine capsules (assessed by plasma exposure of rivastigmine over 24 hours).
Exelon® TTC 9.5 mg/24 hours is equivalent to oral Exelon® 6 mg capsules twice daily (12 mg per day).
When directly comparing the use of 1 dose of the drug Exelon® TTC and oral capsules, intersubject variability in Cmax and AUC0-24h of rivastigmine was 43% and 49% for Exelon® TTC and 74% and 103% for capsules, respectively. With repeated use and reaching an equilibrium state, the interpopulation variability in Cmax and AUC0-24h of rivastigmine in patients with dementia in Alzheimer's disease was also significantly lower for Exelon® TTC compared with oral capsules: 45% and 43% for the transdermal therapeutic system and 71 % and 73% for capsules, respectively.
In patients with dementia of the Alzheimer's type, a clear relationship was noted between body weight and the equilibrium concentration of rivastigmine and the metabolite NAP266-90). In patients with dementia of the Alzheimer's type and weighing 35 kg, the equilibrium concentration of rivastigmine increased by approximately 2 times compared with patients with a body weight of 65 kg; while for patients with a body weight of 100 kg, there was a decrease in the equilibrium concentration of approximately 2 times. The effect of body weight on rivastigmine exposure is particularly important in very low body weight patients when the dose is increased.
Rivastigmine was well released from TTS Exelon® during the 24-hour application period - on the skin (about 50% of the drug content). The highest AUC∞ of rivastigmine and the NAP266-90 metabolite was observed when TTC Exelon® was applied to the upper back, chest or shoulder, AUC∞ decreased by approximately 20-30% when applied to the abdomen and thigh.
No significant plasma accumulation of rivastigmine or the NAP226-90 metabolite was observed in patients with Alzheimer's disease dementia. Except that the plasma concentration of rivastigmine during the second application of TTS Exelon® was higher than on the first day.
Distribution
Rivastigmine is weakly bound to plasma proteins (about 40%) and easily crosses the blood-brain barrier. The apparent volume of distribution is 1.8-2.7 l / kg.
Metabolism
Rivastigmine is rapidly and extensively metabolized with a plasma half-life (T1/2) of approximately 3.4 hours after removal of the transdermal therapeutic system. Elimination was limited by the degree of absorption of rivastigmine (flip-flop kinetics), which explains the increase in T1 / 2 after using TTC Exelon® (3.4 h) compared with oral or intravenous administration (1.4 and 1.7 h, respectively) of the drug. The metabolism of rivastigmine occurs primarily by hydrolysis by cholinesterase to form a decarbamylated metabolite (NAP226-90), which has demonstrated minimal ability to inhibit acetylcholinesterase in vitro (<10%). Основываясь на данных, полученных в in vitro исследованиях, не ожидается взаимодействия с препаратами, метаболизирующимися при помощи следующих изоферментов системы цитохрома: CYP1А2, CYP2D6, CYP3А4/5, CYP2Е1, CYP2С9, CYP2С8, CYP2С19 или CYP2В6. В соответствии с данными, полученными в экспериментальных исследованиях, основные изоферменты цитохрома Р450 в минимальной степени вовлечены в метаболизм ривастигмина. Общий плазменный клиренс ривастигмина составляет около 130 л/ч после внутривенного введения в дозе 0.2 мг и снижается до 70 л/ч после внутривенного введения 2.7 мг, который согласуется с нелинейным, обратно пропорциональным характером фармакокинетики ривастигмина вследствие его элиминации по мере насыщения.
The metabolite-to-parent AUC ratio was 0.7 for the transdermal therapeutic system versus 3.5 for oral capsules, indicating a lower metabolic rate after dermal application. The formation of a smaller amount of the NAP226-90 metabolite is due to the absence of first pass metabolism (the effect of "first pass" through the liver).
breeding
Rivastigmine is excreted mainly by the kidneys as metabolites; almost never found unchanged in the urine. More than 90% of the dose is excreted 24 hours after ingestion. Less than 1% of the dose is excreted in the feces.
Pharmacokinetics in elderly patients
In elderly patients with Alzheimer's disease, there were no age-related changes in exposure when using TTS Exelon®.
Pharmacokinetics in patients with impaired liver function
The study of the use of TTC Exelon® in patients with impaired liver function has not been conducted. In patients with mild to moderate hepatic impairment, after oral administration of rivastigmine, there was an increase in Cmax by approximately 60% and AUC by more than 2 times compared with healthy volunteers.
When taking 3 mg of rivastigmine once or after multiple doses of the drug according to the 6 mg 2 times a day regimen, the clearance of rivastigmine was approximately 60-65% less in patients with mild to moderate hepatic impairment compared with healthy patients. These pharmacokinetic features do not affect the frequency of occurrence and severity of adverse events.
Pharmacokinetics in patients with impaired renal function
The study of the use of TTS Exelon® in patients with impaired renal function has not been conducted. Based on a population analysis, there was no clear effect of creatinine clearance on steady-state plasma concentrations of rivastigmine or its metabolite. In patients with impaired renal function, dose adjustment is not required.

INDICATIONS FOR USE

Mild to moderate dementia of the Alzheimer's type.
Severe dementia of the Alzheimer's type.

CONTRAINDICATIONS

Hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients that make up the drug.
A history of allergic contact dermatitis that arose during the use of Exelon® TTC.
Age up to 18 years.

CAREFULLY

Rivastigmine should be used with caution in patients with sick sinus syndrome or conduction disorders (sinoatrial block, atrioventricular block).

- to increase the secretion of hydrochloric acid in the stomach, so care should be taken when prescribing rivastigmine to patients with gastric and duodenal ulcers in the acute stage or in patients predisposed to these conditions;

Rivastigmine should be used with caution in patients with asthma or a history of obstructive airway disease.

USE IN PREGNANCY AND DURING BREASTFEEDING

Pregnancy
In animal studies, rivastigmine crossed the placenta. There are no data on the ability of rivastigmine to penetrate the hematoplacental barrier in humans.
Experimental data have shown that rivastigmine does not have teratogenic properties. In studies in animals, an increase in the duration of the gestational period was noted. The safety of Exelon® in human pregnancy has not yet been established, therefore, the drug can be used during pregnancy only in cases where the expected benefit of treatment outweighs the potential risk to the fetus.
Breast-feeding
In studies, rivastigmine and its metabolites were excreted in the milk of lactating animals. It is not known whether rivastigmine passes into breast milk, so breastfeeding should be avoided while using the drug.
Fertility
There are no data on the effect of rivastigmine on women of reproductive age.
There are no data on the effect of rivastigmine on human fertility. In animal studies, there was no negative effect on the fertility of males and females, both parents and offspring.

METHOD OF APPLICATION AND DOSES

Therapy with the drug should be carried out only under the supervision of a physician experienced in the treatment of patients with dementia and under the supervision of persons caring for patients. Patients and their carers should be instructed on the specifics of the use of the drug by competent medical professionals
The amount of contained and released rivastigmine depending on the dosage of TTS Exelon® is presented in table 1.

Table 1.
TTS Exelon® Amount of contained rivastigmine Amount of rivastigmine released in vivo within 24 hours
TTS Exelon® 4.6 mg/24 h 9 mg 4.6 mg
TTS Exelon® 9.5 mg/24 h 18 mg 9.5 mg
TTS Exelon® 13.3 mg/24 h 27 mg 13.3 mg

Mild to moderate dementia of the Alzheimer's type.

Treatment with the drug should begin with the use of TTS Exelon® 4.6 mg / 24 hours 1 time per day. After 4 weeks of treatment, at least, if well tolerated, the dose of the drug should be increased to the recommended effective dose by using TTS Exelon® 9.5 mg/24 h, which can be used as long as the therapeutic effect is maintained.
Dose escalation:
For long-term treatment, in the presence of therapeutic efficacy in the patient, the use of TTS Exelon® 9.5 mg / 24 hours is recommended. If the drug is well tolerated and after at least 6 months of treatment with TTS Exelon® 9.5 mg / 24 hours, the attending physician if necessary, to achieve an additional therapeutic effect, may increase the dose to 13.3 mg / 24 h in patients who, despite the use of TTS Exelon® 9.5 mg / 24 h, there is a significant impairment of cognitive functions (for example, worsening results on KShOPS) and / or deterioration in functional status (based on the subjective assessment of the physician).
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 TTS Exelon® 4.6 mg / 24 hours 1 time per day. The dose of the drug should be sequentially increased first to 9.5 mg / 24 hours, and then to an effective dose of 13.3 mg / 24 hours. Each increase in dose is possible only after 4 weeks at least and with good tolerance of the previous dose.
A dose above 13.3 mg/24 hours does not provide a significant benefit, but increases the incidence of side effects.
Treatment interruption:
The clinical effect of therapy with Exelon® TTS should be regularly evaluated. In the absence of a clinical effect of therapy with the use of optimal doses of TTC Exelon®, therapy with the drug should be discontinued.
It is necessary to temporarily stop drug therapy in case of adverse events from the digestive system and / or worsening of existing extrapyramidal symptoms (including tremor) until they resolve. If the break in the use of the drug was no more than three days, you can resume the use of the drug at the same dose. In case of a longer withdrawal period, treatment should be resumed at the initial dose (Exelon® TTC 4.6 mg/24 h).
Patients treated with rivastigmine capsules or oral solution can switch to Exelon® TTS treatment as follows:
In patients receiving oral therapy with rivastigmine at a dose less than or equal to 6 mg per day, treatment should begin with the use of TTS Exelon® 4.6 mg / 24 hours.
In patients receiving oral therapy with rivastigmine at a stable and well-tolerated dose of 9 mg per day, treatment can be started immediately with the use of TTS Exelon® 9.5 mg/24 hours. But if oral therapy was not stable and well tolerated, switching to a transdermal form it is recommended to start with a dose of 4.6 mg/24 hours.
In patients receiving oral therapy with rivastigmine 12 mg per day, treatment can be started immediately with the use of TTS Exelon® 9.5 mg/24 hours.
After 4 weeks of treatment, at least, if well tolerated, the dose of TTS Exelon® 4.6 mg/24 h can be increased by using TTS Exelon® 9.5 mg/24 h.
Treatment with TTS Exelon® is recommended to start the day after the last oral dose of rivastigmine.

Patients weighing less than 50 kg
In patients weighing less than 50 kg, there was a more frequent development of adverse events (AEs) and discontinuation of therapy due to the occurrence of AEs, therefore, when increasing the dose in this group of patients, special care should be taken, the dose should be carefully titrated and monitored for the development of AEs (for example , excessive nausea or vomiting), as well as consider reducing the dose of Exelon TTC to 4.6 mg/24 h in the event of such AEs. Particular care should be taken when titrating a dose above the recommended effective dose of TTC Exelon® 9.5 mg/24 hours.

However, due to the increased exposure to rivastigmine observed with oral rivastigmine in patients with mild to moderate hepatic impairment, it is recommended that the dose of rivastigmine be carefully titrated according to individual tolerability in this category of patients.
Exelon® TTC has not been studied in patients with severe hepatic impairment. Special care should be taken when titrating the dose in patients of this category (see sections "Special instructions", "Pharmacological properties").
In patients with clinically pronounced liver dysfunction, there may be a more frequent development of dose-dependent adverse events, and therefore, in patients of this category, the possibility of using TTS Exelon® 4.6 mg / 24 hours as the initial and maximum dose should be considered.

Correction of the dosing regimen of TTC Exelon® is not required.
However, due to the increased exposure of rivastigmine observed when taking rivastigmine orally in patients with mild to moderate renal impairment, it is recommended that the dose of rivastigmine be carefully titrated according to individual tolerability in this category of patients. Patients with clinically impaired renal function may experience a more frequent development of dose-dependent adverse events, and therefore, in patients of this category, the possibility of using TTS Exelon® 4.6 mg / 24 hours as the initial and maximum dose should be considered.

Use in children
The use of rivastigmine in children has not been studied, so the drug is not recommended for children.

INSTRUCTIONS FOR USE
ATTENTION!!!
Each subsequent Exelon® transdermal therapeutic system (TTS) should be applied only after the previous one has been removed.
Only one Exelon® TTC can be used at a time.
TTS Exelon® must not be cut or divided into parts, or damaged in any way.
Press firmly with the palm of the Exelon® TTC at the attachment site for at least 30 seconds.
Place of attachment of TTS Exelon®
TTS Exelon® is glued to clean, dry, intact skin with minimal hairline.
Do not use creams, lotions, oils, powders and other skin care products in the area where the drug is attached to avoid peeling off.
TTC Exelon® should not be applied to reddened, rashed, irritated or damaged skin.
Only one TTC Exelon® per day should be applied to only one of the areas of the body shown below in Figure 1:
- Left or right shoulder;
- Upper chest on the left or on the right (do not stick on the breast area);
- Upper back left or on right;
- Lower back left or on right.
Rice. 1
Every 24 hours, the previous Exelon® TTC should be removed before applying one new Exelon® TTC to one of the areas shown below.
To avoid skin irritation, each subsequent TTS Exelon® should be glued to a different area of ​​​​the skin (possibly within the same anatomical region). For example, if you attached the TTC Exelon® to the lumbar region on the right, then next time place the system on the left. To minimize the risk of skin irritation, TTC may only be applied to the same area of ​​the skin at intervals of two weeks.
How to attach TTS Exelon®
TTC Exelon® is a thin, opaque, pliable skin patch. Do not remove the Exelon® TTC from the sealed bag and do not remove the previous Exelon® TTC unless you plan to glue a new one.
The drug should be used immediately after removal from the sealed package.
Carefully remove the previous Exelon® TTC.
If you are starting treatment with the drug for the first time or resuming treatment with the drug after a break, please follow the instructions for attaching Exelon® TTC, starting from the next picture below.
The drug is removed from the sealed package immediately before use.
To remove Exelon® TTS, cut the bag along the dotted line or groove.
The adhesive side of TTS Exelon® is covered with a protective film.
It is necessary to carefully remove the protective film on one side, protecting the adhesive side of TTS Exelon®, without touching the adhesive surface.
Immediately after removing the protective film, apply TTC Exelon® 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 top protective layer from the other side of the TTS.
Press firmly with the palm of the Exelon® TTC at the attachment site for at least 30 seconds. You need to make sure that the system fits snugly against the skin, especially around the edges.
If necessary, after gluing, you can write the date of affixing (eg day of the week) on the transdermal therapy system with a fine ballpoint pen.
TTS Exelon® must be worn continuously and replaced with a new one after 24 hours.
Attaching the transdermal therapeutic system to different areas of the skin allows you to choose the most comfortable areas of the body where the system will not come into contact with tight-fitting clothing.
How to remove TTS Exelon®
Gently fold back one of the corners and slowly and carefully remove the transdermal therapy system.
If there is adhesive residue on your skin, lightly dampen the area with warm water and a mild soapy solution or use baby oil to remove adhesive residue. 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 Exelon® TTS. In case of eye contact or redness of the eyes after applying or removing Exelon® TTC, immediately flush eyes with plenty of water and, if symptoms persist, seek medical attention.
How to dispose of used Exelon® TTC
Fold the used transdermal therapy system in half and attach the adhesive parts together.
Place the used Exelon® TTC in the bag. The bag with the used transdermal therapeutic system should be discarded out of the reach of children. After disposing of the drug, wash your hands with soap and water.
Conditions for wearing TTS Exelon® (water procedures, prolonged stay near heat sources)
TTS Exelon® does not peel off during water procedures (shower, bath, pool). - During water procedures, it is necessary to make sure that the system fits snugly against the skin, especially around the edges.
Patients using TTS Exelon® should not be near any external heat sources (excessive solar radiation, saunas, solariums) for a long time.
What to do if TTS Exelon® has peeled off
If Exelon® TTS has peeled off, it must be replaced with a new transdermal therapeutic system before the end of the day. The next day, a new Exelon® TTC should be attached as usual.
When and for how long should Exelon® TTS be used?
For maximum effectiveness of the drug treatment, a new TTS should be applied every day, preferably at the same time.
When using more than one TTC Exelon® at the same time
You should immediately remove all TTS from your skin and inform your doctor about what happened. You may need medical attention. In some cases, with an overdose, nausea, vomiting, diarrhea, increased blood pressure, hallucinations were noted. Bradycardia and/or syncope may also occur.
If you forgot to stick another TTC at the usual time, you should stick it immediately. The application of the next TTC is possible the next day at the usual time. Do not stick two TTCs to make up for a missed dose.

SIDE EFFECT

OVERDOSE

Symptoms. Accidental overdose of the drug for oral use in most cases was not accompanied by any clinical manifestations; almost all patients continued treatment with rivastigmine. In case of overdose, nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, drowsiness, bradycardia, confusion, increased sweating, increased blood pressure, hallucinations and general malaise were noted. Overdose of cholinesterase inhibitors can lead to a cholinergic crisis with the development of symptoms such as severe nausea, vomiting, increased salivation, increased sweating, bradycardia, low blood pressure, respiratory depression and convulsions. Muscle weakness may develop, which can be fatal if the respiratory muscles are involved. Given the vagotonic effect of cholinesterase inhibitors on heart rate (HR), the occurrence of bradycardia and/or syncope cannot be ruled out.
During post-registration use of the drug, as well as in rare cases during clinical trials, application / dosing errors were reported when using TTS Exelon®, due to the imposition of several TTS Exelon® at the same time (the next TTS was used without removing the previous one). Patients and their caregivers should be instructed about the features of the use of the drug.
With an overdose of the drug, rare cases of death were noted, but the relationship with the use of the drug remains unclear. Symptoms and outcome varied in different patients. There was no clear relationship between the dose of the drug taken and the severity of the outcome.
Treatment. Since the half-life of rivastigmine from plasma is about 3.4 hours, and the duration of acetylcholinesterase inhibition is about 9 hours, in cases of asymptomatic overdose, immediate removal of all TTS is recommended, Exelon® TTS should not be used within the next 24 hours. If overdose is accompanied by severe nausea and vomiting, consideration should be given to the use of antiemetics. If other adverse events occur, if necessary, appropriate symptomatic treatment is carried out.
With a significant overdose, atropine can be used, the initial dose of which is 0.03 mg / kg intravenously; subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.

INTERACTION WITH OTHER DRUGS

A special study of the interaction of TTC Exelon® with other drugs has not been conducted.
Rivastigmine is metabolized mainly by hydrolysis with the participation of esterases. The metabolism of rivastigmine with the participation of the main cytochrome P450 isoenzymes occurs to a minimal extent. Thus, the pharmacokinetic interaction of rivastigmine with other drugs metabolized with the participation of these enzymes seems unlikely.
However, rivastigmine may have an inhibitory effect on the butyrylcholinesterase-mediated metabolism of other substances.
Interactions not recommended
metoclopramide
Given the possibility of a cumulative effect of drugs on the extrapyramidal system, the simultaneous use of metoclopramide and rivastigmine is not recommended.
Drugs affecting the cholinergic system
Given the pharmacodynamic characteristics of rivastigmine, its simultaneous use with other cholinomimetics should be avoided due to the possibility of developing their cumulative action. Rivastigmine may interfere with the action of anticholinergics (eg, oxybutynin, tolterodine).
Suxamethonium salts
During anesthesia, rivastigmine, being a cholinesterase inhibitor, can enhance the effects of depolarizing muscle relaxants (muscle relaxants of suxamethonium salts).
Interactions to Consider
Beta blockers
With the simultaneous use of rivastigmine with various beta-blockers (including atenolol), a synergistic interaction was noted, leading to the development of bradycardia, which, in turn, can cause syncope. Despite the fact that simultaneous use with cardioselective beta-blockers is associated with the greatest risk of developing such effects, these AEs were also observed in patients who received other drugs in this group.
Interaction with nicotine
An increase in the absorption of rivastigmine by 23% was shown when administered orally (in the form of capsules at 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 and digoxin, warfarin, diazepam, or fluoxetine. The warfarin-induced increase in prothrombin time was not affected by oral rivastigmine. With the simultaneous use of rivastigmine for oral administration and digoxin, an adverse effect on intracardiac conduction was not observed.
Co-administration of rivastigmine with commonly used drugs such as antacids, antiemetics, hypoglycemic agents, centrally acting antihypertensive agents, slow calcium channel blockers, positive inotropic agents, antianginal agents, estrogens, analgesics, including non-steroidal anti-inflammatory drugs, benzodiazepines and antihistamines, 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 hand-to-eye contact immediately after TTS is attached or removed. Wash hands thoroughly with soap and water after attaching or removing TTS. In case of eye contact or redness of the eyes after applying or removing TTS, immediately flush eyes with plenty of water and, if symptoms persist, seek medical attention.
Gastrointestinal disorders
The incidence and severity of side effects usually increase with increasing doses of rivastigmine, especially during dose changes. If the interruption in the use of the drug Exelon® TTS was more than three days, treatment should be resumed from the initial dose (Exelon® TTS 4.6 mg / 24 hours).
The severity of such dose-dependent adverse events from the gastrointestinal tract (GIT), such as nausea, vomiting and diarrhea, observed at the beginning of treatment or with an increase in the dose of the drug, may decrease with a decrease in the dose of rivastigmine, if there is no effect, TTC Exelon therapy should be interrupted. These AEs are more common in women. In patients who develop signs of dehydration due to prolonged diarrhea or vomiting, intravenous fluids and dose reduction or discontinuation of rivastigmine therapy are recommended, due to the possible risk of serious complications.

Weight loss
Since patients with Alzheimer's disease during therapy with cholinesterase inhibitors, including rivastigmine, may experience a decrease in body weight, during therapy with Exelon TTS, it is necessary to control the weight of patients.

Other adverse events associated with an increase in the activity of the cholinergic system
As with other cholinomimetics, caution should be exercised when using Exelon® TTC in patients with sick sinus syndrome or conduction disorders (sinoatrial block, atrioventricular block); in patients with bronchial asthma or a history of obstructive airways disease.
Cholinergic stimulation can lead to:
- to increase the secretion of hydrochloric acid in the stomach, so care should be taken when using Exelon® TTC in patients with gastric and duodenal ulcers in the acute stage or in patients predisposed to these conditions;
- to the development or exacerbation of urinary tract obstruction and convulsive syndrome, so care should be taken when prescribing rivastigmine to patients predisposed to these conditions.
Like other cholinomimetics, the use of rivastigmine may cause an increase in the severity of extrapyramidal disorders.

Reactions at the site of attachment of TTS Exelon® and skin reactions
Skin reactions that occur during the use of the drug Exelon® TTS, as a rule, are mild or moderate in severity. These reactions are not an indicator of the patient's sensitization to rivastigmine. However, allergic contact dermatitis may occur with the use of Exelon® TTC.
Allergic contact dermatitis should be suspected if a skin reaction occurs at the site of attachment of the TTS that extends beyond the size of the TTS, or skin reactions at the site of attachment become pronounced (for example, increasing erythema, edema, papules, vesicles), and also if the severity of skin reactions do not decrease significantly within 48 hours after removal of the TTS. In these cases, treatment with the drug should be discontinued (see section "Contraindications").
With the development in patients of a reaction at the site of attachment of the TTS, similar to allergic contact dermatitis, against the background of the use of the drug Exelon® 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 during allergological testing is recommended to be transferred to dosage forms rivastigmine for oral administration. Some patients sensitized to rivastigmine due to the use of Exelon® TTC will not be able to use rivastigmine in other dosage forms.
During the post-registration use of the drug, data were obtained on the development of common skin hypersensitivity reactions in some patients when using rivastigmine, regardless of the method of application (orally or transdermally). In these cases, the drug should be completely canceled (see section Contraindications). Patients and their caregivers should be informed of the possibility of developing relevant skin reactions during the use of rivastigmine.

Use in special groups of patients
Use in elderly patients
In clinical studies of Exelon® TTC, 88% of patients were 65 years of age or older, and 55% of patients were over 75 years of age. In general, there were no differences in the safety and efficacy of the drug depending on age. However, an individual higher sensitivity to the effects of the drug in older patients cannot be ruled out.
Patients with impaired liver function
When taking rivastigmine orally in patients with mild to moderate hepatic impairment, an increase in rivastigmine exposure was observed, and therefore a dose reduction may be required in accordance with individual tolerance in patients of this category. The use of rivastigmine in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function
When taking rivastigmine orally in patients with mild to moderate renal impairment, an increase in rivastigmine exposure was observed, and therefore a dose reduction may be required in accordance with individual tolerance in patients of this category.
Patients with low or high body weight
Due to the relationship between body weight and exposure to rivastigmine, the dose should be carefully titrated and monitored in patients with low or high body weight.

EFFECT ON THE ABILITY TO DRIVE AND WORK WITH MECHANISMS
Alzheimer's dementia can cause a gradual deterioration in the ability to drive vehicles or compromise the ability to use them. In patients treated with rivastigmine, dizziness and drowsiness may develop, especially at the beginning of treatment or when the dose of the drug is changed. Rivastigmine may cause fainting or delirium. The ability of a patient with dementia treated with the drug to drive vehicles and / or work with mechanisms should be regularly evaluated by the attending physician.

RELEASE FORM
One transdermal therapeutic system 4.6 mg/24 h or 9.5 mg/24 h, in a multilayer laminate bag (paper coated with polyethylene terephthalate film, aluminum foil and polyacrylonitrile copolymer): 3, 7, 30 bags with instructions for use application in a cardboard box.
One transdermal therapeutic system 13.3 mg/24 h in a multilayer laminate bag (paper coated with polyethylene terephthalate film, aluminum foil and polyacryl nitrate copolymer). On 7, 30 packages together with the application instruction in a cardboard pack.