Dementia patch. Exelon® transdermal therapeutic system

1 transdermal therapeutic system (patch, TTS) may include the following 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 produces 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 preserved 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 insufficiency acetylcholine , including manifestations with And Alzheimer's .

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

When prescribed 3 mg rivastigmine healthy young men, during the first hour and a half, a decrease in activity was observed in their cerebrospinal fluid (CSF). acetylcholinesterase by about 40%. After approximately 9 hours after recording the maximum inhibitory effect rivastigmine , activity acetylcholinesterase returns to original values. Suppression process in the CSF butyrylcholinesterase is also reversible with return to baseline enzyme levels after 3.6 hours.

In case of use rivastigmine patients with Alzheimer's disease dose-dependent (in the daily dosage range up to 12 mg) inhibition is noted acetylcholinesterase in the CSF, as well as butyrylcholinesterase , the level of which decreases by approximately 60% when used rivastigmine in a daily dose of 12 mg. This effectiveness of the drug remained throughout the entire studied period of its use, which was 12 months.

During 12 months of therapy rivastigmine a statistically significant relationship was proven between the indicators of its inhibition in the CSF of both enzymes and positive changes in cognitive functions patients suffering Alzheimer's disease . The studies carried out reliably associated improved test scores attention , memory And reaction speed namely with inhibition in the CSF butyrylcholinesterase .

Prescription of the Exelon patch for patients with mild/moderate symptoms 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 ), increased functional status, and increased daily activity.

TTC Exelon is characterized by slow absorption of the active ingredient rivastigmine . Determination time rivastigmine in, after using the first dose of the patch, was 30-60 minutes. TCmax ranged from 10-16 hours, after which the serum content of the drug gradually decreased over 24 hours.

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

Compared to oral administration rivastigmine its exposure (AUC and Cmax) when using the patch is obviously lower, but the increase in these values ​​is proportional to the increase in the dose of TTS Exelon. In case of increasing the daily dosage of TTC from 4.6 mg to 9.5 mg AUC rivastigmine 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 rivastigmine when using patches with different dosages, the corresponding values ​​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 noticeably 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 dose 12 mg.

Mass part rivastigmine , which is released over 24 hours from TTS Exelon, does not correspond to that after oral administration of a similar dose of this drug (as assessed by plasma exposure rivastigmine within 24 hours). Use of the daily dosage of Exelon 9.5 mg patch is equivalent to the oral daily dose rivastigmine 12 mg.

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

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

Throughout the day rivastigmine Exelon was released quite well from the patch, penetrating the skin by approximately 50% of the full dosage. Highest AUC∞ rivastigmine , as well as its product , – NAP 266-90 was applied when the patch was applied to the shoulder, upper chest or back. If it is impossible to use TTC in these areas of the body, a patch can be applied to the thigh and abdomen, adjusted to reduce the AUC dose by approximately 20-30%.

Significant plasma cumulation himself rivastigmine , like it, was not observed, however, with repeated use, the serum content rivastigmine was more than in the first 24 hours.

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

Metabolic transformations rivastigmine significant and rapid with T1/2 from plasma being approximately 3.4 hours after removal of the patch. Elimination rate rivastigmine was limited by the level of its absorption, which explains the increase in T1/2 after using the patch (3.4 hours) in comparison with oral administration of the drug or its intravenous administration (1.4 and 1.7 hours, respectively). Main route of metabolism rivastigmine is his hydrolysis by cholinesterase with the release of decarbamylated metabolic product - NAP 226-90 , demonstrating minimal (less than 10%) ability to inhibit in vitro acetylcholinesterase .

According to experimental studies and in vitro testing of the drug, the system cytochrome P450 takes minimal part in metabolism rivastigmine . Cumulative serum clearance rivastigmine 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 rivastigmine and is consistent with the inversely proportional, nonlinear nature of the parameters of its pharmacokinetics, due to the elimination of the drug as the body becomes saturated with it.

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

Removal rivastigmine mainly carried out by the kidneys in the form of products of its metabolism. In unchanged form, the drug is practically undetectable in 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 Alzheimer's disease , the use of TTS Exelon did not lead to changes in bioavailability rivastigmine due to age-related changes.

At liver pathologies /kidney The specifics of using the Exelon patch have not been studied.

It is known that after oral administration rivastigmine 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 expressed noted an increase in Cmax and AUC values ​​by more than two times, compared with patients without renal pathologies. However, when severe renal impairment There were no changes to these parameters.

Indications for use

Prescription of TTC Exelon is indicated for the treatment of mild or moderately severe and mildly or moderately severe dementia at .

Contraindications

The use of the Exelon patch is absolutely contraindicated for:

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

TTS Exelon should be used with extreme caution when:

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

Side effects

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

Most often, when using a daily dose of 9.5 mg patch, side effects were noted: Gastrointestinal tract , as a percentage expressed in readings of 7.2% - nausea ; 6,2% – vomit , with identical negative manifestations when taking capsules, 23.1% and 17.0%, respectively (in the group receiving placebo these figures were equal to 5.0% and 3.3%). Other side effects of the drug were less common.

Urinary system:

• infectious pathology .

Nervous system:

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

Metabolism:

The cardiovascular system:

• violations ;
• bradycardia .

Digestive system:

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

Skin:

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

Others:

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

In 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 : , , excitement, decrease, , heart failure . Presumably this is due to increased dosages rivastigmine , 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 outside skin the most common manifestations were: erythema at the site of application, usually disappearing within 24 hours. In clinical studies, the use of TTC Exelon at a daily dose of 9.5 mg resulted in mild (21.8%), moderate (12.5%) and severe (6.5%) redness (erythema ) skin, as well as mild (11.9%), moderate (7.3%) and severe (5%) .

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

Exelon patch, instructions for use

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

Mass fraction contained in the patch and released from it within 24 hours rivastigmine corresponds to: 9 mg:4.6 mg; 18 mg:9.5 mg; 27 mg:13.3 mg.

For maximum effectiveness of therapy, the patch should be applied at the same time of day, after first removing the used dosage form. If the constant time for gluing the TTC is missed, the patch must be replaced as quickly as possible.

Treatment with TTC Exelon should begin with the use of a patch with a daily release of 4.6 mg.

If the patient tolerates this dose well rivastigmine , after 4 weeks of therapy, the daily dose can be increased to 9.5 mg, which is the recommended maintenance dosage if there is adequate therapeutic efficacy.

In some cases, it may be necessary to increase the dosage of TTS Exelon to a maximum daily dose corresponding to 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 drug's tolerability deteriorates when its dose is increased, 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 deterioration of observed extrapyramidal symptoms (including ), up to their complete resolution.

In case of a break in treatment of several days, further therapy should begin with a daily dose of 4.6 mg in order to reduce the risk of resumption of negative effects (in particular severe vomiting ).

Transferring patients who have previously received oral forms of Exelon to the use of TTC is possible while maintaining the following dosage proportions. When taken orally rivastigmine at a daily dose of up to 6 mg inclusive, patch therapy can be continued at a daily released dose of 4.6 mg. With previous oral daily intake 6-12 mg rivastigmine subsequent treatment with TTC can be started immediately with a daily dose of 9.5 mg. It is recommended to transfer the patient from oral forms of the drug to the patch 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 patches should be carried out using clean, dry and undamaged areas of the skin , with a minimum amount (if possible) of hair. The use of any cosmetic or medicinal products on this area of ​​the skin is not recommended. When damage or hyperemia of the skin area presumably selected for gluing the patch, it is prohibited to install TTS Exelon on it.

One patch is intended for use for only 24 hours, after which it must be replaced with a similar one.

The recommended selection of application areas for TTS Exelon includes: shoulder parts , top (right or left) chest (avoiding sticking on mammary gland ), lower or upper (right or left) section backs . To reduce the risk of possible irritation and/or skin manifestations It is recommended to alternate areas of application of the patch (optimally, the patch should be used on one area of ​​the body for no more than 14 days).

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

Correct use of the patch involves first removing it from the package, for which you should cut the package along the line marked on it. After this, you need to remove it from the patch. protective film , without touching its adhesive surface, apply TTC to a pre-selected skin surface and remove the opposite protective layer from the surface of the patch. Using the palms of your hands, press the patch firmly onto the skin and hold it there for at least 30 seconds, making sure continuous fit of the TTS , especially around the edges.

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

After 24 hours, it is necessary to replace the used patch with a new one, for which you should carefully bend the corner of the TTC and pull it until the patch is completely removed. Next you need to wipe off the remaining glue using warm soapy water (should not be used alcohol or other solvents ).

Used TTS 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 away out of the reach of children.

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

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

If the patch accidentally peels off, attach a new one in its place and replace it with the next one at the usual time of the next day.

If you accidentally use two or more TTCs at the same time, you must remove them all and seek medical advice.

Overdose

Unintentional overdose of oral forms rivastigmine , as a rule, was not accompanied by clinically significant negative phenomena requiring discontinuation of treatment. Basically, the symptoms of an overdose manifested themselves nausea /vomiting , increase , and sometimes . Pay attention to vagotonic Exelon effect on Heart rate , it is possible to allow the development fainting states and/or bradycardia . There is information about simultaneous oral administration of 46 mg rivastigmine , after which conservative treatment was prescribed, which led to complete recovery of the patient after 24 hours.

There is 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 rivastigmine , 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, intravenous administration may be prescribed. at an 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

There have been no specialized studies of the interaction of the drug Exelon in the form of a patch with other medications.

Due to the fact that metabolic transformations rivastigmine mainly take place with the participation esterase by hydrolysis and with minimal system influence cytochrome P450 , its pharmacokinetic interactions with other drugs whose metabolism depends on the system cytochrome P450 , unlikely.

When conducting research rivastigmine with the participation of healthy volunteers, no pharmacokinetic interaction with , Digoxin , And Warfarin . Reception-induced increase prothrombin time when used in parallel rivastigmine , remained unchanged. Combined technique rivastigmine c did not lead to an adverse effect of this combination on intracardiac conduction .

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

Due to the influence rivastigmine 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 using Exelon there is a need to , it should be remembered that the effects rivastigmine aimed at inhibiting cholinesterases , which can lead to increased action depolarizing muscle relaxants .

Terms of sale

Purchasing the Exelon patch requires a prescription.

Storage conditions

TTC 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, starting from the date stamped on the secondary packaging.

special instructions

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

Severity of negative phenomena rivastigmine from the outside Gastrointestinal tract , including manifestations nausea /vomiting , most often observed at the beginning of therapy and at the time of increasing dosages, may decrease as the dose of Exelon is reduced.

In the event of a forced break in treatment with Exelon for several days, a return to the use of the patch should begin with the administration 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 , and therefore it is necessary to constantly monitor this physical parameter.

During pregnancy (and lactation)

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

Possibility of penetration rivastigmine V breastfeeding mother's milk it has not been studied what causes abstinence from treatment or refusal .

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

Contraindications Exelon transdermal therapeutic system 4.6 mg/24h

Hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients included in the drug. History of allergic contact dermatitis that arose during the use of TTC Exelon. Age up to 18 years.

Method of administration and dosage Exelon transdermal therapeutic system 4.6 mg/24h

Therapy with the drug should only be carried out under the supervision of a physician experienced in treating patients with dementia and under the supervision of persons caring for the patients. Patients and their caregivers should be instructed about the use of the drug by competent healthcare professionals. The amount of rivastigmine contained and released depending on the dosage of TTC Exelon is presented below. TTC Exelon 4.6 mg/24h - the amount of rivastigmine contained is 9 mg; the amount of rivastigmine released in vivo over 24 hours is 4.6 mg. TTC Exelon 9.5 mg/24h - the amount of rivastigmine contained is 18 mg; the amount of rivastigmine released in vivo over 24 hours is 9.5 mg. TTC Exelon 13.3 mg/24h - the amount of rivastigmine contained is 27 mg; the amount of rivastigmine released in vivo over 24 hours is 13.3 mg. Mild or 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 TTC Exelon 4.6 mg/24 hours 1 time per day. After a minimum of 4 weeks of treatment, if well tolerated, the dose of the drug should be increased to the recommended effective dose by using TTC Exelon 9.5 mg/24 hours, which can be used as long as the therapeutic effect remains. Dose escalation: for long-term treatment, if the patient has therapeutic efficacy, 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 TTC Exelon 9.5 mg/24h, the attending physician, if necessary to achieve an additional therapeutic effect, can increase the dose to 13.3 mg/24h in patients who, despite the use of TTC Exelon 9 ,5 mg/24 hours, there is a significant impairment of cognitive functions (for example, deterioration of results according to the KSHOPS) and/or deterioration of functional status (based on a subjective assessment by a 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 TTC 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 dose increase is possible only after a minimum of 4 weeks of treatment and if the previous dose is well tolerated. 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. If there is no clinical effect from therapy when using optimal doses of TTC Exelon, therapy with the drug should be discontinued. Treatment with the drug should be temporarily discontinued if adverse events from the digestive system occur and/or existing extrapyramidal symptoms (including tremor) worsen until they resolve. If the break in the use of the drug was no more than three days, you can resume using 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 hours). 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 rivastigmine therapy at a dose of less than or equal to 6 mg per day, treatment should begin with TTC Exelon 4.6 mg /24h. In patients receiving oral rivastigmine therapy at 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 hours. But if oral therapy was not stable and well tolerated, it is recommended to start switching to the 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 begin immediately with the use of TTC Exelon 9.5 mg/24 hours. After 4 weeks of treatment, at a minimum, 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 TTC Exelon is recommended to begin the day after the last oral dose of rivastigmine. Patients weighing less than 50 kg: Patients weighing less than 50 kg were more likely to develop adverse events (AEs) and discontinuation of therapy due to AEs, therefore, when increasing the dose in this group of patients, special caution should be used, carefully titrate the dose and monitor for the development of AEs (for example, excessive nausea or vomiting), and also consider 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 the dose above the recommended effective dose of TTC Exelon 9.5 mg/24 hours. Patients with impaired liver function: no dosage adjustment is required for TTC Exelon. However, due to the increased exposure of rivastigmine observed when rivastigmine was taken orally in patients with mild to moderate hepatic impairment, it is recommended that the dose of rivastigmine be carefully titrated to individual tolerance in these patients. The use of TTS Exelon in patients with severe liver dysfunction has not been studied. Particular care should be taken when titrating the dose in patients in this category. In patients with clinically significant liver dysfunction, a more frequent development of dose-dependent adverse events may be observed, and therefore, in patients in this category, the possibility of using TTC Exelon 4.6 mg/24 hours should be considered as the initial and maximum dose. Patients with impaired renal function: no dosage adjustment is required for TTC Exelon. However, due to the increased exposure of rivastigmine observed when oral rivastigmine was taken in patients with mild to moderate renal impairment, it is recommended that the dose of rivastigmine be carefully titrated to individual tolerance in these patients. In patients with clinically significant renal impairment, a more frequent development of dose-dependent adverse events may be observed, and therefore, in patients in this category, the use of TTC Exelon 4.6 mg/24 hours should be considered as the initial and maximum dose. Use in children: The use of rivastigmine in children has not been studied, so the drug is not recommended for children. Instructions for use of TTS. Each subsequent Exelon transdermal therapeutic system (TTS) should be applied only after the previous one has been removed. You can only use one TTS Exelon at a time. TTS Exelon must not be cut or divided into parts, or damaged in any way. The Exelon TTC should be pressed firmly with the palm of the hand 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 hair. Do not use creams, lotions, oils, powders or other skin care products in the area where the drug is attached to prevent it from coming off. TTC Exelon should not be applied to red, rash-covered, irritated or damaged skin. You should stick only one TTS Exelon per day on only one of the body areas shown: left or right shoulder; upper chest left or right (should not be applied to 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 area). For example, if you attached the TTS Exelon to the lumbar area on the right, then next time place the system on the left. To minimize the risk of skin irritation, TTC can be applied to the same area of ​​skin only at intervals of two weeks. How to attach TTC Exelon: TTC Exelon is a thin, opaque, plastic patch for gluing to the skin. Do not remove TTS Exelon from the sealed bag and do not remove the previous TTS Ekselon if you do not plan to glue a new one. The drug should be used immediately after removal from the sealed package. Carefully remove the previous Exelon TTS. 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 the Exelon TTC, starting with the following figure below. The drug is removed from the sealed bag immediately before use. To remove the Exelon TTC, cut the package along the dotted line or groove indicated. The adhesive side of TTS Ekselon is covered with a protective film. You should carefully remove the protective film on one side that protects the adhesive side of the Exelon TTS, 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 on the other side of the TTS. The Exelon TTC should be pressed firmly with the palm of the hand at the attachment site for at least 30 seconds. Make sure that the system fits snugly against the skin, especially around the edges. If necessary, after sticking, you can write the date of attachment (for example, the day of the week) on the transdermal therapeutic system with a thin 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 select the most comfortable areas of the body where the system will not come into contact with tight-fitting clothing. How to remove the Exelon TTC: Carefully peel back one of the corners and slowly and carefully remove the Transdermal Therapy System. If there is adhesive residue on your skin, lightly wet the area with warm water and a mild soap solution or use baby oil to remove any adhesive residue. Do not use alcohol or other liquid solvents (nail polish remover or other solvents). You should wash your hands thoroughly with soap and water after attaching or removing the Exelon TTC. In case of contact with eyes or if eyes become red after attaching or removing Exelon TTC, rinse eyes immediately with plenty of water and, if symptoms persist, seek medical attention. How to dispose of your used Exelon TTC: Fold the used Transdermal Therapy System in half and press the adhesive parts together. Place the used TTC Exelon in the bag. The bag containing the used transdermal therapy system should be discarded out of the reach of children. After disposing of the drug, you must wash your hands with soap. Conditions for wearing TTS Ekselon (water procedures, prolonged stay near heat sources): TTS Ekselon does not come off during water procedures (showers, baths, swimming pool). - During water procedures, you must make sure that the system fits tightly to the skin, especially around the edges. Patients using TTS Exelon should not stay near any external heat sources (excessive solar radiation, saunas, solariums) for a long time. What to do if the TTC Exelon comes off: if the TTC Exelon comes off, it must be replaced with a new transdermal therapeutic system by the end of the day. The next day, you should attach the new Exelon TTS as usual. When and for how long should TTS Exelon be used: for maximum effectiveness of treatment with the drug, a new TTS should be applied every day, preferably at the same time. If you use more than one Exelon TTC at the same time: You should immediately remove all TTC from your skin and inform your healthcare professional. You may need medical attention. In some cases, with an overdose, nausea, vomiting, diarrhea, increased blood pressure, and hallucinations were noted. Bradycardia and/or fainting may also occur. If you forget to stick the next TTS at the usual time, you should stick it immediately. The next TTS can be used the next day at the usual time. You should not apply 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 untreatable ailments as Alzheimer's disease. The neurodegenerative disease was first described back in 1907 by the German psychiatrist Alois Alzheimer, which is where 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 also earlier cases of diagnosing the disease.

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

The Exelon patch is a kind of transdermal therapeutic system (TTS). The main active ingredient of the drug is called rivastigmine. It is precisely because of this that the patch inhibits the enzyme cholinesterase inside the patient’s brain cells. While wearing the patch, the medicinal component gradually penetrates the body and the enzymes butyrylcholinesterase and acetylcholinesterase are temporarily blocked due to their selective suppression.

The active substance of the drug functions in the body for approximately 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 is round in shape, white, with a beige backing. The area of ​​the main contact surface is approximately about five square cm. The excipients of the drug include alpha-tocopherol, methyl methacrylate, butyl methacrylate, acrylic copolymer, silicone copolymer and silicone oil, located directly on the adhesive layers of the patches.

Pharmacological properties

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

The use of the drug helps to increase the level of acetylcholine within the hippocampus and cerebral cortex, thereby improving cholinergic transmission. Due to the fact that most dementia and decline in cognitive functions due to illness are associated, as a rule, with a lack of acetylcholine, it turns out that the medicine 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 the drug in modern medicine is far from uncommon, its indications for use are still quite rare. These include:

• mild dementia associated with the disease;
• moderate 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 immediate presence of the disease.

The use of the drug "Exelon" is prescribed exclusively by the attending physician. upon completion of a thorough examination of the patient. You cannot make a decision about using this medicine on your own. It must be borne in mind that only the attending physician can advise the use of the Exelon patch. The instructions for its use must also contain all 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 several weeks has not caused any deterioration in the functioning of the patient’s body, has a good effect and no harmful or undesirable effects have been diagnosed, then the dosage is usually increased. In cases where the use of a drug gives a clearly positive result on the body, the duration of therapy can be several months or more.

Sometimes the use of a patch is replaced with injections, similar tablets or other medications. If therapy needs to be interrupted for certain reasons, 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 say that complications and possible negative side effects in people undergoing treatment with Exelon appear quite rarely, especially when using patches in the form of the drug. However, exceptions are always possible and there is a certain list of disorders that may well appear with regular use of the medicine. These include:

When the first signs of a complication or side effect appear, you should definitely consult your doctor about this issue. 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 using the medicine say that certain cases of overdose are recorded very rarely and generally do not pose any danger. In addition, after completing the use of the drug, the body returns to its normal state in one or two days. Typical symptoms of overdose include nausea, mild hallucinations, increased blood pressure, and in very rare cases, fainting or even bradycardia.

Cost of medicine

The price of the Exleon patch is determined by several factors, such as dosage, manufacturer and others. Sometimes in some cases the medicine is prescribed free of charge, with a doctor's prescription, if Alzheimer's disease is diagnosed.

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

Analogues of the product

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 choosing 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 Alcenorm. However, it is worth paying attention to the fact that most modern analogs are available in tablet form, in the form of injection solutions or capsules, and this, of course, may not be suitable for all people. Sometimes there may be situations when using 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 are treatable.

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 disorders 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 products.

What are the advantages of the patch?

Many people who are forced to constantly take medications in tablets or injections suffer from problems with the gastrointestinal tract. This is not surprising, since many active components included in medications irritate the gastric mucosa and negatively affect the digestive system as a whole.

In such cases, using a patch is the best solution. The necessary substances enter the body without affecting the stomach and intestines.

Composition and release form

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

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

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

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

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 silicone copolymer, L-tocopherol and dimethicone. This composition allows the treatment to remain on the skin even after contact with water.

Mechanism of action and effectiveness

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

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

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

Thanks to this effect, patients experience persistent improvements in memory and speech, the ability to concentrate, and the intensity of 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 use of the Exelon patch is mild or moderate Alzheimer's disease. Also, the drug can be used for various origins.

It is prohibited 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 that may occur as a result of using the patch;
• under the age of 18.

Instructions for use

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

• wash your hands with soap and, if possible, treat them with an antiseptic solution;
• examine the patch for integrity; if there is damage on the surface, it is not recommended to use the product;
• remove the protective film and attach the patch to an area of ​​the body with minimal hair;
• secure the product 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 must remain on the skin for 24 hours, then it must be removed. In addition, the sticker cannot be cut into pieces, and a new Exelon cannot be attached to the skin until the previous one is removed.

Before using the product, you must wash your hands thoroughly, and if the substance gets into your eyes, you should 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 tolerates the effects of the medication normally for a month, then the dosage can subsequently be gradually increased in accordance with the recommendations of a specialist.

In case of severe disorders, it is allowed to increase the dose to 13.3 mg per day, but this must be done gradually. The substances reach this volume gradually; before this, it is necessary to maintain a dosage of 9.5 mg for at least six months.

However, it should be remembered that as the dose increases, the risk of side effects increases.

Special instructions and patients

There are a number of cases where there is no direct ban on the use of the patch, but the effect of the drug on the body has not been fully studied.

So, the following categories of patients need to be careful when using Exelon:

• in the presence of bronchial asthma and other respiratory diseases;
• during pregnancy and lactation (if the patch is used in the postpartum period, you must stop breastfeeding 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, if the condition worsens at the slightest level, you should immediately stop using the medication and consult your doctor.

Side effects

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

• the patient is depressed or depressed;
• cerebral circulation is impaired;
• develops ;
• appear and ;
• Nausea, vomiting, pain and stomach upset occur for no apparent reason.

A “local” reaction can be defined as the appearance of swelling, itching, burning or redness in the area of ​​the skin where the patch was attached.

Read these instructions carefully before you start taking/using this medicine.
Save the instructions, you may need them again.
If you have any questions, consult your doctor.
This medicine is prescribed for you personally and should not be given to others because it may harm them even if they have the same symptoms as you.

REGISTRATION NUMBER: LSR-007020/08-200315

TRADENAME: Exelon®

INTERNATIONAL NON-PROPENTIAL NAME (MHH): rivastigmine

DOSAGE FORM: transdermal therapeutic system

COMPOUND
1 transdermal therapeutic system (TTS) contains: active substance- rivastigmine 9.00 mg (contained in TTC 4.6 mg/24 h, 5 cm2), 18.00 mg (contained in TTC 9.5 mg/24 h, 10 cm2) or 27.00 mg (contained in 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: polyethylene terephthalate substrate, 23 microns: 5 cm 2 10 cm 2, 15 cm 2; protective fluoropolymer polyethylene terephthalate film, 75 microns: 10.13 cm 2, 20.25 cm 2, 29.16 cm 2.

DESCRIPTION:
Transdermal therapeutic system with beige backing, double adhesive layer and rectangular overlapping protective film, recessed, round. On the TTC substrate there is an overprint: “AMSC” for a dosage of 4.6 mg/24 hours, “BHDI” for a dosage of 9.5 mg/24 hours, “CNFU” for a dosage of 13.3 mg/24 hours.

PHARMACOTHERAPEUTIC GROUP: cholinesterase inhibitor

ATH CODE: N06DA03

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
Rivastigmine, being a selective inhibitor of acetyl- and butyrylcholinesterase of the carbamate type, 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 helps improve cholinergic nerve transmission. Rivastigmine has a positive effect on the decline in cognitive function 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 fragments of the protein precursor beta-amyloid, 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 reduced cerebrospinal fluid (CSF) acetylcholinesterase activity by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, the enzyme activity returns to its original level after approximately 9 hours. Inhibition of butyrylcholinesterase in the CSF is also reversible; enzyme activity is restored to its original level after 3.6 hours.
In patients with Alzheimer's disease, the inhibition of acetylcholinesterase activity in the CSF by rivastigmine is dose-dependent over the studied dose range up to 6 mg twice daily (maximum dose). Inhibition of butyrylcholinesterase activity in the CSF of 14 patients with Alzheimer's disease treated with oral rivastigmine was similar to the inhibition of acetylcholinesterase activity. A dose of 6 mg 2 times a day causes a decrease in enzyme activity by more than 60% compared to 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 inhibition of both enzymes in the CSF by rivastigmine and changes in cognitive function in patients with Alzheimer's disease; Moreover, it is the inhibition of butyrylcholinesterase in the CSF that reliably and consistently correlates with improved results of tests of memory, attention and reaction speed.
The use of the Transdermal Therapeutic System (TTS) Exelon® in patients with mild to moderate dementia due to Alzheimer's disease (10-20 points on the Mini Mental State Examination (MMSE), 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 to placebo.
Pharmacokinetics
Absorption
Absorption of rivastigmine from TTC Exelon® occurs slowly. After using the first dose of the drug, the time to achieve a detectable concentration of rivastigmine was 0.5-1 hour. The maximum concentration (Cmax) in plasma is achieved after 10-16 hours. After reaching Cmax, the plasma concentration slowly decreases during the remaining 24-hour period of use of TTC Exelon®.
The equilibrium concentration of rivastigmine in plasma after replacing the used Exelon® TTC with a new one slowly decreases over an average of approximately 40 minutes, until the absorption of the active substance from the newly glued Exelon® TTC begins to prevail over elimination. Thereafter, 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. Similar temporal characteristics of plasma concentrations 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. Although the exposure (Cmax and area under the concentration-time curve (AUC)) of rivastigmine is obviously lower than with oral administration, its increase is directly proportional to the increase in the dosage of TTS Exelon®.
When the dosage was increased from TTS Exelon® from 4.6 mg/24 hours to 9.5 mg/24 hours, there was an increase in Cmax and AUC of rivastigmine by 2.6 times, and when increased to 13.3 mg/24 hours, by 4.9 times.
The relative difference between the maximum and minimum concentrations of rivastigmine (fluctuation index, IR) ((Cmax - Cmin)/Cavg)) when using TTC 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 over 24 hours from Exelon® TTC (mg dose per 24 hours) is not equivalent to oral administration of the same dose of rivastigmine capsules (assessed by rivastigmine plasma exposure over 24 hours).
Exelon® TTC 9.5 mg/24 hours is equivalent to the use of Exelon® oral capsules at a dose of 6 mg 2 times a day (12 mg per day).
In a direct comparison of the use of 1 dose of TTC Exelon® and oral capsules, intersubject variability in Cmax and AUC0-24h of rivastigmine was 43% and 49% for TTC Exelon® and 74% and 103% for capsules, respectively. With repeated use and achievement of a steady state, the interpopulation variability of Cmax and AUC0-24h of rivastigmine in patients with dementia due to Alzheimer's disease was also significantly lower for TTC Exelon® compared to 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 observed between body weight and the steady-state concentration of rivastigmine and the metabolite NAP266-90). In patients with dementia of the Alzheimer's type and a body weight of 35 kg, the steady-state concentration of rivastigmine increased approximately 2-fold compared with patients with a body weight of 65 kg; while for patients weighing 100 kg, a decrease in steady-state concentration by approximately 2 times was observed. The effect of body weight on rivastigmine exposure is particularly important in patients with very low body weight when the drug dose is increased.
Rivastigmine was well released from Exelon® TTS during a 24-hour period of application to the skin (about 50% of the drug content). The highest AUC∞ of rivastigmine and the NAP266-90 metabolite was observed when Exelon® TTC was applied to the upper half of the back, chest or shoulder; AUC∞ decreased by approximately 20-30% when applied to the abdomen and thigh.
There was no significant accumulation of rivastigmine or the NAP226-90 metabolite in plasma in patients with Alzheimer's disease dementia. With the exception that the plasma concentration of rivastigmine during the second application of TTS Exelon® was higher than on the first day.
Distribution
Rivastigmine binds weakly to plasma proteins (about 40%) and easily penetrates 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 hours) compared to oral or intravenous administration (1.4 and 1.7 hours, respectively) of the drug. 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 AUC ratio of metabolite to parent substance was 0.7 for the transdermal therapeutic system versus 3.5 for oral capsules, indicating a lower rate of metabolism after dermal application. The formation of a smaller amount of the NAP226-90 metabolite is due to the lack of first-pass metabolism (the “first pass” effect through the liver).
Removal
Rivastigmine is excreted primarily by the kidneys in the form of metabolites; almost undetectable in urine unchanged. 24 hours after administration, more than 90% of the dose is eliminated. Less than 1% of the dose is excreted in feces.
Pharmacokinetics in elderly patients
In elderly patients with Alzheimer's disease, no age-related changes in exposure were identified when using TTC Exelon®.
Pharmacokinetics in patients with impaired liver function
The use of TTS Exelon® in patients with impaired liver function has not been studied. In patients with mild to moderate hepatic impairment, after oral administration of rivastigmine, an increase in Cmax of approximately 60% and AUC of more than 2 times was observed compared with healthy volunteers.
When taking 3 mg rivastigmine as a single dose or after multiple doses of 6 mg twice daily, 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 incidence and severity of adverse events.
Pharmacokinetics in patients with impaired renal function
The use of TTS Exelon® has not been studied in patients with impaired renal function. Based on population-based analyses, there was no clear effect of creatinine clearance on steady-state plasma concentrations of rivastigmine or its metabolite. In patients with impaired renal function, no dose adjustment is required.

INDICATIONS FOR USE

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

CONTRAINDICATIONS

Hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients included in the drug.
History of allergic contact dermatitis that arose during the use of the drug 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 caution should be exercised when prescribing rivastigmine to patients with gastric and duodenal ulcers in the acute stage or to patients predisposed to these conditions;

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

USE IN PREGNANCY AND BREASTFEEDING

Pregnancy
In animal studies, rivastigmine crossed the placenta. There is no data on the ability of rivastigmine to penetrate the blood-placental barrier in humans.
Experimental data have shown that rivastigmine does not have teratogenic properties. In animal studies, an increase in the length of the gestational period was noted. The safety of using Exelon® during pregnancy in humans has not yet been established, so 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 unknown whether rivastigmine passes into breast milk, so breastfeeding should be avoided while using the drug.
Fertility
There is no data on the effect of rivastigmine on women of reproductive age.
There are no data on the effects of rivastigmine on fertility in humans. Animal studies have not shown any negative effects on fertility in males or females, either parents or offspring.

METHOD OF APPLICATION AND DOSES

Therapy with the drug should only be carried out under the supervision of a physician experienced in treating patients with dementia and under the supervision of persons caring for the patients. Patients and their caregivers should be instructed about the use of the drug by competent healthcare professionals
The amount of rivastigmine contained and released depending on the dosage of TTC Exelon® is presented in Table 1.

Table 1.
TTC Exelon® Amount of rivastigmine contained Amount of rivastigmine released in vivo over 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 or moderate dementia of the Alzheimer's type.

Treatment with the drug should begin with the use of TTC Exelon® 4.6 mg/24 hours 1 time per day. After a minimum of 4 weeks of treatment, if well tolerated, the dose of the drug should be increased to the recommended effective dose by using TTC Exelon® 9.5 mg/24 hours, which can be used as long as the therapeutic effect remains.
Dose escalation:
For long-term treatment, if the patient has therapeutic efficacy, 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, the dose can be increased to 13.3 mg/24 hours in patients who, despite the use of TTC Exelon® 9.5 mg/24 hours, experience significant impairment of cognitive functions (for example, deterioration in results according to the KSHOPS) and/or deterioration in functional status (based on a subjective assessment by a 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 TTC 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 dose increase is possible only after a minimum of 4 weeks and if the previous dose is well tolerated.
Doses above 13.3 mg/24 hours do not provide significant benefit, but increase the incidence of side effects.
Interruption of treatment:
The clinical effect of therapy with Exelon® TTC should be regularly assessed. If there is no clinical effect from therapy when using optimal doses of TTC Exelon®, drug therapy should be discontinued.
Treatment with the drug should be temporarily discontinued if adverse events from the digestive system occur and/or existing extrapyramidal symptoms (including tremor) worsen until they resolve. If the break in the use of the drug was no more than three days, you can resume using the drug at the same dose. In case of a longer withdrawal period, treatment should be resumed with the initial dose (Exelon® TTC 4.6 mg/24 hours).
Patients treated with rivastigmine in the form of capsules or oral solution can switch to TTC Exelon® treatment as follows:
In patients receiving oral rivastigmine therapy at a dose of less than or equal to 6 mg per day, treatment should be initiated with TTC 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 begin immediately with the use of TTC Exelon® 9.5 mg/24 hours. But if oral therapy was not stable and well-tolerated, switch to the transdermal form It is recommended to start with a dose of 4.6 mg/24 hours.
In patients receiving oral rivastigmine therapy at a dose of 12 mg per day, treatment can begin immediately with the use of TTS Exelon® 9.5 mg/24 hours.
After a minimum of 4 weeks of treatment, if well tolerated, the dose of TTC Exelon® 4.6 mg/24 hours can be increased by using TTC Exelon® 9.5 mg/24 hours.
Treatment with TTC Exelon® is recommended to begin the day after the last oral dose of rivastigmine.

Patients weighing less than 50 kg
Patients weighing less than 50 kg were more likely to experience adverse events (AEs) and discontinuation of therapy due to AEs, so when increasing the dose in this group of patients, special caution should be used, carefully titrate the dose and monitor for the development of AEs (eg , excessive nausea or vomiting), and also consider reducing the dose of TTC Exelon® to 4.6 mg/24 hours in the event of such AEs. Particular care should be taken when titrating the dose above the recommended effective dose of TTC Exelon® 9.5 mg/24 hours.

However, due to the increased exposure of rivastigmine observed when rivastigmine was taken orally in patients with mild to moderate hepatic impairment, it is recommended that the dose of rivastigmine be carefully titrated to individual tolerance in these patients.
The use of TTC Exelon® in patients with severe hepatic impairment has not been studied. Particular care should be taken when titrating the dose in patients in this category (see sections “Special instructions”, “Pharmacological properties”).
Patients with clinically significant liver dysfunction may experience a more frequent development of dose-dependent adverse events, and therefore in patients in this category the possibility of using TTC Exelon® 4.6 mg/24 hours should be considered as the initial and maximum dose.

No adjustment of the dosage regimen for TTS Exelon® is required.
However, due to the increased exposure of rivastigmine observed when oral rivastigmine was taken in patients with mild to moderate renal impairment, it is recommended that the dose of rivastigmine be carefully titrated to individual tolerance in these patients. Patients with clinically significant renal impairment may experience a more frequent development of dose-dependent adverse events, and therefore, in patients in this category, the use of TTS Exelon® 4.6 mg/24 hours should be considered as the initial and maximum dose.

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® TTS can be used at a time.
TTC Exelon® must not be cut or divided into parts, or damaged in any way.
TTC Exelon® should be pressed firmly with the palm of your hand at the attachment site for at least 30 seconds.
Exelon® TTC attachment site
TTC Exelon® is applied to clean, dry, intact skin with minimal hair.
Do not use creams, lotions, oils, powders or other skin care products in the area where the drug is attached to prevent it from coming off.
TTC Exelon® should not be applied to red, rash-covered, irritated or damaged skin.
Only one Exelon® TTC per day should be applied to only one of the body areas shown below in Figure 1:
- Left or right shoulder;
- Upper chest left or on the right (should not be applied to the breast area);
- Upper back left or on right;
- Lower back left or on right.
Rice. 1
Every 24 hours, remove the previous Exelon® TTC before applying one new Exelon® TTC to one of the body areas shown below.
To avoid skin irritation, each subsequent Exelon® TTS should be glued to a different area of ​​the skin (possibly within the same anatomical area). For example, if you attached the Exelon® TTC to the right lumbar region, then next time place the system on the left. To minimize the risk of skin irritation, TTC can be applied to the same area of ​​skin only at intervals of two weeks.
How to attach the Exelon® TTC
TTC Exelon® is a thin, opaque, plastic patch for gluing to the skin. Do not remove the Exelon® TTC from the sealed bag or remove the previous Exelon® TTC unless you plan to attach 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 TTC Exelon®, starting with the following picture below.
The drug is removed from the sealed bag immediately before use.
To remove the Exelon® TTC, cut the bag along the dotted line or groove indicated.
The adhesive side of TTS Exelon® is covered with a protective film.
Carefully remove the protective film on one side that protects the adhesive side of the Exelon® TTC 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 on the other side of the TTS.
TTC Exelon® should be pressed firmly with the palm of your hand at the attachment site for at least 30 seconds. Make sure that the system fits snugly against the skin, especially around the edges.
If necessary, after sticking, you can write the date of attachment (for example, the day of the week) on the transdermal therapeutic system with a thin ballpoint pen.
TTC 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 select the most comfortable areas of the body where the system will not come into contact with tight-fitting clothing.
How to remove TTC Exelon®
By carefully prying back one of the corners, slowly and carefully remove the transdermal therapy system.
If there is adhesive residue on your skin, lightly wet the area with warm water and a mild soap solution or use baby oil to remove any adhesive residue. Do not use alcohol or other liquid solvents (nail polish remover or other solvents).
You should wash your hands thoroughly with soap and water after attaching or removing the Exelon® TTC. In case of eye contact or eye redness following attachment or removal of Exelon® TTC, immediately flush eyes with plenty of water and seek medical attention if symptoms persist.
How to dispose of used Exelon® TTS
Fold the used Transdermal Therapy System in half and press the adhesive parts together.
Place the used Exelon® TTC in the bag. The bag containing the used transdermal therapy system should be discarded out of the reach of children. After disposing of the drug, you must wash your hands with soap.
Conditions for wearing TTC Exelon® (water procedures, prolonged stay near heat sources)
TTC Exelon® does not come off during water procedures (showers, baths, swimming pools). - During water procedures, you must make sure that the system fits tightly to the skin, especially around the edges.
Patients using TTS Exelon® should not stay near any external heat sources (excessive solar radiation, saunas, solariums) for a long time.
What to do if TTS Exelon® comes unstuck
If TTC Exelon® comes off, it must be replaced with a new transdermal therapeutic system by the end of the day. The next day, attach the new Exelon® TTS as usual.
When and for how long should TTC Exelon® be used?
For maximum effectiveness of drug treatment, a new TTS should be applied every day, preferably at the same time.
When using more than one Exelon® TTC at the same time
You should immediately remove all TTS from your skin and inform your healthcare provider about the incident. You may need medical attention. In some cases, with an overdose, nausea, vomiting, diarrhea, increased blood pressure, and hallucinations were noted. Bradycardia and/or fainting may also occur.
If you forget to stick the next TTS at the usual time, you should stick it immediately. The next TTS can be used the next day at the usual time. You should not apply 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 observed. 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, decreased 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®, caused by the application of several TTS Exelon® simultaneously (the next TTS was used without removing the previous one). Patients and caregivers should be instructed about the use of the drug.
Rare cases of death have been reported in cases of drug overdose, but the relationship with the drug remains unclear. Symptoms and outcome varied among patients. There was no clear connection between the dose of the drug taken and the severity of the outcome.
Treatment. Since the half-life of rivastigmine from blood 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 TTCs is recommended; TTC Exelon® should not be used for the next 24 hours. If overdose is accompanied by severe nausea and vomiting, the use of antiemetics should be considered. If other adverse events occur, appropriate symptomatic treatment is provided if necessary.
In case of significant overdose, atropine can be used, the initial dose of which is 0.03 mg/kg intravenously; subsequent dosing depends on clinical response. The use of scopolamine as an antidote is not recommended.

INTERACTION WITH OTHER MEDICINES

No special study of the interaction of TTC Exelon® with other drugs has been conducted.
Rivastigmine is metabolized primarily 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 by 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 their combined action. Rivastigmine may interfere with the action of anticholinergic drugs (eg, oxybutynin, tolterodine).
Suxamethonium salts
During anesthesia, rivastigmine, being a cholinesterase inhibitor, can enhance the effects of depolarizing muscle relaxants (muscle relaxants 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 receiving other drugs in this group.
Interaction with nicotine
An increase in the absorption of rivastigmine by 23% was shown when administered orally (in capsule form at a dose of up to 12 mg/day) in patients taking nicotine.
Interactions with the most commonly co-administered drugs
In healthy volunteers, no pharmacokinetic interactions were observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine. The warfarin-induced increase in prothrombin time was not altered by oral rivastigmine. No adverse effects on intracardiac conduction were observed with concomitant use of oral rivastigmine and digoxin.
Concomitant use of rivastigmine with commonly used drugs such as antacids, antiemetics, hypoglycemic drugs, centrally acting antihypertensive drugs, slow calcium channel blockers, drugs that have a positive inotropic effect, antianginal drugs, estrogens, analgesics, including non-steroidal anti-inflammatory drugs, benzodiazepines and antihistamines were not associated with 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 attachment or removal. You should wash your hands thoroughly with soap and water after attaching or removing the TTC. If contact with eyes occurs or if eyes become red after TTC is attached or removed, immediately flush eyes with plenty of water and seek medical attention if symptoms persist.
Gastrointestinal disorders
The incidence and severity of side effects usually increases with increasing doses of rivastigmine, especially during dose adjustment periods. If the break in the use of Exelon® TTC was more than three days, treatment should be resumed with the initial dose (Exelon® TTC 4.6 mg/24 hours).
The severity of 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, therapy with TTS Exelon® 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 may experience weight loss during therapy with cholinesterase inhibitors, including rivastigmine, patients' weight should be monitored during therapy with TTC Exelon®.

Other adverse events associated with increased activity of the cholinergic system
As with the use of 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 a history of bronchial asthma or obstructive airway diseases.
Cholinergic stimulation can lead to:
- to increase the secretion of hydrochloric acid in the stomach, therefore caution should be exercised 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, therefore caution should be exercised when prescribing rivastigmine to patients predisposed to these conditions.
Like other cholinomimetics, when using rivastigmine, an increase in the severity of extrapyramidal disorders may occur.

Reactions at the attachment site of Exelon® TTC and skin reactions
Skin reactions that occur during the use of Exelon® TTC are usually mild or moderate in severity. These reactions do not indicate 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 TTC, extending beyond the size of the TTC, or skin reactions at the site of attachment have reached a pronounced intensity (for example, increasing erythema, swelling, the appearance of papules, vesicles), and also if the severity of skin reactions do not decrease significantly within 48 hours after removal of TTC. In these cases, treatment with the drug should be stopped (see section “Contraindications”).
If patients develop a reaction at the site of attachment of the TTC, similar to allergic contact dermatitis, while using the drug Exelon® TTC, 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 who are sensitized to rivastigmine due to use of Exelon® TTC will not be able to use rivastigmine in other dosage forms.
During post-registration use of the drug, data were obtained on the development of widespread skin hypersensitivity reactions in some patients when using rivastigmine, regardless of the route of administration (orally or transdermally). In these cases, the drug should be completely discontinued (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 patient groups
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 effectiveness of the drug depending on age. However, individual higher sensitivity to the effects of the drug in older patients cannot be excluded.
Patients with liver dysfunction
When rivastigmine was taken orally in patients with mild to moderate hepatic impairment, an increase in the exposure of rivastigmine was observed, and therefore a dose reduction may be required according to individual tolerance in this category of patients. The use of rivastigmine in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function
When rivastigmine was taken orally in patients with mild to moderate renal impairment, an increase in the exposure of rivastigmine was observed, and therefore a dose reduction may be required according to individual tolerance in this category of patients.
Patients with low or high body weight
Due to the association between body weight and rivastigmine exposure, the dose should be carefully titrated and monitored in patients with low or high body weight.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND OPERATE MACHINERY
Alzheimer's-type dementia can cause a gradual decline in the ability to drive or compromise the ability to use a vehicle. Patients treated with rivastigmine may develop dizziness and drowsiness, 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 receiving treatment with the drug to drive vehicles and/or operate machinery should be regularly assessed by the attending physician.

RELEASE FORM
One transdermal therapeutic system 4.6 mg/24 h or 9.5 mg/24 h, in a multi-laminated pouch (paper coated with polyethylene terephthalate film, aluminum foil and polyacrylonitrile copolymer): 3, 7, 30 pouches along with instructions for use for use in a cardboard box.
One 13.3 mg/24 hour transdermal therapeutic system in a multilayer laminate pouch (paper coated with polyethylene terephthalate film, aluminum foil and polyacrylic nitrate copolymer). 7, 30 packages along with instructions for use in a cardboard box.