Expiration date: 01/2025

The composition and form of issue:

Transdermal therapeutic system TTS. 1 pack contains:

rivastigmine 9 mg

18 mg

(the content in the TTS of rivastigmine is 4.6 mg/day, the area 5??2 and 9.5 mg/day, an area of 10 cm2 respectively) 

excipients: D, L-&alpha-tocopherol polimetilmetakrilat polymethyl methacrylate acrylic copolymer 

adhesive: silicone copolymer is a Dimethicone (silicone oil 12500 cSt) D, L-&alpha-tocopherol 

in the package of a multi-layered laminate 1 TTS in the stack cartons 3, 7 or 30 packages.

Description pharmaceutical form:

Round TTS with the backing of beige color, double adhesive layer and rectangular protective foil overlapped, with recesses. On the substrate of the patch marked: "ASH" for TTS of 4.6 mg/day and "BHDI" for TTS of 9.5 mg/day.

Pharmacokinetics:

Absorption

Absorption of rivastigmine from Exelon TTS, is slow. After applying the first dose the time to reach the designated concentration of rivastigmine was 0.5–1 h. C max is achieved in 10-16 h. After reaching Cmax, the concentration decreases slowly in the remaining 24-hour period of application of the TTS Exelon.

Equilibrium concentration of rivastigmine after the replacement of used TTS Exelon in new slowly reduced on average for about 40 min until the absorption of the active substance and re-glued TTS Exelon begins to predominate over elimination. After that, plasma concentrations of rivastigmine begins to rise slowly again and reaches a maximum after approximately 8 h. In the equilibrium state is the lowest concentration is approximately 50% of the maximum, in contrast to oral administration, wherein between doses the next dose plasma concentration was virtually zero. Similar temporal characteristics of the plasma concentrations of rivastigmine observed when using TTS Exelon, dosage range from 4.6 to 9.5 mg/day. Despite the fact that the exposure (Cmax and AUC) of rivastigmine is obviously less than when administered orally, its increase is directly proportional to the dosage increase Exelon TTS.

With increasing dosage Exelon TTS 4.6 to 9.5 mg/day there was an increase in AUC of rivastigmine 2.6 times.

The relative difference between Cmax and Cmin of rivastigmine (index fluctuations, IR) when using TTS Exelon, was in the range of 0.58 to 0.77, which is significantly less than the oral application (from IR of 3.96 to 6.24).

The amount of rivastigmine released within 24 h of TTS Exelon (dose in mg per 24 h), is not equivalent to oral administration of the same doses of rivastigmine capsules (assessment conducted on the exposure of rivastigmine in plasma within 24 h).

In a direct comparison of the application of 1 dose of TTS Exelon and capsules for oral administration interpopulation variability of Cmax and AUC0–24h of rivastigmine was 43 and 49% for TTS Exelon and 74 and 103% for capsules, respectively. When multiple application and reaching equilibrium interpopulation variability of Cmax and AUC0–24h of rivastigmine in patients with dementia in Alzheimer's disease was also significantly lower for TTS Exelon compared with capsules for oral intake: 45, and 43% for plaster and 71 and 73% for the capsule, respectively.

In patients with dementia in Alzheimer's disease and body weight of 65 kg, the equilibrium concentration of rivastigmine was increased approximately 2 times compared with patients with body weight 35 kg, while for patients with body weight of 100 kg, a decrease of the equilibrium concentration is approximately 2 times. The effect of body weight on exposure of rivastigmine is particularly important for patients with very low body weight with increasing dose.

Rivastigmine was well released from the TTS Exelon within a 24 hour period of an application of the patch to the skin (about 50% of the content of the drug). The highest AUC&infin of rivastigmine and metabolite NAP266-90 was observed when applied in a TTS Exelon on the top half of the back, chest or shoulder. When neither of the above parts of the body maybe sticking on the abdomen and thighs, the doctor should be aware that AUC of rivastigmine in this case is reduced by about 20-30%.

Was not observed significant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with dementia in Alzheimer's disease. However, plasma concentrations of rivastigmine in the second application of Exelon TTS was higher than in the first day.

Distribution

Rivastigmine binds to plasma proteins to a lesser degree (about 40%), easily permeates through GEB. The apparent Vss is 82,7 l/kg.

Metabolism

The rivastigmine is rapidly and largely metabolised T1/2 from plasma of approximately 3.4 hours after removal of the patch. Elimination was limited by the degree of absorption of rivastigmine (flip-flop kinetics), which explains the increase in T1/2 after using TTS Exelon (3,4 h) compared with oral or/in use (1.4 and 1.7 h, respectively) of the drug. The metabolism of rivastigmine is mainly by hydrolysis of cholinesterase education carbamoilirovaniem metabolite, which in vitro showed minimal ability to inhibit acetylcholinesterase (<10%). In accordance with the data obtained in vitro and in experimental studies, the major cytochrome P450 isoenzymes minimally involved in rivastigmine metabolism. Total plasma Cl of rivastigmine is about 130 l/h after I/V injection in a dose of 0.2 mg and decreases to 70 l/h after I/V administration of 2.7 mg, which is consistent with a nonlinear, inversely proportional nature of the pharmacokinetics of rivastigmine due to its elimination as saturation.

The ratio of AUC&infin metabolite to the original substance was 0.7 for transdermal patch against 3.5 when administered orally, indicating lower metabolic rate after cutaneous application. The formation of a smaller quantity of the metabolite NAP226-90 is caused by the lack of first-pass metabolism.

Excretion

Rivastigmine is excreted mainly by the kidneys as metabolites. In unchanged form in the urine is almost undetectable. Through 24 h after administration appears more than 90% of the dose. The feces derived less than 1% of the dose.

Pharmacokinetics in elderly patients. In elderly patients with Alzheimer's disease when using TTS Exelon, there were no changes in bioavailability associated with age.

Pharmacokinetics in patients with impaired liver function. The study of application of TTS Exelon in patients with hepatic impairment were not conducted. In patients with easy and moderate hepatic disorders after oral administration of rivastigmine showed an increase of Cmax by about 60% and AUC by more than 2 times in comparison with healthy persons.

Pharmacokinetics in patients with impaired renal function. The study of application of TTS Exelon in patients with impaired renal function have not been conducted.

In patients with Alzheimer's disease and moderately severe impairment of renal function after oral administration of rivastigmine showed an increase in Cmax and AUC in more than 2 times compared to healthy individuals however, in patients with Alzheimer's disease and severe impaired renal function changes in Cmax and AUC was observed.

Description pharmacological action:

Rivastigmine, as a selective inhibitor of acetyl - and butyrylcholinesterase in brain carbamate type, slows the destruction of acetylcholine, produced by functionally intact neurons, improves neurotransmission. The drug selectively increases the amount of acetylcholine in the cerebral cortex and hippocampus, and thus, improve cholinergic nerve transmission. Rivastigmine has a positive effect in the reduction of cognitive functions, associated with a deficiency of acetylcholine, in particular, in dementia associated with Alzheimer's disease and Parkinson's disease. In addition, there is evidence that cholinesterase inhibition could slow the formation of fragments of the protein precursor of beta-amyloid, accumulation of which leads to the formation of amyloid plaques, one of the main pathological signs of Alzheimer's disease.

Rivastigmine interacts with the enzyme-target with the formation of covalent bonds, which leads to a temporary inactivation of the enzyme.

In young healthy men, the application of the rivastigmine in a dose of 3 mg acetylcholinesterase activity in cerebrospinal fluid (CSF) is reduced by approximately 40% during the first 1.5 h After reaching the maximum inhibitory effect the activity of the enzyme returns to original level after approximately 9 h. the Inhibition of butyrylcholinesterase in CSF also has a reversible, enzyme activity is restored to the original level through 3.6 hours

In patients with Alzheimer's disease by rivastigmine inhibition of acetylcholinesterase activity in CSF is dose-dependent nature in the studied range of doses up to 6 mg 2 times a day (maximum dose). Inhibition of butyrylcholinesterase was also dose-dependent the dose of 6 mg 2 times a day causes a decrease of the enzyme activity by more than 60% compared to the original. This effect of the drug persisted throughout 12 months of therapy (maximum period studied).

Were shown statistically significant correlations between the degree of inhibition by rivastigmine of both enzymes in the CSF and changes of cognitive functions in patients with Alzheimer's disease at the same time, it is the inhibition of butyrylcholinesterase in CSF was significantly and consistently correlated with improvement in tests of memory, attention and speed of reaction.

The use of TTS Exelon in patients with mild and moderate severity of dementia in Alzheimer's disease (10-20 points on a short scale assessment of mental status, Mini Mental State Examination, MMSE). leads to significant improvement of cognitive functions (attention, memory, speech, etc.), functional status, and activity in everyday life, as well as reduced severity of the disease and the severity of mental and behavioral manifestations (such as agitation, tearfulness, delusions, hallucinations, etc.).

Indications:

Mild or moderately severe dementia of Alzheimer's type (Alzheimer's disease, including probable).

Contraindications:

• hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients within the drug
  
• children (use of rivastigmine in children has not been studied, therefore, to appoint drug is not recommended).
  

With caution:

• syndrome weakness sinusnogo hub or violations conductivity (sinoatrialnaya and AV blockade)
  
• obstruction of the urinary tract and convulsive syndrome (cholinergic stimulation can increase the secretion of hydrochloric acid in the stomach, can lead to increased obstruction of the urinary tract and exacerbation of seizures)
  
• bronchial asthma or obstructive respiratory diseases in history (like other cholinomimetics)
  
• patients with body weight less than 50 kg (noted more frequent development of adverse effects and discontinuation of drug therapy due to adverse reactions)
  
• clinically significant hepatic dysfunction (may be more frequent development of adverse events).
  

From the above patients should be used with caution to selection of a dose when the dose of rivastigmine (Exelon TTS 9.5 mg/day).

Application of pregnancy and breast-feeding:

Experimental data showed that rivastigmine has no teratogenic properties. However, the safety of the use of rivastigmine during pregnancy in humans has so far not been established, therefore, the drug can be administered to pregnant women only in cases when the expected benefit of treatment exceeds potential risk to the fetus.

It is unknown if rivastigmine penetrates the breast milk. Therefore, during the use of the drug should abandon breastfeeding.

Side effects:

The overall incidence of adverse events (AES) during therapy with Exelon TTS (50.5 per cent) was lower compared to oral therapy with the use of capsules in a daily dose of 3-12 mg (63,3%) (for comparison, in the placebo group, the figure was 46%).

The most common were adverse events of the digestive system. Nausea (7.2 percent) and vomiting (6.2 percent) were significantly less when using TTS Exelon 9.5 mg/day compared with capsules for oral administration, 23.1 and 17%, respectively (in the placebo group the same figures were 5 and 3.3%).

The incidence of adverse reactions in patients (291 people) with dementia of Alzheimer's type, treated TTS Exelon (all dosages) were evaluated in the following manner: very often (&ge1/10), often (&ge1/100, &le1/10), sometimes (&ge1/1000, &le1/100).

Infections and infestations: often — urinary tract infections.

From the metabolism and metabolism: often — anorexia.

Mental disorders: common — anxiety, depression, delirium.

From the nervous system: often — headache, fainting very rarely — extrapyramidal disorders.

Of the cardiovascular system: sometimes- aetiology, violations of cerebral circulation.

From the digestive system: often — nausea, vomiting, diarrhea, dyspepsia, abdominal pain and sometimes stomach ulcers.

The skin and subcutaneous tissue: often — rash.

From the side of the body and the reaction at the point of attachment of the transdermal patch: often — erythema, edema and itching, irritation, inflammation in your stomach lining, fatigue, asthenia, fever, weight loss.

In clinical studies using the drug in doses higher than 9.5 mg/day following AES were noted more often than in groups of TTS Exelon 9.5 mg/day and placebo: dizziness, insomnia, agitation, decreased appetite, atrial fibrillation, heart failure (possibly associated with higher doses). The frequency of these AES during therapy with Exelon TTS 9.5 mg/day was similar to that in the placebo group.

Irritation of the skin. When using TTS Exelon most frequently observed skin redness (erythema) at the site of application, usually disappearing in most patients within 24 h. In clinical studies with the use of TTS Exelon 9.5 mg/day was noted a slight (21.8 percent), moderate (12.5 percent), pronounced (6,5%) redness of the skin itching easy (11,9%), moderate (7.3%) and severe (5%) degree.

The therapy TTS Exelon 9.5 mg/day itching and erythema was observed in 1.7% and 1.1% of patients, respectively. The majority of skin reactions develop only in the field of application of TTS. When using TTS Exelon 9.5 mg/day cessation of treatment due to the development of dermatological reactions were noted only in 2.4% of cases.

Drug interactions:

A special study of the interaction of TTS Exelon with other drugs have not 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, pharmacokinetic interactions of rivastigmine with other drugs, metaboliziruthan with the participation of these enzymes are not expected.

In healthy volunteers pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam or fluoxetine were not detected. Caused by warfarin increase PV in the appointment of rivastigmine did not change. While the use of rivastigmine and digoxin adverse effects on intracardiac conduction were noted.

Concomitant administration of rivastigmine with these frequently used medications, like antacids, antiemetics, oral hypoglycemic drugs, antihypertensives Central action, beta-blockers, CCB, drugs having a positive inotropic effect, anti-anginal agents, oestrogens, analgesics, including NPRC, benzodiazepines and antihistamines, was not accompanied by any changes in the kinetics of rivastigmine or an increased risk of clinically significant AES.

As rivastigmine has an effect on the cholinergic structures, it should not be administered together with cholinomimetic drugs, and in its concurrent use with anticholinergic drugs should take into account the diversity of action of these drugs and TTC Exelon.

During anesthesia rivastigmine, as a cholinesterase inhibitor, may potentiate the effects of depolarizing muscle relaxants (muscle relaxants succinylcholine type).

Method of application and dose:

Transdermal.

Therapy with this preparation should be carried out only under the supervision of a doctor with experience in treating patients with dementia of Alzheimer's type.

The number of contained and released rivastigmine depending on dosage Exelon TTS are presented in the table.

Table

The number of contained and released rivastigmine depending on the dosage of TTS Exelon

Dosage	The amount of the contained rivastigmine, mg	The amount of rivastigmine released in vivo within 24 h, mg
TTS Exelon 4,6 mg/day	9	4,6
TTS Exelon 9.5 mg/day	18	9,5

Initial dose. The drug treatment should begin with the application of TTS Exelon 4,6 mg/day 1 times a day.

After 4 weeks of treatment, with good tolerability, the dose may be increased by applying TTS Exelon 9.5 mg/day.

Supported dose. For long-term treatment in the presence of therapeutic efficacy, the patient is recommended to use TTS Exelon 9.5 mg/day.

Some patients to achieve a therapeutic effect may require higher doses of the drug.

Should temporarily discontinue treatment with the drug in case of undesirable effects from the digestive system and/or worsening of existing extrapyramidal symptoms (including tremor) to resolve them. If the break in use of the drug amounted to a few days or more, resume treatment should be with the initial dose (TTS Exelon 4,6 mg/day) to reduce the risk of resumption of adverse reactions (e.g. severe vomiting).

If IT persist, the daily dose should be reduced to the previous well patients tolerated dose.

Patients, treatment with rivastigmine which was conducted in the form of capsules or solution for the reception inside can go to the TTS treatment Exelon, as follows:

- patients receiving oral therapy with rivastigmine at a dose less than 6 mg/day, treatment should start with the use of TTS Exelon 4,6 mg/day.

- patients receiving oral therapy with rivastigmine at a dose of 6-12 mg/day, treatment can begin immediately with the application of TTS Exelon 9.5 mg/day.

Treatment of TTS Exelon it is recommended to begin on the day following the last oral dose of rivastigmine.

In patients with impaired renal function or hepatic dosage adjustment Exelon TTS is not required.

Rivastigmine is not recommended for use in children and adolescents under 18 years of age.

Usage instructions

Attention! Simultaneously you can use only one TTS Exelon. Each subsequent TTS Exelon should be pasted only after removing the previous one.

Exelon TTS cannot be cut or divided into parts, or damage in any way.

Where to attach the TTS Exelon:

- TTS Exelon paste on a clean, dry, intact skin with minimal hairline at the top or bottom half of the torso, the forearm or the chest, in areas where the system will not come into contact with tight clothes

- do not use creams, lotions, oils, powders, and other means for skin care in the area of attachment of the drug to prevent it from peeling

- TTS Exelon cannot be pasted on the red, covered with rash, irritated or damaged skin.

To avoid irritation of the skin each subsequent TTS Exelon should stick to another area of the skin (within the same anatomical region). For example, if you are attached to Exelon TTS on the abdomen on the right, then the next time place the system on the left.

On the same area of skin TTS can be pasted only at intervals of 1 week.

How to attach TTS Exelon:

- the drug is extracted from a sealed package immediately before use

- to extract TTS Exelon should cut or break the pack by a dashed line or groove

- the adhesive side of the TTS Exelon is covered with a protective film

- carefully remove the protective film that protects the adhesive side of TTS Exelon without touching adhesive surface with fingers

- immediately after removing the protective film should stick TTS Exelon on the skin of the upper or lower half of the body, the forearm or chest

after the attachment of the TTS to the skin is necessary to remove the other protective layer

- should press firmly with the palm of TTS Exelon at the point of attachment for 30 seconds. You must ensure that the system is tight to the skin, especially around the edges

- if necessary, after gluing it is recommended to write on the TTS slim ballpoint pen the date of attachment (e.g. day of the week).

TTS Exelon is a thin, opaque, plastic patch for sticking on the skin.

The drug should be used immediately after removal from sealed package.

TTS Exelon should be used continuously and replace with the new one after 24 hours.

The attachment of the TTS to the skin allows you to choose the most comfortable area of the body where the system will not come into contact with tight clothing.

How to remove TTS Exelon: you should bend one of the corners and quick movement to remove the TTS.

How to dispose of the used Exelon TTS:

- should be bent in half and used TTS to connect, adhesive part between

- you should place the used TTS Exelon in the package. Pack with used TTS should be thrown out of reach of children. After the disposal of the drug is necessary to wash hands with soap and water.

Carrying TTS Exelon (water treatment, prolonged exposure to sources of heat):

- TTS Exelon does not come unstuck in water procedures (shower, bath, pool). It is possible to swim attaching TTS under a bathing suit. During water procedures, you must ensure that the system is tight to the skin, especially around the edges

- patients who use TTS Exelon, should not be long to be near any external heat sources (excessive sunlight, saunas, solariums).

What to do if Exelon TTS unstuck: if TTS Exelon come off you should replace new TTS until the end of the day. The next day, as usual putting on a new Exelon TTS.

Overdose:

Symptoms: accidental overdose of the drug in most cases was not accompanied by any clinical manifestations almost all patients continued treatment with rivastigmine. The overdose had nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given the vagotonic effect of cholinesterase inhibitors on heart rate frequency, we cannot exclude the occurrence of bradycardia and/or unconscious States. In one case, was made 46 mg of the drug. After conservative treatment after 24 h showed complete recovery.

Data on overdose when using TTS Exelon no.

Treatment: because the T1/2 of rivastigmine from plasma is about 3.4 h, and the duration of inhibition of acetylcholinesterase is about 9 h, in cases of asymptomatic overdose occurring, it is recommended not to use TTS Exelon in over the next 24 hours If overdose accompanied by severe nausea and vomiting, you should consider the use of antiemetics. If you experience other adverse effects if necessary, carry out the appropriate symptomatic treatment.

In large overdose can be applied atropine sulfate, initial dose which is 0.03 mg/kg/subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.

Special instructions:

The frequency and severity of side effects usually increases with increasing dose of rivastigmine, especially in the period of changing the dose.

The severity of these adverse events of the gastrointestinal tract, such as nausea and vomiting observed at the beginning of treatment or when the dose of the drug may decrease at lower doses of rivastigmine.

If the therapy with Exelon is interrupted for a few days, you should again start the titration with TTS Exelon 4,6 mg/day.

Because patients with Alzheimer's disease during therapy with cholinesterase inhibitors, including rivastigmine, may be reduced body weight during therapy Exelon TTS need to control the weight of the patient.

Effects on ability to drive vehicles and operate machinery. In patients receiving therapy with rivastigmine may develop dizziness and insomnia, especially early in treatment or when changing dose. The ability of a patient with dementia receiving treatment with the drug, to drive vehicles and/or operate machinery should be regularly evaluated by the attending physician.