Exelon

Active material: Rivastigmine
When ATH: N06DA03
CCF: Selective inhibitor of brain acetylcholinesterase. Drug for the treatment of dementia
ICD-10 codes (testimony): F00, G30
When CSF: 02.13.01
Manufacturer: NOVARTIS PHARMA AG (Switzerland)

Pharmaceutical form, composition and packaging

Transdermal therapeutic system (TST) with a contact surface 5 cm², round, with beige color mat, double adhesive layer and rectangular protective film overlap, with recesses, overprinted “AMCX” on a patch.

Excipients: D,L-a-токоферол, foot(ʙutilmetakrilat, methyl methacrylate), acrylic copolymer.

The composition of the adhesive layer: Silicone copolymer, Dimethicone (Silicone oil 12.500 CST), D,L-a-токоферол.

1 PC. – sachets of multilayer laminate (3) – packs cardboard.
1 PC. – sachets of multilayer laminate (7) – packs cardboard.
1 PC. – sachets of multilayer laminate (30) – packs cardboard.

Transdermal therapeutic system (TST) with a contact surface 10 cm², round, with beige color mat, double adhesive layer and rectangular protective film overlap, with recesses, overprinted “BHDI” on a patch.

Excipients: D,L-a-токоферол, foot(ʙutilmetakrilat, methyl methacrylate), acrylic copolymer.

The composition of the adhesive layer: Silicone copolymer, Dimethicone (Silicone oil 12.500 CST), D,L-a-токоферол.

1 PC. – sachets of multilayer laminate (3) – packs cardboard.
1 PC. – sachets of multilayer laminate (7) – packs cardboard.
1 PC. – sachets of multilayer laminate (30) – packs cardboard.

Pharmacological action

Cholinesterase inhibitor. Rivastigmine, as a selective inhibitor of acetyl- and butirilholinjesterazy brain carbamatnogo type, slows the destruction of acetylcholine, produced by functionally safe neurons, and enhances neurotransmission. The drug selectively increases acetylcholine in the cortex and hippocampus and, thus, improves nervous holinergicescoy transfer. Rivastigmine has a positive effect by reducing the cognitive functions, associated with a deficiency of acetylcholine, in particular, When dementia, associated with Alzheimer's disease and Parkinson's disease. Besides, There is evidence that, that the inhibition of holinjesteraz formation of protein fragments can slow predecessor beta amyloid, accumulation which leads to the formation of amyloid plaques, being one of the main pathological signs of Alzheimer's disease.

Rivastigmine interacts with an enzyme-target with the formation of the covalent bond, that leads to a temporary inactivation of the enzyme.

Young healthy men when applying rivastigmina dose 3 mg acetylcholinesterase activity in cerebrospinal fluid (CSF) is reduced by approximately 40% during the first 1.5 no. After reaching maximum inhibitory effect enzyme activity returned to the original level after about 9 no. Inhibition of butirilholinjesterazy in the CSF is also reversible, enzyme activity is restored to its original level through 3.6 no.

In patients with Alzheimer's disease rivastigminom inhibition of acetylcholinesterase activity in CSF has a dose-dependent nature of command in the range of doses up to 6 mg 2 times / day (the maximum dose). Inhibition of butirilholinjesterazy also dozozawisimo; rivastigmine dose 6 mg 2 times/day causes decreased enzyme activity by more than 60% compared to the original. The effect of the drug was maintained throughout 12 months of therapy (maximum studied period).

Statistically significant correlations were shown between the degree of inhibition of rivastigminom of both enzymes in the CSF and changes of cognitive function in patients with Alzheimer's disease; While it is the inhibition of butirilholinjesterazy in CSF reliably and stably correlates with improved memory test results, attention and speed of reaction.

Use Jekselona^® in the form of TTC in patients with mild-to-moderate degree of dementia in Alzheimer's disease (10-20 points on the brief scale of assess mental status, Mini Mental State Examination, MMSE) leads to a significant improvement of cognitive function (incl. attention, memory, speeches), functional status and activity in daily life, as well as to reduce the severity of the disease and symptoms of mental and behavioral manifestations (such as psychomotor agitation, tearfulness, illusion, hallucinations).

Pharmacokinetics

Absorption

Absorption of rivastigmina TTC Jekselon^®, happens slowly. After applying the first dosage to achieve defined rivastigmina concentration was 0.5-1 no. C_max achieved through 10-16 no. After reaching C_max concentration is falling slowly in the remaining 24-hour holding period application of TTC.

C_ss rivastigmina after replacing used TTS Jekselon^® the new falling slowly on average for about 40 m, While the absorption of the active substance from the newly glued TTC Jekselon^® will not prevail over the body. Then the plasma concentration of rivastigmina slowly begins to climb again and reaches approximately 8 no. At equilibrium the lowest concentration is approximately 50% Larger, In contrast to have application, in which between meals regular dose concentration in the plasma is actually equal to zero. Similar temporal characteristics of plasma concentration observed in the application of rivastigmina TTC Jekselon^® in the range of doses from 4.6 mg/24 h to 9.5 mg / 24 h. Despite, that exposure (C_max и AUC ) rivastigmina is obviously less, than the oral application, its increase in direct proportion to the increases in dose TTC Jekselon^®.

When increasing doses of TTC with 4.6 mg/24 h to 9.5 mg/24 h increased AUC rivastigmina in 2.6 time.

The relative difference between C_max and C_min rivastigmina (index fluctuations, IR) When applying TTS Jekselon^®, ranged from 0.58 to 0.77, that is significantly less, than the oral application (IR from 3.96 to 6.24).

Number of rivastigmina, released during the 24 h from TTC Jekselon^® (dose in mg/24 h), ingestion is not equivalent to the use of the same dose of rivastigmina capsules (the evaluation was conducted on exposure rivastigmina in plasma during 24 no).

When directly compared 1 dosage TTC Jekselon^® and capsules for oral mezhpopuljacionnaja variabelnosg C_max и AUC_{0-24 no} rivastigmina amounted 43% and 49% for TTC Jekselon^® and 74% and 103% for capsules, respectively. When multiple application and achieving the equilibrium mezhpopuljacionnaja variability (C)_max и AUC_{0-24 no} rivastigmina in patients with dementia in Alzheimer's disease was also significantly lower for TTC Jekselon^® compared with capsules for oral use: 45% and 43% for TTC and 71% and 73% for capsules, respectively.

In patients with dementia in Alzheimer's disease and body weight 65 kg C_ss rivastigmina increased approximately 2 compared with patients with body weight 35 kg; While for patients weighing 100 kg (C) decline_ss about 2 times. Influence of body weight on Exposition rivastigmina is especially important for patients with very low birth weight increased dosage.

Rivastigmine is well became available from TTC Jekselon^® during the 24-hour holding period application patch on skin (about 50% the content of the drug). The greatest indicator of the AUC_∞ rivastigmina and metabolite NAP266-90 was celebrated with the software the upper half of the back PLATE, chest or shoulder. If the above areas, possible gluing on the abdomen and thighs, However, the physician should take into account, AUC rivastigmine that it reduces by about 20-30%.

There was no significant accumulation of rivastigmine or the metabolite NAP226-90 in the blood plasma of patients with dementia in Alzheimer's disease. However, plasma concentrations of rivastigmine in the second application of the transdermal Exelon^® It was higher, than on the first day.

Distribution

Rivastigmine bound to plasma proteins to a lesser degree (about 40%), easily penetrates through the BBB. In Кажущийся_d is 8- 2.7 l / kg

Metabolism

Rivastigmine rapidly and largely metabolized with T_1/2 from the blood plasma of about 3.4 hours after patch removal. Elimination of the limited degree of rivastigmina removals (Flip-flop kinetics), that explains the increase in T_1/2 After applying TTS Jekselon^® (3.4 no) compared to oral or/in use (1.4 and 1.7 h, respectively) product. Rivastigmina metabolism occurs mainly by hydrolysis holinesterzoy education metabolita dekarbamilirovannogo, that in vitro demonstrated minimal ability to inhibit azetilholinesterzu (<10%). In accordance with the data, obtained in vitro and in experimental studies, the main isozyme cytochrome p 450 minimally involved in metabolism of rivastigmina. Total plasma clearance rivastigmina is about 130 l/HR after in/in the dose of 0.2 mg and decreases to 70 l/HR after in/introductions 2.7 mg, that is consistent with a non-linear, back proportional nature of the pharmacokinetics of rivastigmina due to its elimination, to the extent saturation.

The Ratio Of AUS_∞ metabolite to the original substance was 0.7 for TTC against 3.5 upon oral administration, that indicates a lower intensity of metabolism after nakozhnogo application. Education fewer metabolite NAP226-90 due to the lack of presistemnogo metabolism.

Breeding

Rivastigmine is displayed, mainly, kidneys in the form of metabolites; unchanged in the urine almost undetectable. Through 24 h after Administration appears more 90% dose. Faeces thrown less than 1% dose.

Pharmacokinetics in special clinical situations

In elderly patients with Alzheimer's disease when applying TTS Jekselon^® There were no changes in bioavailability, age-related.

Study of application of TTS Jekselon^®, in patients with impaired liver function is not carried out. In patients with easy and moderately expressed liver disorders after oral administration rivastigmina increased C_max about 60% and AUC in more than 2 fold compared with healthy individuals.

Study of application of TTS Jekselon^®, in patients with impaired kidney function had not been.

In patients with Alzheimer's disease and mild acute violations of the kidney after oral administration rivastigmina increased C_max and AUC in more than 2 fold compared with healthy individuals; However, in patients with Alzheimer's disease and severe violations of the kidney changes (C)_max and AUC were observed.

Testimony

-weak or moderate dementia alzgeimerovsky type (probable Alzheimer's disease, Alzheimer's disease).

Dosage regimen

Jekselon therapy^® should be carried out only under the supervision of a physician, has experience in the treatment of patients with dementia alzgeimerovsky type.

The number of contained and rivastigmina released depending on the dosage of TTS Jekselon^® presented in table.

The initial dose. Treatment should start with the use of TTS Jekselon^® 4.6 mg / 24 h 1 time / day.

After 4 weeks of treatment, with good endurance, dose can be increased through the use of TTS Jekselon^® 9.5 mg / 24 h.

Podderzhivajushhajasja dose. For long-term treatment in the presence of therapeutic effectiveness of the patient it is recommended to use TTS Jekselon^® 9.5 mg / 24 h.

Some patients for therapeutic effect, you may need to increase dosage.

Therapy should be suspended in the event of adverse events by the digestive system and/or worsening of existing symptoms extrapiramidale (incl. tremor) to resolve them. If the break in the application of the drug totaled some days and more, resume treatment initial dose should be (Jekselon^® TST 4.6 mg / 24 h) to reduce the risk of resumption of adverse reactions (eg, Severe vomiting).

If undesirable phenomena remain, daily dose should be reduced to the previous well tolerated doses.

Patients, who received treatment rivastigminom in the form of capsules or solution for the reception inside, can translate into treatment TTC Jekselon^®, as follows.

Patients, treated with oral therapy at a dose of less than rivastigminom 6 mg / day, treatment should start with the use of TTS Jekselon^® 4.6 mg / 24 h.

Patients, treated with oral therapy rivastigminom dose 6-12 mg / day, treatment can be started immediately with the use of TTS Jekselon^® 9.5 mg / 24 h.

Treatment Of TTS Jekselon^® It is recommended to start the next day after applying the latest oral dose rivastigmina.

In patients with impaired kidney or liver correction mode TTC Jekselon^® not required.

Side effect

The overall incidence of adverse events while therapy TTC Jekselon^® (50.5%) was lower compared to oral therapy using capsules daily dose 3-12 mg (63.3%) (for comparison, in the placebo group, compared to 46%).

Frequently observed reactions on the part of the digestive system. Nausea (7.2%) and vomiting (6.2%) There were significantly reduced with the use of TTS Jekselon^® 9.5 mg/24 h compared with capsules for oral administration, 23.1% and 17.0% respectively (in the placebo group, those same figures were 5.0% and 3.3%).

Frequency of adverse reactions in patients (291 man) with dementia alzgeimerovsky type, receiving treatment TTC Jekselon^® (all dosages), determined as follows:: Often (≥1/10), often (≥ 1/100, ≤1/10), sometimes (≥1/1000, ≤1/100).

From the urinary system: often – urinary tract infection.

Metabolism: often – anorexia.

CNS: often – anxiety, depression, delirium, headache, fainting; rarely – extrapyramidal disorders.

Cardio-vascular system: sometimes – bradycardia, cerebrovascular accidents.

From the digestive system: often – nausea, vomiting, diarrhea, dyspepsia, abdominal pain; sometimes – ulcerous defeat stomach.

Dermatological reactions: often – rash.

By the body as a whole and reaction at the site of attachment of TTC: often – эritema, swelling and itching, irritation, inflammation at the application, fatigue, asthenia, fever, weight loss.

In clinical studies in the application of the drug in doses more 9.5 mg/24 h following unwanted reactions occurred more frequently, than in groups TTC Jekselon^® 9.5 mg/24 h and placebo: dizziness, insomnia, excitation, decreased appetite, Atrial fibrillation, heart failure (possibly associated with increase in dose). The frequency of these unwanted reactions to therapy TTC Jekselon^® 9.5 mg/24 h was similar to that in the placebo group.

The following adverse reactions, were observed only in the treatment of capsules or solution Jekselon^® for the reception inside and were not registered when applying TTS Jekselon^® 9.5 mg / 24 h: dizziness (Often), excitation, drowsiness, general malaise, tremor, confusion, increased perspiration (often), insomnia, accidental falls, increased hepatic activity (sometimes), convulsions, ulcerous defeat of duodenal ulcer, angina, myocardial infarction (rarely), Arrhythmia (eg, AV блокада, Atrial fibrillation, tachycardia), increased blood pressure, pancreatitis, gastrointestinal bleeding, hallucinations (rarely); in some cases – Severe vomiting, which leads to the rupture of the esophagus (Frequency unknown).

Dermatological reactions

When applying TTS Jekselon^® the most frequently noted a redness of the skin (эritema) in place of application, usually disappears in most patients within 24 no. In clinical studies in the application of TTS Jekselon^® 9.5 mg/24 h noted mild (21.8%), moderate (12.5%), expressed (6.5%) erythema, mild itching (11.9%), moderate (7.3%) and expressed (5%) degrees.

While therapy TTC Jekselon^® 9.5 mg/24 h itching and Erythema was observed in 1.7% and 1.1% patients, respectively. The majority of skin reactions have evolved only in the area of software TTC. When applying TTS Jekselon^® 9.5 mg/24 h cessation of drug treatment due to the development of the dermatological reactions noted only in 2.4% cases.

Contraindications

-hypersensitivity to rivastigminu and other components of the drug;

-hypersensitivity to other derivative carbamata.

FROM caution rivastigmine should be applied (like other holinomimeticalkie funds) in patients with SSSU or violations conductivity (sinoatrialynaya blockade, AV блокада).

Cholinergic stimulation can enhance the secretion of hydrochloric acid in the stomach, lead to increased urinary tract obstruction and convulsive syndrome, Therefore, caution must be exercised in the appointment of rivastigmina sick, who are predisposed to this condition.

The drug should be used with caution in patients with bronchial asthma or obstructive respiratory diseases in history.

The caution should carry out selection of dosage if you exceed the dose rivastigmina (TTC Jekselon^® 9.5 mg / 24 h) in patients weighing less than 50 kg (in such cases more frequent adverse reactions and necessary cessation of therapy) and patients with acute human liver (tk. Perhaps more frequent adverse reactions).

Pregnancy and lactation

Safety of rivastigmina during pregnancy in humans has not been established so far, Therefore, the drug can be prescribed to pregnant women only, When the expected benefits of treatment exceeds potential risk to the fetus.

Unknown, whether allocated rivastigmine with breast milk in humans. Therefore, during the use of the drug should abandon breastfeeding.

IN experimental studies shows, that does not possess the rivastigmine teratogenic properties.

Cautions

The incidence and severity of side effects usually improves when increasing doses of rivastigmina, especially during dose changes.

The severity of such undesirable phenomena on the part of the digestive system, nausea and vomiting, in the beginning of treatment, or if the dose of the drug, may be decreased with decreasing doses of rivastigmina. If the therapy Jekselonom^® suspended for a few days, start again with titration TTC Jekselon^® 4.6mg / 24 h.

Because Alzheimer's patients on therapy cholinesterase inhibitors, including rivastigmine, There may be a decrease in body weight, during therapy, TTC Jekselon^® There is a need to control body weight patients.

Use in Pediatrics

Application of rivastigmina the children have not been studied, so, It is not recommended to appoint drug children and adolescents under the age of 18 years.

Effects on ability to drive vehicles and management mechanisms

Patients, treated with rivastigminom therapy, may develop dizziness and insomnia, especially at the beginning of treatment, or if you change the dosage. The ability of the patient with dementia, receiving drug treatment, drive vehicles and/or operate moving mechanisms should be assessed regularly by your doctor.

Overdose

Symptoms: accidental overdose of medication in most cases has not been associated with any clinical manifestations; almost all of the patients continued treatment rivastigminom. Overdose occurred nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given the vagotonicheskij effect of cholinesterase inhibitors in HEART RATE, You cannot exclude the occurrence of bradycardia and/or unconscious States. In one case, it was decided 46 mg; After conservative treatment 24 h there was a complete recovery.

Data on overdose when applying TTS Jekselon^® no.

Treatment: Since T_1/2 rivastigmina from plasma is about 3.4 no, and the duration of inhibition of acetylcholinesterase is about 9 no, in cases of asymptomatic flowing overdose are recommended not to apply TTC Jekselon^® during subsequent 24 no. If an overdose has been accompanied by a pronounced nausea and vomiting, should consider the use of antiemetics. In case of other undesired phenomena if necessary, conduct appropriate symptomatic treatment.

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

Drug Interactions

Special study of interaction of TTC Jekselon^® with other drugs had not been.

Rivastigmine predominantly metabolized by hydrolysis with esterz. Metabolism of rivastigmina with participation of major isoenzymes of cytochrome p 450 occurs in minimum degree. Thus, Pharmacokinetic interaction rivastigmina with other drugs, those involving data enzymes, not foreseen.

In healthy volunteers pharmacokinetic interaction between rivastigminom and digoxin, varfarinom, diazepam or fluoxetine have been identified. Вызванное варфарином увеличение протромбинового времени при назначении ривастигмина не изменялось. While applying rivastigmina and digoxin adverse effect on vnutriserdecnuu conductivity were observed.

Одновременное применение ривастигмина с такими часто применяющимися препаратами, как антациды, antiemetics, oral hypoglycemic drugs, антигипертензивные средства центрального действия, beta-blockers, Calcium channel blockers, preparations, оказывающие положительное инотропное действие, антиангинальные средства, Estrogens, analgesics, включая НПВС, бензодиазепины и антигистаминные средства, не сопровождалось какими-либо изменениями кинетики ривастигмина или повышением риска возникновения клинически значимых нежелательных явлений.

As rivastigmine affects holinergicakie structure, It should not be administered together with holinomimeticheskimi drugs, а при его одновременном назначении с антихолинергическими препаратами следует учитывать разнонаправленность действия этих препаратов и ТТС Экселон^®.

При проведении анестезии ривастигмин, являясь ингибитором холинэстсразы, может усиливать эффекты деполяризующих миорелаксантов (миорелаксантов сукцинилхолинового типа).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, dry place at temperatures no higher than 25 ° C. Shelf life – 2 year.