Universal reference book for medicines
Product name: EXELON ® (EXELON ® )

Active substance: rivastigmine

Type: Selective inhibitor of brain acetylcholinesterase.
The drug for the treatment of dementia
Manufacturer: NOVARTIS PHARMA (Switzerland) manufactured by NOVARTIS FARMACEUTICA (Spain)
Composition, form of production and packaging
Capsules
opaque, size 2, yellow, marked on the body "EXELON 1.5 mg" red ink radially;
the contents of the capsules are powder from almost white to pale yellow.
1 caps.

rivastigmine (in the form of a hydrotartrate) 1.5 mg

Excipients: silicon colloidal dioxide, hypromellose, magnesium stearate, microcrystalline cellulose (ground powder), microcrystalline cellulose (granular powder).

The composition of the capsule shell: iron oxide yellow (E172), titanium dioxide (E171), gelatin.

14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
14 pcs.
- blisters (4) - packs of cardboard.
14 pcs.
- blisters (8) - packs of cardboard.
Capsules are opaque, size 2, orange, with marking on the body "EXELON 3 mg" red ink radially;
the contents of the capsules are powder from almost white to pale yellow.
1 caps.

rivastigmine (in the form of a hydrotartrate) 3 mg

Excipients: silicon colloidal dioxide, hypromellose, magnesium stearate, microcrystalline cellulose (ground powder), microcrystalline cellulose (granular powder).

The composition of the capsule shell: iron oxide yellow (E172), titanium dioxide (E171), gelatin, iron oxide red (E172).

14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
14 pcs.
- blisters (4) - packs of cardboard.
14 pcs.
- blisters (8) - packs of cardboard.
Capsules are opaque, size 2, red, marked on the body "EXELON 4,5 mg" with white ink radially;
the contents of the capsules are powder from almost white to pale yellow.
1 caps.

rivastigmine (in the form of a hydrotartrate) 4.5 mg

Excipients: silicon colloidal dioxide, hypromellose, magnesium stearate, microcrystalline cellulose (ground powder), microcrystalline cellulose (granular powder).

The composition of the capsule shell: iron oxide yellow (E172), titanium dioxide (E171), gelatin, iron oxide red (E172).

14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
14 pcs.
- blisters (4) - packs of cardboard.
14 pcs.
- blisters (8) - packs of cardboard.
The capsules are opaque, size No. 2, with a red lid and an orange body, marked on the "EXELON 6 mg" casing with red ink radially;
the contents of the capsules are powder from almost white to pale yellow.
1 caps.

rivastigmine (in the form of a hydrotartrate) 6 mg

Excipients: silicon colloidal dioxide, hypromellose, magnesium stearate, microcrystalline cellulose (ground powder), microcrystalline cellulose (granular powder).

The composition of the capsule shell: iron oxide yellow (E172), titanium dioxide (E171), gelatin, iron oxide red (E172).

14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
14 pcs.
- blisters (4) - packs of cardboard.
14 pcs.
- blisters (8) - packs of cardboard.
The solution for oral administration is transparent, yellow.

1 ml

rivastigmine (in the form of tartrate) 2 mg

Excipients: sodium benzoate, citric acid anhydrous, sodium citrate, dihydrate powder, quinoline yellow WS (E104), purified water.

50 ml - bottles of dark glass (1) complete with a dispenser - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

A selective inhibitor of acetyl- and butyrylcholinesterase of the brain, used to treat Alzheimer's disease and dementia in Parkinson's disease.
It has been shown that rivastigmine slows down the destruction of acetylcholine produced by functionally preserved neurons. In this rivastigmine selectively increases the content of acetylcholine in the cerebral cortex and hippocampus, and, thus, contributes to the improvement of the cholinergic neural transmission. Exelon ® can have a positive effect in reducing cognitive function associated with acetylcholine deficiency, particularly in dementia associated with Alzheimer's disease and Parkinson's disease. In addition, there is evidence that inhibition of cholinesterases may slow the formation of protein amyloid precursor beta fragments participating in amyloidogenesis, and thus slow the formation of amyloid plaques, which are one of the main pathological signs of Alzheimer's disease.
Rivastigmine interacts with the target enzyme to form a covalent bond, which leads to a temporary inactivation of the enzyme.
It was shown that in young healthy men, after taking the drug at a dose of 3 mg, the activity of acetylcholinesterase in the cerebrospinal fluid (CSF) decreases by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, the enzyme activity returns to the baseline level after about 9 hours. It was shown that the activity of butyrylcholinesterase in CSF in young healthy volunteers is reversibly reversed and restored to baseline after 3.6 hours. In patients with Alzheimer's disease, inhibition with rivastigmine is active The incidence of acetylcholinesterase in CSF is dose-dependent in the studied range of doses (namely to the highest dose of 6 mg 2 times / day). Inhibition of butyrylcholinesterase is also dose-dependent; a dose of 6 mg 2 times / day causes a decrease in the activity of the enzyme by more than 60% compared to the initial one. This effect of Excelona persisted for 12 months of therapy (the maximum period studied). A statistically significant correlation was found between the extent of excelon inhibition of both CSF enzymes and changes in cognitive function in patients with Alzheimer's disease; In this case, inhibition of butyrylcholinesterase in CSF is significantly and stably correlated with improvements in memory test results, attention and reaction speed.
The effectiveness of Excelon therapy in Alzheimer's disease has been shown in patients with mild to moderate dementia (score on a short scale of assessment of mental status - 10-24).
According to clinical studies, Exelon therapy results in significant improvement in cognitive functions (attention, memory, speech), functional status and activity in daily life, as well as in reducing the severity of the disease and the severity of mental and behavioral manifestations (such as agitation, tearfulness, illusions, hallucinations). Studies have shown that the effect of Exelon therapy is observed around the 12th week and persists for 6 months of therapy, while in the same period the deterioration of the corresponding indicators was observed in the group of patients receiving placebo.
In dementia associated with Parkinson's disease, the efficacy of Excelone was demonstrated in a placebo-controlled 24-week study in patients with mild to moderate dementia (score on a short scale of assessment of mental status - 10-24).
In patients who received Exelon, there was an improvement in cognitive functions (attention, memory, speech), while in patients receiving placebo, similar indicators worsened (the differences are statistically significant).
PHARMACOKINETICS

Suction

Rivastigmine is rapidly and completely absorbed.
C max in plasma is achieved after about 1 h. Due to the interaction of rivastigmine with the target enzyme, increasing the dose of the drug increases its bioavailability by 1.5 times that expected (for a given dose increase). After taking a 3 mg dose, the absolute bioavailability is about 36%. When taking the drug with food, the absorption of rivastigmine is slowed down (the time of reaching C max is increased by 74 min); C max is reduced by 43%;while the AUC increases by approximately 9%.
Distribution

Rivastigmine binds to plasma proteins to a low degree (approximately 40%).
Easily penetrates the BBB. The apparent V d is 1.8-2.7 l / kg.
Metabolism

Rivastigmine is rapidly and largely metabolized (T 1/2 from the plasma is about 1 hour), mainly by hydrolysis with cholinesterase to form a decarbamylated metabolite.
In vitro, this metabolite has a minimal ability to inhibit acetylcholinesterase (<10%). According to the data obtained in vitro and in experimental studies, the main isoenzymes of cytochrome P450 are involved in the metabolism of rivastigmine to a minimal extent. These data also correspond to observations indicating the absence of human interaction of rivastigmine with drugs metabolized with the participation of cytochrome P450.
Excretion

Rivastigmine is excreted mainly by kidneys in the form of metabolites;
in the unchanged form in urine is not found out. After 24 hours after taking more than 90% of the dose. With feces less than 1% of the dose is excreted. In patients with Alzheimer's disease, no cumulation of rivastigmine or its decarbamated metabolite is noted.
Pharmacokinetics in elderly patients

Although the bioavailability of rivastigmine in elderly patients is higher than that of healthy young volunteers, nevertheless, in patients with Alzheimer's disease aged 50 to 92 years, clinical studies have not revealed changes in bioavailability associated with age.

INDICATIONS

- mild or moderate dementia of the Alzheimer's type (probable Alzheimer's disease, Alzheimer's disease);

- mild to moderate dementia in Parkinson's disease.

DOSING MODE

Exelon ® should be taken 2 times / day, during breakfast and dinner.

The initial dose is 1.5 mg 2 times / day.
When using the drug in patients who are particularly sensitive to cholinergic drugs, treatment should begin with the use of the drug at a dose of 1 mg 2 times / day.
Dose selection

The initial recommended dose is 1.5 mg 2 times / day.
If after a minimum of 2 weeks of treatment a good tolerability of this dose is noted, it can be increased to 3 mg 2 times / day. In case of good tolerability of the dose received by the patient, its further increase is possible up to 4.5 mg 2 times / day and further up to 6 mg 2 times / day - with a time interval of at least 2 weeks after each dose increase.
Undesirable effects, namely nausea, abdominal pain, decreased appetite or weight loss observed during treatment, may decrease after missing 1 or more doses of the drug.
If undesirable effects persist, the daily dose of the drug should be reduced to the previous well tolerated dose.
The maintenance dose is 1.5 to 6 mg 2 times / day.
In order to achieve the best therapeutic effect, the dose of the drug should be kept at the maximum tolerable level.
The maximum daily dose is 6 mg 2 times / day.

Renewal of the drug after a break.
If the break in taking the drug for several days or more, the treatment should be resumed from the initial dose to reduce the risk of the resumption of adverse reactions (eg, severe vomiting). Gradual increase in dose is carried out stepwise, as described above.
In patients with impaired renal or hepatic function, correction of the dosage regimen is not required.

Method of application of solution for oral administration

The required amount of solution should be removed from the vial using the dispenser attached to it.
The solution can be taken directly from the dispenser.
Equal doses of the drug, used in the form of capsules and as a solution for oral administration, are interchangeable.

SIDE EFFECT

The most frequently reported adverse events on the part of the digestive system: nausea (38%), vomiting (23%), mainly during the dose selection period.
According to clinical studies, adverse events on the part of the digestive system and weight loss were more frequent in women.
In patients with dementia of the Alzheimer's type who received Exelon therapy, the undesirable reactions indicated in Table 1 were noted. The incidence of adverse events was assessed as follows: very often (≥10%), often (≥1-10%), sometimes ≥ 0.1% - <1%), rarely (? 0.01-0.1%), very rarely (<0.01%), including individual reports.

Table 1.

Side effect Frequency of occurrence

Infections and invasions

Urinary tract infections Very rare

From the side of the central nervous system

Dizziness Very often

Headache Often

Drowsiness Often

Tremor Often

Agitation (anxious arousal) Often

Confusion of consciousness Often

Insomnia Sometimes

Depression Sometimes

Fainting Sometimes

Seizures Rarely

Hallucinations Very rarely

From the side of the cardiovascular system

Arrhythmia (bradycardia, AV blockade, fibrillation, tachycardia) Very rarely

Angina pectoris, myocardial infarction Rarely

Increased blood pressure Very rarely

From the digestive system

Nausea Very often

Vomiting Very often

Diarrhea Very often

Loss of appetite Very often

Abdominal pain and dyspepsia Often

Violations of laboratory parameters of liver function Sometimes

Peptic ulcer of the stomach and duodenum Rarely

Gastrointestinal bleeding Very rare

Severe vomiting, leading to rupture of the esophagus Very rarely

Pancreatitis of mild severity Very rarely

From the skin and subcutaneous tissues

Increased Sweating Often

Rash Rarely

From the body as a whole

Increased fatigue and asthenia Often

General malaise Often

Random falls Sometimes

Other

Decreased body weight Often

The incidence and severity of adverse events tend to increase with increasing doses.

The following adverse reactions were observed only when applying Exelon in the form of a transdermal therapeutic system: cerebral circulation disorder, delirium (sometimes).

Table 2 summarizes the adverse events reported in the 24-week clinical trial of Exelon in patients with dementia in Parkinson's disease.

Table 2.

Side effects in patients with dementia in Parkinson's disease (? 5% in the group taking Excelon ® ) Exelon ® n (%) Placebo n (%)

The total number of patients participating in the study was 362 (100) 179 (100)

Number of patients with undesirable effects 303 (83.7) 127 (70.9)

Nausea 105 (29.0) 20 (11.2)

Vomiting 60 (16.6) 3 (1.7)

Diarrhea 26 (7.2) 8 (4.5)

Loss of appetite 22 (6.1) 5 (2.8)

Dizziness 21 (5.8) 2 (1.1)

Table 3 shows the incidence of events indicating a deterioration in the course of Parkinson's disease recorded in the 24-week clinical trial of Exelon in patients with dementia in Parkinson's disease.

Table 3.

Phenomena of Parkinson's Disease in Patients with Dementia in Parkinson's Disease Exelon® n (%) Placebo n (%)

The total number of patients participating in the study was 362 (100) 179 (100)

The number of patients who report events that indicate a worsening of the course of Parkinson's disease 99 (27.3) 28 (15.6)

Tremor 37 (10.2) 7 (3.9)

Falls 21 (5.8) 11 (6.1)

Parkinson's disease (impairment) 12 (3.3) 2 (1.1)

Increased secretion of saliva 5 (1.4) 0

Dyskinesia 5 (1.4) 1 (0.6)

Parkinsonism 8 (2.2) 1 (0.6)

Hypokinesia 1 (0.3) 0

Traffic violation 1 (0.3) 0

Bradykinesia 9 (2.5) 3 (1.7)

Dystonia 3 (0.8) 1 (0.6)

Violation of gait 5 (1.4) 0

Muscular rigidity 1 (0.3) 0

The violation of the equilibrium 3 (0.8) 2 (1.1)

Muscle stiffness 3 (0.8) 0

Shivering 1 (0.3) 0

Motor dysfunction 1 (0.3) 0

CONTRAINDICATIONS

- age to 18 years (for capsules);

- hypersensitivity to rivastigmine, other carbamate derivatives or other components of the drug.

Exelon ® is contraindicated in patients with severe impairment of liver function, as its use in this population has not been studied.

Exelon ® , like other cholinomimetic drugs, should be used with caution in patients with SSSU or conduction disorders (sinoatrial blockade, AV blockade).

Cholinergic stimulation can increase the secretion of hydrochloric acid in the stomach, lead to increased obstruction of the urinary tract and aggravation of the convulsive syndrome, so caution should be exercised in appointing Exelon to patients prone to these conditions.

Exelon ® , as well as other cholinomimetics, should be used with caution in patients with bronchial asthma or obstructive airway disease in the history.

Taking into account the pharmacodynamic properties of Exelon, it should not be prescribed simultaneously with other cholinomimetic drugs.

During the period of dose selection, as well as with the use of other cholinomimetics, undesirable phenomena were noted for a short period after the dose was raised.The severity of adverse events may decrease in response to a decrease in the dose of the drug.
Otherwise, you must cancel Excelon ® .
PREGNANCY AND LACTATION

The safety of the use of Exelon in pregnancy in humans has not been established to date, therefore, the drug can be prescribed during pregnancy only in those cases when the expected success of treatment exceeds the potential risk for the fetus.

It is not known whether rivastigmine is excreted in breast milk.
Therefore, during the use of the drug should be abandoned breastfeeding.
Experimental studies have shown that rivastigmine does not have teratogenic properties.

APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with impaired renal function, no dosage adjustment is required.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Exelon is contraindicated in patients with severe impairment of liver function, as its use in this population has not been studied.

APPLICATION FOR CHILDREN

Contraindicated at the age of 18 (capsules).

SPECIAL INSTRUCTIONS

As with the use of other holinomimetics, with the administration of rivastigmine, it is possible to develop extrapyramidal disorders or increase their severity.
With the use of rivastigmine in patients with dementia in Parkinson's disease, there was an increase in the severity of motor disorders (including bradykinesia, dyskinesia, gait disorders), as well as an increase in the frequency and severity of tremor (requiring in some cases, withdrawal of drug therapy). Patient status should be monitored regularly to identify these adverse events.
Rivastigmine can influence the activity of anticholinergic and cholinomimetic drugs.

The composition of the solution for oral administration includes sodium benzoate.
Benzoic acid has a slight irritant effect on the skin, mucous membranes and in contact with the eyes.
Use in Pediatrics

The use of Exelon in children has not been studied, so the drug is not recommended for children.
Impact on the ability to drive vehicles and manage mechanisms

Patients treated with Exelon ® , did not reveal any violations of motor function. Nevertheless, the ability of the patient with Alzheimer's disease to drive a car and operate machinery should be regularly evaluated by the treating physician.
OVERDOSE

Accidental overdose of the drug in most cases, was not accompanied by any clinical signs; almost all of these patients continued treatment Exelon.
Symptoms: Nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given vagotonic effect of cholinesterase inhibitors on heart rate, we can not exclude the occurrence of bradycardia and / or syncope. In one case, 46 mg of the drug was taken; after medical treatment after 24 h showed complete recovery.
Treatment: since the half-life of rivastigmine from plasma is about 1 hour, and the duration of inhibition of acetylcholinesterase is about 9 hours, Exelon recommended not to apply in cases of asymptomatic overdose ® within the next 24 hours. If overdose accompanied by severe nausea and vomiting, should consider the use of antiemetics.
If necessary, conduct symptomatic therapy.
When a large overdose can be applied atropine sulfate, which is an initial dose of 0.03 mg / kg / in; subsequent dosing depends on the clinical effect. Use of scopolamine as an antidote is not recommended.
DRUG INTERACTION

Rivastigmine is metabolized mainly through hydrolysis, with the participation of esterases. Drug metabolism involving major cytochrome P450 isoenzymes occurs to a minimum extent. Therefore, the expected pharmacokinetic interactions with other drugs metabolized with the participation of these enzymes is not necessary.
In healthy volunteers, pharmacokinetic interactions between Exelon and digoxin, warfarin, diazepam or fluoxetine were detected. Warfarin-induced increase in prothrombin time in the appointment of Exelon did not change. With simultaneous use of Exelon and digoxin adverse effect on intracardiac conductivity were noted.
The simultaneous use of Exelon such commonly used drugs such as antacids, antiemetics, antidiabetics, antihypertensives central action, beta-blockers, calcium channel blockers, drugs that have a positive inotropic action, antianginal agents, NSAIDs, estrogens, analgesics, benzodiazepines and antihistamines funds, was not accompanied by any changes in the kinetics of Exelon or the increased risk of adverse events.
Exelon ® , a cholinesterase inhibitor may potentiate depolarizing muscle relaxants (relaxants suktsinilholinovogo type) during anesthesia.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C;
Do not freeze. The vial should be stored in an upright position. Shelf life - 3 years.
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