Active substanceRivastigmineRivastigmine Similar drugsTo uncover Alzenorm solution inwards Teva Pharmaceutical Enterprises Co., Ltd. Israel Alzenorm capsules inwards Teva Pharmaceutical Enterprises Co., Ltd. Israel Excelon® solution inwards Novartis Pharma AG Switzerland Excelon® patch through. Novartis Pharma AG Switzerland Excelon® capsules inwards Novartis Pharma AG Switzerland Dosage form: & nbsporal solution Composition:1 ml solution for oral administration contains: active substance rivastigmine 2 mg (in the form of hydrothardate); Excipients: sodium benzoate 1,000 mg, citric acid 7,000 mg, sodium citrate dihydrate 7,087 mg, quinoline dye, yellow WS (E 104) 0.008 mg, purified water up to 1 ml. Description:A clear yellow solution Pharmacotherapeutic group:cholinesterase inhibitor ATX: & nbspN.06.D.A Cholinesterase inhibitorsN.06.D.A.03 Rivastigmine Pharmacodynamics:The active substance of the drug Exelon® is rivastigmine - selective inhibitor of acetylcholinesterase and butyrylcholinesterase of the brain, used to treat Alzheimer's disease and dementia in Parkinson's disease. Rivastigmine slows down the destruction of acetylcholine, produced by functionally preserved neurons. Wherein rivastigmine selectively increases the content of acetylcholine in the cerebral cortex and hippocampus, and thus contributes to the improvement of the cholinergic nervous transmission. Rivastigmine can have a positive effect in reducing the 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 has been shown that in young healthy men, after taking rivastigmine at a dose of 3 mg, the activity of acetylcholinesterase in cerebrospinal fluid (CSF) decreases by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, the enzyme activity returns to its original after about 9 hours.It was shown that the activity of butyrylcholinesterase in CSF in young healthy volunteers is inhibited reversibly and restored to the original one after 3.6 hours. In patients with Alzheimer's disease inhibition of rivastigmine activity of acetylcholinesterase in CSF is dose-dependent in the studied range of doses (namely to the highest dose of 6 mg twice a day). Inhibition of butyrylcholinesterase activity is also dose-dependent; a dose of 6 mg twice a day causes a decrease in enzyme activity by more than 60% compared to the initial one. This effect of rivastigmine persisted for 12 months of therapy (the maximum period studied). A statistically significant correlation was found between the extent of inhibition of both CSF enzymes in rivastigmine and changes in cognitive function in patients with Alzheimer's disease; At the same time, it is the inhibition of the butyrylcholinesterase activity in CSF that correlates reliably and stably with the improvement of memory test results, attention and reaction speed. Pharmacokinetics:SuctionRivastigmine is rapidly and completely absorbed. The maximum concentration in the blood plasma (Cmax) is reached after about 1 hour.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 ± 13%. When taking rivastigmine in the form of a solution for oral ingestion with food, the absorption of rivastigmine is slowed down (the time to reach C max is increased by 74 minutes); The C max value decreases by 43%, while the area under the concentration-time curve (AUC) increases by approximately 9%.DistributionRivastigmine binds to plasma proteins to a low degree (approximately 40%). Rivastigmine is equally distributed in plasma and in blood, the blood-to-plasma distribution coefficient is 0.9 at concentrations from 1 to 400 ng / ml.Easily penetrates the blood-brain barrier, reaching a peak concentration in 1-4 hours, the ratio of AUC of cerebrospinal fluid and plasma is 40%. The apparent volume of distribution after intravenous administration is 1.8-2.7 l / kg.MetabolismRivastigmine is rapidly and largely metabolized (half-life from plasma (T 1/2) is about 1 hour), mainly by hydrolysis with cholinesterase to form a decarbamylated metabolite (NAP226-90). In vitro this metabolite shows a minimal ability to inhibit the activity of acetylcholinesterase (<10%). Based on the data obtained in in vitro studies are not expected to interact with drugs metabolized with the participation of the following isoenzymes of the cytochrome system: CYP1A2, CYP2D6, CYP3A4 / 5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6. According to the data obtained in the 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 interactions of rivastigmine with drugs metabolized with the participation of cytochrome P450. The total clearance of rivastigmine after intravenous administration is approximately 130 l / h at a dose of 0.2 mg, and decreases to 70 l / h at 2.7 mg.ExcretionRivastigmine 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 is withdrawn. 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 patientsIn a study of the effect of age on the pharmacokinetics of rivastigmine after oral administration at a dose of 1.0 mg, it was shown that plasma rivastigmine concentration is higher in older healthy volunteers (61-71 years) than in young (19-40 years). This difference increased with an increase in the dose of rivastigmine (2.5 mg): in elderly healthy volunteers, the concentration of rivastigmine plasma was 30% higher than in young ones. Age did not affect the concentration of decarbamylated phenolic metabolites. In patients with Alzheimer's disease at the age of 50 to 92 years old, clinical trials have not revealed changes in bioavailability associated with age.Impaired renal functionIt was shown that with a single oral dose of 3 mg, the concentration of rivastigmine in plasma does not differ in healthy patients and in patients with impaired renal function of severe degree (GFR <10 ml / min). Rivastigmine clearance was 4.8 l / min and 6.9 l / min in patients and in healthy volunteers, respectively. However, in patients with impaired renal function of moderate severity (GFR 10-50 ml / min), Cmax rivastigmine in blood plasma was increased by almost 2.5 times and the AUC of decarbamylated phenolic metabolites was increased by approximately 50%.The clearance of rivastigmine was 1.7 l / min. The reason for the discrepancy between the severity of renal impairment and the clearance of rivastigmine is not clear.Impaired liver functionAfter ingestion of Cmax rivastigmine was approximately 60% higher and AUC was more than 2 times greater in patients with impaired liver function of mild and moderate severity compared with healthy volunteers. When taking 3 mg of rivastigmine, once or repeatedly, the dose of 6 mg twice daily rivastigmine clearance was approximately 60-65% less in patients with impaired liver function of mild and moderate severity compared with healthy volunteers. These pharmacokinetic features do not affect the incidence and severity of adverse events. Indications:- Weak or moderately expressed dementia of the Alzheimer's type (probable Alzheimer's disease, Alzheimer's disease).- Weak or mild dementia in Parkinson's disease. Contraindications:Hypersensitivity to rivastigmine, other carbamate derivatives or other components that make up the drug.Skin reactions, suspicious for allergic contact dermatitis, against the backdrop of the use of the drug Exselon® TTC.Age to 18 years. Carefully:Exelon ®, like other cholinomimetic drugs, should be used with caution in patients with sinus node weakness syndrome or cardiac conduction disorders (sinoatrial block, atrioventricular block). Cholinergic stimulation can increase the secretion of hydrochloric acid in the stomach, lead to increased obstruction of the urinary tract and exacerbation of the convulsive syndrome, so caution should be exercised when using Excelon® in patients who are predisposed to these conditions.Exelon®, as well as other cholinomimetics, should be used with caution in patients with bronchial asthma or other obstructive airway diseases in history.The use of rivastigmine in patients with severe liver dysfunction is possible under the close supervision of medical staff; studies in this category of patients were not conducted.Taking into account the pharmacodynamic properties of rivastigmine,It should not be used concurrently with other cholinomimetic drugs. Pregnancy and lactation:PregnancyIn studies in animals rivastigmine penetrated through the placenta. There is no data on the ability of rivastigmine to penetrate the human hematoplacental barrier. Experimental data showed that rivastigmine does not have teratogenic properties. In studies in animals, there was an increase in the duration of the gestational period. The safety of the use of the drug Excelon® in pregnancy in humans has not been established so far, so the drug can be used in pregnancy only in those cases when the expected benefit of treatment exceeds the potential risk for the fetus.Breast-feedingIn studies rivastigmine and its metabolites were excreted with the milk of lactating animals. It is not known whether the rivastigmine in breast milk, so during the use of the drug should abandon breast-feeding.FertilityThere is no evidence of the effect of rivastigmine on women of reproductive age.There is no evidence of the effect of rivastigmine on fertility in humans.In studies in animals, there was no negative effect on the fertility of males and females, both parents and offspring. Dosing and Administration:The drug Exelon® should be taken orally 2 times a day, during breakfast and dinner.Initial dose is 1.5 mg twice a day. When using the drug in patients, especially sensitive to the effects of cholinergic drugs, treatment should be started at a dose of 1 mg 2 times a day.Selection of a dose. The initial recommended dose is 1.5 mg (0.75 ml of solution) 2 times a day. If after a minimum of two weeks of treatment a good tolerability is noted, the dose can be increased to 3 mg (1.5 ml solution) 2 times a day. In case of good tolerance, further increase to 4.5 mg (2.25 ml solution) 2 times a day and further up to 6 mg (3 ml solution) 2 times a day with an interval of at least 2 weeks after each dose increase.Undesirable effects, namely, nausea, vomiting, abdominal pain, decreased appetite or weight loss observed during treatment, may decrease after skipping one 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, or stop taking the drug.Maintenance dose is from 3 mg to 6 mg twice a day. In order to achieve the best therapeutic effect, the dose of the drug should be kept at the maximum tolerable level. The effectiveness of the drug with a duration of application of more than 6 months is not established.The maximum daily dose: 6 mg 2 times a day.Supportive treatment can be continued as long as the therapeutic effect remains. Therefore, the therapeutic effect should be evaluated regularly, especially in patients receiving doses less than 3 mg twice a day. If, after 3 months of therapy with the drug in the maintenance dose, the patient does not have a positive dynamics of reducing the symptoms of dementia, treatment should be discontinued. Consideration should also be given to discontinuing therapy with the drug if the previously noted therapeutic effect is no longer observed.Renewal of the drug after a breakThe incidence and severity of adverse events increases with an increase in the dose of rivastigmine. If the interruption in taking the drug is more than three days, resumption of treatment should be from the initial dose in order to reduce the risk of recurrence of adverse reactions (eg, severe vomiting).Gradual increase in dose is carried out stepwise, as described above.Method of application of solution for oral administrationThe 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.In patients with impaired renal or hepatic function correction of the dosing regimen is not required. However, due to an increase in the exposure of the drug in patients with impaired renal function of moderate severity and a violation of mild to moderate liver function, it is recommended that the dose of rivastigmine be carefully selected in patients of this category in accordance with individual tolerability due to the increased risk of developing dose-dependent adverse events. The use of rivastigmine in patients with severe liver dysfunction is possible under the close supervision of medical staff, no studies have been conducted in this category of patients. Side effects:The most frequently reported adverse events (AEs) from the digestive system: nausea (38%), vomiting (23%), mainly during the period of increasing the dose. According to clinical studies, adverse reactions from the digestive system and weight loss were more common in women.The incidence of adverse reactions was estimated as follows: "very often" arising ≥10%, "often" - ≥1% - <10%, "infrequently" - ≥0.1% - <1%, "rarely" - ≥0 , 01% - <0.1%, "very rarely" - <0.01%, including individual spontaneous reports of AEs.In patients with Alzheimer's dementia who received Exelon® therapy, the following AEs were observedInfectious and parasitic diseases: very rarely - urinary tract infections.Disorders of the psyche: often agitation, anxiety, confusion; infrequently-insomnia, depression; very rarely - hallucinations.Impaired nervous system: very often - dizziness; often headache, drowsiness, tremor; rarely - a syncope; rarely convulsive seizures; very rarely - extrapyramidal disorders (including worsening of the course of concomitant Parkinson's disease).Heart Disease: rarely - angina pectoris, myocardial infarction; very rarely, arrhythmia (bradycardia, atrioventricular block, atrial fibrillation, tachycardia).Vascular disorders: very rarely - increased blood pressure (BP).Disorders from the digestive system: very often - nausea, vomiting, diarrhea, decreased appetite; often - abdominal pain and indigestion; rarely - stomach ulcers and duodenal ulcers; very rarely - bleeding of the gastrointestinal tract (GIT), pancreatitis, severe vomiting, leading to rupture of the esophagus.Disturbances from the skin and subcutaneous tissues: often hyperhidrosis; rarely - a rash, itching.Disorders from the metabolism and nutrition: often - weight loss.General disorders and disorders at the site of administration: often - increased fatigue and asthenia, general malaise; infrequently - falling.Disorders from the liver and bile ducts: infrequently - violations of laboratory indicators of liver function.When using the drug Exselon ® TTS in patients with dementia of the Alzheimer type, the following AEs were reported: often - urinary incontinence; infrequently, cerebral circulation, delirium, psychomotor agitation; rarely - erythema, urticaria, blistering, allergic dermatitis.In patients with dementia in Parkinson's disease who received Exelon® therapy in capsules, the following AEs were observed.Disorders of the psyche: often - anxiety, insomnia, anxiety.Impaired nervous system: very often - a tremor; often - dizziness, drowsiness, headache, worsening of Parkinson's disease, bradykinesia, dyskinesia, hypokinesia, rigidity as a "cogwheel"; infrequently - dystonia.Heart Disease: often bradycardia; infrequently - atrial fibrillation, atrioventricular block.Disorders from the digestive system: very often - nausea, vomiting; often diarrhea, abdominal pain and indigestion, increased salivation, decreased appetite.Disturbances from the skin and subcutaneous tissues: often - increased sweating.General disorders and disorders at the site of administration: very often - accidental falls; often - dehydration, increased fatigue and asthenia, gait disturbance.The following AEs were noted in a clinical trial in patients with Parkinson's disease receiving Excelon® as a transdermal therapeutic system (TTC): often agitation, depression.Separate reports of adverse events from post-marketing data (frequency unknown).On the background of therapy with Excellone® (capsules or oral solution), the following undesirable events were noted in the clinical practice (frequency of AE was not established): dehydration, aggression, anxiety, extrapyramidal disorders in patients with Alzheimer's dementia, sinus node weakness syndrome, hepatitis, common allergic dermatitis.According to the clinical study, in patients with dementia caused by Parkinson's disease, the frequency (compared to placebo) of the following AEs, capable of exacerbating the symptoms of Parkinson's disease: a tremor of 10.2% (3.9% in the placebo group) 5.8% (6.1% in the placebo group), worsening of Parkinson's disease - 3.3% (1.1% in the placebo group), increased salivation - 1.4% (not found in the placebo group), dyskinesia - 1.4% (0.6% in the placebo group), parkinsonism -2.2% (0.6% in the placebo group), hypokinesia 0.3% (not detected in the placebo group), motor bunny - 0.3% (not detected in the placebo group), bradykinesia 2.5% (1.7% in the placebo group), dystonia 0.8% (0.6% in the placebo group), gait disturbance -1 , 4% (not detected in the placebo group),muscular rigidity 0.3% (not detected in the placebo group), imbalance 0.8% (1.1% in the placebo group), musculoskeletal stiffness 0.8% (not detected in the placebo group), tremor - 0.3% (not detected in the placebo group), motor dysfunction 0.3% (not detected in the placebo group).If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor. Overdose:Symptoms. Accidental overdose of the drug in most cases was not accompanied by any clinical manifestations; almost all patients continued treatment with Exelon®. In case of an overdose, nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, drowsiness, bradycardia, confusion, increased sweating, increased blood pressure, hallucinations, general malaise. An overdose of cholinesterase inhibitors can lead to a cholinergic crisis with the development of symptoms such as severe nausea, vomiting, excessive salivation, sweating, bradycardia, lowering blood pressure, respiratory depression and seizures.Perhaps the development of muscle weakness, which can lead to a lethal outcome with the involvement of respiratory muscles. Given the vagotonic effect of cholinesterase inhibitors on the heart rate (heart rate), bradycardia and / or syncope can not be ruled out. When an overdose of the drug, there were rare cases of death, but the relationship with the use of the drug remains unclear. Symptoms and outcome varied in different patients. There was no clear connection between the dose taken and the severity of the outcome.Treatment. Since rivastigmine T1 / 2 from the blood plasma is about 1 hour, and the duration of inhibition of acetylcholinesterase activity is about 9 hours, in cases of asymptomatic overdose it is recommended not to use Exelon® for the next 24 hours. If an overdose is accompanied by severe nausea and vomiting, consider the use of anti-emetics. If other undesirable phenomena occur, if necessary, appropriate symptomatic treatment is performed.If a significant overdose can be applied atropine, the initial dose of which is 0.03 mg / kg intravenously; the subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended. Interaction:Rivastigmine is metabolized predominantly by hydrolysis with the participation of esterases. The metabolism of rivastigmine with the participation of the main isoenzymes of cytochrome P450 occurs to a minimal extent. Thus, pharmacokinetic interactions of rivastigmine with other drugs metabolized with the participation of these enzymes are not expected.Unsupported interactionMetoclopramideGiven the possibility of the emergence of the combined effect of drugs on the extrapyramidal system, simultaneous use of metoclopramide and rivastigmine is not recommended.Drugs affecting the cholinergic systemGiven the pharmacodynamic characteristics of rivastigmine, simultaneous use of it with other cholinomimetics should be avoided in connection with the possibility of developing their combined effect. Rivastigmine can affect the effect of cholinergic blockers (eg, oxybutynin, tolterodine).Salts of suxamethoniumWhen conducting anesthesia rivastigmine, being an inhibitor of cholinesterase, can enhance the effects of depolarizing muscle relaxants (muscle relaxants of suxamethonium salts). It is recommended to be careful when choosing anesthetics. If necessary, before the anesthesia may reduce the dose of rivastigmine or temporary stop therapy.Interactions that should be taken into accountBeta-blockersWith the simultaneous use of rivastigmine with various beta-blockers (including atenolol), a synergistic interaction was noted that led to the development of a bradycardia, which, in turn, can cause syncopal conditions. Despite the fact that simultaneous use with cardioselective beta-blockers is associated with the greatest risk of development of such effects, AE data were also observed in patients receiving other drugs of this group.Interaction with nicotineRivastigmine absorption was increased by 23% when administered orally (in the form of capsules at a dose of up to 12 mg / day) in patients taking nicotine.Interaction with the most commonly used drugsIn healthy volunteers, there was no pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine. The increase in prothrombin time caused by warfarin with rivastigmine did not change. With simultaneous application of rivastigmine and digoxin, there was no adverse effect on intracardiac conductivity. The simultaneous use of rivastigmine with such commonly used drugs as antacids, antiemetics, hypoglycemic agents, central-action hypotensive drugs, blockers of "slow" calcium channels, drugs that have a positive inotropic effect, antianginal drugs, nonsteroidal anti-inflammatory drugs, estrogens, analgesics, anxiolytic agents (benzodiazepines) and H1-histamine receptor blockers, was not accompanied by any altered kinetics of rivastigmine or an increased risk of clinically significant adverse events. Special instructions:Treatment should always begin with a dose of 1.5 mg 2 times a day, which is gradually increased to a maintenance dose. If the treatment is interrupted for more than three days, therapy should be resumed from the minimum daily dose to reduce the likelihood of adverse events.Digestive system disorders such as nausea, vomiting and diarrhea may occur at the beginning of treatment or with an increase in the dose of the drug and may be cured with a reduced dose. Otherwise, treatment with Excelon® should be discontinued. Patients who developed signs of dehydration, due to prolonged diarrhea or vomiting, are recommended intravenous fluids and a reduced dose or withdrawal of rivastigmine therapy. Dehydration can have serious consequences.It is necessary to control the body weight of patients with Alzheimer's disease, since this group of patients can lose weight when taking cholinesterase inhibitors, including rivastigmine.Patients with a body weight of less than 50 kg are less likely to tolerate rivastigmine therapy and are more likely to discontinue treatment due to adverse events.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.Like other holinomimetics, the use of rivastigmine may lead to obstruction of the urinary tract, as well as the appearance or increase in the severity of extrapyramidal disorders. When rivastigmine was used in patients with dementia in Parkinson's disease, there was an increase in the severity of Parkinson's symptoms, especially tremor.After an increase in the dose of Excelon®, a short-term increase in blood pressure and hallucinations in patients with Alzheimer's dementia may occur, as well as exacerbation of extrapyramidal disorders (especially tremor) in patients with dementia in Parkinson's disease. These symptoms may disappear when the dose decreases, otherwise the drug should be canceled. It is necessary to regularly assess the condition of patients to identify these adverse events.Skin ReactionsSkin reactions that occur with the use of the drug Exselon® TTS, were usually of mild or moderate severity.These reactions are not indicative of a patient's sensitization to rivastigmine. Nevertheless, against the background of the use of the drug Exselon ® TTS, allergic contact dermatitis may occur.With the development of contact allergic dermatitis in patients with 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 of allergological testing is recommended to be transferred to rivastigmine dosage forms for oral administration. In some patients with sensitization to rivastigmine after the use of the drug Exselon® TTS, the use of rivastigmine in other dosage forms may not be possible.Allergic contact dermatitis should be suspected if a skin reaction occurs outside the size of the TTS at the site of TTS attachment, or skin reactions at the attachment site have reached a marked intensity (eg, increased erythema, edema, papules, vesicles), and if the severity of the skin reactions does not significantly decrease within 48 hours after removal of the TTS.In these cases, treatment with the drug should be discontinued (see section Contraindications).In the postmarketing period, data were obtained on the development of common allergic dermatitis in some patients with rivastigmine, regardless of the route of administration (either inward or transdermally). In these cases, the drug should be completely discontinued (see Contraindications section). Patients and caregivers should be informed of the possibility of developing appropriate skin reactions while using rivastigmine. Effect on the ability to drive transp. cf. and fur:Parkinson's disease and Alzheimer's disease can reduce the ability to drive vehicles and mechanisms. Rivastigmine may cause dizziness and drowsiness, especially at the beginning of therapy and when increasing the dose. Thus, the ability of patients to manage motor vehicles and complex mechanisms should be regularly evaluated by the attending physician. Form release / dosage:Solution for oral administration 50 ml or 120 ml. Packaging:Vials of dark glass, equipped with a stopper with pump tubing and a screw cap with child protection complete withdispenser and instructions for use in a cardboard pack. Storage conditions:Store at a temperature not exceeding 30 ° C. Do not freeze.The bottle should be kept in an upright position.The drug should be stored out of the reach of children. Shelf life:3 years.The drug should not be used after the expiration date. Terms of leave from pharmacies:On prescription Registration number:П N012952 / 01 Date of registration:14.11.2011 The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland Manufacturer: & nbspNOVARTIS PHARMA, AG Switzerland Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC Information update date: & nbsp03.10.2015 Illustrated instructions × Illustrated instructions Instructions