Expiration date: 07/2025
The composition and form of issue:
Capsules. 1 capsule contains rivastigmine (tartrate) 1.5, 3, 4.5 or 6 mg
excipients: magnesium stearate metilgidroksipropilzelluloza the (polymer) microcrystalline silica colloidal anhydrous titanium dioxide (E171) gelatin iron oxide yellow (E172) iron oxide red (E172)
blistere in 14 PCs. in cardboard pack 1, 2, 4 or 8 blisters.
The oral solution 1 FL.
rivastigmine (tartrate) 2 mg
excipients: sodium benzoate citric acid anhydrous sodium citrate dihydrate powder quinoline yellow WS (E104) purified water
in a bottle of dark glass 50 ml complete with pump dispenser in cardboard pack 1 set.
Description pharmaceutical form:
Capsules 1.5 mg: opaque, yellow, size No. 2, with marking on the body, "EXELON 1,5 mg" in red ink radially.
Capsules 3 mg: opaque, orange, size No. 2, with marking on the body "EXELON 3 mg" in red ink radially.
Capsule 4.5 mg: opaque red, size No. 2, with marking on the body, "EXELON 4,5 mg" in white ink radially.
Capsules 6 mg: opaque, red cap and orange body, size No. 2, with marking on the body "EXELON 6 mg" in red ink radially.
The contents of capsules-powder from almost white to pale yellow.
The solution for the reception inside: transparent yellow solution.
Pharmacokinetics:
Suction
Rivastigmine is rapidly and completely absorbed. Cmax in plasma is reached after about 1 h Due to the interaction of rivastigmine with the enzyme-target with increasing doses of the drug increases its bioavailability is 1.5 times higher than expected (increasing the dose). After administration of doses of 3 mg absolute bioavailability is about 36%. While taking the drug Exelon in the form of a solution together with food the absorption of rivastigmine slowed (Tmax increased by 74 min) the value of Cmax is reduced by 43%, while the AUC increased by about 9%.
Distribution
Rivastigmine binds to plasma proteins to a lesser degree (approximately 40%). Easily permeates through GEB. The apparent VSS is 1.8–2.7 l/kg.
Metabolism
Rivastigmine is rapidly metabolized (T1/2 approximately 1 h), mainly by hydrolysis of cholinesterase education decarbamylated metabolite. In vitro, this metabolite shows minimal ability to inhibit acetylcholinesterase (<10%). In accordance with the data obtained in vitro and in experimental studies, the major cytochrome P450 isoenzymes involved in the metabolism of rivastigmine is minimal. These data correspond to observations and testifying to the lack of human interaction of rivastigmine with drugs metabolized with participation of cytochrome P450.
Excretion
Rivastigmine is excreted mainly by the kidneys as metabolites in unchanged form in the urine not detected. Through 24 h after administration appears more than 90% of the dose. The feces derived less than 1% of the dose. In patients with Alzheimer's accumulation of rivastigmine or its metabolite carbamoilirovaniem not marked.
Pharmacokinetics in elderly patients. While bioavailability of rivastigmine in the elderly is higher than in healthy young volunteers, however, in patients with Alzheimer's disease aged 50 to 92 years in clinical studies, there were no changes in bioavailability associated with age.
Description pharmacological action:
Rivastigmine is a selective inhibitor of acetyl - and butyrylcholinesterase in brain used to treat Alzheimer's disease and dementia in Parkinson's disease. Rivastigmine slows the breakdown of neurotransmitter acetylcholine, produced by functionally intact neurons. The rivastigmine selectively increases the amount of acetylcholine in the cerebral cortex and hippocampus, and thus, improve cholinergic nerve transmission. Drug Exelon can have 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, taking part in amyloidogenesis, and thus slow 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. It has been shown that in young healthy men after ingestion of the drug Exelon at 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 of enzyme activity returns to the original level after about 9 hours It is shown that butyrylcholinesterase activity in CSF in young healthy volunteers inhibited reversible and recovered to baseline after 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 (higher doses of 6 mg 2 times a day). 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 Exelon 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 effectiveness of drug therapy Exelon in Alzheimer's disease was shown in patients with mild and moderate severity of dementia (10-24 points on a short scale assessment of mental status, Mini Mental State Examination, MMSE). According to clinical studies, treatment with the drug Exelon 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.). Studies have shown that the effect of drug therapy Exelon is approximately 12 weeks and lasts for 6 months of therapy, thus for the monitoring period in the group of patients treated with placebo, there was deterioration of the relevant indicators.
In dementia associated with Parkinson's disease, efficacy of the drug Exelon has been demonstrated in a placebo-controlled study lasting 24 weeks in patients with mild and moderate severity of dementia (score 10-24 on the MMSE). Patients receiving the drug Exelon was a statistically significant improvement of cognitive functions (attention, memory, speech, etc.), while patients receiving placebo, the same indicators were worse (differences were statistically significant).
Indications:
- mild or moderately severe dementia of Alzheimer's type (Alzheimer's disease, including probable)
- mild or moderately severe dementia in Parkinson's disease.
Contraindications:
- hypersensitivity to rivastigmine, other carbamate derivatives or other ingredients within the drug
- patients with severely impaired liver function (because the application has not been studied)
- children (application of the drug in children has not been studied, therefore, to appoint not recommended).
With caution:
- syndrome of weakness of sinus node or conduction disturbances — sinoatrial and AV blockade (as with other cholinomimetics)
- 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 (same as with other cholinomimetics)
- simultaneous reception with other cholinomimetic drugs (taking into account the pharmacodynamic properties of the drug Exelon).
During the period of dose adjustment, as well as with other cholinomimetics, adverse events were noted within a short period after increasing the dose. The severity of adverse events may decrease in response at a lower dose of the drug. Otherwise the drug Exelon should be abolished (see "Side effects").
Application of pregnancy and breast-feeding:
Experimental data showed that rivastigmine has no teratogenic properties. However, the safety of the drug Exelon 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 whether the drug enters Exelon in breast milk. Therefore, during the use of the drug should abandon breastfeeding.
Side effects:
The most commonly reported adverse reactions gastrointestinal: nausea (38%), vomiting (23%), mainly in the period of increasing doses. According to clinical studies of adverse reactions from the digestive system and weight loss were reported more often in women.
In patients with dementia of Alzheimer's type, treated with the drug Exelon, observed adverse reactions are listed in table 1. The incidence of adverse reactions was assessed as follows: occur very often (&ge10%), often (&ge1%–<10%), sometimes (&ge0,1% –<1%), rare (&ge0,01%–<0,1%), very rare (<0,01%), including isolated reports of adverse reactions.
Table 1
Adverse reactions observed in patients with dementia of Alzheimer's type, treated with the drug Exelon
| ??????? ????????? ? ????????????? ??????? | The incidence of adverse reactions |
Infections and infestations | |
| Urinary tract infection | Very rarely |
Disorders CNS | |
| Agitation | Often |
| Confusion | Often |
| Insomnia | Sometimes |
| Depression | Sometimes |
| Hallucinations | Very rarely |
| Dizziness | Very rarely |
| Headache | Often |
| Drowsiness | Often |
| Tremor | Often |
| Faint | Sometimes |
| Seizures | Rarely |
Violations by the cardiovascular system | |
| Arrhythmia (bradycardia, AV blockade, atrial fibrillation, tachycardia) | Very rarely |
| Angina, myocardial infarction | Rarely |
| A pronounced increase in blood pressure | Very rarely |
Violations by the gastrointestinal tract | |
| Nausea | ????? ????? |
| Vomiting | ????? ????? |
| Diarrhea | ????? ????? |
| Loss of appetite | ????? ????? |
| Abdominal pain and dyspepsia | Often |
| Ulcers of the stomach and duodenum | Rarely |
| Violations of laboratory parameters of liver function | Sometimes |
| Bleeding from the gastrointestinal tract | Very rarely |
| Pancreatitis mild degree | Very rarely |
| Severe vomiting leading to esophageal rupture | Very rarely |
The skin and subcutaneous tissue | |
| Excessive sweating | Often |
| Rash | Rarely |
From the body in General, violations of a General nature | |
| Fatigue and asthenia | Often |
| General malaise | Often |
| Accidental fall | Rarely |
Other | |
The weight loss | Often |
The incidence and severity of adverse events generally increased with increasing dose.
Table 2 summarizes the adverse events registered in 24-week clinical study of the drug Exelon in patients with dementia in Parkinson's disease.
The total number of patients who participated in the study: a group of drug Exelon — 362 (100%), placebo group — 179 (100%).
The number of patients with observed adverse events: the drug Exelon — 303 (83,7%), placebo group — 127 (70.9 per cent).
Table 2
Adverse events, registered in 24-week clinical study of the drug Exelon in patients with dementia in Parkinson's disease
| Side effects in patients with dementia in Parkinson's disease (&ge5% in the group taking the drug Exelon) | Drug Exelon® , n (%) | Placebo, n (%) |
| Nausea | 105 (29) | 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 that may indicate a worsening of Parkinson's disease, was in a 24-week clinical study of the drug Exelon in patients with dementia in Parkinson's disease.
The total number of patients who participated in the study: a group of drug Exelon — 362 (100%), placebo group — 179 (100%).
The number of patients in whom marked phenomena pointing to the worsening of Parkinson's disease: a group of drug Exelon — 99 (27,3%), placebo group — 28 (15.6 per cent).
Table 3
The incidence of events that may indicate a worsening of Parkinson's disease, was in a 24-week clinical study of the drug Exelon in patients with dementia in Parkinson's disease
| Phenomena indicating the worsening of Parkinson's disease patients with dementia in Parkinson's disease | Drug Exelon® , n (%) | Placebo, n (%) |
| Tremor | 37 (10,2) | 7 (3,9) |
| Fall | 21 (5,8) | 11 (15,6) |
| Increased secretion of saliva | 5 (1,4) | - |
| Dyskinesia | 5 (1,4) | 1 (0,6) |
| Parkinsonism | 8 (2,2) | 1 (0,6) |
| Hypokinesia | 1 (0,3) | - |
| Traffic | 1 (0,3) | - |
| Bradykinesia | 9 (2,5) | 3 (1,7) |
| Dystonia | 3 (0,8) | 1 (0,6) |
| Gait disturbance | 5 (1,4) | - |
| Muscle rigidity | 1 (0,3) | - |
| The imbalance | 3 (0,8) | 2 (1,1) |
| Muscle stiffness | 3 (0,8) | - |
| Shake | 1 (0,3) | - |
| Motor dysfunction | 1 (0,3) | - |
Drug interactions:
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 interaction of rivastigmine with other drugs, metaboliziruthan with the participation of these enzymes unlikely.
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, antiemetic, antidiabetic agents, antihypertensives Central action, beta-blockers, CCB, drugs having a positive inotropic effect, anti-anginal agents, NSAIDs, oestrogens, analgesics, benzodiazepines and antihistamines, was not accompanied by any changes in the kinetics of rivastigmine or an increased risk of clinically significant adverse events.
During anesthesia rivastigmine, as a cholinesterase inhibitor, may potentiate the effects of depolarizing muscle relaxants (muscle relaxants succinylcholine type).
Method of application and dose:
Inside, 2 times a day, during Breakfast and dinner.
Initial dose 1.5 mg 2 times a day. In applying the drug in patients especially sensitive to the effects of cholinergic drugs, treatment should begin with the use of the drug in a dose of 1 mg 2 times a day.
Dose selection
The initial recommended dose is 1.5 mg (0.75 ml solution) 2 times a day. If after at least 2 weeks of treatment, there is good tolerability of this dose, it can be increased to 3 mg (1,5 ml) 2 times a day. In the case of good tolerance the patient is taking doses may further increase to 4.5 mg (2,25 ml), 2 times a day and further to 6 mg (3 ml), 2 times a day with an interval time of at least 2 weeks after each dose increase. Adverse events, namely nausea, vomiting, abdominal pain, loss of appetite or weight loss observed during treatment, may decrease after missing 1 or more doses of the drug. If adverse effects persist, the daily dose should be reduced to the previous well patients tolerated dose.
Maintenance dose is 1.5 to 6 mg 2 times a day. To achieve the best therapeutic effect dose of the drug should be stored at maximum good endurance level.
Maximum daily dose of 6 mg 2 times a day.
Resume taking the drug after a break
If a break in taking the drug amounted to a few days or more, resume treatment should be the initial dose to reduce the risk of resumption of adverse reactions (e.g. severe vomiting). Gradual increase of the doses are stepped, as described above.
In patients with impaired renal function or liver correction mode drug dosing is not required.
Equal doses of the drug Exelon used in the form of capsules or in solution for oral administration, are interchangeable.
Recommendations for use of oral solution
The required amount of solution should be removed from the bottle using the attached spout.
The solution can be taken directly from the dispenser.
Overdose:
Symptoms: accidental overdose of the drug in most cases was not accompanied by any clinical manifestations almost all patients continued treatment with Exelon. The overdose had nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given the vagotonic effect of cholinesterase inhibitors on heart rate, 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.
Treatment: because the T1/2 of rivastigmine from plasma is about 1 h, and the duration of inhibition of acetylcholinesterase is about 9 h, in cases of asymptomatic overdoses occurring it is recommended not to use the drug 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:
Rivastigmine may have an effect on the activity of anticholinergic and cholinomimetic drugs.
The composition of the solution for oral administration include sodium benzoate. Benzoic acid has a negligible irritant effect on the skin, mucous membranes and eye contact.
Effects on ability to drive vehicles and operate machinery. Patients receiving the drug Exelon, it was not identified any violations of motor functions. However, the ability of a patient with Alzheimer's to drive vehicles and work with complex mechanisms should be regularly evaluated by the attending physician.
