Pharmacological action Exelon 6 mg
Selective inhibitor of acetyl-and butyrylcholinesterase of the brain used to treat Alzheimer’s disease and dementia in Parkinson’s disease. It was shown that rivastigmine delays the destruction of acetylcholine produced a functionally intact neurons. Thus rivastigmine selectively increases the amount of acetylcholine in the cerebral cortex and hippocampus, and thus enhances the cholinergic nervous transmission. Exelon may have a positive effect in reducing the cognitive deficits associated with acetylcholine, in particular, dementia associated with Alzheimer’s and Parkinson’s disease. In addition, there is evidence that cholinesterase inhibition may slow the formation of fragments of the protein beta-amyloid precursor participating in amiloidogeneze, and thus slow the formation of amyloid plaques, which is one of the main pathological features of Alzheimer’s disease.
Exelon interacts with the enzyme-target with the formation of a covalent bond, which leads to a temporary inactivation of the enzyme. It was shown that in young healthy men after ingestion of a dose of 3 mg of acetylcholinesterase activity in cerebrospinal fluid (CSF) is reduced by approximately 40% during the first 1.5 hours after the maximum inhibitory effect of the enzyme activity returned to baseline levels after about 9 hours It is shown that the activity of butyrylcholinesterase in the CSF in young healthy volunteers inhibited reversibly and restored to original after 3.6 hours in patients with Alzheimer’s Exelon inhibition of acetylcholinesterase activity in CSF is dose-dependent nature of the studied dose range (ie up to the highest dose of 6 mg 2 times / day). Inhibition of butyrylcholinesterase also dose-dependent manner; dose of 6 mg 2 times / day causes a decrease in enzyme activity by more than 60% from baseline. This effect was maintained for Exelon 12 months of therapy (maximum studied period). Has been shown statistically significant correlation between the degree of inhibition of both enzymes Exelon in CSF and changes in cognitive function in patients with Alzheimer’s disease, in this case, namely the inhibition of butyrylcholinesterase in the CSF significantly and consistently correlated with test scores of memory, attention and reaction speed.
The effectiveness of Exelon therapy for Alzheimer’s disease has been shown in patients with mild to moderate dementia (score on a short scale assessing mental status – 10-24). According to clinical studies Exelon therapy leads to significant improvement of cognitive functions (attention, memory, speech), functional status and activities of daily living, as well as to reduce the severity of the disease and the severity of mental and behavioral manifestations (such as agitation, crying, illusions, hallucinations). Studies have shown that the effect of therapy Exelon says about 12th week and continues for 6 months of therapy, with the same period of time in patients receiving placebo, there was a deterioration of the indicators.
Dementia associated with Parkinson’s disease, the effectiveness of Exelon was demonstrated in a placebo-controlled study lasting 24 weeks in patients with mild to moderate dementia (score on a short scale assessing mental status – 10-24). Patients treated with Exelon showed improvement of cognitive functions (attention, memory, speech), while patients receiving placebo, the corresponding figures worsened (the differences are statistically significant).
Pharmacokinetics Exelon 6 mg
Absorption
Rivastigmine is rapidly and completely absorbed. Cmax in the plasma is reached after about 1 h. The interaction with the enzyme, rivastigmine targets with increasing doses of the drug increase its bioavailability is 1.5 times higher than expected (for a given increase in dose). After a dose of 3 mg absolute bioavailability of about 36%. When administered in solution form Exelon with food intake slows rivastigmine (time to Cmax increased by 74 min); Cmax decreased by 43%, while AUC increased by about 9%.
Distribution
Rivastigmine binds to plasma proteins to a lesser degree (approximately 40%). Readily crosses the blood-brain barrier. The apparent Vd is 1.8-2.7 l / kg.
Metabolism
Rivastigmine quickly and largely metabolized (T1 / 2 of plasma is about 1 h), principally by hydrolysis with the formation of cholinesterase dekarbamilirovannogo metabolite. In vitro this metabolite in the lowest ability to inhibit acetylcholinesterase (
Breeding
Rivastigmine is derived mainly by the kidneys as metabolites in the urine in unchanged form is not detected. At 24 h after administration appears more than 90% of the dose. Since feces output of less than 1% of the dose. Patients with Alzheimer’s disease cumulation rivastigmine or its metabolite dekarbamilirovannogo not marked.
Pharmacokinetics in elderly patients
Although the bioavailability of rivastigmine in elderly patients is higher than in healthy young volunteers, however in patients with Alzheimer’s disease at the age of 50 to 92 years in the clinical studies showed no changes in bioavailability associated with age.
Statement Exelon 6 mg
- Mild to moderate dementia of Alzheimer’s type (probable Alzheimer’s disease, Alzheimer’s disease);
- Mild to moderate dementia in Parkinson’s disease.
Dosage and administration Exelon 6 mg
Exelon should be taken 2 times / day, during lunch and dinner.
The initial recommended dose is 1.5 mg to 2 times / day. Using the drug in patients who are particularly sensitive to the effects of cholinergic drugs, treatment should begin with the drug at a dose of 1 mg 2 times / day.
Titration
Initial recommended dose – 1.5 mg (0.75 ml) 2 times / day. If, after at least 2 weeks of treatment indicated a good tolerability of this dose, it can be increased to 3 mg (1.5 ml) 2 times / day. In the case of good tolerance dose accepted by patients may continue its increase – up to 4.5 mg (2.25 ml) 2 times / day and further to 6 mg (3 ml) 2 times / day – with a time interval of at least 2 weeks after each dose increase .
Adverse events, namely nausea, abdominal pain, loss of appetite or weight loss observed during treatment, may diminish after missing 1 or more receiving doses of the drug. If adverse reactions persist, the daily dose should be reduced to the previous well-tolerated dose patients.
The maintenance dose ranges from 1.5 to 6 mg 2 times / day. In order to achieve the best therapeutic effect of the drug dose should be kept to a maximum well-tolerated level.
The maximum daily dose is 12 mg (6 mg 2 times / day).
The resumption of the drug after the break. If the break in taking the drug amounted to a few days or more, resume treatment with the initial dose should be to reduce the risk of resumption of adverse reactions (such as severe vomiting). The gradual increase in dosage is carried out in steps, as described above.
In patients with impaired renal or hepatic correct dosing regimen of the drug is not required.
Dosing solution for oral use
The required amount of solution should be drawn from the vial with the accompanying dispenser. The solution can be taken directly from the dispenser.
Equal doses of the drug used in capsule form and in solution for oral administration, are interchangeable.
Side Effect Exelon 6 mg
The most frequently reported adverse events with the digestive system: nausea (38%), vomiting (23%), mainly during the dose adjustment. In clinical trials adverse events of the digestive system and weight loss were more common in women.
In patients with dementia, Alzheimer type treated with Exelon, there were adverse reactions, listed in Table 1. The incidence of adverse events was assessed as follows: occur “very often” – ≥ 10%, “often” – ≥ 1-10%, “sometimes” – ≥ 0.1% – <1% "rarely" - ≥ 0.01-0.1%, "very rarely" - <0.01% including isolated reports.
Table 1
| side effect | incidence of |
| Infections and infestations | |
| urinary tract infection | Very rarely |
| CNS | |
| Vertigo | Very often |
| Headache | Often |
| Drowsiness | Often |
| Tremor | Often |
| agitation (agitation) | Often |
| Confusion | Often |
| Insomnia | Sometimes |
| Depression | Sometimes |
| Fainting | Sometimes |
| Cramps | Rarely |
| Hallucinations | Very rarely |
| part of the cardiovascular system | |
| arrhythmia (bradycardia, AV-block, atrial fibrillation, tachycardia) | Very rarely |
| Angina | Rarely |
| pronounced increase in blood pressure | Very rarely |
| part of the digestive system | |
| Nausea | Very often |
| Vomiting | Very often |
| Diarrhea | Very often |
| Loss of appetite | Very often |
| abdominal pain and indigestion | Often |
| disorders in laboratory parameters of liver function | Sometimes |
| Peptic ulcer and duodenal ulcer | Rarely |
| Bleeding from the gastrointestinal tract | Very rarely |
| Severe vomiting, which leads to rupture of the esophagus | Very rarely |
| Pancreatitis mild degree | Very rarely |
| Skin and subcutaneous tissue | |
| Increased sweating | Often |
| rash | Rarely |
| part of the body as a whole | |
| Fatigue and asthenia | Often |
| general malaise | Often |
| Random drop | Sometimes |
| Other | |
| weight loss | Often |
The frequency of occurrence and severity of adverse events generally increased with increasing dose.
Table 2 summarizes the adverse events were recorded in 24-week clinical trial of Exelon in patients with dementia in Parkinson’s disease.
Table 2
| Adverse events (> 5% in the group, which took Exelon) | Exelon n (%) |
Placebo n (%) |
| total number of patients who participated in the study | 362 (100) | 179 (100) |
| The number of patients who reported adverse events | 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) |
| Anorexia | 22 (6.1) | 5 (2.8) |
| Vertigo | 21 (5.8) | 2 (1.1) |
Table 3 shows the frequency of events, pointing to the worsening of Parkinson’s disease, reported a 24-week clinical study Exelon in patients with dementia in Parkinson’s disease.
Table 3
| Phenomena | n (%) | Placebo n (%) |
| total number of patients who participated in the study | 362 (100) | 179 (100) |
| The number of patients who reported the phenomenon, pointing to the worsening 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 (worsening) | 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) |
| Hypokinesis | 1 (0.3) | 0 |
| Violation of traffic | 1 (0.3) | 0 |
| bradykinesia | 9 (2.5) | 3 (1.7) |
| Dystonia | 3 (0.8) | 1 (0.6) |
| gait disturbance | 5 (1.4) | 0 |
| muscle stiffness | 1 (0.3) | 0 |
| Imbalance | 3 (0.8) | 2 (1.1) |
| muscle stiffness | 3 (0.8) | 0 |
| Tremor | 1 (0.3) | 0 |
| motor dysfunction | 1 (0.3) | 0 |
Contraindications Exelon 6 mg
- Hypersensitivity to rivastigmine, other carbamate derivatives or other components of the drug.
Exelon is contraindicated in patients with severely impaired liver function, since its use in this population is not known.
Pregnancy and breast feeding Exelon 6 mg
Safety of Exelon during pregnancy in humans has not yet been established, so the drug can be prescribed during pregnancy only in cases where the expected success of the treatment outweighs the potential risk to the fetus.
It is not known whether rivastigmine is allocated in breast milk. Therefore, during treatment should abandon breastfeeding.
Experimental studies have shown that rivastigmine is not teratogenic.
Application of human liver Exelon 6 mg
In patients with impaired liver function correction dosing of the drug is not required.
Exelon is contraindicated in patients with severely impaired liver function, since its use in this population is not known.
Use in renal impairment Exelon 6 mg
In patients with impaired renal function correct dosing regimen of the drug is not required.
Cautions Exelon 6 mg
Exelon, like other cholinomimetic funds should be used with caution in patients with SSS or conduction disorders (sinoatrial block, AV-block).
Cholinergic stimulation may increase the secretion of hydrochloric acid in the stomach and lead to increased urinary obstruction and exacerbation of seizures, so caution should be exercised in the appointment of Exelon patients predisposed to these conditions.
Exelon, as well as other cholinomimetics should be used with caution in patients with bronchial asthma or obstructive airway disease in history.
Taking into account the pharmacodynamic properties of Exelon, it should not be administered concomitantly with other drugs holinomimeticheskimi.
During the titration, as well as the use of other cholinomimetics, adverse events occurred within a short period after increasing the dose. The degree of severity of adverse events may be reduced in response to a reduction in dose. Otherwise, Exelon should be abolished.
Rivastigmine may influence the activity of anticholinergic and cholinomimetic drugs.
The composition of oral solution is sodium benzoate. Benzoic acid has a minor irritant to the skin, mucous membranes and eyes.
Use in Pediatrics
The use of Exelon in children has not been studied, therefore, prescribe a drug not recommended for children.
Effects on ability to drive and control mechanisms
Patients treated with Exelon, there were no any violations of motor function. Nevertheless, the ability of a patient with Alzheimer’s disease to drive and control mechanisms should be evaluated regularly by your doctor.
Overdose Exelon 6 mg
Accidental overdose of the drug in most cases was not accompanied by any clinical manifestations, almost all of these patients continued treatment for Exelon.
Symptoms include nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given the vagotonic effect of cholinesterase inhibitors on heart rate, can not exclude the occurrence of bradycardia and / or fainting. In one case, was taken 46 mg of the drug, after conservative treatment after 24 hours there was a complete recovery.
Treatment: Because the half-life of rivastigmine from plasma is about 1 h, and the duration of inhibition of acetylcholinesterase is about 9 hours, in cases of asymptomatic overdose recommended not to apply Exelon over the next 24 h. If overdose accompanied by severe nausea and vomiting, you should consider applying antiemetics. If necessary, a symptomatic therapy.
When large overdose can be applied atropine sulfate, the initial dose which is 0.03 mg / kg / s; subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.
Drug Interactions Exelon 6 mg
Rivastigmine is metabolized mainly by hydrolysis, with the participation of esterases. The metabolism of the drug with the participation of major cytochrome P450 isoenzymes are minimally. Consequently, the expected pharmacokinetic interactions with other drugs metabolized with these enzymes, is not necessary.
In healthy volunteers, pharmacokinetic interactions between Exelon and digoxin, warfarin, diazepam or fluoxetine were found. Due to warfarin increased prothrombin time in the appointment of Exelon has not changed. With simultaneous use of Exelon and digoxin adverse effect on intracardiac conduction was observed.
The simultaneous use of Exelon with commonly used drugs such as antacids, antiemetics, antidiabetics, antihypertensives central action beta-blockers, calcium channel blockers, drugs that have a positive inotropic effect, antianginal drugs, NSAIDs, estrogens, analgesics, benzodiazepines, and antihistamines funds, was not accompanied by any changes in the kinetics of Exelon or an increased risk of adverse events.
Exelon, a cholinesterase inhibitor, may increase the effects of depolarizing neuromuscular blocking agents (muscle relaxants suktsinilholinovogo type) during anesthesia.
