Alzenorm (Alcenorm)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRivastigmineRivastigmine
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  • 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:In 1 ml of solution contains: active substance rivastigmine hydrotartrate 3.2 mg (in terms of rivastigmine 2.0 mg); Excipients: sodium benzoate 1.0 mg, sodium citrate 7.1 mg, citric acid 6.9 mg, dye yellow 06 098 (quinoline yellow E104 28.0%, dextrose 60.0%, sodium sulfate 11.7%, silicon dioxide 0 , 3%) 0.02 mg, water up to 1 ml.
    Description:Transparent yellow or greenish-yellow solution.
    Pharmacotherapeutic group:Cholinesterase inhibitor
    ATX: & nbsp

    N.06.D.A   Cholinesterase inhibitors

    N.06.D.A.03   Rivastigmine

    Pharmacodynamics:

    Rivastigmine is a selective inhibitor of brain acetyl and butyrylcholinesterase, which 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. In young healthy men, after taking rivastigmine at a dose of 3 mg, the activity of acetylcholinesterase in the cerebrospinal fluid (CSF) decreases by approximately 40% within the first 1.5 hours. After reaching the maximum inhibitory effect, the enzyme activity returns to the baseline level after about 9 hours. Activity of butyrylcholinesterase in CSF in young healthy volunteers is inhibited reversibly and restored to the original at 3.6 h.In patients with Alzheimer's disease, rivastigmine inhibition of acetylcholinesterase activity in the 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 rivastigmine persisted for 12 months. therapy (the maximum period studied). A statistically significant correlation was found between the extent to which rivastigmine inhibited both enzymes in CSF and changes in cognitive function in patients with Alzheimer's disease; at the same time inhibition of butyrylcholinesterase in CSF is significant and stably correlates with improvements in memory test results, attention and speed of response. The effectiveness of rivastigmine therapy has been shown in patients with mild to moderate dementia (according to a brief Mental State Examination (MMSE) score of 10-24 points) associated with Alzheimer's disease. Rivastigmine led to a significant improvement in cognitive functions (attention, memory, speech),functional status and activity in everyday life, as well as to reduce the severity of the disease and the severity of mental and behavioral manifestations (agitation, tearfulness, illusions, hallucinations, etc.). The clinical effect of rivastigmine was observed at the 12th week of treatment and persisted for 6 months of therapy.

    In patients with mild to moderate dementia (MMSE 10-24 points) associated with Parkinson's disease, improvement of cognitive functions (attention, memory, speech, etc.) was observed with rivastigmine for 24 weeks.

    Pharmacokinetics:

    Suction. Rivastigmine quickly and completely absorbed. The maximum concentration (Cmax) in plasma is achieved after about 1 h. Due to the interaction with the target enzyme, with an increase in the dose of rivastigmine, its bioavailability increases by 1.5 times that expected (for a given dose increase). After taking a 3 mg dose, the absolute bioavailability is about 36%. When taken together with food, the absorption slows (the time to reach Cmax increases by 74 minutes); Cmax decreased by 43%; The area under the concentration-time curve (AUC) increases by approximately 9%.

    Distribution. Rivastigmine binds to plasma proteins to a low degree (approximately 40%).Easily penetrates the blood-brain barrier. The apparent volume of distribution (Vd) is 1.8-2.7 l / kg.

    Metabolism. Rivastigmine is rapidly and largely metabolized (half-life (T1 / 2) 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 (less than 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 correspond to observations that indicate the absence of human interaction of rivastigmine with drugs metabolized with the participation of cytochrome P450.

    Excretion. It is excreted mainly by kidneys in the form of metabolites; in the unchanged form in urine is not found out. After 24 hours after ingestion, 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.

    In elderly patients. Despite the fact that the bioavailability of rivastigmine in elderly patients is higher than in healthy young volunteers, nevertheless, in clinical studies in patients with Alzheimer's disease aged 50 to 92 years, no changes in bioavailability associated with age have been revealed.

    In patients with impaired liver function. In persons with mild or moderate impairment of liver function compared to healthy volunteers, Cmax rivastigmine was almost 60% higher, and the AUC value was almost twice as large.

    In patients with impaired renal function. In individuals with moderate renal impairment compared with healthy volunteers, the Cmax and AUC rivastigmina were twice as high, however, in those with severe renal dysfunction, the values ​​of Cmax and AUC did not change.

    Indications:

    - Weakly and moderately expressed dementia of the Alzheimer's type (Alzheimer's disease);

    - mild to moderate dementia in Parkinson's disease.

    Contraindications:

    Hypersensitivity to the active substance, other carbamate derivatives or to any other component of the drug; severe hepatic impairment; deficiency of lactase, lactose intolerance, glucose-galactose malabsorption; the period of breastfeeding.

    It is not recommended to use in children under the age of 18 years (no data on efficacy and safety).

    Carefully:In the syndrome of weakness of the sinus node (SSSU), conduction disorders (sinoatrial block, atrioventricular block); in patients with a predisposition to increased secretion of hydrochloric acid in the stomach, as well as gastric ulcer and duodenal ulcer in the acute stage; obstruction of the urinary tract, seizures in the anamnesis, as well as a predisposition to these conditions; in patients with bronchial asthma and other obstructive airway diseases in history; with the simultaneous use of other cholinomimetic drugs; in the period of dose selection.
    Pregnancy and lactation:

    Experimental studies have shown that rivastigmine does not have teratogenic properties. The safety of rivastigmine in women during pregnancy has not been established so far, therefore Alzenorm is used in pregnancy only when the expected use of the mother is greater than the potential risk to the fetus.

    It is not known whether rivastigmine with breast milk. Therefore, if you need to use the drug Alzenororm should abandon breastfeeding.

    Dosing and Administration:

    Inside, with meals, 2 times a day during breakfast and dinner.

    Dose selection

    The initial dose of 1.5 mg (0.75 ml solution) 2 times a day. When Alzensorm is used in patients particularly sensitive to cholinergic drugs, treatment should be started at a dose of 1 mg (0.5 ml solution) 2 times a day.

    With good tolerability (no earlier than 2 weeks), the dose can be increased to 3 mg (1.5 ml solution). In case of good tolerability, a further dose increase up 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 a time interval of at least 2 weeks after each increasing the dose.

    Undesirable effects (AEs), namely, nausea, vomiting, abdominal pain, decreased appetite or weight loss observed during treatment, may decrease after skipping, one or more doses. If AEs persist, the daily dose of the Alzenorm should be reduced to a dose that the patient tolerated well.

    Maintenance dose from 1.5 mg (0.75 ml solution) to 6 mg (3 ml solution) 2 times a day. In order to achieve a good clinical effect, the dose should be kept at the maximum tolerable level.

    The maximum daily dose 12 mg / day (6 mg twice a day).

    If the Alzensorm has been interrupted for several days, to reduce the risk of developing AEs, treatment should be resumed from the initial dose of 1.5 mg (0.75 ml solution) 2 times a day, gradually increasing the dose.

    In patients with impaired renal function correction of the dose is not required.

    In patients with impaired liver function dose adjustment is not required

    Method of dosing 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.

    Side effects:

    The most frequently reported AEs from the gastrointestinal tract (gastrointestinal tract) (nausea (38%), vomiting (23%)), which were observed mainly in the period of increasing the dose of rivastigmine. According to clinical studies of AE on the part of the gastrointestinal tract and weight loss were more frequent in women.

    AE in the treatment of rivastigmine in patients with dementia associated with Alzheimer's disease

    The frequency of AE is classified in accordance with the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; sometimes - not less than 0.1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%, including isolated cases.

    Infections: very rarely - urinary tract infections.

    From the nervous system: very often - dizziness; often - agitation, confusion, headache, drowsiness, tremor; infrequently - insomnia, depression, fainting; rarely convulsions; very rarely - hallucinations.

    From the cardiovascular system: rarely - angina pectoris, myocardial infarction; very rarely - bradycardia, atrioventricular block, atrial fibrillation, tachycardia, marked increase in blood pressure.

    From the digestive system: very often - nausea, vomiting, diarrhea, anorexia; often - indigestion, pain in the abdomen; infrequently - increased activity of "hepatic" enzymes; rarely - stomach and duodenal ulcer; very rarely - bleeding from the gastrointestinal tract, pancreatitis (slightly pronounced); unknown frequency - severe vomiting, leading to a rupture of the esophagus, hepatitis.

    From the skin and subcutaneous tissue: often - increased sweating; rarely - skin rash.

    Other: often - increased fatigue, asthenia, general malaise, weight loss; infrequently - accidental falls; an unknown frequency is dehydration.
    Frequency of occurrence and severity of AEs, as a rule, increases with increasing dose.

    Table №1. AEs registered in a 24-week clinical trial of rivastigmine in patients with dementia in Parkinson's disease.

    Adverse events

    Number of patients taking rivastigmine, n(%)

    The number of patients taking placebo, n (%)

    Total number of patients participating in the study

    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)

    Increased severity of AEs and worsening of Parkinson's disease

    20 (5,5)

    3 (1,7)
    Table number 2. AEs registered in a 24-week clinical trial of rivastigmine in patients with dementia in Parkinson's disease, indicating a worsening of the course of the disease.

    Adverse events

    Number of patients taking rivastigmine, n(%)

    The number of patients taking placebo, n (%)

    Total number of patients participating in the study

    362 (100)

    179 (100)

    Number of patients with undesirable effects

    303 (83,7)

    127 (70,9)

    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

    Diskenia

    5 (1,4)

    1 (0,6)

    Parkinsonism

    8 (2,2)

    1 (0,6)

    Hypokinesia

    1 (0,3)

    0

    Movement disorder

    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

    Muscle rigidity

    1 (0,3)

    0

    Violation of balance

    3 (0,8)

    2(1,1)

    Muscle stiffness

    3 (0,8)

    0

    Trembling

    1 (0,3)

    0

    Motor dysfunction

    1 (0,3)

    0
    Overdose:

    Symptoms: The occasional overdose of rivastigmine in most cases was not accompanied by any clinical manifestations, all patients continued treatment. There was nausea, vomiting, diarrhea, marked increase in blood pressure, hallucinations. Given the vagotonic effect of cholinesterase inhibitors on the heart rate, bradycardia and / or syncope can not be ruled out. In one case, 46 mg of the drug was taken; after a conservative treatment at 24 h, complete recovery was observed.

    Treatment: since r1 / 2 rivastigmine is about 1 hour, and the duration of inhibition of acetylcholinesterase is about 9 hours, in cases of asymptomatic overdose it is recommended not to apply rivastigmine within the next 24 hours.If an overdose is accompanied by severe nausea and vomiting, consider the use of anti-emetics. When other AEs occur, appropriate symptomatic therapy is performed. If there is a significant overdose, atropine sulfate can be used, the initial dose of which is 0.03 mg / kg intravenously; the subsequent dosing depends on the clinical effect. Scopolamine is not recommended as an antidote.

    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 with other drugs metabolized with these enzymes should not be expected.

    In healthy volunteers, there was no pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine. The increase in prothrombin time caused by warfarin in the appointment of rivastigmine did not change.With simultaneous application of rivastigmine and digoxin, there was no adverse effect on intracardiac conductivity.

    Simultaneous use with antacids, antiemetics, antidiabetics, antihypertensive agents of central action, beta-blockers, calcium channel blockers, preparations with a positive inotropic effect, antianginal agents, nonsteroidal anti-inflammatory drugs, estrogens, analgesics, benzodiazepines and antihistamines was not accompanied by any anti- either changes in the pharmacokinetics of rivastigmine or an increased risk of Nia AEs.

    Rivastigmine as an inhibitor of cholinesterase can enhance the effect of depolarizing muscle relaxants (muscle relaxants succinylcholine type) during anesthesia. Rivastigmine should not be used simultaneously with holinomimeticheskimi drugs, and when combined with anticholinergic drugs should take into account the different directions of their action.

    Special instructions:

    Treatment with Alzenorm should be performed under the supervision of a doctor and under the supervision of a person caring for patients suffering from dementia.

    Equal doses of the preparation Alzenorm, used in the form of capsules and as a solution for oral administration, are interchangeable.

    In case of severe vomiting, it is necessary to select an effective dose of the Alzenorm, which is well tolerated to reduce the manifestation of this AE.

    In patients with Alzheimer's disease, body weight may decrease. During treatment with rivastigmine, the patient's body weight should be monitored.

    Alzensorm, as well as other cholinomimetic drugs, should be used with caution in patients with SSSU, sinoatrial blockade, atrioventricular blockade.

    Just like in the case of other cholinergic drugs, the Alzenorm can cause an increase in the secretion of hydrochloric acid in the stomach. It should be used with caution in patients with peptic ulcer of the stomach or duodenum in the acute stage, as well as in patients who are predisposed to conditions accompanied by increased secretion of hydrochloric acid in the stomach.

    Alzensorm, like other cholinesterase inhibitors, should be used with caution in patients with bronchial asthma or other obstructive airway diseases in history.

    Alzensorm, as well as other cholinomimetic drugs, can provoke or intensify obstruction of the urinary tract. Care should be taken when treating patients with diseases that are accompanied by obstruction of the urinary tract, as well as with a predisposition to these diseases.

    The use of Alzensorm in patients with severe dementia in Alzheimer's disease, Parkinson's disease, other dementias or other types of memory impairment (for example, age-related impairment of cognitive functions) has not been investigated.

    As well as other holinomimetic drugs, the Alzensorm can cause or intensify the manifestation of extrapyramidal disorders. An increase in motor disorders (including bradykinesia, dyskinesia, gait disturbance) and an increased frequency of tremor was observed with rivastigmine in patients with dementia associated with Parkinson's disease.In some cases, these circumstances may require discontinuation of treatment with Alzenorm.

    Alzensorm should be avoided on the skin and mucous membranes, including the mucous membrane of the eyes and respiratory organs, due to the fact that sodium benzoate, included in its composition, can have an irritating effect.

    Effect on the ability to drive transp. cf. and fur:In patients who received rivastigmine, there were no violations of motor function. However, the ability of a patient with Alzheimer's disease to drive a car and control the mechanisms should be regularly evaluated by the attending physician.
    Form release / dosage:Solution for oral administration 2 mg / ml.
    Packaging:

    120 ml of solution in a bottle of dark glass, closed with polypropylene lid with the control of the first opening and the system against opening the children.

    1 bottle together with instructions for use, a syringe for dosing and a stopper for selection in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep in a strictly upright position.

    Keep out of the reach of children.

    Shelf life:

    3 years. The opened bottle is 1 month old.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:PL-000912
    Date of registration:18.10.2011 / 11.09.2012
    Expiration Date:18.10.2016
    The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel
    Manufacturer: & nbsp
    Representation: & nbspTeva Teva Israel
    Information update date: & nbsp19.07.2017
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