Reminil

General characteristics. Structure:

Active agent: Galantaminum hydrobromide - 8, 16 and 24 mg.

Excipients: the sugar spheres (consisting of a sukroza and starch corn), a gipromelloza of 2910 5 MPas x with, a macrogoal 400, ethyl cellulose of 20 MPas x with, diethyl phthalate. The cover of capsules consists of gelatin, titanium of dioxide, ferrous oxide red (for mg capsules 16 and 24), ferrous oxide yellow (for capsules of 24 mg).

Description
Capsules of 8 mg: the solid gelatin capsules No. 4 consisting from opaque cases and lids of white color with the printed symbol of G8. Contents of capsules – granules of white or almost white color.
Capsules of 16 mg: the solid gelatin capsules No. 2 consisting from opaque cases and lids of light pink color with the printed G16 symbol. Contents of capsules – granules of white or almost white color.
Capsules of 24 mg: the solid gelatin capsules No. 1 consisting from opaque cases and lids of pinkish-brown color with the printed G24 symbol. Contents of capsules – granules of white or almost white color.

Pharmacological properties:

Pharmacodynamics. Galantaminum, being tertiary alkaloid, is the selection competitive and reversible inhibitor of acetylcholinesterase. In addition Galantaminum strengthens action inherent in acetylcholine on nicotinic receptors, apparently, owing to linkng with the allosteric site of a receptor. Thanks to increase in activity of cholinergic system cognitive function at patients with dementia of altsgeymerovsky type can improve.

Pharmacokinetics. The slow clearance (the clearance makes about 300 ml/min. of plasma) and moderate volume of distribution is characteristic of Galantaminum (the average volume of distribution is equal in steady state to 175 l). Elimination of Galantaminum has bieksponentsialny character, and the final elimination half-life is equal to about 7-8 h. After single oral administration of 8 mg of Galantaminum it is quickly soaked up from digestive tract; its maximum concentration (Cmax) was reached in 1,2 h and made 43 ± 13 ng/ml, and average area under a curve from zero indefinitely AUC ∞ makes 427 ± 102 нг h/ml. Absolute bioavailability of Galantaminum at oral administration makes 88,5%. Reception of Galantaminum with food slows down its absorption (the maximum concentration decreases by 25%), but does not influence amount of the absorbed drug (AUC).

After multiple dose of Galantaminum in a dose of 12 mg two times a day average concentration at the end of the dose period and Cmax in plasma varied from 30 to 90 ng/ml. The pharmacokinetics of Galantaminum has linear character in the dose range of 4-16 mg two times a day.

Within 7 days after single oral administration of 4 mg 3 N-Galantaminums of 90-97% of radioactivity were allocated with urine and 2,2–6,3% – with a stake. After oral administration of 18-22% of a dose it was excreted in the form of not changed Galantaminum with urine during 24 h, the renal clearance was about 65 ml/min. that makes 20-25% of the general clearance of plasma.

The main ways of metabolism are N-oxidation, N-demethylation, O-demethylation, a glyukuronization and an epimerization. At people with active metabolism of CYP2D6 substrates the most important way of metabolism is O-demethylation. The amount of the radioactive materials removed with urine and a stake at people with bystry and slow metabolism did not differ. The researches in vitro showed that the main isoenzymes of system of P450 cytochrome participating in metabolism of Galantaminum are 2D6 and 3A4. In plasma of people with bystry and slow metabolism the main part of radioactive materials is made by not changed Galantaminum and its glucuronide.

In plasma of people with bystry metabolism glucuronide O-dezmetilgalantamina is also found. After a single dose of Galantaminum at plasma of "bystry and slow metabolizator" any of active metabolites (норгалантамин, Au - demetil-Galantaminum and Au-demetil-norgalantamin) was not present at not conjugated form. Norgalantamin was found in plasma of patients after multiple dose of Galantaminum, but its quantity made no more than 10% of Galantaminum levels.

Results of clinical tests showed that at patients with Alzheimer's disease of concentration of Galantaminum in a blood plasma is 30-40% higher, than at young healthy faces.

Pharmacokinetic parameters of Galantaminum at patients with an easy abnormal liver function (5-6 points on a scale of Chaylda-Pyyu) were similar to those at healthy faces. At patients with a moderate abnormal liver function (7-9 points on a scale of Chaylda-Pyyu) AUC and an elimination half-life of Galantaminum were raised approximately for 30% (see the section "Dosage and Route of Administration"). Distribution of Galantaminum was studied at young patients with different extent of disturbance of functions of kidneys. Removal of Galantaminum was weakened in process of decrease in the clearance of creatinine (CC). At patients with disturbance of functions of moderately severe kidneys (KK of 52-104 ml/min.) concentration of Galantaminum in a blood plasma was increased for 38%, and at patients with heavy disturbance (KK of 9-51 ml/min.) – is increased for 67% in comparison with healthy people of the same age and weight (KK> of 121 ml/min.). The population pharmacokinetic research and the analysis with use of a number of models showed that at patients with Alzheimer's disease and a renal failure the dose of Galantaminum does not need to be adjusted if clearance of creatinine at them not less than 9 ml/min. (see the section "Dosage and Route of Administration") as the clearance of Galantaminum at patients with Alzheimer's disease is reduced.

Linkng with proteins of plasma: extent of linkng of Galantaminum with proteins of plasma is small and makes 17,7 ± 0,8%. In whole blood Galantaminum is preferential in uniform elements (52,7%) and in plasma (39,0%) whereas the egofraktion connected with proteins of plasma makes only 8,4%. Ratio of concentration of Galantaminum blood/plasma equally 1,17.

In a comparative research of bioavailability of Reminil in the form of capsules with long release of the active agent accepted in a dose of 24 mg once a day and in the form of the pill with immediate release of active agent taken in a dose of 12 mg 2 times a day bioequivalence of these dosages on indicators the area under curve 24 h and the minimum concentration of Cmin in an equilibrium state is shown. Cmax reached in 4,4 hours after reception of capsules in a dose of 12 mg once a day was about 24% less, than after reception of tablets in a dose of 12 mg 2 times a day. Meal did not influence Reminil's bioavailability in the form of capsules with long release of active agent in an equilibrium state. In a research of dose dependence of pharmacokinetics Reminila in the form of capsules with long release of active agent at healthy elderly and young people equilibrium concentration in a blood plasma of people of both age groups was reached within 6 days at all doses (8, 16 or 24 mg). In both age groups the pharmacokinetics in an equilibrium state directly depended on a dose in the studied range of doses (8-24 mg).

Indications to use:

Реминил® it is shown for treatment of dementia of altsgeymerovsky type of easy and average degree, including with chronic disturbances of cerebral circulation.

Route of administration and doses:

Scheme of reception.

Initial dose.

Реминил® in the form of capsules of the prolonged action it is necessary to accept inside once a day (morning), it is desirable during meal. The recommended initial dose makes 8 mg a day.

The patients who are already accepting Reminil® in other forms with immediate release of active agent (tablet) can pass to administration of drug of Reminil® in the form of capsules of the prolonged action by reception of the last dose of the drug Reminil® in the form of tablets in the evening and the beginnings of administration of drug of Reminil® in the form of capsules the next morning once a day. Upon transition from the drug Reminil® in the form of the tablets with immediate release of active agent accepted 2 times a day on Reminil® in the form of the capsules of the prolonged action accepted once a day the general daily dose has to remain invariable.

During treatment it is necessary to accept enough liquid.

Maintenance dose:

• The initial maintenance dose makes 16 mg a day, patients have to accept this dose not less than 4 weeks.

• The issue of increase in a maintenance dose to most recommended 24 mg a day should be resolved after comprehensive assessment of a clinical situation, in particular the reached effect and portability.

• After sharp cancellation of Reminil (for example, at a preparation for surgery) the aggravation of symptoms does not arise.

At a break in administration of drug within several days it is necessary to accept an initial dose of the drug Reminil® and then to raise a dose according to the stated above scheme to a former maintenance dose.

Children.

There is no significant experience of use of the drug Reminil® for children.

Patients with diseases of a liver and kidneys.

At patients with moderate and severe damage of a liver of concentration of Galantaminum in plasma can be higher, than at patients without such defeats. At patients with a moderate abnormal liver function the initial dose (proceeding from pharmacokinetic data) has to make 8 mg once a day every other day, it should be accepted in the morning within not less than one week. After that patients can accept 8 mg for not less than 4 weeks once a day. The daily dose should not exceed 16 mg. Reminil® is not recommended to patients with a heavy abnormal liver function (more than 9 points on a scale of Chaylda-Pyyu). Reminil® is not recommended to patients with a heavy renal failure (clearance of creatinine less than 9 ml/min.) (due to the lack of data). At patients with clearance of creatinine more than 9 ml/min. Reminil's dose do not need to be adjusted.

The accompanying therapy.

If the patient receives strong inhibitors of coenzymes of CYP2D6 or CYP3A4, then there can be a need to lower Reminil's dose. 

Features of use:

Reminil's use at other types of dementia or at other disturbances of memory.

Positive effects of use of Reminil for patients with other types of dementia and other types of disturbance of memory are not shown.

Safety at patients with the weak cognitive disturbance (WCD).

Реминил® it is not intended for patients with the weak cognitive disturbance (WCD), i.e. for patients with the isolated memory disturbance exceeding the expected level for their age and education, but to not meeting criteria of Alzheimer's disease.

Two two-year researches at patients with SKN did not reveal efficiency of drug. Higher was shown (in comparison with placebo) mortality from various undesirable reactions (about a half of cases are connected with reactions from cardiovascular system). Taking into account the data obtained from a considerable share of the patients who stopped treatment before end of the double blind period there are no bases to believe that eventually at the patients receiving treatment by the drug Reminil®, the risk of death increases. From group of placebo there are more patients, than from group of Galantaminum, interrupted treatment before death that can explain initially registered difference in mortality.

Results of researches SKN differ from results of researches of Alzheimer's disease. In the integrated researches of Alzheimer's disease (n = 4614) death rate was in number higher in group of placebo, than in the group receiving treatment by the drug Reminil®.

Diagnosis has to be carried out according to the current guides due to illness of Alzheimer. Therapy has to be carried out under control of the doctor and can be begun only provided that the looking after person is capable to provide constant administration of drug.

Control of weight.

Patients with Alzheimer's disease grow thin. Treatment by acetylcholinesterase inhibitors, including Galantaminum, is followed by decrease in body weight of such patients and therefore during treatment it is necessary to monitor changes of body weight.

Skin reactions in heavy degree.

Emergence of skin reactions in heavy degree (Stephens-Johnson's syndrome and acute generalized ekzentematozny пустулез) was observed at the patients accepting the drug Reminil®. It is recommended to inform patients on signs of skin reactions in heavy degree and on need of phase-out of the drug Reminil® at the first emergence of skin rash.

As well as other cholinomimetics, Reminil® should be applied with care at the following diseases:

Disturbances from heart: owing to the pharmacological action cholinomimetics can cause vagotonic effects from heart (for example, bradycardia). Effects of such effects can be the most serious at patients with a sick sinus syndrome and with other supraventricular disturbances of conductivity, at patients who at the same time receive the drugs reducing heart rate such as digoxin or beta adrenoblockers, and also at patients with electrolytic disturbances (for example, with a hyperpotassemia, a hypopotassemia).

It is necessary to be careful at use of Galantaminum for patients with cordial vascular diseases, including during the period after recently postponed myocardial infarction, at acute fibrillation of auricles, AV-blockade of the II degree above, chronic heart failure (in particular the III-IV functional class on NYHA classification).

Treatment by Reminil was followed by a faint and is rare – the expressed bradycardia. It is necessary to apply with care at unstable stenocardia.

Gastrointestinal diseases: patients with the increased risk have development of a peptic ulcer, for example having a peptic ulcer in the anamnesis or predisposed to it, including at reception of non-steroidal anti-inflammatory drugs, it is necessary to carry out monitoring of the corresponding symptoms. It should be noted, however, that clinical trials did not reveal at the patients receiving Reminil®, increases in comparison with patients who received placebo, frequencies of round ulcers and gastrointestinal bleedings. Реминил® it is not recommended to apply at patients with obstruction of digestive tract, and also at patients on whom digestive organs operation was performed recently.

Neurologic diseases: at use of the drug Reminil® spasms were observed. It is necessary to remember, however, that convulsive activity can be display of the Alzheimer's disease. In rare instances increase in a cholinergic tone can lead to deterioration in disease of Parkinson. The analysis of the integrated these placebos - controlled researches showed that at the patients with dementia of altsgeymerovsky type receiving treatment by Galantaminum cerebrovascular disturbances were infrequently observed. It should be considered at use of Galantaminum for patients with cerebrovascular pathologies.

Pulmonary diseases: because of cholinomimetic activity of Reminil® it is necessary to apply with care at the patients having heavy bronchial asthma, an obstructive pulmonary disease or acute pulmonary infections.

Urinogenital diseases: Реминил® it is not recommended to apply at patients with obstruction of uric ways, and also at patients who underwent bladder operation recently.

Surgical and medical procedures: Galantaminum which is a cholinomimetic probably will strengthen a muscular relaxation of suktsinilkholinovy type during anesthesia, especially at deficit of pseudo-cholinesterase.

Influence on driving of the car and work with mechanisms.

Alzheimer's disease can negatively influence ability to driving of the car and work with mechanisms. Besides, Reminil®, as well as other cholinomimetics, is capable to cause drowsiness and dizziness which negatively affect driving of the car and work with mechanisms, especially in the first weeks after an initiation of treatment this drug.

Side effects:

Side effects which on the basis of complex assessment of the available information were referred to use of Galantaminum of hydrobromide are presented in this section. In some cases relationship of cause and effect cannot be authentically established with reception of Galantaminum of hydrobromide. Besides, as clinical trials are conducted in different conditions, frequencies of emergence of the adverse phenomena in clinical trials of drug cannot directly be compared to frequencies in clinical trials of other drug and can not reflect frequencies of emergence of the adverse phenomena in clinical practice.

Nausea and vomiting – the most frequent undesirable phenomena at conduct of clinical trials (frequency of 20,7% and 10,5% respectively) – were observed at selection of a dose of drug, proceeded in most cases within less than 1 week and generally were incidental. Purpose of antiemetic drugs and ensuring sufficient consumption of liquid is most effective in such cases. Side effects of the drug Reminil® are given in therapeutic doses with distribution on the frequency and systems of bodies. Frequency of side effects was classified as follows: very frequent (≥1/10 cases), frequent (≥1/100, <1/10 cases), infrequent (≥1/1000 and <1/100 cases), rare (≥1/10000 and <1/1000 cases) and very rare (<1/10000 cases).

Disturbances from immune system:

- infrequently: hypersensitivity.

Disturbances of metabolism and food:

- often: loss of appetite; infrequently: dehydration.

Mental disturbances:

- often: depression, hallucinations;

- infrequently: visual and auditory hallucinations.

Disturbances from a nervous system:

- often: dizziness, headache, tremor, syncope, block, drowsiness;

- infrequently: food faddism; hypersomnia, paresthesia, spasms.

Spasms are a class - the effect observed at use of inhibitors of acetylcholinesterase - means for treatment of dementia, and including spasms and attacks.

Ophthalmologic disturbances: infrequently: the obscured sight.

Disturbances from an ear and a labyrinth:

- infrequently: sonitus.

Disturbances from cardiovascular system:

- often: bradycardia, increase in arterial pressure;

- infrequently: atrioventricular block of the first degree, heart consciousness, sinus bradycardia, supraventricular premature ventricular contraction, "inflows", lowering of arterial pressure.

Disturbances from digestive tract:

- very often: nausea, vomiting;

- often: diarrhea, pains in a stomach, dyspepsia, gastrointestinal discomfort; infrequently: emetic desires.

Gepatobiliarny disturbances:

- seldom: hepatitis.

Disturbances from skin and hypodermic fabrics:

- infrequently: the strengthened sweating;

- very seldom: Stephens-Johnson's syndrome, acute generalized ekzentematozny пустулез, multiformny erythema.

Disturbances from a musculoskeletal system and connecting fabric:

- often: muscular spasms;

- infrequently: muscular weakness.

General disturbances:

- often: exhaustion, weakness, indisposition.

Disturbances of measurements and laboratory indicators:

- often: body degrowth;

- infrequently: increase in activity of liver enzymes.

Injuries, intoxications and complications of manipulations:

- often: falling, avulsive wounds.

Interaction with other medicines:

Pharmakodinamichesky interactions.

Owing to the action mechanism inherent to it Galantaminum cannot be applied along with other cholinomimetics. Galantaminum is an antagonist of anticholinergic drugs. As well as other cholinomimetics, Galantaminum can enter pharmakodinamichesky interactions with drugs which reduce heart rate (for example, digoxin and beta adrenoblockers). Being a cholinomimetic, Galantaminum can strengthen the block of neuromuscular conductivity of depolyarizatsionny type during an anesthesia (for example, when using as a peripheral muscle relaxant of succinylcholine of bromide).

Pharmacokinetic interactions.

Various metabolic ways and renal excretion participate in elimination of Galantaminum. The researches in vitro showed that the major role in metabolism of Galantaminum is played by coenzymes of CYP2D6 and CYP3A4. Oppression of secretion of a gastric juice does not break absorption of Galantaminum.

Other drugs influencing metabolism of Galantaminum. The drugs which are strong inhibitors of coenzymes of CYP2D6 and CYP3A4 can increase AUC of Galantaminum. Pharmacokinetic researches with multiple dose of drugs showed that AUC of Galantaminum increases by 30 and 40% at its simultaneous use according to ketokonazoly and paroksetiny. At simultaneous use with erythromycin which is also inhibitor of CYP3A4, AUC enzyme of Galantaminum increases only approximately for 10%. Pharmacokinetic researches at patients with Alzheimer's disease showed that the clearance of Galantaminum decreased approximately by 25-33% at simultaneous use of this drug with such known inhibitors of CYP2D6 enzyme as amitriptyline, fluoxetine, флувоксамин, пароксетин or quinidine. Thus, in an initiation of treatment strong inhibitors of CYP2D6 and CYP3A4 enzymes the frequency of the cholinergic undesirable phenomena, mainly nausea and vomitings can increase. In these situations, depending on portability of therapy by the specific patient, it can be necessary to lower a maintenance dose of Galantaminum.

The antagonist of receptors of N-methyl-D-aspartate (NMDA) мемантин in a dose of 10 mg a day within 2 days, then 10 mg 2 times a day within 12 days did not influence Galantaminum pharmacokinetics in an equilibrium state after reception of a dose of 16 mg a day.

Influence of Galantaminum on metabolism of other drugs Therapeutic doses of Galantaminum (12 mg two times a day) did not influence kinetics of digoxin and warfarin. Galantaminum did not influence the increase in a prothrombin time caused by warfarin. The researches in vitro showed that Galantaminum has very weak ability to inhibit the main forms of R-450 cytochrome of the person.

Contraindications:

- Patients cannot appoint drug with hypersensitivity to Galantaminum to hydrobromide or to any excipient which is a part of this drug.

- Owing to lack of data on Reminil's use for patients with a heavy renal failure (clearance of creatinine less than 9 ml/min.), this drug is contraindicated to such patients.

- Heavy abnormal liver functions.

With care:

General anesthesia, bronchial asthma, chronic obstructive pulmonary disease, bradycardia, atrioventricular block, sick sinus syndrome, unstable stenocardia; the accompanying therapy by the drugs which are slowing down the heart rate (digoxin, beta adrenoblockers); a peptic ulcer of a stomach and a 12-perstny gut, obstruction of digestive tract, the period after the undergone operation on bodies of a GIT, epilepsy, obstruction of uric ways, the period after the undergone bladder operation.

Overdose:

Symptoms.

It is supposed that objective and subjective symptoms of the expressed overdose of Galantaminum will be similar to similar symptoms at overdose of other cholinomimetics. Generally toxic effects from the central nervous system are observed, a parasympathetic nervous system and neuromuscular synapses. In addition to muscular weakness or a fastsikulyation some or all symptoms of cholinergic crisis can be observed: severe nausea, vomiting, spastic abdominal pains, the strengthened salivation, dacryagogue, an incontience of urine and a calla, strong perspiration, bradycardia, a lowering of arterial pressure, a collapse and spasms. The expressed muscular weakness in combination with hypersecretion of a mucous membrane of a trachea and a bronchospasm can lead to lethal blockade of respiratory tracts. In the messages received at post-marketing control development of bidirectional and spindle-shaped ventricular tachycardia, lengthening of an interval of QT, ventricular tachycardia with a short-term loss of consciousness at accidental reception of 32 mg of Reminil a day is described.

Treatment.

As well as at overdose of any other drug, it is necessary to carry out the ordinary supporting actions. In hard cases as the general antidote it is possible to use such anticholinergic drugs as atropine. In the beginning it is recommended to enter 0,5-1,0 mg intravenously, the frequency and size of the subsequent doses depend on dynamics of a clinical condition of the patient. The strategy of treatment of overdoses are constantly improved and therefore it is necessary to address to the nearest center for treatment of poisonings for obtaining the latest recommendations concerning treatment of overdose of Galantaminum.

Storage conditions:

To store at a temperature of 15 - 30 °C in the place, unavailable to children. 

Issue conditions:

According to the recipe

Packaging:

Capsules of the prolonged action of 8 mg, 16 mg, 24 mg. On 7 capsules in blisters from the combined material (PVC, polyethylene, polyvinylidene chloride, and aluminum foil); on 300 capsules in bottles from polyethylene. 8 mg: on 1 or 4 blisters or 1 bottle together with the instruction on a medical use in a cardboard pack. 16 mg: on 4, 8 or 12 blisters or 1 bottle together with the instruction on a medical use in a cardboard pack of 24 mg: on 2, 4, 8 or 12 blisters or 1 bottle together with the instruction on a medical use in a cardboard pack.