Remineral - instructions for use, doses, side effects, contraindications

Reminil® in the form of sustained release capsules contains galanthamine hydrobromide in an amount corresponding to 8, 16 and 24 mg of base galantamine.

Inactive ingredients are: sugar spheres (consisting of sucrose and corn starch), hypromellose 2910 5 mPa x s, macrogol 400, ethyl cellulose 20 mPas x s, diethyl phthalate. The capsule shell consists of gelatin, titanium dioxide, iron oxide red (for capsules 16 and 24 mg), iron oxide yellow (for capsules 24 mg).

Description:

Capsules 8 mg: hard gelatin capsules No. 4 consisting of an opaque body and a white lid with a printed "G8 ".The contents of the capsules are granules of white or almost white color.

Capsules 16 mg: hard gelatin capsules number 2 consisting of an opaque body and a cap of light pink color with a printed symbol "G16 ".The contents of the capsules are granules of white or almost white color.

Capsules 24 mg: hard gelatin capsules No. 1 consisting of an opaque body and a cap of a pinkish-brown color with a printed symbol "G24". The contents of the capsules are white or granules. almost white.

Pharmacotherapeutic group:cholinesterase inhibitor

ATX: & nbsp

N.06.D.A.04 Galantamine

Pharmacodynamics:

Galantamine, being a tertiary alkaloid, is a selective competitive and reversible inhibitor of acetylcholinesterase. Besides galantamine enhances the effect of acetylcholine on nicotinic receptors, apparently due to binding to the allosteric portion of the receptor. By increasing the activity of the cholinergic system, cognitive function can improve in patients with Alzheimer's dementia.

Pharmacokinetics:

Galantamine is characterized by a slow clearance (clearance from the plasma is about 300 ml / min) and a moderate volume of distribution (the average volume of distribution in the steady state is 175 liters).Elimination of galantamine is bi-exponential, and the final half-life is approximately 7-8 hours. After a single oral intake of 8 mg galantamine, it is rapidly absorbed from the gastrointestinal tract; its maximum concentration (FROM_mOh) was achieved after 1.2 hours and was 43 ± 13 ng / ml, and the average area under the curve from zero to infinity AUC_∞, is 427 ± 102 ng h / ml. The absolute bioavailability of galantamine when taken orally is 88.5%. The intake of galantamine with food slows its absorption (the maximum concentration is reduced by 25%), but does not affect the amount of absorbed drug (AUC).

After repeated administration of galantamine at a dose of 12 mg twice a day, the average concentrations at the end of the dose period and FROM_mOhin plasma ranged from 30 to 90 ng / ml. The pharmacokinetics of galantamine is linear in the dose range of 4-16 mg twice daily.

Within 7 days after a single oral administration of 4 mg ³N-galantamine 90-97% of radioactivity was excreted in the urine and 2,2-6,3% - with feces. After oral administration, 18-22% of the dose was excreted as unchanged galantamine in urine for 24 hours, the kidney clearance was about 65 ml / min, which is 20-25% of the total clearance from the plasma.

The main ways of metabolism are N-oxidation, N-Demethylation, O-demethylation, glucuronization and epimerization. In people with active metabolism of substrates CYP2D6 The most important way of metabolism is O-demethylation. The number of radioactive substances excreted in urine and feces in people with fast and slow metabolism did not differ. Research in vitro showed that the main isoenzymes of the cytochrome P450 system involved in the metabolism of galantamine are 2D6 and 3A4.

In the plasma of people with fast and slow metabolism, most of the radioactive substances are unchanged galantamine and its glucuronide. In the plasma of people with rapid metabolism, glucuronide O-desmethyl galantamine is also found.

After a single intake of galantamine. in the plasma of "fast and slow metabolizers," none of the active metabolites (norgalanthamn, O-dimethyl-galantamine and O-dimethyl-norgalanthamine) was present in the unconjugated form. Norgalantamine was detected in the plasma of patients after repeated administration of galantamine, but its amount was no more than 10% of the levels of galantamine.

The results of clinical trials have demonstrated that in patients with Alzheimer's disease the concentration of galantamine in blood plasma is 30-40% higher than in young healthy individuals.

Pharmacokinetic parameters of galantamine in patients with mild violations of the liver function (5-6 points on the Child-Pugh scale) were similar to those of healthy individuals. In patients with moderate impaired hepatic function (7-9 on the Child-Pugh scale) AUC and half-life of galantamine have been increased by approximately 30% (see the section "Dosage and route of administration").

The distribution of galantamine was studied in young patients with varying degrees of renal dysfunction. The excretion of galantamine was weakened as the creatinine clearance (CC) decreased. In patients with impaired renal function of moderate severity (KK 52-104 ml / min), the concentration of galantamine in blood plasma was increased by 38%, and in patients with severe impairment (CK 9-51 ml / min) - increased by 67% with healthy people of the same age and weight (CC> 121 ml / min). Population pharmacokinetic study and analysis using a number of models have shown that in patients with Alzheimer's disease and renal dysfunction, the dose of galantamine should not be adjusted if creatinine clearance is at least 9 ml / min (see Table 1).Dosage section and method of application), since the clearance of galantamine in patients with Alzheimer's disease is reduced.

Binding to plasma proteins: The degree of galantamine binding to plasma proteins is small and amounts to 17.7 ± 0.8%. In whole blood galantamine It is advantageously shaped elements (52.7%) and in plasma (39.0%), whereas the fraction thereof related to plasma proteins is only 8.4%. The ratio of galanthamine blood / plasma concentrations is 1.17.

In a comparative study of bioavailability Reminila® in capsule form with prolonged release of active substances in the received one dose of 24 mg once a day, and in the form of tablets with immediate release of the active substance to be taken in a dose of 12 mg 2 times a day, is shown at dosages of bioequivalence the area under the 24-hour curve and the minimum concentration C_min in the equilibrium state. FROM_mOhAchieved through 4.4 hours after ingestion of the capsules at a dose of 12 mg 1 time per day was approximately 24% less than after ingestion of the tablets at a dose of 12 mg 2 times a day. Eating does not affect the bioavailability Reminila® in capsule form with sustained release of the active substance in an equilibrium state.In the study of the dose dependence of Reminil® pharmacokinetics in the form of capsules with sustained release of active substance in healthy elderly and young people, the equilibrium plasma concentration in people of both age groups was achieved within 6 days at all doses (8, 16 or 24 mg). In both age groups, the pharmacokinetics in the equilibrium state directly depended on the dose in the investigated dose range (8-24 mg).

Indications:

Reminil® is indicated for the treatment of dementia of the Alzheimer's type of mild or moderate degree, including chronic disorders of the cerebral circulation.

Contraindications:

- Reminil® can not be administered to patients with hypersensitivity to galantamine hydrobromide or to any auxiliary substance included in this preparation;

- due to the lack of data on the use of Reminil in patients with severe renal impairment (creatinine clearance less than 9 ml / min), this drug is contraindicated in such patients;

- tsevere hepatic impairment.

Carefully:

General anesthesia, bronchial asthma, chronic obstructive pulmonary disease, bradycardia, atrioventricular block,syndrome of weakness of the sinus node, unstable angina; concomitant therapy with drugs that slow heart rate (digoxin, beta-blockers); peptic ulcer and duodenal ulcer, gastrointestinal tract obstruction, period after surgery on the gastrointestinal tract, epilepsy, urinary tract obstruction, post-operative period on the urinary bladder.

Pregnancy and lactation:

Pregnancy

Studies of the use of Reminil® in pregnant women was not carried out. Reminil® can be given to pregnant women only if the potential benefit to them outweighs the possible risk to the fetus.

Lactation

It is not known whether Reminil® is excreted in human milk, studies involving lactating women have not been conducted. Women receiving Reminil ® should refrain from breastfeeding.

Dosing and Administration:

Reception scheme

Initial dose

Reminil® in the form of prolonged-action capsules should be taken orally once a day (in the morning), preferably during meals. The recommended initial dose is 8 mg per day.

For patients already taking Reminil ® in other forms with immediate release of the active substance (tablets), they can switch to Reminil® in the form of prolonged-action capsules by taking the last dose of Reminil® in the form of tablets in the evening and the beginning of Reminil® in the form of capsules 1 time per day the next morning.

When moving from Reminil® in the form of tablets with immediate release of the active substance taken 2 times a day, on Reminil® in the form of prolonged-action capsules, taken once a day, the total daily dose should remain unchanged.

During treatment, you must take a sufficient amount of fluid.

Maintenance dose

- The initial maintenance dose is 16 mg per day, patients should take this dose for at least 4 weeks.

- The question of increasing the maintenance dose to the maximum recommended 24 mg per day should be addressed after a comprehensive assessment of the clinical situation, in particular the effect achieved and tolerability.

- After the abrupt withdrawal of Reminil (for example, when preparing for surgery), there is no aggravation of symptoms.

When taking a break for several days, you should takethe initial dose of Reminil and then increase the dose according to the above scheme to the previous maintenance dose.

Children

Reminil is not recommended for children. Data on the use of Reminil in children are absent.

Patients with liver and kidney disease

In patients with moderate to severe liver damage, plasma galantamine concentrations may be higher than in patients without such lesions. In patients with moderate impaired hepatic function, the initial dose (based on pharmacokinetic data) should be 8 mg once a day every other day, it should be taken in the morning for at least one week. After that, patients can take 8 mg once a day for at least 4 weeks. The daily dose should not exceed 16 mg.

Patients with severe impaired liver function (more than 9 points on the Child-Pugh scale) Reminil® Not recommended.

Patients with severe renal impairment (creatinine clearance less than 9 mL / min) Reminil® is not recommended (due to lack of data).

In patients with a creatinine clearance greater than 9 mL / min, the dose of Reminil® do not need to correct.

Concomitant therapy

If the patient receives strong inhibitors of coenzymes CYP2D6 or CYP3A4, it may be necessary to reduce the dose of Reminil®.

Side effects:

This section presents side effects, which, on the basis of a comprehensive assessment of available information, have been attributed to the use of galanthamine hydrobromide. In some cases, the causal relationship with the intake of galanthamine hydrobromide can not be reliably established. In addition, because clinical studies are conducted under different conditions, the incidence of adverse events in clinical trials of the drug can not be directly compared with the frequencies in clinical studies of another drug and may not reflect the incidence of adverse events in clinical practice.

Nausea and vomiting - the most common adverse events in clinical trials (frequency 20.7% and 10.5%, respectively) - were observed with the choice of dose, continued in most cases during less than 1 week and were mostly episodic. The administration of antiemetics and the provision of sufficient fluid intake are most effective in such cases.

Side effects of Reminil® in therapeutic doses are given with frequency distribution and organ systems. The 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).

Immune system disorders:

infrequently: hypersensitivity.

Violations metabolism and power supply:

often: decreased appetite; infrequently: dehydration.

Mental disorders:

often: depression, hallucinations;

infrequently: visual and auditory hallucinations.

Disturbances from the nervous system:

often: dizziness, headache, tremor, fainting, retardation, drowsiness;

infrequently: perversion of taste; hypersomnia, paresthesia, convulsions. Seizures are a class effect observed with the use of acetylcholinesterase inhibitors - agents for the treatment of dementia, and including seizures and seizures.

Ophthalmic disorders:

infrequently: blurred vision.

Ear and labyrinth disorders:

infrequently: noise in the ears.

Disorders from the cardiovascular systems:

often: bradycardia, increased blood pressure;

infrequently: atrioventricular blockade of the first degree, palpitation, sinus bradycardia, supraventricular extrasystole, "hot flashes", lowering of arterial pressure.

Disorders from the gastrointestinal tract:

very often: nausea, vomiting;

often: diarrhea, abdominal pain, indigestion, gastrointestinal discomfort;

infrequent: vomiting.

Hepatobiliary disorders:

rarely: hepatitis.

Disturbances from the skin and subcutaneous fabrics:

infrequently: increased sweating;

very rarely: Stevens-Johnson syndrome, acute generalized exenthematous pustulosis, erythema multiforme.

Disturbances from the musculoskeletal system and connective tissue:

often: muscle spasms;

infrequently: muscle weakness.

Common violations:

often: fatigue, weakness, malaise.

Violations of measurements and laboratory indicators:

often: weight loss;

infrequently: increased activity of liver enzymes.

Trauma, intoxication and complications of manipulation:

often: falling, lacerations.

Overdose:

Symptoms

It is assumed that the objective and subjective symptoms of a severe overdose of galantamine will be similar to similar symptoms in overdosage of other cholinomimetics. There are mainly toxic effects from the central nervous system, the parasympathetic nervous system and neuromuscular synapses. In addition to muscle weakness or fasciculation, some or all of the symptoms of the cholinergic crisis can be observed: severe nausea, vomiting, abdominal cramping, increased salivation, lacrimation, urinary and fecal incontinence, severe sweating, bradycardia, lowering of blood pressure, collapse and convulsions. Pronounced muscular weakness in combination with hypersecretion of the mucous membrane of the trachea and bronchospasm can lead to a lethal blockade of the airways.

Post-marketing control reports describe the development of bidirectional-spindle ventricular tachycardia, lengthening of the interval QT, ventricular tachycardia with short-term loss of consciousness with a random intake of 32 mg of Reminil® per day.

Treatment

As with an overdose of any other drug, it is necessary to carry out the usual supportive measures.In severe cases, anticholinergics can be used as a general antidote. atropine. Initially, it is recommended to administer 0.5-1.0 mg intravenously, the frequency and magnitude of subsequent doses depend on the dynamics of the patient's clinical condition.

Overdose management strategies are constantly being improved, and therefore, you should contact the nearest poison treatment center for the latest recommendations regarding the treatment of a galantamine overdose.

Interaction:

Pharmacodynamic interactions

Because of its mechanism of action galantamine It can not be used simultaneously with other holinomimetics. Galantamine is an antagonist of anticholinergic drugs. Like other holinomimetics, galantamine can enter into pharmacodynamic interactions with drugs that reduce the heart rate (for example, digoxin and beta-blockers).

Being a holinomimetic, galantamine can strengthen the neuromuscular block of the depolarization type during anesthesia (for example, when using as a peripheral myorexxantum suksametonium bromide).

Pharmacokinetic interactions

Various metabolic pathways and renal excretion are involved in the elimination of galantamine. Research in vitro showed that the main role in the metabolism of galantamine is played by coenzymes CYP2D6 and CYP3A4.

The suppression of secretion of gastric juice does not impair the absorption of galantamine.

Other drugs that affect the metabolism of galantamine

Drugs that are potent inhibitors of coenzymes CYP2D6 and CYP3A4, can increase AUC galanthamine. Pharmacokinetic studies with multiple drug administration have shown that AUC galantamine is increased by 30 and 40% with simultaneous application of it, respectively, with ketoconazole and paroxetine.

When used concurrently with erythromycin, which is also an inhibitor of the enzyme CYP3A4, AUC galantamine increases by only about 10%.

Pharmacokinetic studies in patients with Alzheimer's disease showed that the clearance of galantamine decreased by about 25-33% with the simultaneous use of this drug with such known inhibitors of the enzyme CYP2D6, as amitriptyline, fluoxetine, fluvoxamine, paroxetine or quinidine. Thus, at the beginning of treatment with potent enzyme inhibitors CYP2D6 and CYP3A4, the frequency of cholinergic adverse events, mainly nausea and vomiting, may increase. In these situations, depending on the tolerability of therapy for a particular patient, it may be necessary to reduce the maintenance dose of galantamine.

The antagonist of N-methyl-O-aspartate (NMDA) receptors memantine in a dose of 10 mg per day for 2 days, then 10 mg twice a day for 12 days did not affect the pharmacokinetics of galantamine in the equilibrium state after taking a dose of 16 mg per day. Effect of galantamine on the metabolism of other drugs

Therapeutic doses of galantamine (12 mg twice daily) did not affect the kinetics of digoxin and warfarin. Galantamine did not affect the increase in prothrombin time caused by warfarin.

Research in vitro showed that galantamine has a very weak ability to inhibit the main forms of human cytochrome P-450.

Special instructions:

Application of Remineral® for other types of dementia or other memory disorders

The positive effects of Reminil® in patients with other types of dementia and other types of memory impairment have not been demonstrated.

Safety in patients with mild cognitive impairment (SCN)

Reminil® is not intended for patients with mild cognitive impairment (SCN), i.e. for patients with isolated memory impairment exceeding the expected level for their age and education, but not satisfying the criteria of Alzheimer's disease.

Two biennial studies in patients with SCN did not reveal the effectiveness of the drug. It was shown a higher (in comparison with placebo) mortality from various adverse reactions (about half of cases are associated with reactions from the cardiovascular system). Given the data obtained from a significant proportion of patients who discontinued treatment before the completion of the double-blind period, there is no reason to believe that the risk of death increases with the passage of time in patients treated with Reminil®. Of the placebo group, more patients than from the galantamine group interrupted treatment before death, which could explain the initially recorded difference in mortality.

The results of SKN studies differ from the results of studies of Alzheimer's disease. In combined studies of Alzheimer's disease (n = 4614), the mortality rate was numerically higher in the placebo group than in the group treated with Reminil®.

The diagnosis should be carried out in accordance with the current guidelines for Alzheimer's disease. Therapy should be carried out under the supervision of a doctor and can be started only if the caregiver is able to ensure a constant intake of the drug.

Weight Control

Patients with Alzheimer's disease lose weight. Treatment with acetylcholinesterase inhibitors, including galantamine, is accompanied by a decrease in the body weight of such patients, and therefore during treatment it is necessary to monitor changes in body weight.

Severe skin reactions Severe skin reactions (Stevens-Johnson syndrome and acute generalized exenthematous pustulosis) have been observed in patients taking Reminil®. It is recommended to inform patients about the signs of skin reactions in severe degree and about the necessity of stopping the use of Reminil ® at the first appearance of skin rash.

Like other cholinomimetics, Reminil® follows use with caution in the following conditions:

Heart Disease: owing to its pharmacological action holinomimetiki can cause vagotonic effects from the heart (for example, bradycardia). The consequences of such effects may be most serious in patients with sinus node weakness syndrome and with other supraventricular conduction disorders, in patients who simultaneously receive drugs, Reducing the heart rate, such as digoxin or beta-blockers, as well as in patients with electrolyte disorders (for example, with hyperkalemia, hypokalemia). Care should be taken when using galantamine in patients with cardiovascular diseases, including in the period after the recently transferred myocardial infarction, with acute atrial fibrillation, AB blockade of II degree and above, chronic heart failure (in particular III-IV functional class by classification NYHA).

Treatment with Remineral® accompanied by a faint and a rarely expressed bradycardia. Use with caution in unstable angina.

Gastrointestinal diseases: in patients with an increased risk of developing a peptic ulcer, for example having a history of ulcer disease or predisposed to it,including when taking non-steroidal anti-inflammatory drugs, it is necessary to monitor the relevant symptoms. It should be noted, however, that clinical studies have not shown an increase in patients receiving Reminil ®, compared with patients who received placebo, the incidence of peptic ulcers and gastrointestinal bleeding. Reminil® is not recommended for patients with gastrointestinal obstruction, as well as for patients who have recently undergone digestive surgery.

Neurological diseases: at Reminiel® was cramped. It should be remembered, however, that convulsive activity may be a manifestation of Alzheimer's disease itself. In rare cases, an increase in the cholinergic tone may lead to a worsening of the course of Parkinson's disease. Combined data from placebo-controlled trials showed that in patients with Alzheimer's dementia receiving galantamine treatment, cerebrovascular disorders were rarely observed. This should be taken into account when using galantamine in patients with cerebrovascular pathologies.

Pulmonary diseases: due to cholinomimetic activity Reminil® should be used with caution in patients with severe bronchial asthma, obstructive pulmonary disease or acute pulmonary infections.

Genitourinary diseases: Reminil® is not recommended for patients with urinary tract obstruction, as well as for patients who have recently undergone bladder surgery.

Surgical and medical procedures: galantamine, which is cholinomimetic, is likely to enhance muscle relaxation of succinylcholine type during anesthesia, especially with pseudocholinesterase deficiency.

Safety in patients with mild cognitive impairment (SCN)

Effect on the ability to drive transp. cf. and fur:

Alzheimer's disease can adversely affect the ability to drive cars and work with mechanisms. In addition, Reminil® itself, like other cholinomimetics, can cause drowsiness and dizziness,which negatively affect the driving of the car and work with mechanisms, especially in the first weeks after the beginning of treatment with this drug.

Form release / dosage:

Capsules of prolonged action, 8 mg, 16 mg, 24 mg.

Packaging:

7 capsules in blisters of combined material (PVC, polyethylene, polyvinylidene chloride, and aluminum foil); 300 capsules in polyethylene bottles.

8 mg: 1 or 4 blisters or 1 bottle together with instructions for medical use in a cardboard box.

16 mg: 4, 8 or 12 blisters or 1 bottle together with instructions for medical use in a cardboard pack

24 mg: for 2, 4, 8 or 12 blisters or 1 bottle together with instructions for medical use in a cardboard box.

Storage conditions:

Store at 15-30 ° C, out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007756/08

Date of registration:01.10.2008

Expiration Date:Unlimited

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp19.07.2016

Illustrated instructions

Instructions

Reminil® (Reminyl®)