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

Reminil® in the form of tablets contains galantamine hydrobromide in an amount of 5,127 mg, 10,254 mg, 15,380 mg, (equivalent to galantamine 4 mg, 8 mg and 12 mg).

Inactive ingredients of the core tablets are: lactose monohydrate and microcrystalline cellulose premix (in a ratio of 75% and 25%, respectively), crospovidone, magnesium stearate, silicon dioxide colloidal anhydrous.

The shell of the tablets consists of hypromellose 2910 (viscosity 5 mPaXs), propylene glycol, titanium dioxide (E171) and talc.In addition, 4 mg tablets contain iron oxide yellow oxide (E172), 8 mg tablets contain iron oxide red (E172), 12 mg tablets contain red iron oxide (E172) dye and orange-yellow dye S (E110).

Description:

Tablets 4 mg: round, biconvex tablets, covered with a film shell of white or almost white color, on one side of the tablets there is an engraving "JANSSEN", on the other - "G4".

Tablets 8 mg: round, biconvex tablets, covered with a film shell of pink color, on one side of the tablets there is an engraving "JANSSEN", on the other - "G8".

Tablets 12 mg: round, biconvex tablets, covered with a film shell of orange brown color, on one side of the tablets there is engraving "JANSSEN", on the other - "G12".

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 (C_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 renal 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-desmethylgalanthamine is also found.

After a single administration of galanthamine in the plasma of people with fast and slow metabolism, 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 liver function (5-6 points on the Child-Pugh scale) were similar to those in 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 Dosage section and method of use).

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 medium 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% compared with healthy people of the same age and weight (CK> 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 the creatinine clearance is at least 9 ml / min (see Dosage and 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 is found mainly in shaped elements (52.7%) and in plasma (39,0%), whereas its fraction bound to plasma proteins is only 8.4%. The ratio of galanthamine blood / plasma concentrations is 1.17.

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 that is part of this drug;

- ata consequence of 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;

- severe violations of the liver.

Carefully:

General anesthesia, bronchial asthma, chronic obstructive pulmonary disease, bradycardia, atrioventricular blockade, sinus node weakness syndrome, 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 have not been conducted. 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, as studies involving lactating women have not been performed.Women receiving Reminil ® should refrain from breastfeeding.

Dosing and Administration:

Reception scheme

Reminil® should be taken orally twice a day, preferably during the morning and evening meals.

Initial dose

The recommended initial dose is 8 mg per day (4 mg twice a day), it should be taken within 4 weeks.

In the process of treatment, ensure sufficient fluid intake.

Maintenance dose

- The initial maintenance dose is 16 mg per day (8 mg twice a 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 (12 mg twice a 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.

If you take a break for a few days, take the 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 the treatment of 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 liver function, the initial dose of immediate-release tablets should be 4 mg once a day, it should be taken in the morning for at least one week, after that the dose can be increased to 4 mg twice a day for not less than 4 weeks. The total daily dose should not exceed 16 mg. Patients with severe impaired liver function (more than 9 points on the Child-Pugh scale) Reminil® is contraindicated. In patients with a creatinine clearance of more than 9 ml / min, the dose of Reminil® should not be adjusted.

Concomitant therapy

If the patient receives strong inhibitors of coenzymes CYP2D6 or CYP3A4, it may be necessary to reduce the dose of Reminil® (see Interactions with other drugs and other forms of interaction).

Side effects:

Nausea and vomiting - the most common adverse events in clinical trials - were observed with the choice of dose, continued in most cases for 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.

The side effects of Reminil® in therapeutic doses are given with a 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).

Metabolic and nutritional disorders: often: decreased appetite, anorexia; infrequently: dehydration (including, in rare cases, severe, leading to kidney failure);

Mental disorders: hasto: depression (very rarely with suicide); very rarely: visual and auditory hallucinations;

Disturbances from the nervous system: often: dizziness, headache, tremor, syncope, retardation, drowsiness; infrequently: perversion of taste; hypersomnia; paresthesia;

Ophthalmic disorders: infrequently: blurred vision;

Ear and labyrinth disorders: very rarely: tinnitus;

Disorders from the cardiovascular system: often: aetiology; infrequently: atrioventricular blockade of the first degree, palpitations, supraventricular extrasystole, hot flashes, lowering of arterial pressure.

Disorders from the gastrointestinal tract: very often: nausea, vomiting, often: diarrhea, abdominal pain, indigestion, gastrointestinal discomfort;

Hepatobiliary disorders: very rarely: hepatitis;

Disturbances from the skin and subcutaneous tissues: often: increased sweating;

Disturbances from the musculoskeletal system and connective tissue: often: muscle spasms; infrequently: muscle weakness;

Common violations: often: fatigue, weakness;

Disorders of measurements and laboratory indicators: often: weight loss; very rare: an increase in the level of liver enzymes.

In the placebo-controlled clinical trials of Reminil®, the following undesirable events were very rarely observed: hematuria, urinary tract infections, rhinitis, anemia, and increased blood pressure. The incidence of these phenomena in the placebo group is comparable to the frequency of occurrence ingroup of Reminil ® and, thus, the relationship of these phenomena with the use of Reminil ® is not justified.

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 the occasional 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 suxamethonium).

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 (see the section on "Dosage and route of administration").

The receptor antagonist M-methyl-Daspartate (NMDA) memantine at a dose of 10 mg / day for 2 days, then 10 mg twice daily for 12 days did not affect the pharmacokinetics of galantamine in the equilibrium state after taking a dose of 16 mg / 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:

Reminil® is indicated for the treatment of dementia of the Alzheimer's type of mild or moderate degree, including with concomitant cerebral circulatory insufficiency.The use of Reminil® in patients with other types of dementia and other types of memory impairment has not been demonstrated.

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.

Like other cholinomimetics, Reminil® follows apply with caution with the following diseases:

Cardiovascular diseases: due 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, as well as in patients who simultaneously receive drugs that reduce heart rate, such as digoxin or beta-blockers. Treatment with Reminil ® was accompanied by a syncope and 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 an anamnesis in history or predisposed to it, it is necessary to monitor the relevant symptoms. It should be noted, however, that clinical trials did not reveal 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: it is believed that holinomimetiki have a certain ability to cause generalized convulsions. It should be remembered, however, that convulsive activity may be a manifestation of Alzheimer's disease itself. In clinical trials, there was no increase in seizure frequency in patients taking Reminil ®, compared to patients receiving placebo.

Pulmonary diseases: because of the cholinomimetic activity of Reminil® should be used with caution in patients with severe bronchial asthma or obstructive pulmonary disease.

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

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.

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®, like other holinomimetics, can cause drowsiness and dizziness, which adversely affect the driving and handling of the vehicle, especially in the first weeks after the start of treatment with this drug.

Form release / dosage:Tablets, film-coated, 4 mg, 8 mg, 12 mg.

Packaging:

For 14 tablets, coated with a film sheath, in a blister.

For 1, 2 or 4 blisters 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:П N014598 / 01

Date of registration:17.03.2009

Expiration Date:Unlimited

Date of cancellation:2017-11-14

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: & nbsp14.11.2017

Illustrated instructions

Instructions

Reminil® (REMINYL®)