Galantamine - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 63.474 mg; cellulose microcrystalline - 20,000 mg; croscarmellose sodium - 4,000 mg; povidone-K25 - 3.0 mg; silicon dioxide colloidal - 0,500 mg; magnesium stearate - 0.900 mg.

Shell composition: hypromellose - 1,700 mg; Macrogol-4000 - 0.400 mg; titanium dioxide - 0.900 mg.

Dosage of 8 mg

Active substance: galantamine hydrobromide - 10,253 mg (in terms of galantamine - 8.0 mg).

Excipients: lactose monohydrate (sugar milk) - 126,947 mg; microcrystalline cellulose - 40,000 mg; croscarmellose sodium -8,000 mg; povidone-K25 - 6,000 mg; silicon dioxide colloid - 1,000 mg; magnesium stearate - 1,800 mg.

Shell composition: hypromellose - 3,400 mg; Macrogol-4000 - 0.800 mg; titanium dioxide - 1,800 mg.

Dosage of 12 mg

Active substance: galantamine hydrobromide - 15.380 mg (in terms of galantamine - 12.0 mg).

Excipients: lactose monohydrate (sugar milk) - 121,820 mg; microcrystalline cellulose - 40,000 mg; croscarmellose sodium - 8,000 mg; Povidone-K25 - 6,000 mg; silicon dioxide colloid - 1,000 mg; magnesium stearate - 1,800 mg.

Shell composition: hypromellose - 3,400 mg; Macrogol-4000 - 0.800 mg; titanium dioxide - 1,800 mg.

Description:

Dosage 4 mg and 12 mg

Round, biconvex tablets, covered with film)or almost white.

Dosage 8 mg

Round, biconvex tablets with a risk on one side, covered with a film shell of white or almost white color.

On a cross-section of tablets of any dosage, two layers are visible: the nucleus is almost white and the film membrane.

Pharmacotherapeutic group:Dementia remedy

ATX: & nbsp

N.06.D.A.04 Galantamine

Pharmacodynamics:

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

Pharmacokinetics:

Galantamine is the basic compound with a single dissociation constant (pKa 8.2). It has a weak lipophilicity with a distribution coefficient (LogP) between n-octanol and a buffer solution (pH 12) of 1.09. Solubility in water (pH 6) is 31 mg / ml. Galantamine has 3 chiral centers. S, R, S-Configuration is natural (natural). Galantamine partially metabolized by various cytochromes, mainly by isoenzymes CYP2D6 and CYP3A4. Some of the metabolites formed during the degradation of galantamine are active in conditions in vitro, but do not play an important role in the conditions in vivo.

General characteristics of galantamine

Suction

The absorption rate is high, the time to reach the maximum concentration (TC_mOh) is about 1 hour. The absolute bioavailability of galantamine is high - 88.5 ± 5.4%. Eating lowers the absorption rate and reduces the maximum concentration (C_mOh) by about 25%, without affecting the degree of asbortion (AUC).

Distribution

Average volume of distribution (Vd) is 175 liters. The connection with plasma proteins is low and is 18%.

Metabolism

Research in vitro showed that the main isoenzymes of the cytochrome P450 system participating in the biotransformation of galantamine are - CYP2D6 and CYP3A4. Isozyme CYP2D6 is involved in the formation of O-desmethylgalanthamine, and isoenzyme CYP3A4 - N-Galanthamine oxide. Excretion of radioactive dose by the kidneys and through the intestine does not differ in patients with "slow" and "fast" metabolism (low and high isoenzyme activity CYP2D6 respectively). In the plasma of patients with "fast" and "slow" metabolism, most of the radioactive substances are unchanged galantamine and its glucuronide. After a single administration of galantamine, none of the active metabolites of galantamine (norgalanthamn, O-desmethylgalanthamine and O-desmethylnoghalanthamine) were detected in unconjugated form in the plasma of patients with "fast" and "slow" metabolism. Norgalantamine was detected in the plasma of patients after prolonged use of the drug, while its concentration was no more than 10% of the concentration of galantamine. Research in conditions in vitro indicate a very low ability of the main isoenzymes of the human cytochrome P450 system to inhibit galantamine.

Excretion

The excretion of galantamine is of a bi-exponential nature. The final half-life (T_1/2) in healthy volunteers is 7-8 hours. According to the results of the study of immediate release galantamine in population studies, the clearance with oral galantamine intake in the target population is usually about 200 ml / min with interindividual variability 30%. In 7 days after a single oral administration of 4 mg of 3H-galantamine, 90-97% of the radioactive dose is excreted by the kidneys in the form of unchanged galantamine and 2.2-6.3% - intestines. After intravenous administration and oral administration, 18-22% of the dose was excreted as unchanged galantamine by the kidneys for 24 hours. The renal clearance was 68.4 ± 22 ml / min (20-25% of the total plasma clearance).

Linearity of pharmacokinetics

Pharmacokinetics is linear in the range of 4-16 mg when taken 2 times a day. In patients who took galantamine in a dose 12 or 16 mg twice a day, cumulations in the range from 2 to 6 months was not observed.

Pharmacokinetics of special groups of patients

The results of clinical studies have shown that in patients with Alzheimer's disease the concentration of galantamine in plasma is 30-40% higher than in young healthy individuals. Based on the analysis of population pharmacokinetics data, the clearance in women is 20% lower compared to men. Galantamine clearance in patients with low isoenzyme activity CYP2D6 to 25% lower in comparison with patients with "fast" metabolism, while bimodality in the population is not observed. Thus, the patient's metabolic status is not considered clinically significant in the total population.

Impaired liver function: in patients with mild violations of liver function (5-6 points on the Child-Pugh scale), the pharmacokinetic parameters of galantamine were similar to those of healthy people. In patients with impaired liver function of an average degree (7-9 points on the Child-Pugh scale), the area under the pharmacokinetic curve "concentration-time" (AUC) and T_1/2galantamine have been increased by about 30% (see section "Method of administration and dose").

Impaired renal function: Elimination of galantamine is reduced along with a decrease in creatinine clearance (CC) (results of the study in subjects with impaired renal function).In comparison with patients with Alzheimer's disease, the maximum and minimum plasma concentrations in patients with QC ≥ 9 mL / min did not increase. Consequently, an increase in the incidence of adverse events is not expected, no dose adjustment is required.

Pharmacokinetic-pharmacodynamic relationship

In large-scale Phase III trials with galantamine dosage regimen of 12 mg and 16 mg twice daily, there was no apparent correlation between mean plasma concentrations and efficacy (changes in scales ADAS-cog11 and CIBIC-plus on 6month of therapy).

Concentrations in blood plasma in patients with syncope were in the same range as in other patients taking the same dose.

The occurrence of nausea correlates with increased maximum plasma concentration.

Indications:Symptomatic treatment of dementia of Alzheimer's type of mild and moderate severity.

Contraindications:

Hypersensitivity to galantamine hydrobromide and other components of the drug.

In connection with the lack of data on the use of galantamine in patients with severe hepatic (more than 9 points on the scale Child-Pugh) and severe renal (SC less than 9 ml / min) deficiency, the use of galantamine in these groups of patients is contraindicated.

Galantamine is contraindicated in patients with a combination of significant renal and hepatic impairment, severe bronchial asthma, obstructive pulmonary disease, acute infectious lung diseases (eg, pneumonia).

Children under 18 years of age (insufficient data on effectiveness and safety).

Lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Pregnancy and lactation:

Pregnancy

Clinical data on the use of galantamine in pregnant women are absent. Studies in animals have revealed reproductive toxicity. Care should be taken when using galantamine in pregnant women.

Breast-feeding

There is no data on the penetration of galantamine into breast milk. Clinical studies in breastfeeding women have not been carried out, therefore, when using galantamine, breastfeeding should be stopped.

Dosing and Administration:

Adults / Seniors

Mode of application

Galantamine should be taken orally twice a day, preferably during morning and evening meals.It should be ensured that sufficient fluids are received during therapy (see section "Side effect").

Before the start of therapy

It is necessary to properly diagnose dementia in Alzheimer's disease in accordance with the current clinical guidelines (see section "Special instructions").

Initial dose

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

Maintenance dose

It is necessary to regularly assess the sufficiency of the dose and the tolerability of galantamine, preferably within three months after initiation of therapy. Further clinical benefit preparation and patient tolerability should be assessed in accordance with current recommendations. Supportive therapy should continue as long as there is therapeutic benefit and there is a satisfactory transferthe drug. When the disappearance of the therapeutic effect or intolerance of the drug treatment is canceled.

The initial maintenance dose is 16 mg per day (by 8 mg twice daily), 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 (according to 12 mg twice daily) should be addressed after a comprehensive assessment of the clinical situation, in particular the effect achieved and tolerability.

In patients who do not respond or do not tolerate 24 mg per day, the dose should be reduced to 16 mg per day.

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

Children

Significant experience in the use of the drug in children is absent.

Patients with hepatic and renal insufficiency

In patients with moderate or severe hepatic or renal insufficiency, the plasma concentration of galantamine is increased. In patients with moderate hepatic impairment, based on pharmacokinetic modeling, the initial dose should be 4 mg once daily for at least 1 week. Then patients should be transferred to 4 mg twice a day for at least 4 weeks. In these patients, the daily dose should not exceed 8 mg 2 times a day. Patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale) galantamine contraindicated (seesection "Contraindications"). In patients with mild hepatic insufficiency, dose adjustment is not required.

In patients with QC greater than 9 ml / min, dose adjustment is not required. Patients with severe renal failure (CC less than 9 mL / min) galantamine contraindicated (see section "Contraindications").

Combination Therapy

With the simultaneous use of potent inhibitors of isoenzymes CYP2D6 or CYP3A4, a dose reduction may be required (see "Interaction with other drugs").

Side effects:

The results of seven placebo-controlled double-blind clinical trials are summarized below (N= 4457), five open clinical trials (N= 1454) and postregistered spontaneous messages. The most frequent adverse reactions were nausea (25%) and vomiting (13%). In general, the adverse reactions were episodic, were observed in the selection of a dose of galantamine and Pin most cases, less than a week. In these cases, it is advisable to use antiemetics and provide sufficient fluid intake.

Classification of the frequency of development of side effects of the World Health Organization (WHO): very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1/10000 up to <1/1000) and very rarely (<1/10000).

From the immune system: infrequently hypersensitivity.

From the side of metabolism and nutrition: often - decreased appetite, anorexia; infrequently - Dehydration (including, in rare cases, severe, leading to renal insufficiency).

From the side of the psyche: often - Depression, hallucinations; infrequently - visual and auditory hallucinations.

From the nervous system: often - dizziness, headache, tremor, retardation, drowsiness; infrequently - dysgeusia, hypersomnia, convulsions *.

From the side of the organ of vision: infrequently - blurred vision.

From the side of the hearing organ and labyrinthine disorders: infrequently - noise in ears.

From the heart: often - bradycardia; infrequently - atrioventricular blockade of the first degree, palpitation, supraventricular extrasystole, sinus bradycardia.

From the side of the vessels: often - arterial hypertension; infrequently - arterial hypotension, "hot flashes".

From the gastrointestinal tract: Often - nausea, vomiting; often - diarrhea, abdominal pain, upper abdominal pain, dyspepsia, a feeling of discomfort in the stomach, a feeling of discomfort in the abdomen; infrequently - the urge to vomit.

From the liver and biliary tract: rarely - hepatitis.

From the skin and subcutaneous tissues: often - Hyperhidrosis.

From the side of the musculoskeletal and connective tissue: often - muscle spasms; infrequently: muscle weakness.

General disorders and disorders at the site of administration: often - increased fatigue, asthenia, malaise.

Laboratory and instrumental data: often - weight loss; infrequently - increased activity of "liver" enzymes.

Injuries, intoxication and complications by manipulation: often - falling, injury.

* The class effects reported in the use of acetylcholinesterase inhibitors used in dementia include seizures / seizures (see section "Special instructions").

Overdose:

Symptoms

Symptoms of a galantamine overdose are similar to the symptoms of an overdose of other cholinomimetics. Usually, changes are noted from the central nervous system, the parasympathetic nervous system and neuromuscular junction. There may be muscle weakness or fasciculation, as well as some or all of the symptoms of the cholinergic crisis: severe nausea, vomiting, abdominal cramping, increased salivation, lacrimation, urinary and fecal incontinence, increased sweating, bradycardia, lowering blood pressure, collapse and convulsions.Increasing muscle weakness in conjunction with tracheal mucosa hypersecretion and bronchospasm may cause life-threatening airway patency.

When the post-registration surveillance registered messages bidirectionally-spindle (polymorph) of ventricular tachycardia type "pirouette", lengthening the interval QT, Bradycardia, ventricular tachycardia with transient loss of consciousness with an inadvertent overdose of galantamine. In one of these cases, the patient ingested 32 mg galantamine within one day.

Also described two cases of accidental use of galantamine 32 mg (nausea, vomiting and dryness of the oral mucosa, nausea, vomiting and chest pain) and one case - 40 mg (vomiting) with full recovery. One patient with hallucinations history for the previous two years (which was assigned to 24 mg / day) Accidental application of galanthamine at a dose of 24 mg twice a day for 34 days, developed hallucinations that required hospitalization. Another patient (who was prescribed 16 mg galantamine per day,solution for ingestion) an hour later after the accidental use of galantamine at a dose of 160 mg (40 ml solution for oral administration) increased sweating, vomiting, bradycardia and a condition close to fainting, which required hospitalization of the patient. Symptoms of overdose resolved within 24 hours.

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 mg intravenously, the frequency and magnitude of subsequent doses depend on the dynamics of the clinical condition of the patient.

Strategies for treating overdoses are constantly being improved, and he is kissing the nearest poison treatment center for the latest recommendations on the treatment of galantamine overdose.

Interaction:

Pharmacodynamic interactions

Simultaneous application with other cholinomimetics (ambenonium chloride, donepezil, neostigmine methylsulfate, pyridostigmine bromide, rivastigmine or pilocarpine systemic action) is contraindicated.

Galantamine is an antagonist of anticholinergic drugs. With the sudden reversal of the anticholinergic drug, for example, atropine, it is possible to enhance the effect of galantamine.

As in the treatment with other holinomimetics, pharmacodynamic interaction with drugs contributing to a decrease in heart rate is possibledigoxin, beta-adrenoblockers), some blockers of the "slow" calcium channels (BCC) and amiodarone.

Care should be taken when using drugs that have the potential to cause a polymorphic ventricular tachycardia of the pirouette type. In such cases it is necessary to undergo ECG-controlled treatment.

Galantamine, being holinomimetikom, can strengthen the blockade of neuromuscular transmission depolarizing type during anesthesia (when used as a peripheral muscle relaxant suksametoniya), especially when pseudocholinesterase is deficient.

Pharmacokinetic interactions

Elimination of galantamine occurs by metabolic reactions and excretion by the kidneys. The risk of clinically significant pharmacokinetic interaction is low.However, in some cases, clinically significant interaction is not excluded. The ingestion of food slows the absorption of galantamine, while not affecting the degree of absorption. Galantamine it is recommended to take during meals to reduce possible cholinergic unwanted reactions.

Other drugs that affect the metabolism of galantamine

The bioavailability of galantamine is increased by about 40% when used simultaneously with paroxetine (a potent inhibitor of isoenzyme CYP2D6) and 30% and 12%, respectively - with simultaneous use with ketoconazole and erythromycin (inhibitors of the isoenzyme CYP3A4). Therefore, at the beginning of treatment with potent inhibitors of isoenzyme CYP2D6 (eg, quinidine, paroxetine or fluoxetine) or isoenzyme inhibitors CYP3A4 (eg, ketoconazole or ritonavir), an increase in the incidence of cholinergic unwanted reactions, mainly nausea and vomiting, is possible. In these cases, it is advisable to reduce the maintenance dose of the drug (see the section "Method of administration and dose").

Simultaneous use of a receptor antagonist N-methyl-O-aspartate (NMDA) memantine in a dose 10 mg once daily for 2 days, and then on 10 mg twice daily for 12 days did not affect the equilibrium pharmacokinetics of galantamine after taking 16 mg galantamine in the form of prolonged-action capsules once a day.

Effect of galantamine on the metabolism of other drugs

Galantamine in therapeutic doses (24 mg / day) did not affect the pharmacokinetics of digoxin, the pharmacodynamic interaction is not excluded.

Galantamine in therapeutic doses (24 mg / day) also did not affect the pharmacokinetics of warfarin and prolongation of prothrombin time.

Special instructions:

Galantamine is indicated for the treatment of dementia of the Alzheimer's type of mild and moderate severity. The effectiveness of galantamine in patients with other types of dementia and other memory disorders has not been established. There is also no positive effect of galantamine (during 2 years) to slow cognitive impairment and slow the transition to clinically pronounced dementia in patients with the syndrome of "soft" cognitive decline ("soft" types of memory impairment that do not meet the criteria of dementia of the Alzheimer's type).Mortality galantamine group was significantly higher than in the placebo group, 14/1026 (1.4%) patients treated with galantamine, and 3/1022 (0.3%) of patients receiving placebo. The causes of deaths were different. About half of the deaths in the galantamine group were due to various vascular complications (myocardial infarction, stroke, and sudden death). The significance of the data obtained for the treatment of patients with Alzheimer's dementia is unknown. Placebo-controlled studies of patients with Alzheimer's dementia were performed only during 6 months. In these studies, mortality in the galantamine group did not increase.

The diagnosis of Alzheimer's dementia should be made in accordance with current recommendations. Treatment should be conducted under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should be started only if there is a carer who will regularly monitor the patient taking the medication.

In patients with Alzheimer's disease, body weight decreases. Treatment with cholinomimetics, including galantamine, accompanied by a decrease in body weight, so during therapy should monitor this figure.

Like other holinomimetics, galantamine should be used with caution in the following conditions:

Heart Disease

Due to the pharmacological effect, cholinomimetics can cause vagotonic effects (eg, bradycardia). Consequently galantamine should be used with caution in patients with sinus node weakness syndrome and other disorders of supraventricular conduction, with simultaneous therapy with drugs that reduce the heart rate (digoxin and beta-blockers), and in patients with impaired electrolyte metabolism (hyperkalaemia, hypokalemia), in the period after the acute myocardial infarction; with newly diagnosed atrial fibrillation; in patients with atrioventricular blockade of grade II-III, unstable angina or chronic heart failure, especially III-IV functional class by classification NYHA.

Against the backdrop of galantamine-induced dementia of the Alzheimer's type, the risk of some unwanted reactionsside of the cardiovascular system (see section "Side effect").

Disorders from the gastrointestinal tract

In patients with an increased risk of developing erosive-ulcerative gastrointestinal lesions (for example, peptic ulcer and duodenal ulcer in the history, therapy with non-steroidal anti-inflammatory drugs), it is necessary to monitor the condition for the purpose of early detection of the corresponding pathological symptoms. Galantamine It is not recommended for use in patients with gastrointestinal obstruction or after a recent surgery on the digestive tract.

Disturbances from the nervous system

The use of cholinomimetics can cause seizures. It should be remembered that convulsive activity may be a manifestation of Alzheimer's disease itself. In rare cases, the strengthening of cholinergic tone may cause a worsening of Parkinson's disease. A pooled analysis of placebo-controlled trials in patients with Alzheimer's dementia using galantamine, showed the infrequent development of cerebrovascular complications (see the "Side effect" section). This should be considered in the appointment of galantamine to patients with cerebrovascular disease.

Disorders from the kidneys and urinary tract

Galantamine is not recommended for use in patients with obstruction of the urinary tract or who have recently undergone surgical intervention on the urinary tract a bubble.

Surgical and medical interventions

With sudden discontinuation of treatment (for example, before surgery), the "cancellation" syndrome does not develop.

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

Galantamine has a weak or moderate effect on the ability to drive vehicles and work with mechanisms. This, among other things, is caused by dizziness and drowsiness, especially in the first weeks after the initiation of therapy. During the treatment period, one should refrain from driving vehicles and working with mechanisms.

Form release / dosage:

Tablets, film-coated, 4 mg, 8 mg, 12 mg.

Packaging:

For 10, 14, 25, 30 or 50 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 10, 20, 30, 40, 50, 56, 60 or 100 tablets in cans of polyethylene terephthalate or in cans of polymeric for medicines.

One bank or 1, 2, 3, 4, 5, 6 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003452

Date of registration:09.02.2016

Expiration Date:09.02.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp12.03.2017

Illustrated instructions

Instructions

Galantamine (GALANTAMINE)