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

Galantamine pellets 8% 100 mg, including: active substance: galantamine hydrobromide 10,254 mg, calculated on galantamine, 8 mg; Excipients: hypromellose E5 (hydroxypropyl methylcellulose) 2.46 mg, diethyl phthalate 0.57 mg, microcrystalline cellulose 84.43 mg, ethyl cellulose 2.29 mg.

Excipients: magnesium stearate 0.5 mg, talc 0.5 mg.

Capsule hard gelatin №3:

body - gelatin 29.6341 mg, indigo carmine dye 0.0207 mg, titanium dioxide 0.6052 mg;

cap - gelatin 17.3731 mg, indigo carmine dye 0.0121 mg, titanium dioxide 0.3548 mg.

1 capsule prolonged action of 16 mg contains:

Galantamine pellets 8% 200 mg, including: active substance: galantamine hydrobromide 20,508 mg, calculated on galantamine 16 mg; Excipients: hypromellose E5 hydroxypropyl methyl cellulose) 4.92 mg, diethyl phthalate 1.14 mg, microcrystalline cellulose 168.86 mg, ethyl cellulose 4.58 mg.

Excipients: magnesium stearate 1 mg, talc 1 mg.

Capsule hard gelatin №2:

body - gelatin 37.2416 mg, indigo carmine dye 0,1062 mg, dye patented blue V 0.7622 mg;

cap - gelatin 22.3844 mg, a dye patented blue V 0.0638 mg, titanium dioxide 0.4578 mg.

1 capsule prolonged action of 24 mg contains:

Galantamine pellets 8% 300 mg, including: active substance: galantamine hydrobromide 30.761 mg, calculated on galantamine 24 mg; Excipients: hypromellose E5 (hydroxypropyl methylcellulose) 7.38 mg, diethyl phthalate 1.71 mg, microcrystalline cellulose 253.29 mg, ethyl cellulose 6.87 mg.

Excipients: magnesium stearate 1.5 mg, talc 1.5 mg.

Capsule hard gelatin №1:

body - gelatin 45.2956 mg, titanium dioxide 0.9244 mg;

cap - gelatin 29.1844 mg, titanium dioxide 0.5956 mg.

Description:

Hard gelatin capsules No. 3,lid and casing of blue color (dosage 8 mg); hard gelatin capsules No. 2, lid and body of blue color (dosage: 16 mg); hard gelatin capsules No. 1, lid and white body (dosage 24 mg). The contents of the capsules are white or almost white spherical pellets.

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 action 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). Has a weak lipophilicity with a distribution coefficient (LogP) between n-octanol and a buffer solution (pH 12) of 1.09. The 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 isoenzymes CYP2D6 and CYP3A4. Some of the metabolites formed during the degradation of galantamine are active in conditions in vitro, but do not have a significant value in the conditions in vivo.

Suction

Absolute bioavailability of galantamine when ingested is high - 88.5 ± 5.4%. Indices of the area under the curve "concentration-time" (AUC_24h) and minimum concentration (C_min) in the blood plasma are similar to those when taking galantamine immediate release twice a day. Maximum concentration (FROM_m_Oh) in blood plasma is achieved through 4.4 h. With_m_Oh galantamine prolonged action is 24% lower than after taking galantamine immediate release. Eating does not have a significant effect on AUC, at the same time, causes an increase in C_m_Ohby about 12% and the extension of the time to reach C_m_Oh (TC_m_Oh) - for about 30 minutes. However, these changes have no clinical significance.

Distribution

Average volume of distribution (V_d) is 175 liters. The degree of binding to plasma proteins is low and amounts to (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 participates 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 blood 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 blood plasma of patients with "fast" and "slow" metabolism. Norgalantamine was detected in the blood 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 8-10 hours. Based on 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 an interindividual variability of 30%.

7 days after a single oral administration of 4 mg ³N-galantamine 90-97% of the radioactive dose is excreted by the kidneys in the form of unchanged galantamine and 2.2-6.3% through the intestine. After intravenous administration and oral administration, 18-22% of the dose was excreted as unchanged galantamine through the kidneys for 24 hours. The kidney clearance was 65 ml / min (20-25% of the total plasma clearance).

Pharmacokinetics is linear in the dose range from 8 mg to 24 mg once a day in elderly patients and young patients.

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 blood plasma is 30-40% higher than in young healthy individuals.

Based on the analysis of population pharmacokinetics data, the clearance women are 20% lower compared to men.

Galantamine clearance in patients with a "slow" isozyme metabolism CYP2D6 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 moderate impaired liver function (7-9 on the Child-Pugh scale) AUC and T_1/2galantamine were increased by about 30%.

Impaired renal function: in patients with Alzheimer's disease and renal dysfunction (creatinine clearance (CC) ≥ 9 mL / min) no dose adjustment is required.

Pharmacokinetic-pharmacodynamic relationship

The major phase III trials with galantamine dosage regimen of 12 mg and 16 mg twice a day was observed apparent correlation between average plasma concentrations and performance indicators (change scale evaluations of cognitive functions in Alzheimer's disease (ADAS-cog/11) and the scale of assessment of the patient's condition on the basis of impressions of the doctor and carers of patients (CIBIC-plus) on the 6th month 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 is correlated with a higher peak in plasma concentration.

Indications:

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

Contraindications:

Hypersensitivity to galanthamine hydrobromide and other components of the drug, severe violations of liver function (more than 9 on the Child-Pugh scale), severe renal dysfunction (QC less than 9 mL / min), children under 18 years of age (insufficient data on efficacy and safety) .

Carefully:

Syndrome of weakness of the sinus node (SSSU), incl. bradycardia, disorders supraventricular conduction, period after acute myocardial infarction, hyperkalemia, hypokalemia, atrioventricular blockade of grade II-III, unstable angina, chronic heart failure of III-IV functional class according to NYNA classification, first detected atrial fibrillation, concomitant use with medications that reduce heart rate (HR) (digoxin, beta-adrenoblockers), sedatives, ethanol; hypertension, epilepsy, peptic ulcer and duodenal ulcer in the anamnesis, simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), gastrointestinal tract obstruction, condition after surgery on the gastrointestinal tract and bladder, obstruction of the urinary tract, bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), acute infectious lung diseases, general anesthesia.

Pregnancy and lactation:

There are no clinical data on the use of galantamine in pregnant women. Studies in animals have revealed reproductive toxicity. Care should be taken when using galantamine in pregnant women.

There is no data on the isolation of galantamine with breast milk. There have been no clinical studies on breastfeeding women, so the use of galantamine during breastfeeding is not recommended.

Dosing and Administration:

Inside, 1 time per day (in the morning), preferably during meals. Capsule to swallow whole, squeezed a small amount of liquid.Capsules should not be chewed or broken.

Patients who have difficulty in swallowing capsules can take the contents out of the capsule and swallow whole with water. The contents of the capsule should not be chewed or broken.

Initial dose is 8 mg / day for 4 weeks.

Maintenance dose is 16 mg / day for at least 4 weeks.

It is necessary to regularly monitor the patient's condition within 3 months from the start of therapy. In the future, the effectiveness of the drug and the patient's condition are regularly assessed in accordance with clinical recommendations. Supportive therapy can be continued as long as the therapeutic effect remains and with good tolerability of therapy. If there is no therapeutic effect or poor tolerability of therapy, the drug should be discarded.
The initial maintenance dose is 16 mg / day. Patients should take this dose for at least 4 weeks.
The question of increasing the maintenance dose to the maximum recommended 24 mg / day should be decided based on an analysis of the clinical situation, therapeutic effectiveness and tolerability of the therapy.
If increasing the dose to 24 mg / day does not lead to an increase in the effectiveness of treatment or is accompanied by a deterioration in tolerability, it is possible to reduce the dose to 16 mg per day.
With the sudden cessation of treatment (for example, before surgery), the "cancellation" syndrome does not develop.

Transition from the therapy of galantamine in immediate-release tablets to long-acting capsule therapy

When switching from galantamine in immediate-release tablets, taken 2 times a day, to prolonged-release capsules taken once a day, the daily dose should remain unchanged. The patient should take the last tablet with immediate release in the evening and the next day, in the morning to start taking prolonged-action capsules 1 time per day.

In case of a break in taking the drug for several days, you should take the initial dose of the drug Galantamine Canon for a prolonged-action capsule and then increase the dose according to the above scheme to the previous maintenance dose.

Impaired liver function

In patients with moderate and severe impairment of liver and / or kidney function, the concentration of galantamine in the blood plasma may increase.

In patients with moderate impairment of liver function, the recommended initial dose is 8 mg 1 time per day every other day, preferably in the morning, for one pedal. In the future, the dose is increased to 8 mg / day for 4 weeks. In such patients, the daily dose should not exceed 16 mg.

In patients with mild violations of the liver, dose adjustment is not required.

Impaired renal function

In patients with QC greater than 9 ml / min, dose adjustment is not required.

Combination Therapy

With the simultaneous use of potent inhibitors of isoenzymes CYP2D6 or CYP3A4 it may be necessary to reduce the dose of galantamine (see section "Interaction with other drugs").

Side effects:

The most frequent undesirable effects were nausea and vomiting. In general, the adverse events were episodic, were observed when choosing a dose of the drug and continued, in most cases, less than a week. In these cases, it is advisable to use antiemetics and provide adequate fluid intake. The frequency and nature of adverse events with galantamine in the form of prolonged-action hard gelatin capsules are comparable to those obtained with immediate-release tablets once daily.

Classification of the frequency of development of side effects of the World Health Organization (WHO):

Often	≥1/10
often	from ≥1 / 100 to <1/10
infrequently	from ≥1 / 1000 to <1/100
rarely	from ≥1 / 10000 to <1/1000
rarely	<1/10000

Classification by MedDRA	Frequency
Classification by MedDRA	Often	Often	Infrequently	Rarely	Rarely
Immune system disorders:			Hypersensitivity
Disorders from the metabolism and nutrition:		Decrease appetite, anorexia	Dehydration (in rare cases leading to the development of renal failure)
Disorders of the psyche:		Hallucinations, depression (very rarely with suicide)	Spotting hallucinations, auditory hallucinations, aggression, agitation
Impaired nervous system:		Fainting, dizziness, tremor, head pain, drowsiness, retardation, insomnia, fever	Paresthesia, taste perversion, hypersomnia, convulsions *, cerebrovascular disease, transient ischemic heart disease		Exacerbation of Parkinson's disease, seizures
Disorders from the side of the organ of vision:			Unclear visual perceptions
Hearing disorders and labyrinthine disturbances:			Noise in ears
Heart Disease:		Bradycardia	Supraventricular extrasystole, atrioventricular block I degree, sinus bradycardia, palpitations, arrhythmia, acute myocardial infarction, ischemic heart disease, tachycardia
Vascular disorders:		Arterial hypertension	Arterial hypotension, sensation of "hot flashes"
Violations from hand gastrointestinal tract:	Vomiting, nausea	Abdominal pain, upper abdominal pain, diarrhea, dyspepsia, a feeling of discomfort in the stomach, a feeling of discomfort in the abdomen	Desires for vomiting		Dysphagia, gastrointestinal bleeding
Disorders from the liver and bile ducts:				Hepatitis
Disturbances from the skin and subcutaneous tissues:		Hyperhidrosis		Skin rash
Violations from hand skeletal-muscular and connective fabric:		Muscle Cramps	Muscle weakness
Are common disorders and disorders at the site of administration:		Increased fatigue, asthenia, malaise, weakness
Laboratory and instrumental data:		Weight loss	Increase activity "hepatic" Enzymes
Injuries, intoxication and complications manipulation:		A fall, injuries

* Potentially cholinomimetic drugs can cause seizures.

Overdose:

Symptoms: perhaps the symptoms of galantamine overdose are similar to the symptoms of an overdose by other cholinomimetics. Changes in the central nervous system, parasympathetic nervous system and neuromuscular synapses. 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. The expressed muscular weakness in a combination to a hypersecretion of a mucosa of a trachea and a bronchospasm can lead to life threatening a disturbance of patency of respiratory ways.

In post-marketing surveillance, there were reports of bi-directionally-fusiform (polymorphic) ventricular tachycardia such as pirouette, lengthening of the interval QT, bradycardia, ventricular tachycardia with short-term loss of consciousness with unintentional overdose of galantamine.In one of these cases, the patient ingested 32 mg galantamine within one day.

In addition, two cases of accidental use of galanthamine at a dose of 32 mg (nausea, vomiting and dryness of the oral mucosa, nausea, vomiting and retrosternal pain) and one case in a dose of 40 mg (vomiting) with complete recovery. One patient with a history of hallucinations within the previous two years (who was prescribed 24 mg / day galantamine) with the deliberate use of galantamine at a dose of 24 mg twice daily for 34 days developed hallucinations requiring hospitalization. Another patient (who was prescribed 16 mg / day of galantamine, a solution for oral administration) developed an excessive sweating, vomiting, bradycardia and a condition close to fainting an hour after the accidental application of galantamine at a dose of 160 mg (40 ml of oral solution) that required hospitalization of the patient. Symptoms of an overdose disappeared within 24 hours.

Treatment: symptomatic therapy. In severe cases, as an antidote, intravenously atropine in a dose of 0.5-1.0 mg, then the dose is selected taking into account the patient's condition.

Interaction:

Pharmacodynamic interaction

Simultaneous application from other cholinomimetic drugs (ambenonium chloride, donepezil, neostigmine methylsulfate, pyridostigmine bromide, rivastigmine or pilocarpine system action) it is contraindicated.

Galantamine is an antagonist of anticholinergic drugs. With a sudden reversal of the anticholinergic drug, for example, atropine it is possible to enhance the effect of galantamine. As with other cholinomimetic agents, pharmacodynamic interaction is possible from drugs that help to reduce heart rate (digoxin, beta-adrenoblockers), some blockers of the "slow" calcium channels (BCCC) and amiodarone.

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

Galantamine, which is holinomimetic, can enhance the blockade of neuromuscular transmission of the depolarizing type (miorelaxation) caused by general anesthesia (when used as a peripheral muscle relaxant suksametoniya), especially with pseudocholinesterase deficiency.

With simultaneous application galantamine strengthens the action depolarizing muscle relaxants, weakens - Nondepolarizing muscle relaxants, is a weak antagonist of morphine and its structural analogues in relation to the inhibitory effect on the respiratory center.

Strengthens the action ethanol and sedative drugs.

Restores neuromuscular conduction, blocked non-depolarizing muscle relaxants (tubocurarine, etc.).

M-holinoblokatory (atropine and etc.) eliminate peripheral muscarine-like effects of galantamine, Nondepolarizing muscle relaxants and ganglion blockers - nicotine-like effects of galantamine.

Pharmacokinetic interaction

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 possible. The ingestion of food slows the absorption of galantamine, without affecting the degree of absorption.Galantamine Capsules The canon is recommended to be taken with meals to reduce possible cholinergic side effects.

Other drugs that affect the metabolism of galantamine

When used simultaneously with paroxetine (a potent inhibitor of the isoenzyme CYP2D6) or with ketoconazole and erythromycin (inhibitors of the isoenzyme CYP3A4) increases the bioavailability of galantamine (magnitude AUC) by about 40% or 30% and 12%, respectively. Therefore, at the beginning of treatment powerful inhibitors of isoenzyme CYP2D6 (eg, quinidine, paroxetine or fluoxetine) or isoenzyme inhibitors CYP3A4 (e.g., ketoconazole or ritonavir) it is possible to increase the incidence of cholinergic adverse reactions, mainly nausea and vomiting. In these cases, it is advisable to reduce the maintenance dose of the preparation Galantamine Canon (see section "Method of administration and dose").

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

The influence of galantamine on the metabolism of other drugs (LS)

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

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

Research in vitro showed that galantamine has a weak inhibitory ability in respect of basic isoenzymes of cytochrome P450.

Special instructions:

The drug Galantamine Canon sustained-action capsules is shown for the treatment of dementia of the Alzheimer's type of mild or moderate severity.

The effectiveness of galantamine in patients with other types dementia and other memory disorders is not established. Also, the positive effect of galantamine (2 years) on slowing cognitive impairment and slowing 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 cases of deaths in the galantamine group was a result of various vascular causes (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 for 6 months. In these studies, mortality in the galantamine group did not increase.

Treatment with Galantamine Canon should only be carried out under the supervision of a doctor and under the supervision of a person who provides care for the patient.

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

Like other holinomimeticheskie means, the drug Galantamine Canon should be used cautiously in the following diseases:

Diseases of the cardiovascular system

Due to pharmacological action holinomimeticheskie funds can cause vagotonic effects (for example, bradycardia).It should be used with caution in patients with SSSU and other disorders of supraventricular conduction, with simultaneous therapy with drugs that lower heart rate (digoxin and beta-adrenoblockers) and in patients with electrolyte metabolism disorders (hyperkalemia, hypokalemia), in the period after acute myocardial infarction; with newly diagnosed atrial fibrillation; in patients with atrioventricular blockade II-III degree, unstable angina or chronic heart failure, especially III-IV functional class by classification NYHA.

Against the background of therapy with the drug Galantamine Canon dementia Alzheimer's type may increase the risk of developing unwanted reactions from the cardiovascular system.

Diseases of the digestive system

In patients with an increased risk of developing erosive-ulcerative lesions of the gastrointestinal tract (GI tract) (for example, peptic ulcer and 12 duodenal ulcer in the anamnesis, therapy with NSAIDs), it is necessary to monitor the condition for the purpose of early detection of the corresponding pathological symptoms.The drug Galantamine Canon is not recommended for patients with gastrointestinal obstruction or after a recent surgery on the gastrointestinal tract.

Diseases of the nervous system

The use of cholinomimetic agents 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.

In patients with dementia of the Alzheimer's type, galantamine, rarely noted the development of cerebrovascular events. This should be considered in the appointment of galantamine to patients with cerebrovascular disease.

Diseases of the respiratory system

Canon drug galantamine should be given with caution to patients with severe asthma, COPD, pulmonary acute infectious diseases (such as pneumonia).

Diseases of the kidneys and urinary tract

Canon drug galantamine is not recommended in patients with obstruction of the urinary tract, recently underwent surgery on the bladder.

General anesthesia

Galantamine, which is holinomimetic, can strengthen the blockade neuromuscular transmission depolarizing type (miorelaxation), caused by general anesthesia (when used as a peripheral muscle relaxant suksametoniya), especially when pseudocholinesterase is deficient.

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

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

The preparation Galantamine Canon, like other cholinomimetic drugs, can cause drowsiness and dizziness, which adversely affect the management of transport and other mechanisms, especially in the first weeks after the start of treatment.

Form release / dosage:

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

Packaging:

7 capsules per contour cell packaging made of polyvinyl chloride film, PVC / PVC film or PVC / PCTFE and aluminum printed lacquered foil.

For 1, 2, 4, 8, 12 contour cell packs of 7 capsules, together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C, in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004043

Date of registration:27.12.2016

Expiration Date:27.12.2021

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp25.01.2017

Illustrated instructions

Instructions

Galantamine Canon (Galantamine Canon)