Composition, form of production and packaging
Capsules of prolonged action 1 caps.
galanthamine (in the form of hydrobromide) 16 mg
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (6) - packs of cardboard.
Capsules of prolonged action 1 caps.
galanthamine (in the form of hydrobromide) 24 mg
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (6) - packs of cardboard.
Capsules of prolonged action 1 caps.
galanthamine (in the form of hydrobromide) 8 mg
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (6) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Galantamine (tertiary alkaloid) is a selective, competitive and reversible inhibitor of acetylcholinesterase. In addition, 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). It 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 is partially metabolized by various cytochromes, mainly isoenzymes CYP2D6 and CYP3A4. Some of the metabolites formed during galantamine degradation are active in vitro , but are not significant in in vivo conditions .
Suction
Absolute bioavailability of galantamine when ingested is high - 88.5 В± 5.4%. The area under the AUC curve of 24 h and C min in the blood plasma is similar to that when taking galantamine immediate release twice a day. With MAX in the blood plasma is achieved through 4.4 hours. With MAX galantamine prolonged action is 24% lower than after taking galantamine immediate release. The intake of food does not significantly affect the AUC, while it causes an increase in C max of about 12% and an elongation of the time to reach C max (TC max ) - approximately 30 minutes. However, these changes have no clinical significance.
Distribution
The average volume of distribution (Vd) is 175 liters. The degree of binding to plasma proteins is low and is 18%.
Metabolism
In vitro studies have shown that the main isoenzymes of the cytochrome P450 system involved in biotransformation of galantamine are CYP2D6 and CYP3A4.Isozyme CYP2D6 is involved in the formation of O-desmethylgalanthamine, and the isoenzyme CYP3A4 - N-oxide-galantamine. Excretion of radioactive dose by the kidneys and through the intestine does not differ in patients with "slow" and "fast" metabolism (low and high activity of the isoenzyme CYP2D6, respectively). In the blood plasma of patients with "fast" and "slow" metabolism, the main part of radioactive substances is 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 the non-conjugated 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. Studies 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 bi-exponential. The final T 1/2 in healthy volunteers is 8-10 hours. Based on the results of the study of immediate release galantamine in population studies, clearance with oral galantamine intake in the target population is usually about 200 ml / min with an interindividual variability of 30%.
After 7 days after a single oral intake of 4 mg of 3 N-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 by 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 in women is 20% lower compared to men. The clearance of galantamine in patients with a "slow" metabolism of the CYP2D6 isoenzyme is 25% lower compared to 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.
Dysfunction of the liver: in patients with mild violations of the liver (5-6 points on the scale Child-Pugh) pharmacokinetic parameters of galantamine were similar to those in healthy people. In patients with moderate impaired liver function (7-9 on the Child-Pugh scale), AUC and T 1/2 of galantamine were increased by approximately 30%.
Disturbance of kidney function: in patients with Alzheimer's disease and renal dysfunction (creatinine clearance (CC) 9 ml / min), dose adjustment is not required.
Pharmacokinetic-pharmacodynamic relationship
In large phase III studies 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 the Alzheimer's Cognitive Function Score (ADAS-cog / 11) and the scale assessment of the patient's condition on the basis of impressions of the doctor and carers of patients (CIBIC-plus) at 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 the Alzheimer's type of mild and moderate severity.
DOSING MODE
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 swallowing can take the contents out of the capsule and swallow whole and drink with water. The contents of the capsule should not be chewed or broken.
The initial dose is 8 mg / day for 4 weeks.
The 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 the 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 sudden discontinuation 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 capsules GilnoraВ® CP
When switching from galantamine in immediate-release tablets, taken 2 times a day, to therapy with prolonged-action capsules of Gnanol В® CP, 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, start taking the drug Galnor В® CP once a day.
In case of a break in taking the drug for several days, you should take the initial dose of the drug Galnor В® SR 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 week.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 CYP2D6 or CYP3A4 isozymes, it may be necessary to reduce the dose of Glanol В® CP (see the section "Interaction with other drugs").
SIDE EFFECT
The most frequent undesirable effects were nausea and vomiting. In general, the adverse events were episodic, were observed with the selection of a dose of galantamine and lasted, 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 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
very rarely <1/10000
frequency is unknown - can not be estimated from the available data.
Classification by Med-DRA Frequency
Very often Very infrequent Rarely Very rare
Immune system disorders: Hypersensitivity
Metabolic and nutritional disorders: Decreased appetite, anorcsy Drainage (in rare cases, leading to the development of renal failure)
Mental disorders: Hallucinations, depression (very often with suicide) Visual hallucinations, auditory hallucinations, aggression, agitation
Disturbances from the nervous system: Fainting, dizziness, tremor, headache, drowsiness, inhibition, insomnia, fever Paresthesia, taste distortion, hypersomnia, convulsions *, cerebrovascular disease, transient ischemic heart disease. Exacerbation of Parkinson's disease, convulsions
Disturbances from the side of the eye: Blurred vision
Hearing disorders and labyrinthine disorders: Noise in the ears
Heart Disease: Bradycardia Supraventricular extrasystole, atrioventricular block of the 1st degree, sinus bradycardia, palpitations, arrhythmia, acute myocardial infarction, ischemic heart disease, tachycardia
Vascular disorders: Arterial hypertension. Arterial hypotension, sensation of "hot flashes"
Disorders from the gastrointestinal tract: Vomiting, nausea Abdominal pain, upper abdominal pain, diarrhea, indigestion, feeling uncomfortable in the stomach, a feeling of discomfort in the abdomen Vomiting in vomiting Dysphagia, gastrointestinal bleeding
Disorders from the liver and bile ducts: Hepatitis
Disturbances from the skin and subcutaneous tissues: Hyperhidrosis Skin rash
Disorders from the musculoskeletal and connective tissue: Muscle muscle spasms Muscle weakness
General disorders and disorders at the site of administration: Increased fatigue, asthenia, malaise, weakness
Laboratory and instrumental data: Weight loss Increased activity of "liver" enzymes
Injuries, intoxications and complications of manipulation: Falling, injuries
* Potentially cholinomimetic drugs can cause seizures.
CONTRAINDICATIONS
- hypersensitivity to galantamine hydrobromide and other components of the drug;
- severe violations of the liver (more than 9 points on the scale Child-Pugh);
- severe renal dysfunction (CC less than 9 ml / min);
- Children's age under 18 years (not enough data on efficiency and safety).
With caution: syndrome of weakness of the sinus node (SSSU), including bradycardia, violations of supraventricular conduction, period after acute myocardial infarction, hyperkalemia, hypokalemia, atrioventricular blockade of II-III degree, unstable angina, chronic heart failure of III-IV functional class according to the NYNA classification, for the first time detected atrial fibrillation, concomitant use with medications that reduce heart rate (digoxin, beta-adrenoblockers), sedatives, ethanol; hypertension, epilepsy, peptic ulcer and duodenal ulcer in the anamnesis, simultaneous application of NSAIDs, gastrointestinal obstruction, condition after surgical intervention on the gastrointestinal organs and the 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 the drug Galnor В® SR in pregnant women.
There is no data on the isolation of galantamine with breast milk. There have been no clinical studies on women breastfeeding, so the use of the drug Galnor В® CP during breastfeeding is not recommended.
APPLICATION FOR FUNCTIONS OF THE LIVER
The drug is contraindicated in patients with severe violations of the liver (more than 9 points on the scale Child-Pugh).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The drug is contraindicated in patients with severe impairment of kidney function (QC less than 9 ml / min).
APPLICATION FOR CHILDREN
The drug is contraindicated in children under the age of 18 years (not enough data on efficacy and safety).
SPECIAL INSTRUCTIONS
The drug Galnor В® CP 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 (2 years) on cognitive impairment and delay in 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 in the galantamine group was significantly higher than in the placebo group, 14/1026 (1.4%) of patients receiving 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 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 the drug Galnor В® CP should be carried out only under the supervision of a doctor and under the supervision of a person providing care for the patient.
In patients with Alzheimer's disease, body weight decreases. Treatment with cholinomimetic drugs, including galantamine, is accompanied by a decrease in body weight, so during therapy, this indicator should be monitored. Like other cholinomimetic drugs, the drug Galnor В® CP should be used with caution 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 medications that lower heart rate (digoxin and beta-adrenoblockers) and in patients with impaired electrolyte metabolism (hyperkalemia, hypokalemia), after acute myocardial infarction ; with newly diagnosed atrial fibrillation: in patients with atrioventricular blockade of grade II-III, unstable angina or chronic heart failure, especially the III-IV functional class according to the NYHA classification.
Against the background of therapy with the drug Galnor В® CP dementia Alzheimer's type, the risk of unwanted reactions from the cardiovascular system increases.
Diseases of the digestive system
In patients with an increased risk of developing erosive-ulcerative gastrointestinal lesions (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 Galnora В® the CP is not recommended in patients with gastrointestinal obstruction or after recently undergone surgical intervention on the digestive tract.
Disorders of the nervous system
Use of cholinomimetic agents may cause convulsions. 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, Alzheimer's type, applying galantamine, rarely mentioned the development of cerebrovascular events. This should be considered in the appointment of galantamine to patients with cerebrovascular disease.
Diseases of the respiratory system
drug Galnora В® CP should be used with caution in patients with severe asthma, COPD, acute infectious pulmonary diseases (e.g., pneumonia).
Kidney and urinary tract
drug Galnora В® CP is not recommended for patients with urinary tract obstruction, patients who have recently undergone surgery on the bladder.
General anesthesia
galantamine being cholinomimetics, blockade can enhance neuromuscular transmission depolarizing type (muscle relaxation) caused by general anesthesia (when used as a peripheral muscle relaxant suxamethonium), especially when failure pseudocholinesterase.
When sudden cessation of treatment (e.g., before surgery), "cancel" syndrome is not developed.
The effect on the ability of transport control and other technical devices: Galnora preparation В® CP, like other cholinomimetic agents may cause drowsiness and dizziness, which adversely affect the management of transport and other mechanisms, particularly in the first weeks after beginning treatment.
OVERDOSE
Symptoms: possible symptoms of overdose are similar to the symptoms of an overdose of galantamine other holinomimetikami. Usually marked changes in the central nervous system, the parasympathetic nervous system and neuromuscular synapses. There are muscle weakness or fastsikulyaiiya, as well as some or all of the symptoms of cholinergic crisis: severe nausea, vomiting, crampy abdominal pain, excessive salivation, lacrimation, incontinence, sweating, bradycardia, decreased blood pressure, collapse and convulsions. Severe muscle weakness in conjunction with tracheal mucosa hypersecretion and bronchospasm may cause life-threatening airway patency.
In post-marketing surveillance reports of registered bidirectionally-veretonoobraznoy (polymorph) of ventricular tachycardia type "pirouette", QT prolongation, bradycardia, ventricular tachycardia with transient loss of consciousness with an inadvertent overdose of galantamine. In one of these cases, the patient one day to ingest 32 mg galantamine.
Additionally described two cases 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 requiring hospitalization. Another patient (who was given 16 mg / day of galantamine, oral solution) one hour after the accidental use of galanthamine in a dose of 160 mg (40 ml of oral solution) developed increased sweating, vomiting, bradycardia and state close to fainting that It requires hospitalization. Overdose symptoms disappeared within 24 hours.
Treatment: symptomatic therapy. In severe cases, as an antidote atropine must intravenously at a dose of 0.5-1.0 mg, more dose is selected taking into account the patient's condition.
DRUG INTERACTION
Pharmacodynamic interaction
simultaneous use of e holinomimeticheskimi other drugs (ambenonium chloride, donepezil, neostigmine methylsulfate, pyridostigmine, rivastigmine or pilocarpine systemic action) is contraindicated.
Galanthamine is an antagonist anticholinergics. With the sudden cancellation of an anticholinergic drug such as atropine may increase the effect of galantamine. As with the treatment of other nicotinic agents may pharmacodynamic interaction with drugs, contributing to a decrease in heart rate (digoxin, beta-blockers), some blockers "slow" calcium channel (BCCI) and amiodarone. Caution must be exercised while the use of drugs that have the potential to cause polymorphic ventricular tachycardia type "pirouette". In such cases it is necessary to spend treatment under ECG control. Galantamine being cholinomimetics, blockade can enhance neuromuscular transmission depolarizing type (muscle relaxation)induced general anesthesia (when used as a peripheral muscle relaxant suxamethonium), especially when psevdoholinestsrazy failure.
With simultaneous use of gatantamin enhances the effect of depolarizing miorelaksaitov weakens - non-depolarizing muscle relaxant, it is a weak antagonist of morphine and its structural analogs against inhibitory effect on the respiratory center. Strengthens the action of ethanol and sedative drugs.
Restores neuromuscular conduction blocked non-depolarizing muscle relaxants (tubocurarine bromide, etc.).
M-holinoblokatory (. Atropine, etc.) muskarinopodobnye peripheral eliminate effects of galanthamine and non-depolarizing muscle relaxants ganglioplegic - nikotinopodobnye galatamina effects.
Pharmacokinetic interaction
Excretion gatantamiia occurs through metabolic reactions, and excretion by the kidneys. The risk of developing clinically significant pharmacokinetic interaction is low. However, in some cases, a clinically significant interaction is possible. Eating slows down the absorption of galantamine, in this case, does not affect the extent of absorption. Galnora Capsules В® the CP is recommended to be taken with food to reduce the possible cholinergic side effects.
Other drugs affecting the metabolism of galantamine
While the use of paroxetine (a potent inhibitor of isozyme CYP2D6) and ketoconazole or erythromycin (inhibitors isoenzyme CYP3A4) increased bioavailability galantamiia (value AUC) of about 40% or 30% and 12%, respectively. Therefore, early treatment potent inhibitors isoenzyme CYP2D6 (e.g., quinidine, fluoxetine or paroxetine), or isozyme inhibitors of CYP3A4 (e.g., ketoconazole or ritoiavirom) may increase the incidence of cholinergic adverse reactions, primarily nausea and emesis. In these cases it is expedient to decrease the maintenance dose formulation Galnora В® CP ( В«Dosing and dose" section cm.).
Simultaneous application receptor antagonist N-methyl-D-aspartate (NMDA) memantine in a dose of 10 mg once a day for 2 days, then 10 mg twice a day for 12 days did not affect the pharmacokinetics of galanthamine in the equilibrium state after receiving 16 mg of galanthamine in capsule long acting once a day.
The influence of galanthamine on the metabolism of other medicines (drugs)
galantamine in therapeutic doses (24 mg / day) had no effect on the pharmacokinetics of digoxin, while not excluded pharmacodynamic interaction.
Galantamine at therapeutic doses (24 mg / day) also had no effect on the pharmacokinetics of warfarin and prolongation of prothrombin time.
Studies in conditions in vitro It demonstrated that galantamine iigibiruyuschey has a weak ability for basic cytochrome P450 isoenzymes.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
In a dry place at a temperature not higher than 25 В° C, in the original package. Keep out of the reach of children. Shelf life - 2 years.
