Expiration date: 03/2025
The composition and form of issue:
Long-acting capsules. 1 capsule contains:
galantamine hydrobromide (calculated as base) 8, 16 or 24 mg
excipients: sugar spheres (composed sucrose and maize starch) hypromellose 2910 (5 MPa×s) macrogol 400 ethyl cellulose (20 MPa×s) diethyl
capsule shell: gelatin, titanium dioxide, iron oxide red (for capsules 16 and 24 mg), iron oxide yellow (for capsules 24 mg)
in e blisters 7 PC or vial 300 PCs. in cardboard pack 1, 4 blisters (capsules 8 mg) 4, 8, 12 blisters (capsules 16 mg), 2, 4, 8, 12 blisters (capsules 24 mg) or 1 vial (for all dosages).
Description pharmaceutical form:
Capsules 8 mg: hard gelatin capsules No. 4 consisting of the opaque body and cap of white color with printed symbol "G8".
Capsules 16 mg: hard gelatin capsules No. 2 consisting of the opaque body and cap light pink color with printed symbol "G16".
Capsules 24 mg: hard gelatin capsules ?1 consists of an opaque body and cap pinkish-brown color with printed symbol "G24".
The contents of capsules — pellets white, or almost white.
Pharmacokinetics:
After a single oral dose of 8 mg of galantamine, it is rapidly absorbed from the gastrointestinal tract, its Cmax was reached after 1.2 h and was (43±13) ng/ml, and the average area under the curve from zero to infinity (AUC&infin) (427 ±102) ng h/ml. the Absolute bioavailability of galantamine in oral administration of 88.5%. Reception of galantamine with food slows down its absorption (Cmax reduced by 25%), but does not affect the number absorbirowawrzayasa of the drug (AUC).
After repeated administration of galantamine at a dose of 12 mg 2 times a day average concentrations at the end of the dose period, and C Max in plasma ranged from 30 to 90 ng/ml. the Pharmacokinetics of galantamine is linear in the dose range 4-16 mg 2 times a day.
Within 7 days after a single oral dose of 4 mg 3 H-galantamine 90-97% of the radioactivity was allocated with urine and 2.2–6.3% of the feces. After oral administration of 18-22% of the dose was ekskretiruetsja in the form of unchanged galantamine in the urine in 24 hours, renal clearance was approximately 65 ml/min, accounting for 20 -25% of the total clearance from plasma.
The main routes of metabolism are N-oxidation, N-demethylation, O - demethylation, glukuronizatia and epimerization. People with active metabolism of substrates of CYP2D6, the most important way of metabolism is O-demethylation. The amount of radioactivity excreted in the urine and feces, people with fast and slow metabolism did not differ. In vitro studies showed that the major isoenzymes of cytochrome P450 involved in the metabolism of galantamine are 2D6 and 3A4.
In the plasma of people with fast and slow metabolism is the main part of radioactive substances are unchanged galantamine and its glucuronide. In the plasma of people with fast metabolism also detected the glucuronide of desmetilselegilina.
After a single dose of galantamine in the plasma of fast and slow metabolization no active metabolites (horgalaten, dimethylhydantoin and On - dimethyldodecylamine) is not present in the unconjugated form. Horgalaten was discovered in plasma of patients after repeated administration of galantamine, but the amount was not more than 10% of the galantamine levels.
The results of clinical trials have demonstrated that patients with Alzheimer's concentration of galantamine in plasma is 30-40% higher than in young healthy individuals.
Pharmacokinetic parameters of galantamine in patients with a slight impaired function of the liver (5-6 points on a scale child-Pugh) were similar to those seen in healthy individuals. patients with moderately impaired liver (7-9 points on a scale child-Pugh) the AUC and T 1/2 of galantamine were increased by about 30% (see "Method of application and dosage").
The distribution of galantamine has been studied in young patients with different degree of impairment of renal function. Excretion of galantamine attenuated the decrease in creatinine Cl. In patients with renal failure of moderate severity (creatinine Cl 52-104 ml/min), the concentration of galantamine in plasma was increased by 38%, and in patients with severe defect (Cl creatinine 9-51 ml/min) — increased by 67% compared with healthy people of the same age and weight (Cl creatinine >121 ml/min). Population pharmacokinetic study and analysis using a number of models showed that patients with Alzheimer's disease and impaired renal function the dose of galantamine to adjust is not necessary if Cl creatinine have not less than 9 ml/min (see "Method of application and dosage"), because the clearance of galantamine in patients with Alzheimer's reduced.
The plasma protein binding: the degree of binding of galantamine to plasma proteins and small amounts (17,7±0,8)%. In whole blood galantamine is primarily in the formed elements (52,7%) and in plasma (39,0%), while its fraction associated with plasma proteins is only 8.4 percent. The ratio of the concentrations of galantamine blood/plasma is equal to 1.17.
For galantamine characterized by slow clearance (clearance from plasma is about 300 ml/min) and moderate volume of distribution (mean volume of distribution at steady state is equal to 175 liters). Elimination of galantamine is bieksponencialny character, and the final T1/2 equal to about 7-8 h.
In a comparative study of the bioavailability of the drug Reminyl® in capsule form with prolonged release of the active substance, taken at a dose of 24 mg of 1 times a day, and in the form of tablets with immediate release of the active substance, taken at a dose of 12 mg 2 times a day shown the bioequivalence of these doses on indicators of AUC 24 h and SMP in the equilibrium state. Cmax achieved through 4.4 h after administration of the capsules at a dose of 12 mg of 1 times a day, was about 24% less than after taking the pills in the dose of 12 mg 2 times a day. Ingestion not affect the bioavailability of the drug Reminyl in capsule form with prolonged release of the active substance in the equilibrium state. In the study the dose dependence of the pharmacokinetics of the drug Reminyl in capsule form with prolonged release of the active substance in healthy elderly and young adults equilibrium concentration in the blood plasma of people in both age groups was achieved within 6 days at all doses (8, 16, or 24 mg). In both age groups pharmacokinetics in equilibrium directly dependent on the dose in the investigated range of doses (8-24 mg).
Description pharmacological action:
Galantamine, as a tertiary alkaloid is a selective, competitive and reversible acetylcholinesterase inhibitor. In addition, galantamine enhances the inherent acetylcholine action on nicotinic receptors, presumably due to binding to an allosteric site of the receptor. By increasing the activity of cholinergic system can get better cognitive function in patients with dementia of Alzheimer's type.
Indications:
Reminyl is indicated for the treatment of dementia of Alzheimer's type mild or moderate degree, including with chronic disorders of cerebral circulation.
Contraindications:
- hypersensitivity to galantamine hydrobromide or to any auxiliary substance included in the composition of the drug
- patients with severe impairment of renal function (Cl creatinine less than 9 ml/min) due to lack of data on the application
- severe violations of liver function.
With caution:
- General anesthesia
- bronchial asthma, COPD
- bradycardia, AV blockade syndrome weakness sinusnogo hub, unstable angina
- concomitant therapy with drugs that slow heart rate (digoxin, beta-blockers)
- ulcers disease stomach and duodenal ulcers, obstruction of the gastrointestinal tract, the period after undergoing surgery on the digestive tract
- epilepsy
- obstruction of the urinary tract, period after undergoing surgery on his bladder.
Application of pregnancy and breast-feeding:
Studies of the drug Reminyl in pregnant women have not been conducted.
Reminyl you can assign pregnant women only if the potential benefit to them outweighs the potential risk to the fetus.
It is unknown whether Reminyl is excreted in breast milk, studies involving lactating women were not conducted. Woman receiving Reminyl should refrain from breastfeeding.
Side effects:
Nausea and vomiting — the most common adverse reactions in clinical trials were observed in the selection of the dose, lasted in most cases for less than 1 week and was largely episodic. The appointment of antiemetic drugs, and ensuring adequate fluid intake is most effective in such cases.
Side effects of the drug Reminyl at therapeutic doses is given with the distribution by frequency and organ systems. The incidence of side effects were classified as follows: very common (&ge1/10 cases), often (&ge1/100, <1/10), infrequently (&ge1/1000 and <1/100), rare (&ge1/10,000 and <1/1000) and very rare (<1/10000 cases).
Disorders of metabolism and nutrition: often — decreased appetite, anorexia infrequently — dehydration (in rare cases — serious leading to kidney failure).
Mental disorders: often — depression (very rarely with the suicide) very rarely — visual and auditory hallucinations.
Violations of the nervous system: often — dizziness, headache, tremor, syncope, lethargy, drowsiness, rarely — dysgeusia, hypersomnia, paresthesia.
Ophthalmic disorders: rarely — blurred vision.
Violations of the ear and labyrinth: very rarely — tinnitus.
Violations by the cardiovascular system: often — aetiology rare — AV blockade of I degree, palpitations, supraventricular extrasystoles, flushing, decrease in blood pressure.
Violations by the gastrointestinal tract: very often — nausea, vomiting, often diarrhoea, pain in the abdomen, indigestion, gastrointestinal discomfort.
Hepatobiliary disorders: very rarely — hepatitis.
Violations of the skin and subcutaneous tissue: often — increased sweating.
Violations of the musculoskeletal system and connective tissue: often — muscle spasms infrequently — muscle weakness.
General disorders: often — fatigue, weakness.
Changes of measurement and laboratory parameters: often — reducing body weight very rarely — increased levels of liver enzymes.
In placebo-controlled clinical trials of the drug Reminyl have been observed very rarely, the following unwanted effects: hematuria, urinary tract infection, rhinitis, anemia, increased blood pressure. The incidence of these phenomena in the placebo group is comparable with the frequency of occurrence in the group of the drug Reminyl and, thus, the relation of these phenomena with the use of the drug Reminyl is not justified.
Drug interactions:
Pharmacodynamic interaction
Due to its inherent mechanism of action of galantamine cannot be used concomitantly with other cholinomimetics.
Galantamine is an antagonist anticholinergic drugs. As with other cholinomimetics, galantamine can join pharmacodynamic interactions with drugs which reduce heart rate (e.g. digoxin and beta-adrenoblokatora).
As cholinomimetics, galantamine may increase the block of neuromuscular depolarization time type of anesthesia (for example, when used as a peripheral muscle relaxant suxamethonium bromide).
Pharmacokinetic interaction
In the elimination of galantamine involves various metabolic pathways and renal excretion. In vitro studies have shown that the main role in the metabolism of galantamine playing coenzymes CYP2D6 and CYP3A4.
Inhibition of secretion of gastric juice does not violate the absorption of galantamine.
Other drugs affecting the metabolism of galantamine
Drugs that are strong inhibitors of co-enzymes CYP2D6 and CYP3A4 may increase the AUC of galantamine. Pharmacokinetic studies with repeated administration of drugs showed that the AUC of galantamine increased 30% and 40%, while the use of it accordingly with ketoconazole and paroxetine.
In concurrent use with erythromycin, which is also an inhibitor of the enzyme CYP3A4, AUC of galantamine increased only by about 10%. Pharmacokinetic studies in patients with Alzheimer's disease showed that the clearance of galantamine was decreased about 25-33% while 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 potent inhibitors of enzymes CYP2D6 and CYP3A4 may increase the frequency of cholinergic adverse events, mainly nausea and vomiting. In these situations, depending on the acceptability of the therapy to a particular patient, you may need to reduce the maintenance dose of galantamine.
Receptor antagonist N-methyl-D-aspartate (N???) memantine in a dose of 10 mg 1 time per day for 2 days, then 10 mg 2 times a day for 12 days did not affect the pharmacokinetics of galantamine at steady state after administration of doses of 16 mg 1 time per day.
The effect of galantamine on the metabolism of other drugs
Therapeutic doses of galantamine (12 mg 2 times a day) did not affect the kinetics of digoxin and warfarin. Galantamine did not affect the increase in PV caused by the warfarin.
In vitro studies showed that galantamine has a very weak ability to inhibit major forms of cytochrome P450 human.
Method of application and dose:
Inside, 1 time a day (morning), preferably with a meal.
Regimen
The recommended starting dose is 8 mg per day.
Patients already receiving Reminyl in other forms with immediate release of active substance (table). you can go for the drug Reminyl in the form of capsules prolonged action by last dose in tablet form evenings and start taking in the form of capsules 1 times a day the next morning.
In the transition from drug Reminyl in the form of tablets with immediate release of the active substance, taken 2 times a day, Reminyl in the form of capsules prolonged action, taken 1 time a day, the total daily dose should remain unchanged.
During treatment it is necessary to take a sufficient amount of liquid.
Maintenance dose
The initial maintenance dose is 16 mg per day, patients should take this dose at least 4 weeks.
The issue of increasing maintenance dose to the maximum recommended 24 mg / day should be addressed after a thorough evaluation of the clinical situation, in particular the achieved effect and tolerability.
After abrupt discontinuation of the drug Reminyl (e.g. in preparation for surgery) worsening of symptoms occurs.
When a break in taking the drug within a few days you should take the initial dose of the drug Reminyl and then increase the dose according to the above scheme to the previous maintenance dose.
Children
Reminyl is not recommended for the treatment of children. Data on the use of Reminyl drug in children are missing.
Patients with diseases of the liver and kidneys
In patients with moderate and severe liver concentration of galantamine in plasma may be higher than in patients without such lesions. In patients with moderate hepatic impairment initial dose (based on pharmacokinetic data) should be 8 mg once a day a day, it should be taken in the morning for at least 1 week. After that, patients can take 8 mg once a day for at least 4 weeks. Daily dose should not exceed 16 mg.
Patients with severe hepatic impairment (> 9 points on a scale child-Pugh) Reminyl is not recommended.
Patients with severe impairment of renal function (Cl creatinine <9 ml/min) Reminyl is not recommended (due to lack of data).
Patients with Cl creatinine more than 9 ml/min adjusted dose not necessary.
Concomitant therapy
If the patient receives a strong inhibitor of CYP2D6 or CYP3A4 coenzyme, it may be necessary to reduce the dose of the drug Reminyl.
Overdose:
Symptoms: it is assumed that the objective and subjective symptoms of severe overdosing of galantamine are similar to those symptoms of overdose of other cholinomimetics. Observed mainly toxic effects in the Central nervous system, the parasympathetic nervous system and neuromuscular synapses. In addition to muscle weakness or fasciculations may experience some or all of the symptoms of cholinergic crisis: severe nausea, vomiting, spastic abdominal pain, increased salivation, lacrimation, urinary incontinence and fecal incontinence, severe sweating, bradycardia, decreased blood pressure, collapse and convulsions. Expressed muscle weakness combined with hypersecretion of mucous membranes trachea and bronchospasm may lead to a lethal blockade of the respiratory tract.
In the reports received during post-marketing control, describes the development of bi-directionally - fusiform ventricular tachycardia, elongation QT interval, ventricular tachycardia with transient loss of consciousness in case of accidental ingestion of 32 mg Reminyl a day.
Treatment: as with the overdose of any other drug, you need to carry out regular support activities. In severe cases, as a General antidote can be used anticholinergic drugs such as atropine. It is recommended to inject 0.5–1.0 mg/in, the frequency and amount of subsequent doses depend on the dynamics of the clinical condition of the patient.
Treatment strategies overdoses are constantly evolving, and therefore you should contact the nearest treatment center for poisoning to get the latest recommendations on the treatment of overdose of galantamine.
Special instructions:
The use of the drug Reminyl at other types of dementia or other memory impairment.
The positive effects of the drug Reminyl in patients with other types of dementia and other types of memory impairment is not demonstrated.
Patients with Alzheimer's disease lose weight. Treatment with acetylcholinesterase inhibitors, including galantamine, accompanied by a decrease in body mass of these patients, and therefore during treatment necessary to monitor changes in body weight.
As with other cholinomimetics, Reminyl should be used with caution in the following conditions:
Cardiovascular disease: because of their pharmacological action, cholinomimetics may cause vagotonic effects on the heart (e.g., bradycardia). The consequences of such effects may be most severe in patients with the syndrome sick sinus and other supraventricular conduction disorders, and in patients who simultaneously receive drugs that reduce heart rate such as digoxin or beta-blockers. Treatment with Reminyl were accompanied by fainting, and rarely — expressed aetiology. Should be used with caution in unstable angina.
Gastrointestinal diseases: patients with increased risk of development of peptic ulcer disease, such as having peptic ulcer disease in anamnesis or predisposed to it, it is necessary to monitor the relevant symptoms. It should be noted, however, that clinical trials did not reveal in patients receiving Reminyl, increase, compared with patients who received placebo, the frequency of peptic ulcers and gastrointestinal bleeding. Reminyl is not recommended in patients with obstruction of the gastrointestinal tract, and also in patients who recently had surgery on the digestive system.
Neurological diseases: it is believed that cholinomimetics have some potential to cause generalized convulsions. It should be remembered, however, that seizure activity may be a manifestation of Alzheimer's disease. In clinical trials there was no increase in the frequency of seizures in patients taking Reminyl compared to patients treated with placebo.
Lung disease: due to the cholinomimetic activity of Reminyl should be used with caution in patients with severe asthma or obstructive pulmonary disease.
Urogenital disease: Reminyl is not recommended in patients with obstruction of the urinary tract, and in patients who have recently undergone surgery on the bladder.
Safety in patients with mild cognitive impairment (SKN)
Reminyl is not intended for patients with SCN, i.e., for patients with isolated violation of memory, above the expected level for their age and education but not satisfying the criteria of Alzheimer's disease.
Effect on driving and operating machinery
Alzheimer's disease can negatively affect the ability to drive a car or work with mechanisms. Moreover, Reminyl, like other cholinomimetics that can cause drowsiness and dizziness, which affect driving and operating machinery, especially during the first weeks after beginning treatment with this drug.
