Reminyl^® (Tablets, Capsules, Solution) Instructions for Use

ATC Code

N06DA04 (Galantamine)

Active Substance

Galantamine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Selective inhibitor of acetylcholinesterase in the brain. A drug for the treatment of Alzheimer’s disease

Pharmacotherapeutic Group

Anticholinesterase agent

Pharmacological Action

Galantamine, being a tertiary alkaloid, is a selective, competitive, and reversible inhibitor of acetylcholinesterase.

In addition, Galantamine enhances the inherent effect of acetylcholine on nicotinic receptors, apparently due to binding to the allosteric site of the receptor.

By increasing the activity of the cholinergic system, cognitive function may improve in patients with dementia of the Alzheimer’s type.

Pharmacokinetics

Galantamine is characterized by slow clearance (plasma clearance is about 300 ml/min) and a moderate V_d (mean V_d at steady state is 175 L).

The elimination of galantamine is biexponential, and the terminal T_1/2 is approximately 7-8 hours.

After a single oral dose of 8 mg of galantamine, it is rapidly absorbed from the gastrointestinal tract; its C_max was reached in 1.2 hours and was 43±13 ng/ml, and the AUC_0-∞ is 427±102 ng·h/ml.

The absolute bioavailability of galantamine after oral administration is 88.5%. Taking galantamine with food slows its absorption (C_max decreases by 25%), but does not affect the amount of drug absorbed (AUC).

After multiple doses of galantamine 12 mg twice daily, the mean concentrations at the end of the dosing interval and C_max in plasma ranged from 30 to 90 ng/ml.

The pharmacokinetics of galantamine are linear in the dose range of 4-16 mg twice daily.

Within 7 days after a single oral dose of 4 mg ³H-galantamine, 90-97% of the radioactivity was excreted in the urine and 2.2-6.3% in the feces.

After oral administration, 18-22% of the dose was excreted as unchanged galantamine in the urine within 24 hours, renal clearance was about 65 ml/min, which is 20-25% of the total plasma clearance.

The main metabolic pathways are N-oxidation, N-demethylation, O-demethylation, glucuronidation, and epimerization.

In people with active metabolism of CYP2D6 substrates, the most important metabolic pathway is O-demethylation. The amount of radioactive substances excreted in urine and feces did not differ between people with rapid and slow metabolism. In vitro studies have shown that the main cytochrome P450 isoenzymes involved in the metabolism of galantamine are 2D6 and 3A4.

In the plasma of people with rapid and slow metabolism, the main part of the radioactive substances consists of unchanged Galantamine and its glucuronide.

In the plasma of people with rapid metabolism, the glucuronide of O-desmethylgalantamine is also detected. After a single dose of galantamine, none of the active metabolites (norgalantamine, O-demethyl-Galantamine, and O-demethylnorgalantamine) were present in unconjugated form in the plasma of “rapid and slow metabolizers”.

Norgalantamine was detected in the plasma of patients after multiple doses of galantamine, but its amount was no more than 10% of galantamine levels.

Results from clinical trials have demonstrated that plasma concentrations of galantamine are 30-40% higher in patients with Alzheimer’s disease than in young healthy subjects.

The pharmacokinetic parameters of galantamine in patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) were similar to those in healthy subjects.

In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), the AUC and T_1/2 of galantamine were increased by approximately 30%.

The distribution of galantamine was studied in young patients with varying degrees of renal impairment.

The excretion of galantamine was attenuated as creatinine clearance decreased. In patients with moderate renal impairment (creatinine clearance 52-104 ml/min), plasma concentrations of galantamine were increased by 38%, and in patients with severe impairment (creatinine clearance 9-51 ml/min) they were increased by 67% compared to healthy people of the same age and weight (creatinine clearance >121 ml/min).

A population pharmacokinetic study and analysis using a number of models showed that in patients with Alzheimer’s disease and renal impairment, the dose of galantamine does not need to be adjusted if their creatinine clearance is not less than 9 ml/min, because the clearance of galantamine is reduced in patients with Alzheimer’s disease.

Binding to plasma proteins: the degree of binding of galantamine to plasma proteins is low and is 17.7 ± 0.8%.

In whole blood, Galantamine is found predominantly in formed elements (52.7%) and in plasma (39.0%), while its fraction bound to plasma proteins is only 8.4%. The blood/plasma concentration ratio of galantamine is 1.17.

A comparative bioavailability study of Reminyl^® in the form of extended-release capsules taken at a dose of 24 mg once a day and in the form of immediate-release tablets taken at a dose of 12 mg twice a day showed the bioequivalence of these dosages in terms of AUC_{0-24 h} and C_min at steady state.

C_max, achieved 4.4 hours after taking the capsules at a dose of 12 mg once a day, was approximately 24% lower than after taking the tablets at a dose of 12 mg twice a day. Food intake did not affect the bioavailability of Reminyl^® in the form of extended-release capsules at steady state.

In a dose-dependency study of the pharmacokinetics of Reminyl^® in the form of extended-release capsules in healthy elderly and young people, steady-state plasma concentrations in people of both age groups were reached within 6 days at all doses (8, 16, or 24 mg).

In both age groups, steady-state pharmacokinetics were directly dependent on the dose in the studied dose range (8-24 mg).

Indications

• Dementia of the Alzheimer’s type of mild or moderate degree, including with chronic cerebrovascular accidents.

ICD codes

Dosage Regimen

Solution

For oral administration, the daily dose is 5-10 mg, the frequency of administration is 3-4 times/day after meals, the duration of treatment is 4-5 weeks. High doses are taken for a shorter period of time.

For subcutaneous administration, single doses for adults are 2.5-10 mg; for children aged 1-2 years – 0.25-0.5 mg, 3-5 years – 0.5-1 mg, 6-8 years – 0.75-2 mg, 9-11 years – 1.25-3 mg, 12-14 years – 1.75-5 mg, 15-16 years – 2-7 mg, if necessary the dose can be increased, but strictly individually. For adults, the maximum single dose is 10 mg, the daily dose is 20 mg. Frequency of application is 1-2 times/day. Therapy is started with minimal doses, which are gradually increased; frequency of application in high doses is 3 times/day. The course of treatment lasts up to 50 days; if necessary, 2-3 repeated courses can be conducted with an interval of 1-1.5 months.

For intravenous administration, single doses for adults are 10-25 mg; for children 1-2 years – 1-2 mg, 3-5 years – 1.5-3 mg, 6-8 years – 2-5 mg, 9-11 years – 3-8 mg, 12-15 years – 5-10 mg.

Capsules

Initial dose

Reminyl^® in the form of extended-release capsules should be taken orally once a day (in the morning), preferably with food. The recommended initial dose is 8 mg/day.

Patients already taking Reminyl^® in other immediate-release forms (tablets) can switch to taking Reminyl^® in the form of extended-release capsules by taking the last dose of Reminyl^® in tablet form in the evening and starting to take Reminyl^® in capsule form once a day the next morning.

When switching from Reminyl^® in the form of immediate-release tablets taken twice a day to Reminyl^® in the form of extended-release capsules taken once a day, the total daily dose should remain unchanged.

During treatment, sufficient fluid intake should be maintained.

Maintenance dose

The initial maintenance dose is 16 mg/day, patients should take this dose for at least 4 weeks.

The decision to increase the maintenance dose to the maximum recommended 24 mg/day should be made after a comprehensive assessment of the clinical situation, in particular the achieved effect and tolerability.

No exacerbation of symptoms occurs after abrupt withdrawal of Reminyl^® (for example, in preparation for surgery). If the drug is interrupted for several days, the initial dose of Reminyl^® should be taken and then the dose should be increased according to the above scheme to the previous maintenance dose.

There is no significant experience with the use of Reminyl^® in children.

In patients with moderate and severe liver damage, plasma concentrations of galantamine may be higher than in patients without such damage. In patients with moderate hepatic impairment, the initial dose (based on pharmacokinetic data) should be 8 mg once a day every other day, it should be taken in the morning for at least one week. After that, patients can take 8 mg once a day for at least 4 weeks. The daily dose should not exceed 16 mg.

Patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale) are not recommended to take Reminyl^®.

Patients with severe renal impairment (creatinine clearance less than 9 ml/min) are not recommended to take Reminyl^® (due to lack of data). In patients with creatinine clearance greater than 9 ml/min, the dose of Reminyl^® does not need to be adjusted.

If the patient is taking strong inhibitors of the CYP2D6 or CYP3A4 coenzymes, it may be necessary to reduce the dose of Reminyl^®.

Tablets

Reminyl^® should be taken twice a day, preferably with morning and evening meals.

The initial dose is 8 mg/day (4 mg twice a day), it should be taken for 4 weeks.

The maintenance dose is 16 mg/day (8 mg twice a day), it should also be taken for at least 4 weeks. The decision to increase the maintenance dose to the maximum recommended 24 mg/day (12 mg twice a day) should be made after a comprehensive assessment of the clinical situation, in particular the achieved effect and tolerability.

In moderate hepatic impairment, the initial dose should be 4 mg once a day, it should be taken in the morning for at least 1 week. After that, patients can take 4 mg twice a day for at least 4 weeks.

In renal impairment (creatinine clearance >9 ml/min), no adjustment of the Reminyl^® dose is required.

When taken concomitantly with strong inhibitors of the CYP2D6 or CYP3A4 isoenzymes, it may be necessary to reduce the dose of Reminyl^®.

Adverse Reactions

Nausea and vomiting are the most common adverse events in clinical trials – observed during dose titration of the drug, lasted in most cases for less than 1 week and were mostly episodic.

Prescription of antiemetics and ensuring adequate fluid intake is most effective in such cases.

The side effects of Reminyl^® at therapeutic doses are presented with distribution by frequency and organ systems. The frequency of side effects was classified as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000 and <1/100), rare (>1/10000 and <1/1000) and very rare (<1/10000).

Immune system disorders uncommon – hypersensitivity.

Metabolism and nutrition disorders common – decreased appetite, anorexia; uncommon – dehydration (including, in rare cases, severe, leading to renal failure).

Psychiatric disorders common – depression (very rarely with suicide), hallucinations; uncommon – visual and auditory hallucinations.

Nervous system disorders common – dizziness, headache, tremor, syncope, lethargy, somnolence; uncommon – taste perversion; hypersomnia; paresthesia.

Eye disorders uncommon – blurred vision.

Ear and labyrinth disorders very rare – tinnitus.

Cardiac and vascular disorders common – bradycardia; uncommon – first-degree AV block, palpitations, supraventricular extrasystole, flushing, decreased blood pressure.

Gastrointestinal disorders very common – nausea, vomiting; common – diarrhea, abdominal pain, dyspepsia, gastrointestinal discomfort.

Hepatobiliary disorders very rare – hepatitis.

Skin and subcutaneous tissue disorders common – increased sweating.

Musculoskeletal and connective tissue disorders common – muscle spasms; uncommon – muscle weakness.

General disorders and administration site conditions common – fatigue, asthenia.

Investigations common – weight loss; very rare – increased liver enzyme activity.

In placebo-controlled clinical trials of Reminyl^®, the following adverse events were very rarely observed: hematuria, urinary tract infections, rhinitis, anemia, increased blood pressure.

The frequency of these events in the placebo group was comparable to the frequency in the group taking Reminyl^® and, thus, the relationship of these events with the use of Reminyl^® has not been proven.

Contraindications

• Severe renal failure (creatinine clearance <9 ml/min);
• Severe hepatic impairment;
• Hypersensitivity to galantamine hydrobromide or to any excipient that is part of this drug.

With caution the drug should be used for general anesthesia, in patients with bronchial asthma, COPD, with bradycardia, AV block, sick sinus syndrome, unstable angina; with concomitant therapy with drugs that slow the heart rate (digoxin, beta-blockers), with peptic ulcer of the stomach and duodenum, gastrointestinal obstruction, the period after surgery on the gastrointestinal tract, epilepsy, urinary tract obstruction, the period after surgery on the bladder.

Use in Pregnancy and Lactation

No studies on the safety of Reminyl^® use during pregnancy have been conducted. Reminyl^® can be prescribed during pregnancy only in cases where the potential benefit of treatment for the mother outweighs the possible risk to the fetus.

It is not known whether Galantamine is excreted in human breast milk. Women receiving Reminyl^® should refrain from breastfeeding.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Use in Renal Impairment

The drug is contraindicated in severe renal impairment (creatinine clearance less than 9 ml/min).

Pediatric Use

Reminyl^® is not recommended for the treatment of children. There are no data on the efficacy and safety of Reminyl^® use in pediatric practice.

Special Precautions

Use of Reminyl^® for other types of dementia or other memory impairments

Positive effects of Reminyl^® use in patients with other types of dementia and other types of memory impairment have not been demonstrated.
Patients with Alzheimer’s disease lose weight. Treatment with acetylcholinesterase inhibitors, including Galantamine, is accompanied by a decrease in body weight in such patients, and therefore changes in body weight should be monitored during treatment.

Like other cholinomimetics, Reminyl^® should be used with caution in the following diseases

Cardiovascular diseases due to their pharmacological action, cholinomimetics can cause vagotonic effects on the heart (e.g., bradycardia). The consequences of such effects can be most serious in patients with sick sinus syndrome and other supraventricular conduction disorders, as well as in patients who are simultaneously receiving drugs that reduce heart rate, such as digoxin or beta-blockers. Treatment with Reminyl^® has been accompanied by syncope and rarely – marked bradycardia. Should be used with caution in unstable angina.

Gastrointestinal diseases in patients with an increased risk of developing peptic ulcer, for example, those with a history of peptic ulcer or predisposed to it, it is necessary to monitor for relevant symptoms. It should be noted, however, that clinical trials did not reveal an increase in the frequency of peptic ulcers and gastrointestinal bleeding in patients receiving Reminyl^® compared with patients receiving placebo. Reminyl^® is not recommended for use in patients with gastrointestinal obstruction, as well as in patients who have recently undergone surgery on the digestive organs.

Neurological diseases cholinomimetics are believed to have some potential to cause generalized seizures. It should be remembered, however, that seizure activity may be a manifestation of Alzheimer’s disease itself. Clinical trials did not show an increase in the frequency of seizures in patients taking Reminyl^® compared with patients receiving placebo.

Pulmonary diseases due to the cholinomimetic activity of Reminyl^{® ®} should be used with caution in patients suffering from severe bronchial asthma or obstructive pulmonary disease.

Urogenital diseases Reminyl^{® ®} is not recommended for use in patients with urinary tract obstruction, as well as in patients who have recently undergone bladder surgery.

Safety in patients with mild cognitive impairment

Reminyl^® is not intended for patients with mild cognitive impairment, i.e., for patients with isolated memory impairment exceeding the expected level for their age and education, but not meeting the criteria for Alzheimer’s disease.

Effect on ability to drive vehicles and operate machinery

Alzheimer’s disease may impair the ability to drive and operate machinery. In addition, the use of Reminyl^®, like other cholinomimetics, can cause drowsiness and dizziness, which negatively affect driving and operating machinery, especially in the first weeks after starting treatment with this drug.

Overdose

Symptoms. It is assumed that the objective and subjective symptoms of a pronounced galantamine overdose will be similar to those of an overdose of other cholinomimetics.

Primarily, toxic effects on the central nervous system, the parasympathetic nervous system, and neuromuscular synapses are observed. In addition to muscle weakness or fasciculations, some or all symptoms of a cholinergic crisis may occur: severe nausea, vomiting, cramping abdominal pain, increased salivation, lacrimation, urinary and fecal incontinence, severe sweating, bradycardia, decreased blood pressure, collapse, and convulsions.

Pronounced muscle weakness combined with hypersecretion of the tracheal mucosa and bronchospasm can lead to lethal airway obstruction.

Reports obtained from post-marketing surveillance have described the development of bidirectional spindle-shaped ventricular tachycardia, QT interval prolongation, and ventricular tachycardia with brief loss of consciousness following accidental intake of 32 mg of Reminyl^® per day.

Treatment. As with an overdose of any other drug, general supportive measures should be implemented.

In severe cases, anticholinergic drugs such as atropine can be used as a general antidote.

An initial intravenous administration of 0.5-1 mg is recommended; the frequency and size of subsequent doses depend on the dynamics of the patient’s clinical condition.

Overdose treatment strategies are constantly being improved, and therefore, the nearest poison control center should be contacted for the latest recommendations regarding the treatment of galantamine overdose.

Drug Interactions

Due to its inherent mechanism of action, Galantamine should not be used concurrently with other cholinomimetics.

Galantamine is an antagonist of anticholinergic drugs.

Like other cholinomimetics, Galantamine may engage in pharmacodynamic interactions with drugs that reduce heart rate (e.g., digoxin and beta-blockers).

Being a cholinomimetic, Galantamine may enhance the depolarizing-type neuromuscular blockade during anesthesia (e.g., when suxamethonium bromide is used as a peripheral muscle relaxant).

Pharmacokinetic Interactions

Various metabolic pathways and renal excretion are involved in the elimination of galantamine.

In vitro studies have shown that the coenzymes CYP2D6 and CYP3A4 play a major role in the metabolism of galantamine.

Inhibition of gastric acid secretion does not impair the absorption of galantamine.

Drugs that are strong inhibitors of the CYP2D6 and CYP3A4 coenzymes may increase the AUC of galantamine.

Multiple-dose pharmacokinetic studies have shown that the AUC of galantamine increases by 30% and 40% when co-administered with ketoconazole and paroxetine, respectively.

When used concomitantly with erythromycin, which is also an inhibitor of the CYP3A4 enzyme, the AUC of galantamine increases by only about 10%.

Pharmacokinetic studies in patients with Alzheimer’s disease have shown that the clearance of galantamine decreased by approximately 25-33% when this drug was used concomitantly with known inhibitors of the CYP2D6 enzyme, such as amitriptyline, fluoxetine, fluvoxamine, paroxetine, or quinidine.

Thus, at the initiation of treatment with strong inhibitors of the CYP2D6 and CYP3A4 enzymes, the frequency of cholinergic adverse events, mainly nausea and vomiting, may increase.

In these situations, depending on the therapy tolerance of the specific patient, it may be necessary to reduce the maintenance dose of galantamine.

The N-methyl-D-aspartate (NMDA) receptor antagonist memantine at a dose of 10 mg/day for 2 days, then 10 mg twice daily for 12 days, did not affect the steady-state pharmacokinetics of galantamine after a dose of 16 mg/day.

Effect of Galantamine on the Metabolism of Other Drugs

Therapeutic doses of galantamine (12 mg twice daily) did not affect the kinetics of digoxin and warfarin.

Galantamine did not affect the increase in prothrombin time caused by warfarin.

In vitro studies have shown that Galantamine has a very weak ability to inhibit the major forms of human cytochrome P450.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.