Galnora^® SR (Capsules) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

N06DA04 (Galantamine)

Active Substance

Galantamine (Rec.INN registered by WHO)

Dosage Forms

	Galnora® SR	Extended-release capsules 8 mg: 7, 28, 30, 56, 60, 84 or 90 pcs.
		Extended-release capsules 16 mg: 7, 28, 30, 56, 60, 84 or 90 pcs.
		Extended-release capsules 24 mg: 7, 28, 30, 56, 60, 84 or 90 pcs.

Dosage Form, Packaging, and Composition

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (6) – cardboard packs.

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (6) – cardboard packs.

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Dementia treatment agent

Pharmacological Action

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

In addition, Galantamine enhances the effect of acetylcholine on nicotinic receptors, probably by 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 a base with one dissociation constant (pKa 8.2).

It has low lipophilicity with a distribution coefficient (LogP) between n-octanol and buffer solution (pH 12) equal to 1.09.

Solubility in water (pH 6) is 31 mg/ml.

Galantamine has 3 chiral centers.

The S, R, S-configuration is natural.

Galantamine is partially metabolized by various cytochromes, mainly the CYP2D6 and CYP3A4 isoenzymes.

Some of the metabolites formed during the degradation of galantamine are active in vitro, but are not significant in vivo.

Absorption

The absolute bioavailability of galantamine after oral administration is high – 88.5 ± 5.4%.

The AUC_24h and C_min plasma levels are similar to those of immediate-release galantamine taken twice daily.

C_max in plasma is reached after 4.4 hours.

The C_max of extended-release galantamine is 24% lower than after taking immediate-release galantamine.

Food intake does not significantly affect AUC, while it causes an increase in C_max by approximately 12% and an extension of the time to reach C_max (T_max) by approximately 30 minutes.

However, these changes are not clinically significant.

Distribution

The mean volume of distribution (Vd) is 175 L.

The degree of binding to plasma proteins is low and is 18%.

Metabolism

In vitro studies have shown that the main cytochrome P450 isoenzymes involved in the biotransformation of galantamine are CYP2D6 and CYP3A4.

The CYP2D6 isoenzyme is involved in the formation of O-desmethylgalantamine, and the CYP3A4 isoenzyme is involved in the formation of N-oxide-galantamine.

The excretion of the 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 CYP2D6 isoenzyme, respectively).

In the plasma of patients with “fast” and “slow” metabolism, the main part of radioactive substances is unchanged Galantamine and its glucuronide.

After a single dose of galantamine, none of the active metabolites of galantamine (nor-galantamine, O-desmethylgalantamine and O-desmethylnor-galantamine) were detected in unconjugated form in the plasma of patients with “fast” and “slow” metabolism.

Nor-galantamine was found in the plasma of patients after long-term use of the drug, and its concentration was no more than 10% of the galantamine concentration.

In vitro studies indicate a very low ability of the main human cytochrome P450 isoenzymes to inhibit Galantamine.

Excretion

The elimination of galantamine is biexponential.

The terminal T_1/2 in healthy volunteers is 8-10 hours.

Based on studies of immediate-release galantamine in population studies, the clearance after oral administration of galantamine in the target population is generally about 200 ml/min with an interindividual variability of 30%.

Seven days after a single oral dose of 4 mg ³H-galantamine, 90-97% of the radioactive dose is excreted by the kidneys as 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 within 24 hours.

Renal clearance was 65 ml/min (20-25% of total plasma clearance).

Pharmacokinetics are linear in the dose range from 8 mg to 24 mg when taken once daily in elderly patients and young patients.

Pharmacokinetics in special patient groups

Results from clinical studies have shown that in patients with Alzheimer’s disease, plasma concentrations of galantamine are 30-40% higher than in young healthy individuals.

Based on population pharmacokinetic data analysis, clearance in women is 20% lower than in men.

Clearance of galantamine in patients with “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 metabolic status of the patient is not considered clinically significant in the general population.

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

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%.

Renal impairment In patients with Alzheimer’s disease and renal impairment (creatinine clearance (CrCl) ≥ 9 ml/min), no dose adjustment is required.

Pharmacokinetic-pharmacodynamic relationship

In large phase III studies with galantamine dosing regimens of 12 mg and 16 mg twice daily, no apparent correlation was observed between mean plasma concentrations and efficacy measures (changes in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog/11) and the Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus) at the 6th month of therapy).

Plasma concentrations in patients with syncope were in the same range as in other patients taking the same dose.

The occurrence of nausea correlates with a higher peak plasma concentration.

Indications

• Symptomatic treatment of mild to moderate dementia of the Alzheimer’s type.

ICD codes

Dosage Regimen

Orally, once a day (in the morning), preferably with food.

The capsule should be swallowed whole with a small amount of liquid.

The capsules should not be chewed or broken.

Patients who have difficulty swallowing may extract the contents from the capsule and swallow it whole with water.

The capsule contents 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.

The patient’s condition should be regularly monitored for 3 months from the start of therapy.

Subsequently, the effectiveness of the drug and the patient’s condition are regularly assessed in accordance with clinical guidelines.

Maintenance therapy can be continued as long as the therapeutic effect persists and the therapy is well tolerated.

In the absence of a therapeutic effect or poor tolerance of therapy, the drug should be discontinued.

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 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 treatment effectiveness 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), no withdrawal syndrome develops.

Transition from therapy with immediate-release galantamine tablets to therapy with Galnora^® SR extended-release capsules

When switching from immediate-release galantamine tablets taken twice a day to therapy with Galnora^® SR extended-release capsules taken once a day, the daily dose should remain unchanged.

The patient should take the last immediate-release tablet in the evening and the next day, in the morning, start taking Galnora^® SR once a day.

In case of a break in taking the drug for several days, the initial dose of Galnora^® SR should be taken and then the dose should be increased according to the above scheme to the previous maintenance dose.

Hepatic impairment

In patients with moderate and severe hepatic and/or renal impairment, plasma concentrations of galantamine may increase.

In patients with moderate hepatic impairment, the recommended initial dose is 8 mg once daily every other day, preferably in the morning, for one week.

Subsequently, 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 hepatic impairment, no dose adjustment is required.

Renal impairment

In patients with CrCl greater than 9 ml/min, no dose adjustment is required.

Combination therapy

When used concomitantly with potent inhibitors of the CYP2D6 or CYP3A4 isoenzymes, a dose reduction of Galnora^® SR may be required (see section “Drug Interactions”).

Adverse Reactions

The most common adverse effects were nausea and vomiting.

Adverse events were mostly episodic, observed during galantamine dose titration, and lasted, in most cases, less than a week.

In these cases, it is advisable to use antiemetics and ensure adequate fluid intake.

The frequency and nature of adverse events when using galantamine in the form of extended-release capsules once a day are comparable to those when taking immediate-release tablets.

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

Very common ≥ 1/10

Common from ≥ 1/100 to < 1/10

Uncommon from ≥ 1/1000 to < 1/100

Rare from ≥ 1/10000 to < 1/1000

Very rare < 1/10000

Frequency unknown – cannot be estimated from available data.

*Potentially cholinomimetic drugs may cause seizures.

Contraindications

• Hypersensitivity to galantamine hydrobromide and other components of the drug;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Severe renal impairment (CrCl less than 9 ml/min);
• Children under 18 years of age (insufficient data on efficacy and safety).

With caution sick sinus syndrome (SSS), incl. bradycardia, supraventricular conduction disorders, period after acute myocardial infarction, hyperkalemia, hypokalemia, second- and third-degree atrioventricular block, unstable angina, chronic heart failure of functional class III-IV according to the NYHA classification, newly diagnosed atrial fibrillation, simultaneous use with drugs that help reduce heart rate (digoxin, beta-blockers), sedatives, ethanol; arterial hypertension, epilepsy, history of gastric and duodenal ulcer, simultaneous use of NSAIDs, gastrointestinal obstruction, condition after surgery on the gastrointestinal tract and bladder, urinary tract obstruction, bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), acute infectious lung diseases, general anesthesia.

Use in Pregnancy and Lactation

There are no clinical data on the use of galantamine in pregnant women.

Animal studies have revealed reproductive toxicity.

Caution should be exercised when using Galnora^® SR in pregnant women.

There are no data on the excretion of galantamine in breast milk.

No clinical studies have been conducted in breastfeeding women, so the use of Galnora^® SR during breastfeeding is not recommended.

Use in Hepatic Impairment

The drug is contraindicated in patients with severe renal impairment (CrCl less than 9 ml/min).

Use in Renal Impairment

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

Pediatric Use

The drug is contraindicated in children under 18 years of age (insufficient data on efficacy and safety).

Special Precautions

Galnora^® SR is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

The effectiveness of using galantamine in patients with other types of dementia and other memory disorders has not been established.

No positive effect of using galantamine (for 2 years) on slowing cognitive impairment and slowing the transition to clinically significant dementia in patients with “mild” cognitive impairment syndrome (“mild” types of memory impairment that do not meet the criteria for dementia of the Alzheimer’s type) has been established.

Mortality in the galantamine group was significantly higher than in the placebo group, 14/1026 (1.4%) patients receiving Galantamine and 3/1022 (0.3%) patients receiving placebo.

The causes of death were varied.

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 dementia of the Alzheimer’s type is unknown.

Placebo-controlled studies in patients with dementia of the Alzheimer’s type were conducted for only 6 months.

In these studies, mortality in the galantamine group was not increased.

Treatment with Gallynora^® CP should be carried out only under the supervision of a physician and under the supervision of a person providing care for the patient.

Patients with Alzheimer’s disease experience weight loss. Treatment with cholinomimetic agents, including Galantamine, is associated with weight loss, so this parameter should be monitored during therapy. Like other cholinomimetic agents, Gallynora^® CP should be used with caution in the following conditions.

Cardiovascular diseases

Due to their pharmacological action, cholinomimetic agents can cause vagotonic effects (e.g., bradycardia). It should be used with caution in patients with sick sinus syndrome and other supraventricular conduction disorders, during concomitant therapy with drugs that reduce heart rate (digoxin and beta-blockers), in patients with electrolyte imbalances (hyperkalemia, hypokalemia), in the period after acute myocardial infarction; in newly diagnosed atrial fibrillation: in patients with atrioventricular block II-III degree, unstable angina or chronic heart failure, especially NYHA functional class III-IV.

During therapy with Gallynora^® CP for dementia of the Alzheimer’s type, the risk of adverse reactions from the cardiovascular system increases.

Digestive system diseases

In patients with an increased risk of erosive and ulcerative lesions of the gastrointestinal tract (e.g., history of gastric and duodenal ulcers, NSAID therapy), the condition should be monitored for early detection of relevant pathological symptoms. Gallynora^® CP is not recommended for use in patients with gastrointestinal obstruction or after recent gastrointestinal surgery.

Nervous system diseases

The use of cholinomimetic agents can cause seizures. It should be remembered that seizure activity may be a manifestation of Alzheimer’s disease itself. In rare cases, increased cholinergic tone may cause worsening of Parkinson’s disease.

Cerebrovascular events were uncommonly reported in patients with dementia of the Alzheimer’s type using Galantamine. This should be taken into account when prescribing galantamine to patients with cerebrovascular pathology.

Respiratory system diseases

Gallynora^® CP should be prescribed with caution to patients with severe asthma, COPD, acute infectious lung diseases (e.g., pneumonia).

Kidney and urinary tract diseases

Gallynora^® CP is not recommended for use in patients with urinary tract obstruction, or who have recently undergone bladder surgery.

General anesthesia

Galantamine, being a cholinomimetic, may enhance depolarizing neuromuscular blockade (muscle relaxation) caused by general anesthesia (when suxamethonium is used as a peripheral muscle relaxant), especially in cases of pseudocholinesterase deficiency.

Abrupt discontinuation of treatment (e.g., before surgery) does not cause a withdrawal syndrome.

Effect on the ability to drive vehicles and operate machinery Gallynora^® CP, like other cholinomimetic agents, may cause drowsiness and dizziness, which negatively affect the ability to drive vehicles and operate machinery, especially during the first weeks after starting treatment.

Overdose

Symptoms Symptoms of galantamine overdose are likely similar to those of overdose with other cholinomimetics. Changes in the CNS, parasympathetic nervous system, and neuromuscular synapses are usually noted. Muscle weakness or fasciculations are possible, as well as some or all symptoms of cholinergic crisis: severe nausea, vomiting, cramping abdominal pain, increased salivation, lacrimation, urinary and fecal incontinence, increased sweating, bradycardia, decreased blood pressure, collapse, and convulsions. Severe muscle weakness combined with hypersecretion of the tracheal mucosa and bronchospasm can lead to life-threatening airway obstruction.

Post-marketing surveillance has reported cases of bidirectional fusiform (polymorphic) ventricular tachycardia of the “torsades de pointes” type, QT interval prolongation, bradycardia, ventricular tachycardia with brief loss of consciousness following unintentional galantamine overdose. In one of these cases, the patient took 32 mg of galantamine orally in one day.

Additionally, two cases of accidental intake of galantamine at a dose of 32 mg (nausea, vomiting, and dry oral mucosa; nausea, vomiting, and retrosternal pain) and one case at a dose of 40 mg (vomiting) with full recovery were described. One patient with a history of hallucinations over the previous two years (prescribed 24 mg/day) developed hallucinations requiring hospitalization after unintentionally taking galantamine 24 mg twice daily for 34 days. Another patient (prescribed 16 mg/day galantamine oral solution) developed increased sweating, vomiting, bradycardia, and near-syncope one hour after accidental intake of 160 mg of galantamine (40 ml of oral solution), requiring hospitalization. Overdose symptoms resolved within 24 hours.

Treatment Symptomatic therapy. In severe cases, atropine should be administered intravenously as an antidote at a dose of 0.5-1.0 mg, then the dose is adjusted according to the patient’s condition.

Drug Interactions

Pharmacodynamic interactions

Concomitant use with other cholinomimetic drugs (ambenonium chloride, donepezil, neostigmine methylsulfate, pyridostigmine bromide, rivastigmine, or systemically acting pilocarpine) is contraindicated.

Galantamine is an antagonist of anticholinergic drugs. Sudden withdrawal of an anticholinergic drug, such as atropine, may enhance the effect of galantamine. As with treatment with other cholinomimetic agents, pharmacodynamic interaction with drugs that contribute to a decrease in heart rate (digoxin, beta-blockers), some “slow” calcium channel blockers (CCBs) and amiodarone is possible. Caution should be exercised when used concomitantly with drugs that have the potential to cause polymorphic ventricular tachycardia of the “torsades de pointes” type. In such cases, treatment should be carried out under ECG monitoring. Galantamine, being a cholinomimetic, may enhance depolarizing neuromuscular blockade (muscle relaxation) caused by general anesthesia (when suxamethonium is used as a peripheral muscle relaxant), especially in cases of pseudocholinesterase deficiency.

When used concomitantly, Galantamine enhances the effect of depolarizing muscle relaxants, weakens the effect of non-depolarizing muscle relaxants, and is a weak antagonist of morphine and its structural analogs in terms of their depressant effect on the respiratory center. It enhances the effect of ethanol and sedative drugs.

It restores neuromuscular conduction blocked by non-depolarizing muscle relaxants (tubocurarine bromide, etc.).

M-cholinoblockers (atropine, etc.) eliminate the peripheral muscarinic-like effects of galantamine; non-depolarizing muscle relaxants and ganglion blockers eliminate the nicotinic-like effects of galantamine.

Pharmacokinetic interactions

Galantamine is eliminated through metabolic reactions and renal excretion. The risk of clinically significant pharmacokinetic interaction is low. However, in some cases, clinically significant interaction is possible. Food intake slows the absorption of galantamine without affecting the extent of absorption. Gallynora^® CP capsules are recommended to be taken with meals to reduce possible cholinergic side effects.

Other drugs affecting the metabolism of galantamine

Concomitant use with paroxetine (a potent inhibitor of the CYP2D6 isoenzyme) or with ketoconazole and erythromycin (inhibitors of the CYP3A4 isoenzyme) increases the bioavailability (AUC) of galantamine by approximately 40%, 30%, and 12%, respectively. Therefore, when starting treatment with potent inhibitors of the CYP2D6 isoenzyme (e.g., quinidine, paroxetine, or fluoxetine) or inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole or ritonavir), an increase in the frequency of cholinergic adverse reactions, mainly nausea and vomiting, is possible. In these cases, a reduction in the maintenance dose of Gallynora^® CP is advisable (see section “Dosage and Administration”).

Concomitant use of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine at a dose of 10 mg once daily for 2 days, then 10 mg twice daily for 12 days did not affect the steady-state pharmacokinetics of galantamine after administration of 16 mg galantamine as extended-release capsules once daily.

Effect of galantamine on the metabolism of other drugs

Galantamine at therapeutic doses (24 mg/day) did not affect the pharmacokinetics of digoxin, although a pharmacodynamic interaction cannot be ruled out.

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

In vitro studies have shown that Galantamine has weak inhibitory capacity against the major cytochrome P450 isoenzymes.

Storage Conditions

In a dry place, at a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

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.