Galantamine-Teva (Tablets) Instructions for Use

Marketing Authorization Holder

Teva (Israel)

Manufactured By

Teva Pharmaceutical Industries, Ltd. (Israel)

ATC Code

N06DA04 (Galantamine)

Active Substance

Galantamine (Rec.INN registered by WHO)

Dosage Forms

	Galantamine-Teva	Film-coated tablets, 4 mg: 14 pcs.
		Film-coated tablets, 8 mg: 14 or 56 pcs.

Dosage Form, Packaging, and Composition

14 pcs. – blisters (1) – cardboard packs.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (4) – 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 is a tertiary alkaloid and a cholinesterase inhibitor.

As a selective, competitive, and reversible cholinesterase inhibitor, it enhances and prolongs the action of endogenous acetylcholine on nicotinic receptors, probably due to binding to the allosteric site of the receptor.

By increasing the activity of the cholinergic system through stimulation of central cholinoreactive systems, it may improve cognitive function in patients with dementia of the Alzheimer’s type.

Pharmacokinetics

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

Absorption. After a single oral dose of 8 mg, galantamine is rapidly absorbed from the gastrointestinal tract. C_max in plasma is reached after 1.2 hours and is about 43 ng/ml.

Distribution. The absolute bioavailability after oral administration is 88.5%. Taking galantamine with food slows its absorption (C_max decreases by 25%), but does not affect the AUC. After multiple doses of galantamine 12 mg twice daily, the mean end-of-course concentrations and C_max in plasma ranged from 30 ng/ml to 90 ng/ml. The volume of distribution is 175 L. The binding of galantamine to plasma proteins is about 18%. In whole blood, galantamine is found predominantly in blood cells (52.7%) and in plasma (39%), while its fraction bound to plasma proteins is only 8.4%.

Metabolism. In vitro studies have shown that the main cytochrome P450 isoenzymes involved in the metabolism of galantamine are the CYP2D6 isoenzyme, associated with the formation of O-desmethylgalantamine, and the CYP3A4 isoenzyme, associated with the formation of N-oxide galantamine. The amounts of radioactive substances excreted in urine and feces did not differ between people with rapid and slow metabolism. In the plasma of people with rapid and slow metabolism, the main part of the radioactive substances is unchanged galantamine and its glucuronide. After a single dose of galantamine, none of the active metabolites (nor-galantamine, O-desmethylgalantamine, and O-desmethylnor-galantamine) were present in unconjugated form in the plasma of either rapid or slow metabolizers. Nor-galantamine was detected in the plasma of patients after multiple doses of galantamine, but its concentration was no more than 10% of the galantamine concentration. The elimination of galantamine is biexponential. The terminal T_1/2 is 7-8 hours. The plasma clearance of galantamine is about 200 ml/min. Within 7 days after a single oral dose of 3H-galantamine 4 mg, 90-97% of the radioactivity was excreted in the urine and 2.2-6.3% in the feces. After intravenous administration and oral intake, 18-22% of galantamine is excreted unchanged in the urine within 24 hours, renal clearance is about 65 ml/min, which is 20-25% of the total plasma clearance.

In patients with Alzheimer’s disease, the plasma concentration of galantamine is 30-40% higher than in healthy individuals.

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

A population pharmacokinetic study and analysis using a number of models showed that in patients with Alzheimer’s disease and impaired renal function with a creatinine clearance (CrCl) of at least 9 ml/min, no dose adjustment of galantamine is required.

Indications

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

ICD codes

Dosage Regimen

Orally, twice a day, preferably with morning and evening meals. The tablets should be swallowed whole, without chewing, with a sufficient amount of water. The initial dose is 8 mg/day (4 mg twice daily) for 4 weeks. The maintenance dose is 16 mg/day (8 mg twice daily) for at least 4 weeks. The decision to use higher doses of Galantamine-Teva should be made after assessing the patient’s clinical condition, including the effect achieved and individual tolerance. The maximum recommended dose is 24 mg/day (12 mg twice daily).

If the intake of Galantamine-Teva is interrupted for several days, treatment should be resumed at the initial dose and then increased to the previous maintenance dose according to the scheme above.

In patients with moderate hepatic impairment, the initial dose is 4 mg once a day, daily, in the morning, for at least 1 week. After that, patients can take 8 mg/day (4 mg twice daily) for at least 4 weeks. The daily dose should not exceed 8 mg/day.

In patients with impaired renal function (CrCl greater than 9 ml/min), no dose adjustment is required.

Adverse Reactions

The frequency of side effects is classified according to the recommendations of the World Health Organization: very common – at least 10%; common – at least 1%, but less than 10%; uncommon – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%; very rare – less than 0.01%, including isolated reports.

Metabolism and nutrition disorders common – anorexia, weight loss; rare – dehydration (in rare cases leading to renal failure), hypokalemia.

Nervous system disorders common – dizziness, headache, drowsiness, syncope, tremor, confusion, depression (very rarely with suicide), insomnia, asthenia, malaise, fatigue, fever; uncommon – paresthesia, cerebrovascular disease, transient ischemic circulatory disorder, aggression, agitation, hallucinations, tinnitus; very rare – exacerbation of Parkinson’s disease, convulsions, sweating.

Cardiac disorders uncommon – arrhythmia, acute myocardial infarction, coronary heart disease, tachycardia; rare – bradycardia; very rare – atrioventricular block.

Gastrointestinal disorders very common – vomiting, nausea; common – abdominal pain, diarrhea, dyspepsia; very rare – dysphagia, gastrointestinal bleeding.

Skin and subcutaneous tissue disorders rare – skin rash.

Musculoskeletal and connective tissue disorders common – fall, injury; uncommon – leg muscle cramps, muscle weakness.

Renal and urinary disorders common – urinary tract infection.

Other common – infectious rhinitis.

Contraindications

• Hypersensitivity to galantamine and other components of the drug;
• Severe hepatic impairment (Child-Pugh class C);
• Severe renal impairment (CrCl less than 9 ml/min);
• Lactose intolerance;
• Lactase deficiency;
• Glucose-galactose malabsorption syndrome;
• Children under 18 years of age;
• Pregnancy;
• Breastfeeding period;
• Obstructive diseases of the gastrointestinal tract and urinary tract or recent surgery on the gastrointestinal tract and urinary tract, including the bladder.

With caution

Sick sinus syndrome; supraventricular conduction disorders; hyperkalemia; hypokalemia; period after acute myocardial infarction; newly diagnosed atrial fibrillation; atrioventricular block II-III degree, unstable angina; chronic heart failure (CHF) functional class III and IV according to NYHA classification; simultaneous use with drugs that help reduce heart rate (digoxin, beta-blockers), sedatives, ethanol; arterial hypertension; epilepsy; COPD; infectious lung diseases; anesthesia.

Use in Pregnancy and Lactation

The use of Galantamine-Teva during pregnancy is contraindicated.

Breastfeeding should be discontinued during therapy with Galantamine-Teva.

Use in Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

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

Pediatric Use

The drug is contraindicated in children under 18 years of age.

Special Precautions

Galantamine-Teva is used in patients with mild to moderate dementia of the Alzheimer’s type.

The effectiveness of Galantamine-Teva in patients with other types of dementia and other types of memory impairment has not been established.

A positive effect of the drug on slowing cognitive impairment or slowing the transition to clinically pronounced dementia in patients with mild cognitive impairment syndrome (“mild” types of memory impairment that do not meet the criteria for dementia in Alzheimer’s disease) has also not been established.

Therapy with Galantamine-Teva should be carried out under the supervision of a physician and under the observation of a person who cares for the patient.

Taking Galantamine-Teva is accompanied by weight loss, so this indicator must be monitored during treatment.

Galantamine-Teva should not be used simultaneously with other cholinesterase inhibitors.

Galantamine-Teva should be used with caution in cardiovascular diseases, because due to its pharmacological action, cholinomimetics can cause vagotonic effects (e.g., bradycardia).

Galantamine-Teva (like other cholinomimetics) is used with caution in patients with sick sinus syndrome; supraventricular conduction disorders; during simultaneous therapy with drugs that reduce heart rate (digoxin, beta-blockers); electrolyte balance disorders (hyperkalemia, hypokalemia); in the period after acute myocardial infarction; with newly diagnosed atrial fibrillation, atrioventricular block II-III degree; unstable angina, CHF functional class III and IV according to the NYHA classification.

When treating dementia of the Alzheimer’s type with Galantamine-Teva, the risk of adverse reactions from the cardiovascular system may increase (see section “Adverse Reactions”).

In patients with an increased risk of erosive and ulcerative lesions of the gastrointestinal tract, for example, those with a history of peptic ulcer disease, it is necessary to monitor the condition for the early detection of relevant pathological symptoms. Galantamine-Teva is not recommended for use in patients with gastrointestinal obstruction, as well as in patients who have recently undergone surgery on the digestive organs.

Cholinomimetics have a certain ability to cause generalized seizures. It should be remembered that seizure activity may be a manifestation of Alzheimer’s disease itself. Cases of worsening of Parkinson’s disease have been described. The possibility of developing cerebrovascular accident in patients with Alzheimer’s disease against the background of cerebral vascular diseases cannot be excluded. Galantamine-Teva should be used with caution in patients with severe bronchial asthma, COPD and infectious lung diseases due to its cholinomimetic activity.

Galantamine-Teva is not recommended for use in patients with urinary tract obstruction, as well as in persons who have recently undergone surgery on the bladder.

It must be taken into account that Galantamine-Teva, as a cholinomimetic, increases muscle relaxation during succinylcholine-type anesthesia.

No exacerbation of symptoms occurs after abrupt withdrawal of Galantamine-Teva (for example, in preparation for surgery).

Effect on ability to drive vehicles and operate machinery

During therapy with Galantamine-Teva, one should refrain from driving vehicles and operating other mechanisms that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms muscle weakness, fasciculation, 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, convulsions) are possible.

Severe muscle weakness combined with hypersecretion of the tracheal mucosa and bronchospasm can lead to death.

Reports received in the post-marketing period have described cases of bidirectional spindle-shaped ventricular tachycardia, QT interval prolongation, ventricular tachycardia accompanied by short-term loss of consciousness with accidental intake of 32 mg of galantamine.

Treatment symptomatic therapy is carried out if necessary.

In severe cases, atropine is administered intravenously as an antidote (initial dose – 0.5-1 mg; the frequency of administration and subsequent doses depend on the dynamics of the patient’s clinical condition).

Drug Interactions

Simultaneous food intake somewhat slows down the rate of absorption of galantamine, but does not affect its extent. Patients are recommended to take Galantamine with food to minimize possible cholinergic adverse events.

Concomitant use of galantamine with other cholinomimetic drugs is contraindicated.

Pharmacodynamic interaction of galantamine is possible with drugs that significantly reduce heart rate, such as digoxin, beta-blockers, slow calcium channel blockers and amiodarone. Caution should be exercised when used concomitantly with drugs that have the potential to cause torsades de pointes type arrhythmia. In these cases, treatment should be carried out under the control of electrocardiogram parameters.

Galantamine may enhance the blockade of neuromuscular transmission of the depolarizing type during general anesthesia (when used as a peripheral muscle relaxant suxamethonium).

When used concomitantly, Galantamine enhances the effect of depolarizing muscle relaxants, weakens the effect of non-depolarizing muscle relaxants; is a weak antagonist of morphine and its structural analogs in relation to the depressant effect on the respiratory center. Enhances the effect of ethanol and sedative drugs. Restores neuromuscular conduction blocked by non-depolarizing muscle relaxants (tubocurarine, etc.).

M-cholinoblockers (atropine, etc.) eliminate the peripheral muscarinic-like effects of galantamine, non-depolarizing muscle relaxants and ganglioblockers eliminate the nicotine-like effects of galantamine.

When used concomitantly with drugs that are active inhibitors of the CYP2D6 or CYP3A4 isoenzymes (such as ketoconazole, paroxetine, erythromycin, amitriptyline, fluoxetine, fluvoxamine, quinidine), the AUC increases by 10-40% and the risk of adverse effects (mainly nausea and vomiting) due to the cholinergic action of galantamine increases, which may require a reduction in the dose of galantamine.

When used in doses up to 12 mg twice daily, Galantamine did not change the pharmacokinetic parameters of digoxin and warfarin and did not affect the increase in prothrombin time caused by warfarin.

Galantamine is an antagonist of morphine and its structural analogs in relation to the depressant effect on the respiratory center.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2.5 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.