4.1. Therapeutic indications

Galantamine Krka is indicated for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer type.

4.2. Posology and method of administration

Posology

Adults/Elderly

Before start of treatment

The diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines (see section 4.4).

Starting dose

The recommended starting dose is 8 mg/day for 4 weeks.

Maintenance dose

- The tolerance and dosing of galantamine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of galantamine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as therapeutic benefit is favourable and the patient tolerates treatment with galantamine. Discontinuation of galantamine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

- The initial maintenance dose is 16 mg/day and patients should be maintained on 16 mg/day for at least 4 weeks.

- An increase to the maintenance dose of 24 mg/day should be considered on an individual basis after appropriate assessment including evaluation of clinical benefit and tolerability.

- In individual patients not showing an increased response or not tolerating 24 mg/day, a dose reduction to 16 mg/day should be considered.

Treatment withdrawal

There is no rebound effect after abrupt discontinuation of treatment (e.g. in preparation for surgery).

Switching to Galantamine Krka prolonged-release capsules from galantamine tablets or galantamine oral solution

It is recommended that the same total daily dose of galantamine is administered to patients. Patients switching to the once-daily regimen should take their last dose of galantamine tablets or oral solution in the evening and start Galantamine Krka prolonged-release capsules once daily the following morning.

Renal impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe renal impairment (see section 5.2).

For patients with a creatinine clearance ≥9 ml/min, no dosage adjustment is required.

The use of galantamine is contraindicated in patients with creatinine clearance less than 9 ml/min (see section 4.3).

Hepatic impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment (see section 5.2). In patients with moderately impaired hepatic function (Child-Pugh score 7-9), based on pharmacokinetic modelling, it is recommended that dosing should begin with 8 mg prolonged-release capsule once every other day, preferably taken in the morning, for one week. Thereafter, patients should proceed with 8 mg once daily for four weeks. In these patients, daily doses should not exceed 16 mg. In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of galantamine is contraindicated (see section 4.3).

No dosage adjustment is required for patients with mild hepatic impairment.

Concomitant treatment

In patients treated with potent CYP2D6 or CYP3A4 inhibitors, dose reductions can be considered (see section 4.5).

Paediatric population

There is no relevant use of galantamine in the paediatric population.

Method of administration

Galantamine Krka prolonged-release capsules should be administered orally, once daily in the morning, preferably with food. The capsules should be swallowed whole together with some liquid.

The capsules must not be chewed or crushed.

For patients with difficulty swallowing: The capsules may be emptied and the tablet core(s) swallowed whole together with some liquid. The capsule contents (tablet cores) must not be chewed or crushed.

Ensure adequate fluid intake during treatment (see section 4.8).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Because no data are available on the use of galantamine in patients with severe hepatic impairment (Child-Pugh score greater than 9) and in patients with creatinine clearance less than 9 ml/min, galantamine is contraindicated in these populations. Galantamine is contraindicated in patients who have both significant renal and hepatic dysfunction.

4.4. Special warnings and precautions for use

Types of dementia

Galsya XL is indicated for a patient with mild to moderately severe dementia of the Alzheimer type. The benefit of galantamine in patients with other types of dementia or other types of memory impairment has not been demonstrated. In 2 clinical trials of two years duration in individuals with so called mild cognitive impairment (milder types of memory impairment not fulfilling the criteria of Alzheimer's dementia), galantamine therapy failed to demonstrate any benefit either in slowing cognitive decline or reducing the clinical conversion to dementia. The mortality rate in the galantamine group was significantly higher than in the placebo group, 14/1026 (1.4%) patients on galantamine and 3 /1022 (0.3%) patients on placebo. The deaths were due to various causes. About half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death). The relevance of this finding for the treatment of patients with Alzheimer's dementia is unknown.

No increased mortality in the galantamine group was observed in a long-term, randomized, placebocontrolled study in 2045 patients with mild to moderate Alzheimer's disease. The mortality rate in the placebo group was significantly higher than in the galantamine group. There were 56/1021 (5.5%) deaths in patients on placebo and 33/1024 (3.2%) deaths in patients on galantamine (hazard ratio and 95% confidence intervals of 0.58 [0.37 – 0.89]; p=0.011).

A diagnosis of Alzheimer's dementia should be made according to current guidelines by an experienced physician. Therapy with galantamine should occur under the supervision of a physician and should only be initiated if a caregiver is available who will regularly monitor medicinal product intake by the patient.

Serious skin reactions

Serious skin reactions (Stevens Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving Galsya XL (see section 4.8). It is recommended that patients be informed about the signs of serious skin reactions, and that use of Galsya XL should be discontinued at the first appearance of skin rash

Weight monitoring

Patients with Alzheimer's disease lose weight. Treatment with cholinesterase inhibitors, including galantamine, has been associated with weight loss in these patients. During therapy, patient's weight should be monitored.

Conditions requiring caution

As with other cholinomimetics, galantamine should be given with caution in the following conditions:

Cardiac disorders

Because of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate including bradycardia and all types of atrioventricular node block (see section 4.8). The potential for this action may be particularly important to patients with ”sick sinus syndrome” or other supraventricular cardiac conduction disturbances or in those who use medicinal products that significantly reduce heart rate concomitantly, such as digoxin and beta-blockers or for patients with an uncorrected electrolyte disturbance (e.g. hyperkalaemia, hypokalaemia).

Caution should therefore be exercised when administering galantamine to patients with cardiovascular diseases, e.g. immediate post-myocardial infarction period, new-onset atrial fibrillation, second degree heart block or greater, unstable angina pectoris or congestive heart failure, especially NYHA group III – IV.

There have been reports of QTc prolongation in patients using therapeutic doses of galantamine and of torsade de pointes in association with overdoses (see section 4.9). Galantamine should therefore be used with caution in patients with prolongation of the QTc interval, in patients treated with drugs affecting the QTc interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

In a pooled analysis of placebo-controlled studies in patients with Alzheimer dementia treated with galantamine an increased incidence of certain cardiovascular adverse events were observed (see section 4.8).

Gastrointestinal disorders

Patients at increased risk of developing peptic ulcers, e.g. those with a history of ulcer disease or those predisposed to these conditions, including those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. The use of galantamine is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.

Nervous system disorders

Seizures have been reported with galantamine (see section 4.8). Seizure activity may also be a manifestation of Alzheimer's disease. An increase in cholinergic tone may worsen symptoms related to extrapyramidal disorders (see section 4.8).

In a pooled analysis of placebo-controlled studies in patients with Alzheimer's dementia treated with galantamine cerebrovascular events were uncommonly observed (see section 4.8). This should be considered when administering galantamine to patients with cerebrovascular disease.

Respiratory, thoracic and mediastinal disorders

Cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease or active pulmonary infections (e.g. pneumonia).

Renal and urinary disorders

The use of galantamine is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.

Surgical and medical procedures

Galantamine, as a cholinomimetic is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per prolonged-release capsule, that is to say essentially "sodium-free".

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Because of its mechanism of action, galantamine should not be given concomitantly with other cholinomimetics (such as ambenonium, donepezil, neostigmine, pyridostigmine, rivastigmine or systemically administered pilocarpine). Galantamine has the potential to antagonise the effect of anticholinergic medication. Should anticholinergic medication such as atropine be abruptly stopped there is a potential risk that galantamine's effects could be exacerbated. As expected with cholinomimetics, a pharmacodynamic interaction is possible with medicinal products that significantly reduce the heart rate such as digoxin, beta-blockers, certain calcium-channel blocking agents and amiodarone. Caution should be taken with medicinal products that have potential to cause torsades de pointes. In such cases an ECG should be considered.

Galantamine, as a cholinomimetic, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.

Pharmacokinetic interactions

Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine. The possibility of clinically relevant interactions is low. However, the occurrence of significant interactions may be clinically relevant in individual cases.

Concomitant administration with food slows the absorption rate of galantamine but does not affect the extent of absorption. It is recommended that Galantamine Krka be taken with food in order to minimise cholinergic side effects.

Other medicinal products affecting the metabolism of galantamine

Formal drug interaction studies showed an increase in galantamine bioavailability of about 40% during co-administration of paroxetine (a potent CYP2D6 inhibitor) and of 30% and 12% during cotreatment with ketoconazole and erythromycin (both CYP3A4 inhibitors). Therefore, during initiation of treatment with potent inhibitors of CYP2D6 (e.g. quinidine, paroxetine or fluoxetine) or CYP3A4 (e.g. ketoconazole or ritonavir) patients may experience an increased incidence of cholinergic adverse reactions, predominantly nausea and vomiting. Under these circumstances, based on tolerability, a reduction of the galantamine maintenance dose can be considered (see section 4.2).

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, at a dose of 10 mg once a day for 2 days followed by 10 mg twice a day for 12 days, had no effect on the pharmacokinetics of galantamine 16 mg prolonged-release capsules taken once a day at steady state.

Effect of galantamine on the metabolism of other medicinal products

Therapeutic doses of galantamine 24 mg/day had no effect on the kinetics of digoxin, although pharmacodynamic interactions may occur (see also pharmacodynamic interactions).

Therapeutic doses of galantamine 24 mg/day had no effect on the kinetics and prothrombin time of warfarin.

4.6. Fertility, pregnancy and lactation

Pregnancy

For galantamine no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Breast-feeding

It is not known whether galantamine is excreted in human breast milk and there are no studies in lactating women. Therefore, women on galantamine should not breast-feed.

Fertility

The effect of galantamine on human fertility has not been evaluated.

4.7. Effects on ability to drive and use machines

Galantamine has minor to moderate influence on the ability to drive and use machines. Symptoms include dizziness and somnolence, especially during the first weeks after initiation of treatment.

4.8. Undesirable effects

The table below reflects data obtained with galantamine in eight placebo-controlled, double-blind clinical trials (N=6,502), five open-label clinical trials (N=1,454), and from postmarketing spontaneous reports. The most commonly reported adverse reactions were nausea (21%) and vomiting (11%). They occurred mainly during titration periods, lasted less than a week in most cases and the majority of patients had one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.

In a randomised, double-blind, placebo-controlled clinical trial, the safety profile of once-daily treatment with galantamine prolonged-release capsules was similar in frequency and nature to that seen with tablets.

Frequency estimate:

- Very common (≥1/10)

- Common (≥1/100 to <1/10)

- Uncommon (≥1/1,000 to <1/100)

- Rare (≥1/10,000 to <1/1,000)

- Very rare (<1/10,000)

- Not known (cannot be estimated from the available data)

System organ class

ADR frequency

Very common

Common

Uncommon

Rare

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Decreased appetite

Dehydration

Psychiatric disorders

Hallucination, depression

Hallucination visual, hallucination auditory

Nervous system disorders

Syncope, dizziness, tremor, headache, somnolence, lethargy

Paraesthesia, dysguesia, hypersomnia, seizures*, extrapyramidal disorder

Eye disorders

Blurred vision

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Bradycardia

Supraventricular extrasystoles, atrioventricular block first degree, sinus bradycardia, palpitations

Atrioventricular block complete

Vascular disorders

Hypertension

Hypotension, flushing

Gastrointestinal disorders

Vomiting, nausea

Abdominal pain, abdominal pain upper, diarrhoea, dyspepsia, abdominal discomfort

Retching

Hepatobiliary disorders

Hepatitis

Skin and subcutaneous tissue disorders

Hyperhidrosis

StevensJohnson Syndrome, acute generalized exanthematous pustulosis, erythema multiforme

Musculoskeletal and connective tissue disorders

Muscle spasms

Muscular weakness

General disorders and administration site conditions

Fatigue, asthenia, malaise

Investigations

Weight decreased

Hepatic enzyme increased

Injury, poisoning and procedural complications

Fall, laceration

* Class-related effects reported with acetylcholinesterase-inhibitor antidementia drugs include convulsions/seizures (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the signs of a cholinergic crisis may develop: severe nausea, vomiting, gastro-intestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions. Increasing muscle weakness together with tracheal hypersecretions and bronchospasm, may lead to vital airway compromise.

There have been post-marketing reports of torsade de pointes, QT prolongation, bradycardia ventricular tachycardia and brief loss of consciousness in association with inadvertent overdoses of galantamine. In one case where the dose was known, eight 4 mg tablets (32 mg total) were ingested on a single day.

Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting) resulted in brief hospitalisations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalisation. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 ml) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Treatment

As in any case of overdose, general supportive measures should be used. In severe cases, anticholinergics such as atropine can be used as a general antidote for cholinomimetics. An initial dose of 0.5 to 1.0 mg intravenously is recommended, with subsequent doses based on the clinical response.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.