- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdministrationGalsya XL prolonged-release capsules should be administered 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). Before start of treatmentThe diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines (see section 4.4).
Starting doseThe 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.• There is no rebound effect after abrupt discontinuation of treatment (e.g. in preparation for surgery).Switching to Galsya XL prolonged-release capsules from galantamine tablets or galantamine oral solutionIt 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 Galsya XL prolonged- release capsules once daily the following morning.
Paediatric populationThere is no relevant use of galantamine in the paediatric population.
Hepatic and renal impairmentGalantamine plasma levels may be increased in patients with moderate to severe hepatic or renal impairment. In patients with moderately impaired hepatic function, 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.For patients with a creatinine clearance greater than 9 ml/min no dosage adjustment is required. In patients with severe renal impairment (creatinine clearance less than 9 ml/min), the use of galantamine is contraindicated (see section 4.3).
Concomitant treatmentIn patients treated with potent CYP2D6 or CYP3A4 inhibitors, dose reductions can be considered (see section 4.5).
Cardiac disordersBecause of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate (e.g. bradycardia). 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.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 disordersPatients 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 disordersAlthough cholinomimetics are believed to have some potential to cause seizures, seizure activity may also be a manifestation of Alzheimer's disease. In rare cases an increase in cholinergic tone may worsen Parkinsonian symptoms.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 disordersCholinomimetics 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 disordersThe use of galantamine is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.
Surgical and medical proceduresGalantamine, as a cholinomimetic is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.
Pharmacodynamic interactionsBecause 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 effect 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 interactionsMultiple 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 Galsya XL 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 co-treatment 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.
PregnancyFor 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-feedingIt 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.
|System organ class||ADR frequency|
|Immune system disorders||Hypersensitivity|
|Metabolism and nutrition disorders||Decreased appetite, anorexia||Dehydration|
|Psychiatric disorders||Hallucination, depression||Hallucination visual, hallucination auditory|
|Nervous system disorders||Syncope, dizziness, tremor, headache, somnolence, lethargy||Paraesthesia, dysguesia, hypersomnia, Seizures*|
|Eye disorders||Blurred vision|
|Ear and labyrinth disorders||Tinnitus|
|Cardiac disorders||Bradycardia||Supraventricular extrasystoles, atrioventricular block first degree, sinus bradycardia, palpitations|
|Vascular disorders||Hypertension,||Hypotension flushing|
|Gastrointestinal disorders||Vomiting. nausea||Abdominal pain, abdominal pain upper, diarrhoea, dyspepsia, stomach discomfort, abdominal discomfort||Retching|
|Skin and subcutaneous tissue disorders||Hyperhidrosis|
|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|
Reporting of suspected adverse reactionsReporting 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 SchemeWebsite: www.mhra.gov.uk/yellowcard
SymptomsSigns 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 galantamine 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.
TreatmentAs 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 i.v. 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.
Clinical studiesGalantamine was originally developed in the form of immediate-release tablets for twice-daily administration. The dosages of galantamine effective in these placebo-controlled clinical trials with a duration of 5 to 6 months were 16, 24 and 32 mg/day. Of these doses 16 and 24 mg/day were determined to have the best benefit/risk relationship and are the recommended maintenance doses.The efficacy of galantamine has been shown using outcome measures which evaluate the three major symptom complexes of the disease and a global scale: the ADAS-cog/11 (a performance based measure of cognition), DAD and ADCS-ADL-Inventory (measurements of basic and instrumental Activities of Daily Living), the Neuropsychiatric Inventory (a scale that measures behavioural disturbances) and the CIBIC-plus (a global assessment by an independent physician based on a clinical interview with the patient and caregiver).Composite Responder Analysis Based on at Least 4 Points Improvement in ADAS-cog/11 Compared to Baseline and CIBIC-plus Unchanged + Improved (1-4), and DAD/ADL Score Unchanged + Improved. See Table below.
|Treatment||At least 4 points improvement from baseline in ADAS-cog/11 and CIBIC-plus Unchanged + Improved|
|Change in DAD ≥ 0 GAL-USA-1 and GAL-INT-1 (Month 6)||Change in ADCS/ADL-inventory ≥ 0 GAL-USA-10 (Month 5)|
|n||n(%) of responder||Comparison with placebo||n||n(%) of responder||Comparison with placebo|
|Diff (95% CI)||p-value+||Diff (95% CI)||p-value+|
|Placebo||422||21 (5.0)||-||-||273||18 (6.6)||-||-|
|Gal 16 mg/d||-||-||-||-||266||39 (14.7)||8.1 (3.13)||0.003|
|Gal 24 mg/d||424||60 (14.2)||9.2 (5.13)||<0.001||262||40 (15.3)||8.7 (3.14)||0.002|
|Placebo||412||23 (5.6)||-||-||261||17 (6.5)||-||-|
|Gal 16 mg/d||-||-||-||-||253||36 (14.2)||7.7 (2.13)||0.005|
|Gal 24 mg/d||399||58 (14.5)||8.9 (5.13)||<0.001||253||40 (15.8)||9.3 (4.15)||0.001|
|* ITT: Intent To Treat + CMH test to difference from placebo # LOCF: Last Observation Carried Forward|
|GAL-INT-10||Placebo (n=245)||GAL-IR# (n=225)||GAL-PR* (n=238)||p-value (GAL-PR* vs. placebo)|
|Composite response: n (%)||20 (8.2)||43 (19.1)||38 (16.0)||0.008|
|# Immediate-release tablets * Prolonged-release capsules|
General characteristics of galantamine
AbsorptionThe absolute bioavailability of galantamine is high, 88.5 ± 5.4%. Galantamine prolonged-release capsules are bioequivalent to the twice-daily immediate- release tablets with respect to AUC24h and Cmin. The Cmax value is reached after 4.4 hours and is about 24% lower than that of the tablet. Food has no significant effect on AUC of the prolonged-release capsules. Cmax was increased by about 12% and tmax increased by about 30 minutes when the capsule was given after food. However, these changes are unlikely to be clinically significant.
DistributionThe mean volume of distribution is 175 l. Plasma protein binding is low, 18%.
BiotransformationUp to 75% of galantamine dosed is eliminated via metabolism. In vitro studies indicate that CYP2D6 is involved in the formation of O-desmethylgalantamine and CYP3A4 is involved in the formation of N-oxide-galantamine. The levels of excretion of total radioactivity in urine and faeces were not different between poor and extensive CYP2D6 metabolisers. In plasma from poor and extensive metabolisers, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity. None of the active metabolites of galantamine (norgalantamine, O-desmethylgalantamine and O-desmethyl- norgalantamine) could be detected in their unconjugated form in plasma from poor and extensive metabolisers after single dosing. Norgalantamine was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the galantamine levels. In vitro studies indicated that the inhibition potential of galantamine with respect to the major forms of human cytochrome P450 is very low.
EliminationGalantamine plasma concentration declines bi-exponentially, with a terminal half-life around 8-10 hours in healthy subjects. Typical oral clearance in the target population is about 200 ml/min with intersubject variability of 30% as derived from the population analysis of immediate-release tablets. Seven days after a single oral dose of 4 mg 3H-galantamine, 90-97% of the radioactivity is recovered in urine and 2.2-6.3% in faeces. After i.v. infusion and oral administration, 18-22% of the dose was excreted as unchanged galantamine in the urine in 24 hours, with a renal clearance of 68.4 ± 22.0 ml/min, which represents 20-25% of the total plasma clearance.
Linearity/non-linearityGalantamine pharmacokinetics of prolonged-release capsules are dose proportional within the studied dose range of 8 mg to 24 mg once-daily in elderly and young age groups.
Characteristics in patientsData from clinical trials in patients indicate that the plasma concentrations of galantamine in patients with Alzheimer's disease are 30% to 40% higher than in healthy young subjects primarily due to the advanced age and reduced kidney function. Based upon the population pharmacokinetic analysis, clearance in female subjects is 20% lower as compared to males. The galantamine clearance in poor metabolisers of CYP2D6 is about 25% lower than in extensive metabolisers, but no bimodality in the population is observed. Therefore, the metabolic status of the patient is not considered to be of clinical relevance in the overall population.The pharmacokinetics of galantamine in subjects with mild hepatic impairment (Child-Pugh score of 5 to 6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), AUC and half-life of galantamine were increased by about 30% (see section 4.2).Elimination of galantamine decreases with decreasing creatinine clearance as observed in a study with renaly impaired subjects. Compared to Alzheimer patients, peak and trough plasma concentrations are not increased in patients with a creatinine clearance ≥ 9 ml/min. Therefore, no increase in adverse events is expected and no dosage adjustments are needed (see section 4.2).
Pharmacokinetic/pharmacodynamic relationshipNo apparent correlation between average plasma concentrations and efficacy parameters (i.e., change in ADAS-cog/11 and CIBIC-plus at month 6) were observed in the large Phase III trials with a dose-regimen of 12 and 16 mg twice-daily.Plasma concentrations in patients experiencing syncope were within the same range as in the other patients at the same dose.The occurrence of nausea is shown to correlate with higher peak plasma concentrations (see section 4.5).
Prolonged-release tablet core:Sodium laurilsulfateAmmonio methacrylate copolymer (type B) HypromelloseCarbomers Hydroxypropylcellulose Magnesium stearateTalc
Capsule shell:GelatinTitanium dioxide (E171) Iron oxide, red (E172) Iron oxide, yellow (E172) Black ink:ShellacPropylene glycolAmmonia solution, concentrated Iron oxide, black (E172) Potassium hydroxide
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888