Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pharmathen S.A., Dervenakion 6, Pallini, Attiki, 153 51, Greece
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Since 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.
Consion XL is indicated for patients 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 2 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, 14/1,026 (1.4 %) patients on galantamine and 3/1,022 (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, placebo-controlled study in 2,045 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 56/1,021 (5.5 %) deaths in patients on placebo and 33/1,024 (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 who will regularly monitor medicinal product intake by the patient is available.
Serious skin reactions (Stevens Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving galantamine (see section 4.8). It is recommended that patients be informed about the signs of serious skin reactions, and that use of galantamine be discontinued at the first appearance of skin rash.
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.
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.
In a pooled analysis of placebo-controlled studies in patients with Alzheimer’s 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 gastrointestinal obstruction or recovering from gastrointestinal 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. 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 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.
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 anticholinergics 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.
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 be taken with food in order to minimise cholinergic side effects.
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 (as galantamine prolonged-release capsules 16 mg once a day) at steady-state.
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.
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.
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.
The effect of galantamine on human fertility has not been evaluated.
Galantamine has minor or moderate influence on the ability to drive and use machines. Symptoms include dizziness and somnolence, especially during the first weeks after initiation of treatment.
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 galantamine 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); and very rare (<1/10,000).
Uncommon: Hypersensitivity
Common: Decreased appetite
Uncommon: Dehydration
Common: Hallucination; Depression
Uncommon: Hallucination visual; Hallucination auditory
Common: Syncope; Dizziness; Tremor; Headache; Somnolence; Lethargy
Uncommon: Paraesthesia; Dysgeusia; Hypersomnia, Seizures*
Uncommon: Vision blurred
Uncommon: Tinnitus
Common: Bradycardia
Uncommon: Supraventricular extrasystoles; Atrioventricular block first degree; Sinus bradycardia; Palpitations
Rare: Atrioventricular block complete
Common: Hypertension
Uncommon: Hypotension; Flushing
Very common: Vomiting; Nausea
Common: Abdominal pain; Abdominal pain upper; Diarrhoea; Dyspepsia; Abdominal discomfort
Uncommon: Retching
Rare: Hepatitis
Uncommon: Hyperhidrosis
Rare: Stevens-Johnson Syndrome; Acute generalized exanthematous pustulosis; Erythema multiforme
Common: Muscle spasms
Uncommon: Muscular weakness
Common: Fatigue; Asthenia; Malaise
Common: Weight decreased
Uncommon: Hepatic enzyme increased
Common: Fall, Laceration
* Class-related effects reported with acetylcholinesterase-inhibitor antidementia medicines include convulsions/seizures (see section 4.4)
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 the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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