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Drug Details

REMINYL

• Drug Class Description
  Anticholinesterases (cholinomimetics).
• Generic Name
  Galantamine
• Presentation
  Film-coated tablet. Reminyl 4 mg tablet: Off-white, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G4” on the other side Reminyl 8 mg tablet: Pink, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G8” on the other side Reminyl 12 mg tablet: Orange-brown, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G12” on the other side
• Description
  Reminyl 4 mg Tablets Reminyl 8 mg Tablets Reminyl 12 mg Tablets
• Indications
  

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

• Adult Dosage
  

  Adults/Elderly

  Administration

  Reminyl tablets should be administered twice a day, preferably with morning and evening meals. Ensure adequate fluid intake during treatment.

  Before start of treatment

  The diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines

  Starting dose

  The recommended starting dose is 8 mg/day (4 mg twice a day) for four 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 (8 mg twice a 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 (12 mg twice a 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).

  Hepatic and renal impairment

  Galantamine 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 4 mg once daily, preferably taken in the morning, for at least one week. Thereafter, patients should proceed with 4 mg twice-daily for at least 4 weeks. In these patients, daily doses should not exceed 8 mg twice-daily. In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of galantamine is contraindicated. 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.

  Concomitant treatment

  In patients treated with potent CYP2D6 or CYP3A4 inhibitors dose reductions can be considered.

• Child Dosage
  

  Galantamine is not recommended for use in children due to a lack of data on safety and efficacy.

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

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

• Special Precautions
  

  Reminyl 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 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 dementia is unknown. In Alzheimer dementia, placebo-controlled studies of only 6 months duration have been conducted. In these studies no increased mortality in the galantamine groups appeared.

  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.

  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 (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.

  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

  Although 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. 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 succinylcholinetype muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.

  Other

  Orange yellow S aluminium lake (E110), present in the 12 mg tablet, may cause allergic reactions.

  Reminyl tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

• Interactions
  

  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 Reminyl 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.

  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 Reminyl XL prolonged-release capsules 16 mg once a day) at steady state.

  Effect of galantamine on the metabolism of other medicinal products

  Therapeutic doses of galantamine 24mg/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.

• Adverse Drug Reactions
  

  The most common adverse events observed in clinical trials (incidence 5% and twice the frequency of placebo) were nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, anorexia, fatigue, dizziness, headache, somnolence and weight decrease. Nausea, vomiting and anorexia were more commonly observed in women.

  Other common adverse events observed in clinical trials (incidence 5% and placebo) were confusion, depression, fall, injury, insomnia, rhinitis and urinary tract infection.

  The majority of these adverse events occurred during the titration period. Nausea and vomiting, the most frequent adverse events, lasted less than a week in most cases and the majority of patients had only one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.

  Adverse events observed during clinical trials and post marketing experience.

  System Organ Class	Very Common	Common	Uncommon	Rare	Very Rare
  Infections and infestations		Rhinitis Urinary tract infections
  Metabolism and nutrition disorders		Anorexia Weight decrease		Dehydration(leading to renal insufficiency and renal failure) Hypokalaemia
  Psychiatric disorders		Confusion Depression(very rarely with suicidality) Insomnia		Aggression Agitation Hallucinations
  Nervous system disorders		Dizziness Somnolence Syncope Tremor	Paraesthesia	Seizures	Worsening of Parkinsonism
  Ear and labyrinth disorders			Tinnitus
  Cardiac disorders			Atrial arrhythmia Myocardial infarction Myocardial ischaemia Palpitation	Bradycardia (severe)	AV block
  Vascular disorders		Hypertension	Cerebrovascular disease Transient ischaemic attack		Hypotension
  Gastrointestinal disorders	Vomiting Nausea	Abdominal pain Diarrhoea Dyspepsia			Dysphagia Gastrointestinal bleeding
  Hepatobiliary disorders					Elevated liver enzymes Hepatitis
  Skin and subcutaneous tissue disorders				Rash	Increased sweating
  Musculoskeletal and connective tissue disorders			Leg Cramps
  General disorders and administration site conditions		Asthenia Fatigue Fever Headache Malaise
  Injury, poisoning and procedural complications		Fall Injury

  Frequencies are defined as: 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).

  Some of these adverse events may be attributable to cholinomimetic properties of galantamine or in some cases may represent manifestations or exacerbations of the underlying disease processes common in the elderly population.