Reminyl Cr Range 8mg. 16mg. 24mg Prolonged Release Capsules

REMINYL CR is indicated for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer type. Efficacy data beyond 6 months has not been established (see section 4.4)

Adults

Posology

• Starting dose : The recommended starting dose is 8 mg/day for 4 weeks.
• Maintenance dose
• 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 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.
• Maintenance treatment can be continued for as long as therapeutic benefit for the patient exists. Therefore, the clinical benefit of galantamine should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present.
• Treatment Withdrawal
• There is no rebound effect after abrupt discontinuation of treatment (e.g.in preparation for surgery).

Renal impairment

REMINYL CR plasma concentrations may be increased in patients with moderate to severe renal impairment. For patients with a creatinine clearance u2265 9 ml/min, no dosage adjustment is required. In patients, with severe renal impairment [(creatinine clearance less than 9 ml/min)], the use of REMINYL CR is contraindicated.

Hepatic impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment. For prolonged release capsules, based on pharmacokinetic modelling, dosing should begin with 8 mg every other day for at least one week, preferably taken in the morning. Thereafter, patients should take 8 mg once daily for prolonged release capsules at least four weeks. In these patients total daily doses should not exceed 16 mg. In patients with severe hepatic impairment (CHILD- PUGH score >9), the use of REMINYL CR is contraindicated.

Concomitant treatment

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

Children:

Use of REMINYL CR in children is not recommended. No data on the use of REMINYL CR in paediatric patients are available.

Method of Administration

REMINYL CR prolonged release capsules should be administered once daily in the morning, preferably with food.

REMINYL CR should not be administered to patients with a known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulations. Severely impaired hepatic and renal function, as safety has not been demonstrated. The use of REMINYL CR is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.

Types of dementia other than Alzheimer's dementia

REMINYL CR is indicated for patients with mild to moderately severe dementia of the Alzheimeru2019s type. The benefit of REMINYL CR in patients with other types of dementia or other types of memory impairment has not been demonstrated.

Serious skin reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalised exanthematous pustulosis) have been reported in patients receiving REMINYL CR. It is recommended that patients be informed about the signs of serious skin reactions, and that the use of REMINYL CR be discontinued at the first appearance of skin rash.

Weight monitoring

Treatment with cholinesterase inhibitors, including REMINYL CR, has been associated with weight loss in patients with Alzheimeru2019s disease. During therapy patientu2019s weight should be monitored.

Conditions requiring caution:

REMINYL CR should be given with caution in the following conditions:

Cardiovascular conditions

Bradycardia: The potential for bradycardia and all types of atrioventricular node block (See section 4.8) may be particularly important to patients with u2018u201dsick sinus syndromeu201d or other supraventricular cardiac conduction disturbances or who use medicines that significantly reduce the heart rate concomitantly such as digoxin and beta blockers. In clinical trials, use of REMINYL CR has been associated with syncope and with bradycardia.

Gastro-intestinal conditions

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 nonsteroidal anti-inflammatory drugs (NSAIDS), should be monitored for symptoms. The use of REMINYL CR is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.

Neurological conditions

Convulsions have been reported with REMINYL CR (See section 4.8, Postmarketing data). Seizure activity may also be a manifestation of Alzheimer's disease.

Pulmonary conditions

Because of their cholinomimetic actions, REMINYL CR should be prescribed with care for patients with a history of asthma or obstructive bronchitis.

Genitourinary

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

Safety in Subjects with Mild Cognitive Impairment (MCI)

REMINYL CR is not indicated for individuals with mild cognitive impairment (MCI), i.e., those who demonstrate isolated memory impairment greater than expected for their age and education, but do not meet criteria for Alzheimeru2019s disease. Two, 2-year controlled trials in subjects with MCI treated with REMINYL CR or placebo did not meet dual primary efficacy outcomes. Although mortality in both treatment arms was low, more deaths were initially recorded in subjects randomized to REMINYL CR than to placebo, but the incidence of serious adverse events was identical between treatment groups. The deaths were due to various causes that are not unexpected in an elderly population. When data retrieved from the large proportion of patients who discontinued prior to completion of the double-blind period was included, there was no evidence of a statistically significant increasing risk of death in REMINYL CR treated subjects over time. More subjects from the placebo than the REMINYL CR group discontinued prior to death, which may account for the difference in mortality initially recorded. REMINYL CR capsules contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose mal-absorption or sucrase-isomaltase insufficiency should not take REMINYL CR.

Pharmacodynamic interactions

Because of its mechanism of action, REMINYL CR should not be given concomitantly with other cholinomimetics. REMINYL CR antagonises the effect of anticholinergic medication. As expected with cholinomimetics, a pharmacodynamic interaction is possible with medicines that significantly reduce the heart rate e.g. digoxin and beta blockers (See section 4.4). REMINYL CR as a cholinomimetic, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Pharmacokinetic interactions

Based on in-vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of REMINYL CR. Inhibition of gastric acid secretion will not impair the absorption of REMINYL CR. Other medicines affecting the metabolism of REMINYL CR Drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC of REMINYL CR. Multiple dose pharmacokinetic studies demonstrated that the AUC of REMINYL CR increased 30 u2013 40 %, respectively, during co-administration of ketoconazole and paroxetine. As co-administered with erythromycin, another CYP3A4 inhibitor, the REMINYL CR AUC only increased approximately 10 %. Population PK analysis for patients with Alzheimeru2019s disease showed that the clearance of REMINYL CR was decreased about 25-33 % by concurrent administration of amitriptyline, fluoxetine, fluvoxamine, paroxetine and quinidine, known inhibitors of CYP2D6. Therefore, during initiation of treatment with potent inhibitors of CYP2D6 or CYP3A4 patients may experience an increased incidence of cholinergic side effects, predominantly nausea and vomiting. Under these circumstances, based on tolerability, a reduction of the REMINYL CR maintenance dose can be considered. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, at a dose of 10 mg/daily for 2 days followed by 10 mg twice a day for 12 days had no effect on the pharmacokinetics of REMINYL CR 16 mg/day at steady state.

Effect of REMINYL CR on the metabolism of other medicines

Therapeutic doses of REMINYL CR (12 mg twice a day) had no effect on the kinetics of digoxin and warfarin. REMINYL CR did not affect the increased prothrombin time induced by warfarin.

In vitro studies indicated that the inhibition potential of REMINYL CR with respect to the major forms of human cytochrome P450 is very low.

Pregnancy

No studies are available on the use of REMINYL CR in pregnant women. REMINYL CR should not be used during pregnancy.

Lactation

It is not known whether REMINYL CR is excreted in human breast milk and there are no studies in lactating women. REMINYL CR should not be used during breastfeeding.

Alzheimeru2019s disease may cause gradual impairment of driving performance or compromise the ability to use machinery. REMINYL CR may cause adverse reactions (such as dizziness and somnolence), which could affect the ability to drive or use machines, especially during the first weeks after initiation of treatment.

Clinical Trial Data

Table 1. Adverse Drug Reactions Reported in Clinical Trials

System/Organ Class Frequency category Very common Common Uncommon Rare Not known Body as a Whole u2013 General Disorders Fatigue; Syncope; Asthenia; Malaise; Fall; Injury; Back pain; Chest pain; Fever Central & Peripheral Nervous system Disorder Dizziness ; Headache; Tremor ; Lethargy Dysgeusia; Hypersomnia; Paresthaesia; Vertigo; Hypertonia; Convulsions; Involuntary muscle contractions; Ataxia; Hypokinesia; Hyperkinesia; Apraxia; Aphasia; Leg cramps; Tinnitus; Transient ischaemic attack; Cerebrovascular accident

Table 2. Adverse Drug Reactions Reported in Clinical Trials

System/Organ Class Frequency category Very common Common Uncommon Rare Not known Gastrointestinal System Disorders Nausea; Vomiting; Diarrhoea; Abdominal pain; Abdominal pain upper; Dyspepsia; Stomach discomfort; Abdominal discomfort; Constipation; Flatulence Retching; Gastritis; Melaena; Dysphagia Rectal haemorrhage; Dry mouth; Increased salivation; Diverticulitis; Gastroenteritis; Hiccup; Oesophageal perforation Cardiac Disorders Bradycardia First degree atrioventricular block; Palpitations; Sinus bradycardia; Supraventricular extrasystoles; Cardiac failure; Myocardial ischaemia or infarction; Atrial dysrhythmias; Atrial fibrillation; Supraventricular tachycardias, Prolonged QT interval; Bundle branch block;

Table 3. Adverse Drug Reactions Reported in Clinical Trials

System/Organ Class Frequency category Very common Common Uncommon Rare Not known T-wave inversion; Ventricular tachycardia; Severe bradycardia Metabolic and Nutritional Disorders Decreased appetite; Weight decreased Dehydration; Hyperglycaemia; alkaline phosphate Musculoskeletal and Connective Tissue Disorders Muscle spasms Muscular weakness Psychiatric Disorders Anorexia; Depression Insomnia; Somnolence; Hallucination; Agitation; Confusion; Anxiety Apathy; Paroniria; Paranoid reaction; Increased libido; Delirium; Suicidal ideation; Suicide Respiratory System Disorder Rhinitis ; Upper respiratory tract infection ; Bronchitis ; Coughing Skin and Sub -cutaneous Tissue Disorders Hyperhydrosis

Table 4. Adverse Drug Reactions Reported in Clinical Trials

System/Organ Class Frequency category Very common Common Uncommon Rare Not known Urinary system Disorders Urinary tract infection; Haematuria; Urinary incontinence Micturition frequency; Cystitis; Urinary retention; Nocturia; Renal calculi Vascular and Blood cell Disorders Anaemia; Peripheral oedema; Hypertension Flushing; Hypotension; Postural hypotension; Dependent oedema; Purpura; Epistaxis; Thrombocytopenia

Post-marketing data

Table 2 includes adverse events from post-approval controlled and uncontrolled clinical trials and post-marketing experience observed in patients treated with REMINYL CR. These adverse events may or may not be causally related to the medicine.

Table 2. Adverse Reactions Identified During Postmarketing Experience with REMINYL CR

System/Organ Class Frequency category Very common Common Uncommon Rare Not known Immune System Disorders Hypersensitivity Body as a Whole u2013 General Disorders Dehydration (including, severe cases leading to renal insufficiency and renal failure). Psychiatric Disorders Hallucination Hallucination visual; hallucination auditory Aggression

Table 2. Adverse Reactions Identified During Postmarketing Experience with REMINYL CR

System/Organ Class Frequency category Very common Common Uncommon Rare Not known Gastrointestinal System Disorders Abdominal discomfort Upper and lower GI bleeding; stomach discomfort Hepatobiliary Disorders Elevated liver enzymes Hepatitis Metabolic & Nutritional Disorders Hypokalaemia Nervous System Disorders Lethargy Dysgeusia; hypersomnia; convulsions Ear and Labyrinth Disorders Tinnitus Cardiac Disorders Atrioventricular block complete Eye disorders Blurred vision Vascular Disorders Hypertension Skin and subcutaneous tissue disorders Stevens- Johnson Syndrome; acute generalized exanthematous pustulosis; erythema multiforme

Symptoms

Signs and symptoms of significant overdosing of REMINYL CR 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 loss of consciousness in association with inadvertent overdoses of galantamine.

Treatment

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.