PRIFET Film-coated tablet Ref.[115309] Active ingredients: Donepezil

Treatment should be initiated by a doctor experienced in the treatment of Alzheimer's dementia. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of PRIFET TABLETS should be reassessed on a regular basis. When evidence of a therapeutic effect is no longer present, discontinuation should be considered. Individual response to PRIFET TABLETS cannot be predicted.

The use of PRIFET TABLETS in patients with severe dementia, other types of dementia or other types of memory impairment (e.g. age related cognitive decline), has not been established.

Anaesthesia: PRIFET TABLETS, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Cardiovascular Conditions: Due to their pharmacological action, PRIFET TABLETS 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 conditions such as sinoatrial or atrioventricular block. Syncopal episodes have been reported in association with the use of donepezil.

Gastrointestinal Conditions: Gastric acid production may be promoted by PRIFET TABLETS. Therefore patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk of developing ulcers e.g. those with a history of ulcer disease or those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDs). Donepezil, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhoea, nausea and vomiting. These effects, when they occur, appeared more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil Genitourinary: PRIFET TABLETS may cause bladder outflow obstruction.

Neurological Conditions: PRIFET TABLETS are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease.

Pulmonary Conditions: Due to their cholinomimetic actions, PRIFET TABLETS should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. The administration of PRIFET TABLETS concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.

Patients recovering from bladder or gastrointestinal surgery: PRIFET TABLETS use is not recommended in patients recovering from bladder or gastrointestinal surgery.

Medicines Highly Bound to Plasma Proteins

Medicine displacement studies have been performed in vitro between this highly bound medicine (96%) and other medicines such as furosemide, digoxin and warfarin. PRIFET TABLETS at concentrations of 0,3-10 μg/ml does not affect the binding of furosemide (5 μg/ml), digoxin (2 μg/ml), and warfarin (3 μg/ml) to human albumin. Similarly, the binding of PRIFET TABLETS to human albumin is not affected by furosemide, digoxin and warfarin.

Effect of PRIFET TABLETS on the Metabolism of Other Medicines

No in vivo clinical trials have investigated the effect of PRIFET TABLETS on the clearance of medicines metabolised by CYP3A4 (e.g. cisapride) or by CYP2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Whether PRIFET TABLETS has any potential for enzyme induction is not known.

Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophyline, warfarin, cimetidine, digoxin, thioridazine, risperidone and sertraline in humans. In a study of Parkinson's disease patients on optimal treatment with L-dopa/carbidopa, administration of donepezil for 21 days had no effects on L-dopa or carbidopa blood levels. In this study, no effects on motor activity were observed.

Effects of Other Medicines on the Metabolism of PRIFET TABLETS

Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. Whether there is a clinical effect of these inhibitors is not known. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by 30%. These increases are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway and are not likely to be clinically relevant. Administration of donepezil had no effect on the pharmacokinetics of ketoconazole. Inducers of CYP2D6 and CYP3A4 (e.g. phenytoin, carbamazepine, alcohol, dexamethasone, rifampicin and phenobarbital) could increase the rate of elimination of PRIFET TABLETS.

Formal pharmacokinetic studies demonstrated that the metabolism of donepezil is not significantly affected by concurrent administration of digoxin, cimetidine, thioridazine, risperidone or sertraline.

Use with anticholinergics

PRIFET TABLETS have the potential to interfere with the activity of anticholinergic medications, because of their mechanism of action.

Use with Cholinomimetics and other Cholinesterase Inhibitors

A synergistic effect may be expected when PRIFET TABLETS are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol or beta blocking agents which have an effect on cardiac conduction, but an in vitro study showed that donepezil hydrochloride had minimal effects on hydrolysis of succinylcholine.

The safety of PRIFET TABLETS in pregnancy and lactation has not been established.

Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, PRIFET TABLETS can induce fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The treating doctor should routinely evaluate the ability of patients on PRIFET TABLETS to continue driving or operating complex machines.

Side-effects

Infections and infestations

Frequent: Common cold, influenza

Metabolism and nutrition disorders

Less frequent: Dehydration, hyponatraemia

Psychiatric disorders

Frequent: Insomnia, abnormal dreams, agitation, delusions, depression, hallucinations

Less frequent: Abnormal crying, aggressive behaviour, increased libido, irritability, nervousness, restlessness, confusion

Nervous system disorders

Frequent: Dizziness, headache, somnolence

Less frequent: Aphasia, ataxia, paraesthaesia, syncope, tremor, seizure, extrapyramidal symptoms

Eye disorders

Less frequent: Cataract, eye irritation, blurred vision

Ear and labyrinth disorders

Less frequent: Vertigo

Cardiac disorders

Less frequent: Atrioventricular block, bradycardia, sinoatrial block, angina

Vascular disorders

Less frequent: Hot flushes, hypertension, hypotension, vasodilation

Respiratory, thoracic and mediastinal disorders

Less frequent: Dyspnoea, sore throat, bronchitis

Gastrointestinal disorders

Frequent: Diarrhoea, nausea, vomiting, anorexia, pancreatitis, faecal incontinence, abdominal disturbance

Less frequent: Gastrointestinal haemorrhage, epigastric pain, bloating, toothache, duodenal ulcer, gastric ulcer

Hepato-biliary disorders

Less frequent: Hepatitis

Skin and subcutaneous tissue disorders

Less frequent: Diaphoresis, ecchymosis, pruritus, urticaria, rash

Musculoskeletal, connective tissue and bone disorders

Frequent: Muscle cramps, arthritis

Renal and urinary disorders

Frequent: Frequent urination

Less frequent: Nocturia, urinary incontinence, urinary tract infection

General disorders and administrative site conditions

Frequent: Fatigue, pain

Less frequent: Chest pain

Investigations

Frequent: Weight decrease

Less frequent: Minor increases in serum concentrations of creatine kinase, increased liver transaminases

Injury and poisoning

Less frequent: Accident, bone fracture

Special Precautions

The use of donepezil is associated with weight loss. Patients' weight should be monitored during treatment with PRIFET TABLETS.

Female patients are more susceptible to nausea, vomiting, anorexia and weight loss.

PRIFET TABLETS contains lactose and should not be given to patients with rare hereditary problems, or a history of galactose intolerance, Lapp-lactose deficiency or glucose-galactose malabsorption.