Donepezil

Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity.

In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil metabolism. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%.

Patients at increased risk for developing ulcers, e.g. those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. However, the clinical studies with donepezil showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Due to possible increased exposure in mild to moderate hepatic impairment, dose escalation should be performed according to individual tolerability.

Donepezil as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

The administration of donepezil concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care.

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Because of their pharmacological action, cholinesterase inhibitors 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.

There have been reports of syncope and seizures. In investigating such patients the possibility of heart block or long sinusal pauses should be considered.

Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.

There are no adequate data from the use of donepezil in pregnant women.

Studies in animals have not shown teratogenic effect but have shown pre and post natal toxicity. The potential risk for humans is unknown.

Donepezil should not be used during pregnancy unless clearly necessary.

Donepezil is excreted in the milk of rats. It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Therefore, women on donepezil should not breast feed.

Donepezil has minor or moderate influence on the ability to drive and use machines.

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

The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. 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); very rare (<1/10,000) and not known (cannot be estimated from available data).

Infections and infestations

Common: Common cold

Metabolism and nutrition disorders

Common: Anorexia

Psychiatric disorders

Common: Hallucinations**, Agitation**, Aggressive behaviour**, Abnormal dreams and Nightmares**

Nervous system disorders

Common: Syncope*, Dizziness, Insomnia

Uncommon: Seizure*

Rare: Extrapyramidal symptoms

Very Rare: Neuroleptic malignant syndrome

Cardiac disorders

Uncommon: Bradycardia

Rare: Sino-atrial block, Atrioventricular block

Gastrointestinal disorders

Very Common: Diarrhoea, Nausea

Common: Vomiting, Abdominal disturbance

Uncommon: Gastrointestinal haemorrhage, Gastric and duodenal ulcers, Salivary hypersecretion

Hepato-biliary disorders

Rare: Liver dysfunction including hepatitis***

Skin and subcutaneous tissue disorders

Common: Rash, Pruritis

Musculoskeletal, connective tissue and bone disorders

Common: Muscle cramps

Very Rare: Rhabdomyolysis****

Renal and urinary disorders

Common: Urinary incontinence

General disorders and administration site conditions

Very Common: Headache

Common: Fatigue, Pain

Investigations

Uncommon: Minor increase in serum concentration of muscle creatine kinase

Injury and poisoning

Common: Accident

* In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses should be considered.
** Reports of hallucinations, abnormal dreams, nightmares, agitation and aggressive behaviour have resolved on dose-reduction or discontinuation of treatment.
*** In cases of unexplained liver dysfunction, withdrawal of donepezil should be considered.
**** Rhabdomyolysis has been reported to occur independently of Neuroleptic Malignant syndrome and in close temporal association with donepezil initiation or dose increase.