Dozemo ODT

Donepezil hydrochloride.

Each orodispersible tablet contains 5 mg donepezil hydrochloride.
Each orodispersible tablet contains 10 mg donepezil hydrochloride.
Excipients/Inactive Ingredients: Mannitol, microcrystalline cellulose, aspartame, silica, colloidal anhydrous, croscarmellose sodium, peppermint flavour, zinc sulfate monohydrate, magnesium stearate, color premix (10 mg).

Pharmacotherapeutic Group: Anti-dementia drugs, anticholinesterases. ATC Code: N06DA02.
Pharmacology: Pharmacodynamics: Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is in vitro over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme that is present mainly outside the central nervous system.
Pharmacokinetics: Absorption: Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.
Distribution: Following multiple-dose administration, steady state is reaches within 15 days. Donepezil is approximately 96% bound to human plasma proteins.
Metabolism: Donepezil is excreted in urine. It is metabolized by CYP-450 enzyme 2D6 and 3A4, and undergoes glucuronidation.
Excretion: The elimination half-life of donepezil is approximately 70 hours and the mean apparent plasma clearance is 0.13 L/h/kg.

Donepezil is indicated for the sympathetic treatment of mild, moderate and severe Alzheimer's disease; vascular dementia (dementia associated with cerebrovascular disease). Dementia with Lewy bodies.

Adults/Elderly: Treatment is initiated at 5 mg/day (once-a-day dosing). Donepezil should be taken orally, in the evening, just prior to retiring. The orodispersible tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water according to patient preference. The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.
For patient with DLB, the dose may be decreased to 5 mg depending on the symptoms of the patient. Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made according to accepted guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a caregiver is available who will regularly monitor drug intake for the patient. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil cannot be predicted.
Upon discontinuation of treatment, a gradual abatement of the beneficial effects of donepezil is seen.
Renal and hepatic impairment: A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil hydrochloride is not affected by this condition.
Due to possible increased exposure in mild to moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions), dose escalation should be performed according to individual tolerability. There are no data for patients with severe hepatic impairment.
Children and adolescents: Donepezil is not recommended for use in children and adolescents below 18 years of age.

The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice and rats is 45 and 32 mg/kg, respectively, or approximately 225 and 160 times the maximum recommend human dose of 10 mg per day.
Symptoms: Dose-related signs of cholinergic stimulation were observed in animals and included reduced spontaneuos movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.
Overdose with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Treatment: As in any case of overdose, general supportive measures should be utilised. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil overdose. Intravenous atropine sulphate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (haemodialysis, peritoneal dialysis, or hemofiltration).

Donepezil is contraindicated in patients with a known hypersensitivity to donepezil, piperidine derivatives, or to any excipients used in the formulation.

The use of donepezil in patients with severe Alzheimer's dementia, other types of dementia or other types of memory impairment (e.g., age-related cognitive decline), has not been investigated.
Anaesthesia: Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.
Cardiovascular Conditions: 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.
Gastrointestinal Conditions: Patients at risk for developing ulcers, e.g. those with a history of ulcer disease or those receiving concurrent non-steroidal 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.
Genitourinary: Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder outflow obstruction.
Neurological Conditions: Seizures: Cholinomimetics are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer's Disease.
Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially life-threatening condition characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatinine phosphokinase levels, has been reported to occur very rarely in association with donepezil, particularly in patients also receiving concomitant antipsychotics.
Additional signs may include myoglubinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, treatment should be discontinued.
Pulmonary Conditions: Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
The administration of donepezil concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.
Severe Hepatic Impairment: There are no data for patients with severe hepatic impairment.
Effects on Ability to Drive and Use Machines: 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.

Pregnancy: There are no adequate data from the use of donepezil in pregnant women.
Studies in animals have not shown teratogenic effect but have shown peri and postnatal toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown.
Donepezil should not be used during pregnancy unless clearly necessary.
Lactation: Donepezil is excreted in the milk of rats. It is not known whether donepezil hydrochloride is excreted in human breastmilk and there are no studies in lactating women. Therefore, women on donepezil should not breast feed.

The most common adverse events as diarrhoea, muscle cramps, fatigue, nausea, vomiting, headache and insomnia.
Adverse reactions reported as more than an isolated case are listed as follows, 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 the available data).
Infections and infestations: Common: Common cold.
Metabolism and nutrition disorders: Common: Anorexia.
Psychiatric disorders: Common: Hallucinations^**, agitation**, agressive 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: Sinoatrial block, atrioventricular block.
Gastrointestinal disorders: Very common: Diarrhoea, nausea.
Common: Vomiting, abdominal disturbance.
Uncommon: Gastrointestinal haemorrhage, gastric and duodenal ulcers.
Hepatobiliary disorders: Rare: Liver dysfunction including hepatitis.***
Skin and subcutaneous tissue disorders: Rash, pruritis.
Musculoskeletal and connective tissue 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, poisoning and procedural complications: Common: Accident.
*In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses should be considered (see Precautions).
**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.

Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine. 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%. 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 medicinal product combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta blocking agents which have effects on cardiac conduction.

Incompatibilities: Not applicable.

Do not store above 30°C.

Neurodegenerative Disease Drugs

N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.

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