Dementis (Tablets) Instructions for Use

Marketing Authorization Holder

Elpen Pharmaceutical Co., Inc (Greece)

ATC Code

N06DA02 (Donepezil)

Active Substance

Donepezil (Rec.INN registered by WHO)

Dosage Forms

	Dementis	Film-coated tablets, 5 mg: 28 or 98 pcs.
		Film-coated tablets, 10 mg: 28 or 98 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, slightly biconvex.

Excipients: lactose monohydrate – 91.75 mg, corn starch – 20 mg, microcrystalline cellulose – 15 mg, hydroxypropyl cellulose – 3 mg, magnesium stearate – 0.25 mg.

Film coating composition: sepifilm 752 white: [hypromellose – 2 mg, microcrystalline cellulose – 1.6 mg, macrogol stearate – 0.4 mg, titanium dioxide E171 – 1 mg] – 140 mg.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (7) – cardboard packs.

Film-coated tablets yellow, round, slightly biconvex.

Excipients: lactose monohydrate – 183.5 mg, corn starch – 40 mg, microcrystalline cellulose – 30 mg, hydroxypropyl cellulose – 6 mg, magnesium stearate – 0.5 mg.

Film coating composition: sepifilm 003 white: [hypromellose – 3 mg, microcrystalline cellulose – 2.4 mg, macrogol stearate – 0.6 mg, titanium dioxide E171 – 1 mg]; coating sepispers dry 3244 yellow: [hypromellose – 2.4 mg, microcrystalline cellulose – 0.4 mg, titanium dioxide E171 – 1 mg, iron oxide yellow E172 – 0.2 mg] – 282 mg.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of dementia, cholinesterase inhibitor

Pharmacotherapeutic Group

Anticholinesterase agent

Pharmacological Action

Donepezil is a selective and reversible inhibitor of acetylcholinesterase, which is the predominant type of cholinesterase in the brain. Donepezil inhibits this enzyme more than 1000 times more strongly than butyrylcholinesterase, which is found mainly outside the CNS.

After a single dose of donepezil at doses of 5 mg or 10 mg, the degree of inhibition of acetylcholinesterase activity, measured in erythrocyte membranes, was 63.6% and 77.3%, respectively.

It slows the progression of Alzheimer’s disease, reduces the severity of cognitive symptoms, in some cases restores the daily activity of patients and facilitates their care. It corrects behavioral disorders, reduces apathy, hallucinations, and meaningless repetitive movements.

Pharmacokinetics

After oral administration, the C_max of donepezil in blood plasma is reached in approximately 3-4 hours. Plasma concentrations and AUC increase proportionally to the dose. The T_1/2 from plasma is approximately 70 hours, therefore, with systematic use in single doses, C_ss is usually reached within 2-3 weeks after the start of therapy. After reaching a steady state, the concentration of donepezil in plasma and the associated pharmacodynamic effects do not change significantly during the day. Food intake does not affect the absorption of donepezil.

Plasma protein binding is about 95%. It is assumed that Donepezil and/or its metabolites may persist in the body for more than 10 days.

Donepezil is metabolized in the liver and excreted, as well as its metabolites formed with the participation of cytochrome P450 system isoenzymes, mainly by the kidneys unchanged: approximately 57% of the administered dose was found in the urine (17% unchanged) and 14.5% in feces.

After a single dose of 5 mg, the concentration of unchanged donepezil in plasma is 30% of the taken dose, 6-O-desmethyldonepezil – 11% (the only metabolite with activity similar to donepezil hydrochloride), Donepezil-cis-N-oxide – 9%, 5-O-desmethyldonepezil – 7% and the glucuronic conjugate of 5-O-desmethyldonepezil – 3%.

The T_1/2 of donepezil is about 70 hours.

In patients with mild or moderate hepatic impairment, increased C_ss of donepezil in blood plasma may be observed.

Indications

Symptomatic treatment of mild to moderate Alzheimer’s type dementia.

ICD codes

Dosage Regimen

Adults (including elderly patients) are prescribed an initial dose of 5 mg once/day. Administration at the initial dose is continued for at least 4-6 weeks to achieve steady-state concentrations of donepezil and determine the early clinical effect of therapy. After 1 month, the dose can be increased to 10 mg/day.

The maximum daily dose is 10 mg/day.

Maintenance therapy can be continued as long as the therapeutic effect persists, which should be regularly assessed.

Adverse Reactions

From the cardiovascular system uncommon – bradycardia; rare – sinoatrial block, AV block.

From the nervous system common – syncope, increased fatigue, dizziness, headache, insomnia, hallucinations, agitation, aggressive behavior; uncommon – seizures; rare – extrapyramidal symptoms.

From the digestive system very common – diarrhea, nausea; common – vomiting, dyspepsia, anorexia, gastrointestinal disorders; uncommon – gastrointestinal bleeding, gastric and duodenal ulcers; rare – impaired liver function, including hepatitis.

From the urinary system common – urinary incontinence.

Dermatological reactions common – rash, skin itching.

Laboratory tests uncommon – slight increase in the activity of the muscle fraction of CPK in blood serum.

Other pain of various localization, flu-like syndrome, muscle cramps.

Contraindications

Pregnancy, lactation (breastfeeding), childhood and adolescence under 18 years, hypersensitivity to donepezil and piperidine derivatives.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Pediatric Use

The safety and efficacy of donepezil in children have not been studied, therefore the drug is not recommended for this category of patients.

Special Precautions

Use with caution in patients with a history of obstructive pulmonary diseases (including bronchial asthma), with cardiac rhythm disorders, during anesthesia, as well as in patients with an increased risk of developing ulcers (for example, patients with a history of peptic ulcer disease or receiving concomitant NSAID therapy), simultaneously with NSAIDs, anticholinergics or other cholinesterase inhibitors.

Treatment should be prescribed and conducted by a physician experienced in the management of patients with Alzheimer’s disease.

Maintenance therapy can be continued as long as the therapeutic effect persists. If the therapeutic effect disappears, then Donepezil should be discontinued. After discontinuation of treatment, a gradual decrease in the effect of donepezil is observed; there are no reports of withdrawal syndrome in case of abrupt discontinuation. The individual response to donepezil therapy cannot be predicted.

The efficacy of donepezil in patients with severe Alzheimer’s type dementia, other types of dementia or other types of memory impairment (for example, age-related cognitive decline) has not been studied.

Donepezil, being a cholinesterase inhibitor, may enhance succinylcholine-type muscle relaxation during anesthesia.

Cholinesterase inhibitors (including Donepezil) may have a vagotonic effect on heart rate (in particular, cause bradycardia). The potential for such an effect may be important for patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or AV block.

Cholinomimetics are believed to be capable of causing generalized seizures. However, the occurrence of seizures during treatment with donepezil may also be a manifestation of Alzheimer’s disease.

Effect on ability to drive vehicles and operate machinery

Alzheimer’s type dementia itself may be accompanied by impaired ability to drive a car and use complex equipment. In addition, Donepezil, mainly at the beginning of treatment or when increasing the dose, may cause fatigue, dizziness and muscle cramps. The issue of the ability of a patient with Alzheimer’s type dementia to drive a car or use complex equipment during the use of donepezil should be decided by the doctor after assessing the individual patient’s response to treatment.

Drug Interactions

Clinical experience with donepezil is limited, so when using it, the risk of manifestations of interaction with other drugs that are unknown to date should be taken into account.

Donepezil is metabolized with the participation of the CYP3A4 isoenzyme and to a lesser extent – CYP2D6. Ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6, respectively, inhibit the metabolism of donepezil. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, may inhibit the metabolism of donepezil. In healthy volunteers, ketoconazole increased the average concentrations of donepezil by approximately 30%. However, this effect was not comparable to the effect of ketoconazole on other substances metabolized with the participation of CYP3A4, so it is unlikely to be of clinical significance.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and ethanol, may cause a decrease in donepezil. However, the degree of such inhibitory or inducing action is unknown (caution is required when used concomitantly).

Donepezil may affect the action of drugs with anticholinergic activity. In addition, with simultaneous use, Donepezil may enhance the effect of succinylcholine, other muscle relaxants or cholinergic receptor agonists and beta-blockers that affect cardiac conduction, although an in vitro study showed that Donepezil has a minimal effect on the hydrolysis of succinylcholine.

Cases of atypical changes in blood pressure and heart rate have been described with the simultaneous use of donepezil with other cholinomimetics and quaternary anticholinergic drugs, such as glycopyrrolate.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.