Divare

Diware is a drug used in dementia; it inhibits cholinesterase activity.

Indications Divare

It is used to eliminate the symptoms of Alzheimer's disease, which occurs in a moderate or mild form.

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Release form

The drug is released in tablet form, in the amount of 14 pieces inside a cell plate. In a pack - 1 or 2 such plates.

Pharmacodynamics

The substance is an inhibitor with reversible selective properties in relation to the activity of acetylcholinesterase (the key cholinesterase type inside the brain). By slowing down the action of cholinesterase inside the brain, the component donepezil prevents the processes of the breakdown of the element acetylcholine, which transmits impulses of nervous excitation to the CNS. The substance donepezil slows down acetylcholinesterase much more strongly (more than 1000 times) than pseudocholinesterases, which are located inside structures mainly located outside the CNS.

With a single use of donepezil in doses of 5 or 10 mg, the severity of suppression of the action of acetylcholinesterase is reflected in the erythrocyte walls and is equal to 63.6% and 77.3%, respectively.

The slowing down of acetylcholinesterase inside erythrocytes under the influence of drugs correlates with changes in the ADAS-cog scale indicators.

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Pharmacokinetics

Plasma Cmax values are recorded after 3-4 hours from the moment of drug administration. Plasma values and AUC levels increase proportionally to the dosage increase. The half-life is approximately 70 hours, due to which, with repeated administration of the drug once a day, its equilibrium values are gradually determined (this occurs over 3 weeks from the start of treatment). Equilibrium values of donepezil in blood plasma, as well as its pharmacodynamics, change insignificantly during the day. Food does not affect the absorption of the drug.

Intraplasmic synthesis of donepezil with protein is 95%. The activity of component distribution within various tissues has been poorly studied. In theory, the substance with its metabolic products can remain in the body for up to 10 days.

The drug is excreted unchanged in the urine; the substance undergoes transformation under the influence of the hemoprotein P450 system, during which many metabolic products are formed, some of which could not be identified.

A single dose of 5 mg of the drug labeled with 14C produces the following results:

• unchanged active component in blood plasma – 30% of the portion;
• 6-O-desmethyl donepezil accounts for 11% (this is the only metabolic product with activity similar to donepezil);
• donepezil-cis-N-oxide – equals 9%;
• 5-O-desmethyldonepezil – equal to 7%;
• glucuronic conjugate of the component 5-O-desmethyldonepezil – makes up 3%.

About 57% of the applied dose is registered in urine (17% in unchanged state), and another 14.5% in feces. This fact demonstrates that the initial routes of excretion of the drug are transformation and excretion with urine. Information on enterorenal recirculation of the active substance or its metabolic products is absent. The reduction of plasma parameters of donepezil occurs with a half-life of approximately 70 hours.

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Dosing and administration

Therapy begins with a dose of 5 mg per day (single administration). This dosage should be used for at least 1 month - to ensure the earliest possible clinical response to the evaluation therapy and to obtain an equilibrium indicator of donepezil. After performing a clinical evaluation of therapy with a dosage of 5 mg per day, during the 1st month the dose of the drug can be increased to 10 mg per day (single administration).

No more than 10 mg of the substance should be consumed per day. Portions greater than 10 mg per day have not been studied in clinical trials. The drug is used at night, before bedtime.

Maintenance treatments are continued as long as the drug is effective. Therefore, the clinical impact of Divare must be constantly re-evaluated. In the absence of evidence of a drug effect, the option of discontinuing the drug should be considered. It is impossible to predict a personal response to donepezil.

After discontinuation of the drug, a gradual decrease in the positive effect of donepezil is observed.

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Use Divare during pregnancy

Divaré should not be prescribed to pregnant women.

There is no information on whether donepezil hydrochloride passes into human breast milk; tests involving lactating women have not been performed. Therefore, breastfeeding should be discontinued while using the medication.

Contraindications

It is contraindicated to use the medication in case of intolerance associated with donepezil, piperidine derivatives or other auxiliary components of the drug.

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Side effects Divare

The use of the drug may lead to the occurrence of some side effects:

• parasitic or infectious lesions: rhinitis or a common cold often appears;
• metabolic or alimentary disorders: anorexia often occurs;
• mental disorders: often developing a feeling of agitation** or anxiety, aggressive behavior** or hallucinations;
• problems with the functioning of the nervous system: dizziness, syncope* or insomnia often occur. Sometimes convulsions* or epileptic seizures occur. Extrapyramidal symptoms develop occasionally. NMS occurs sporadically;
• cardiac dysfunction: bradycardia sometimes occurs. Sinoatrial or AV block is occasionally observed;
• Gastrointestinal disorders: mainly diarrhea or nausea. Abdominal discomfort, vomiting or dyspepsia often also occur. Ulcers or bleeding in the gastrointestinal tract are sometimes observed;
• disorders of the biliary tract and liver: liver dysfunction occasionally appears (this includes hepatitis***);
• lesions of the subcutaneous layers and epidermis: itching or rash often occurs;
• problems with the function of connective tissues and the musculoskeletal system: muscle cramps are often observed;
• disorders in the functioning of the urinary tract and kidneys: urinary incontinence often occurs;
• systemic disorders: headaches are mainly observed. Pain and increased fatigue also appear quite often;
• changes in test results: sometimes serum values of muscle CPK increase slightly;
• intoxication, trauma and complications of various procedures: trauma often develops.

*patients are examined for seizures or syncope taking into account the risk of developing heart block or prolonged sinus pauses.

**It is known that the feeling of excitement, hallucinations, and aggressive behavior disappear when the dose is reduced or the medication is discontinued.

***in case of liver dysfunction that cannot be explained by obvious factors, it is necessary to evaluate the issue of discontinuing the use of donepezil.

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Overdose

Poisoning with agents that inhibit cholinesterase activity may provoke a cholinergic crisis, which is characterized by vomiting, hyperhidrosis, severe nausea, hypersalivation, respiratory depression, decreased blood pressure, and also bradycardia, convulsions, or collapse. Muscle weakness may be potentiated; if respiratory muscle disorders occur, a fatal outcome is possible.

As with any intoxication, systemic supportive procedures should be carried out. In such cases, tertiary anticholinergic agents (e.g., atropine) are used as an antidote. Atropine sulfate should be administered intravenously, titrating the dose until the result is obtained: the initial dosage is 1-2 mg, with subsequent changes taking into account the clinical response.

There are data on atypical manifestations associated with blood pressure and heart rate indicators when using other cholinomimetics together with quaternary anticholinergic elements (for example, glycopyrrolate).

There is no information whether donepezil hydrochloride or its metabolic products can be excreted by dialysis (peritoneal, as well as hemodialysis, as well as hemofiltration).

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Interactions with other drugs

Donepezil hydrochloride with its metabolic products slows down the metabolic processes of warfarin, digoxin and theophylline with cimetidine.

In vitro tests demonstrate that donepezil metabolism processes are carried out by the enzyme 3A4 of the hemoprotein P450, as well as the element 2D6 (less intensively).

In vitro drug interaction testing has shown that quinidine and ketoconazole (which inhibit 2D6 and CYP3A4 activity, respectively) inhibit drug metabolism processes. Therefore, these and other drugs that inhibit CYP3A4 activity (e.g., erythromycin and itraconazole), as well as substances that inhibit CYP2D6 activity (e.g., fluoxetine), are capable of inhibiting donepezil metabolism processes.

In tests with volunteers, the ketoconazole component increased mean donepezil values by approximately 30%.

Enzyme inducing agents (phenytoin with rifampicin, alcoholic beverages, and carbamazepine) can reduce the Diware index. Since there is no information on the magnitude of the inducing or inhibiting effect, such drugs should be combined very carefully.

Donepezil has the potential to interact with medications that have an anticholinergic effect.

At the same time, there is a possibility of mutual potentiation of the effect when used in combination with the drug such drugs as succinylcholine and other substances that block neuromuscular activity, as well as cholinomimetics or β-blockers that can affect conduction within the heart.

The combination of the drug with other cholinomimetics and quaternary anticholinergic drugs (eg, glycopyrrolate) sometimes leads to atypical changes in heart rate and blood pressure.

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Storage conditions

Divare must be kept in a place closed to small children.

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Shelf life

Diware can be used within 24 months from the date of manufacture of the therapeutic product.

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Application for children

The drug cannot be used in pediatrics.

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Analogues

The analogs of the drug are Alzamed, Servonex, Arizil and Alzepil with Aricept, as well as Almer, Donerum, Aripezil with Yasnal, Palixid-Richter and Doenza-Sanovel.