Divare

Divara is a drug used in dementia; slows cholinesterase activity.

Indications Divare

It is used to eliminate the signs of Alzheimer's disease, occurring in moderate or mild form.

[1], [2], [3], [4]

Release form

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

Pharmacodynamics

The substance is an inhibitor with reversible selective properties with respect to acetylcholinesterase activity (a key cholinesterase type inside the brain). By slowing down the action of cholinesterase inside the brain, the component donepezil prevents the decomposition of the element acetylcholine, which translates nerve excitation impulses to the central nervous system. The substance donepezil slows down acetylcholinesterase much more (more than 1000 times) than pseudocholinesterase, which are located inside the structures, mostly outside the central nervous system.

When 1 dose of donepezil is used in portions of 5 or 10 mg, the severity of the suppression of the action of acetylcholinesterase affects the erythrocyte walls and is 63.6%, respectively, and 77.3%, respectively.

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

[5], [6]

Pharmacokinetics

Plasma values Cmax are recorded after 3-4 hours from the moment of using the drug. An increase in plasma values and AUC level is proportional to the increase in dosage. The half-life is approximately 70 hours, which is why when you re-administer the drug 1-fold, its equilibrium values are determined once per day (this happens for 3 weeks after the start of treatment). The equilibrium indicators of donepezil within the blood plasma, as well as its pharmacodynamics, change insignificantly throughout the day. Food does not affect the absorption of drugs.

Intraplasmic synthesis of donepezil with protein equals 95%. The distribution activity of the component inside a variety of tissues is poorly understood. In theory, a substance with its metabolic products can be stored inside the body for up to 10 days.

Excretion of the drug in unchanged condition is carried out with 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 determined.

A single use of 5 mg of the drug labeled with the element 14C, displays the following indicators:

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

About 57% of the applied dosage is recorded inside the urine (by 17% - in an unchanged condition), and another 14.5% - inside the feces. This fact demonstrates that the initial pathways of drug excretion are transformation and excretion with urine. Information regarding the enterovascular recycle of the active substance or its metabolic products is missing. The reduction of plasma indicators of donepezil is carried out with a half-life of about 70 hours.

[7], [8],

Dosing and administration

Therapy begins with a dose of 5 mg per day (1-time use). This dosage must be applied for at least 1 month to ensure the earliest possible clinical response to the evaluation therapy and to obtain an equilibrium value of donepezil. After completing the clinical evaluation of therapy with a dosage of 5 mg per day, for the first month, the dose of the drug can be increased to 10 mg per day (1 administration).

During the day it is required to consume no more than 10 mg of the substance. Portions of more than 10 mg per day have not been studied in clinical tests. The drug is used at night, before bedtime.

Maintenance procedures continue until the drug has an effect. Therefore, the clinical impact of Divara must be constantly overestimated. In the absence of evidence of a medical outcome, the drug withdrawal option should be evaluated. It is impossible to predict a personal response to donepezil.

After the abolition of drugs, there is a gradual decrease in the positive effects of donepezil.

[16]

Use Divare during pregnancy

Do not appoint Divara pregnant.

There is no information as to whether donepezil hydrochloride passes into human breast milk; tests in which lactating women would participate were not performed. Because of this, at the time of use of the medication you need to abandon breastfeeding.

Contraindications

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

[9], [10], [11], [12],

Side effects Divare

The use of medication can cause some side effects:

• parasitic or infectious lesions: often rhinitis or a simple cold;
• disruption of metabolism or nutritional activity: anorexia often occurs;
• mental disorders: a feeling of excitement ** or anxiety, aggressive behavior ** or hallucinations often develops;
• problems with the work of the National Assembly: often there is dizziness, syncope * or insomnia. Sometimes there are convulsions * or epilepsy attacks. Occasionally, extrapyramidal signs develop. There is a single ZNS;
• damage to cardiac function: sometimes bradycardia occurs. Sinoatrial or AV blockade is rarely observed;
• disorders associated with the work of the digestive tract: mainly diarrhea or nausea. Often, abdominal discomfort, vomiting, or dyspepsia also occurs. Sometimes there are ulcers or bleeding in the gastrointestinal tract;
• Violations of the GIB and liver: occasionally liver dysfunction appears (this includes hepatitis ***);
• lesions of the subcutaneous layer and epidermis: itching or rash often occur;
• problems with connective tissue function and ODA: muscle cramps are often observed;
• disorders of the urethra and kidneys: urinary incontinence often appears;
• systemic disorders: mainly headaches. Quite often, pain and increased fatigue also appear;
• changes in test readings: sometimes the serum values of muscle CPK are slightly increased;
• intoxication, injuries and complications of various procedures: injuries often develop.

* Patients are examined for seizures or syncope in view of the risk of heart block or prolonged sinus pauses.

** It is known that the feeling of excitement, hallucinations, as well as aggressive behavior disappear in the case of a smaller portion or withdrawal of the medication.

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

[13], [14], [15]

Overdose

Poisoning with agents that slow down cholinesterase activity can provoke a cholinergic crisis, in which vomiting, hyperhidrosis, severe nausea, hypersalivation, respiratory depression, decreased blood pressure, and besides bradycardia, convulsions, or collapse are noted. Muscular weakness may potentiate; with the occurrence of disorders associated with respiratory muscles, death is possible.

As with any intoxication, system supporting procedures should be carried out. In the form of an antidote in such cases, tertiary anticholinergic substances are used (for example, atropine). It is required in / in the way to introduce atropine sulfate, titrating the dose to obtain the result: the initial dosage is 1-2 mg, with further changes, taking into account the clinical response.

There is evidence of atypical manifestations associated with indicators of blood pressure and heart rate, when using other cholinomimetics with quaternary anticholinergic elements (for example, glycopyrolate).

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

[17]

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 the metabolism of donepezil is performed using the enzyme ZA4 hemoprotein P450, as well as the element 2D6 (less intensively).

Testing drug interactions in vitro revealed that quinidine with ketoconazole (inhibit the activity, respectively, 2D6 and CYP3A4) inhibit drug metabolism. Therefore, these and other drugs that slow down the activity of CYP3A4 (for example, erythromycin with itraconazole), and in addition to this substance, inhibiting the activity of CYP2D6 (for example, fluoxetine), can slow down the metabolic processes of donepezil.

When testing with volunteers, the ketoconazole component increased the average values of donepezil by approximately 30%.

Enzyme inducing agents (phenytoin with rifampicin, alcoholic drinks, and also carbamazepine) are capable of decreasing Divare. Because there is no information regarding the magnitude of the inducing or slowing effect, these drugs must be combined very carefully.

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

At the same time, there is a possibility of mutual potentiation of the effect with combined use of drugs such as succinylcholine and other substances that block neuromuscular activity with the drug, and besides cholinomimetics or β-blockers that can affect conduction inside the heart.

The combination of a drug with other cholinomimetics and quaternary anticholinergic drugs (for example, glycopyrolate) sometimes leads to an atypical change in the values of heart rate and blood pressure.

[18]

Storage conditions

The divara is required to be kept in a place closed from the penetration of small children.

[19],

Shelf life

Divara can be used within a 24-month period from the date of manufacture of the therapeutic product.

[20]

Application for children

Do not use the drug in pediatrics.

[21]

Analogs

Analogues of the drug are Alzamed, Servonex, Arizil and Alzepil with Aricept, and also Almer, Donerum, Aripezil with Jasnal, Palixid-Richter and Doenza-Sanovel.