Zhedon Donepezil Tablets

3. PHARMACEUTICAL FORM
Film-coated tablet.
White colored, biconvex, round, film coated tablets.
4. CLINICAL PROPERTIES
4.1. Therapeutic indications
ZHEDON® is a symptomatic treatment of mild to moderate Alzheimer type dementia
indicated.
For special warnings and precautions for use in this indication, refer to 4.4. Special use
See warnings and precautions.
4.2. Posology and application pattern
Posology / application frequency and duration:
Adults / elderly:
The treatment is started with a single dose of 5 mg daily. Earliest clinic to be treated
response and the concentration of donepezil hydrochloride steady-state
the dose of 5 mg / day should be continued for at least one month. One month
by evaluating the clinical response provided by the 5 mg daily dose
The dose of ZHEDON® can be increased to 10 mg once daily. Highest recommended
the daily dose is 10 mg.
In the case of treatment interruption, donepezil hydrochloride has beneficial effects
a sensible reduction is seen. After the treatment is stopped suddenly,
"Rebound" effect or withdrawal effect.
Method of Application:
ZHEDON® should be taken orally once a day and just before bedtime.
Additional information relevant to special populations:
Kidney failure: Donepezil hydrochloride clearance of these conditions
a dose program similar to patients with renal impairment
applicable.

Hepatic insufficiency: Lack of potential for mild to moderate hepatic insufficiency
dose adjustment should be made according to individual tolerability because of exposure increase.
In a study involving 10 patients with stable alcoholic cirrhosis,
hydrochloride of the 10 healthy individuals who were subjected to clearance, age and gender
compared to the previous year.
Pediatric population: efficacy in children with Donepezil hydrochloride and
it is not recommended to use it in children.
Geriatric population: Originally the dose of donepezil hydrochloride pharmacokinetics
a study was not conducted to investigate the relationship between However,
The mean plasma plasma levels followed in patients with Alzheimer's disease
concentrations can be compared to those seen in young healthy volunteers
State.
4.3. contraindications
ZHEDON (R), piperidine derivatives or any of the compounds
is contraindicated in patients known to be hypersensitivity to substance.
4.4. Special use warnings and precautions
Treatment is to diagnose Alzheimer's type of dementia and treat the disease.
should be initiated and directed by a physician who is experienced. Diagnosis, acceptance
(for example, DSM IV, ICD 10). Donepezil treatment,
only a responsible person who can regularly check the medication intake of the patient (patient
close, caregiver etc.). Therapeutic benefit from patient medication
the treatment should continue. For this reason, donepezil
benefits should be reassessed for a certain period of time. Presence of therapeutic effect
When there is no evidence, it should be decided to stop the medicine. If the pigs donepezile
the answer they will give is unpredictable.
Donepezil hydrochloride may cause other dementia types and other memory impairments (e.g.
Amnesic Mild Cognitive Impairment)
It is under construction.
Anesthesia: Donepezil hydrochloride, a cholinesterase inhibitor,
succinylcholine type may increase muscle relaxation.
Cardiovascular states: Pharmacological effects of cholinesterase inhibitors
may cause vagotonic effects on the heart beat (such as bradycardia). It
"sick sinus syndrome" with potential for efficacy, sinoatrial or atrioventricular
other supraventricular cardiac conduction disorders such as bladder
it may be particularly important for patients.
Reports of syncope and convulsions are available. When these patients are examined, heart
block or long sinus pause.
Gastrointestinal conditions: Cholinomimetics can increase gastric acid production.
Nonsteroidal antiinflammatory drug (NSAID) with or without ulcer story
Patients with a high risk of developing ulcers, such as areas,
should be followed. However, the donepezil hydrochloride with placebo

In comparative clinical trials, peptic ulcer or gastrointestinal bleeding
no increase in incidence has been shown.
Genitourinary system: Donepezil hydrochloride in clinical trials
Although not observed, cholinomimetics lead to bladder outlet obstruction
It can open.
Central nervous system: Seizures: Cholinomimetics lead to generalized convulsions
are believed to have the potential to open. However, the seizures are Alzheimer's
It may also be a sign of your illness. Extrapyramidal indications of cholinomimetics
there is a potential to induce or increase.
Pulmonary system: Depending on the cholinomimetic effects, cholinesterase inhibitors
careful in patients with asthma or obstructive pulmonary disease
It should be used. Donepezil hydrochloride, other acetylcholinesterase (AChE)
with cholinergic system agonists or antagonists
should be avoided.
Mortality in vascular dementia clinical trials: High-probability or possible
individuals who meet the NINDS-AIREN criteria for vascular dementia (VaD)
three 6-month clinical trials were conducted. NINDS-AIREN criteria,
to identify patients with dementia caused entirely by vascular causes and
The patients with Alzheimer's disease were designed to leave the study.
When the mortality rates in these three VaD studies are combined, donepezil
The mortality rate in the hydrochloride group (1.7%) was calculated as placebo
mortality rate (1,1%). However, this result is statistically
.
In patients receiving donepezil hydrochloride or placebo,
vascular originated causes, such that the underlying vascular
is an expected result for the elderly population with diseases.
Analysis of vascular events, whether fatal or not, donepezil hydrochloride
showed no difference in the frequency of appearance compared to placebo.
When Alzheimer's disease studies were combined (n = 4146)
when combined with other dementia studies including dementia (n = 6888)
the mortality frequency in the placebo group was quantified as donepezil hydrochloride
mortality rate in this group.
This drug contains lactose. Rare hereditary galactose intolerance, Lapp lactose insufficiency
or patients with glucose-galactose malabsorption problem
they should not use.
4.5. Interactions with other medicinal products and other interaction patterns
Donepezil hydrochloride and other cholinesterase inhibitors
should be avoided.
Donepezil hydrochloride and / or any of its metabolites may be administered to humans in the presence of theophylline,
metabolism of warfarin, cimetidine, digoxin, thioridazine, risperidone and sertraline
does not inhibit. Donepezil hydrochloride metabolism, digoxin, cimetidine,
thioridazine, risperidone and sertraline.

A study of patients with Parkinson's disease who received optimal treatment with L-Dopa / carbidopa
In the study, administration of donepezil hydrochloride for 21 days was performed using L-Dopa or
carbidopa have no effect on blood levels. In this study,
There is no effect on activity. In vitro studies have shown that in donepezil metabolism,
the role of the cytochrome P450 isoenzyme CYP3A4 and, to a lesser extent, of the isoenzyme CYP2D6
he showed you. In vitro drug interaction studies, CYP3A4 inhibitor
ketoconazole and the CYP2D6 inhibitor quinidine, donepezil metabolism
lt; / RTI & gt; For this reason, this and other CYP3A4 inhibitors (itraconazole
and erythromycin) and CYP2D6 inhibitors (such as fluoxetine) such as donepezil
metabolism. In a study of healthy volunteers,
ketoconazole increased the mean donepezil concentrations by 30%. It
on other agents sharing ketoneconazole CYP-3A4 system
it is less likely to be of clinical interest.
Donepezil administration did not have an effect on the pharmacokinetics of ketoconazole.
Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol, donepezil
levels. The importance of the effect of inducing or inducing
such combinations of drugs should be used with caution. Donepezil
hydrochloride has potency to interact with drugs with anticholinergic activity.
Also, succinylcholine, other neuromuscular blockade agents, or
cholinergic agonists or beta-blocker agents with effects on cardiac conduction
There is also synergistic activity potential with simultaneous treatments such as drugs.
4.6. Pregnancy and lactation
General advice
Pregnancy category is C
Women with childbearing potential / Birth control
(Contraception):
There is no adequate and fully controlled work done in pregnant women.
Donepezil should not be used during pregnancy unless absolutely necessary.
Pregnancy period
The doses given to humans are about 80 times more pregnant rats
human dose

4.7. Effects on vehicle and machine use
Alzheimer type dementia may cause deterioration of driving performance
or the ability to use the machine. In addition, donepezil
fatigue, dizziness and muscle cramps at baseline or during dose escalation
Can. The treating physician is the person who is receiving the donepezil treatment.
should regularly evaluate the ability to use complex machines.
8.4. Undesirable effects
The most common undesirable effects are diarrhea, muscle cramps, fatigue, nausea, vomiting, and
Insomnia.
Alzheimer's patients in all stages using donepezil hydrochloride
The frequency of confrontation with undesirable effects is specified.
The incidents reported more than once, the frequency of seeing and the system organ class
listed: [Very common (≥1 / 10); common (≥1 / 100, <1/10); unusual
(≥1 / 1.000, <1/100) and infrequent (≥1 / 10.000, <1 / 1.000), very infrequent (<1 /
unknown (can not be predicted from the given data)].
Infections and infestations:
Common: Colds
Metabolism and nutritional disorders:
Common: Anorexia
Psychiatric disorders:
Common: hallucination **, agitation **, aggressive behavior **, abnormal dreams
Nervous system disorders:
Common: Syncope *, dizziness, insomnia
Uncommon: Seizure *
Rare: Extrapyramidal symptoms
Cardiac disorders:
Uncommon: Bradycardia
Rare: Sinoatrial block, atrioventricular block
Gastrointestinal disorders:
Very common: diarrhea, nausea
Common: Vomiting, abdominal discomfort
Uncommon: gastrointestinal bleeding, gastric and duodenal ulcers
Hepato-bilious disorders:
Rare: liver dysfunction including hepatitis ***
Skin and subcutaneous tissue disorders:
Common: Rash, rash
Musculoskeletal, connective tissue and bone disorders:
Common: Muscle cramps

Kidney and urinary system disorders:
Common: Urinary incontinence
Relevant disorders in general and practice area:
Very common: Bass pain
Common: Pain, exhaustion
Research studies:
Uncommon: Muscle creatine kinase concentrations in the serum are mild
elevations
Injury and poisoning:
Common: Accident
* When patients are examined for syncope or seizures, heartbeat or sinus rhythm
the possibility of a long pause should be considered. (see Section 4.4)
** Declaration on hallucination, agitation and aggressive behavior dose reduction
or the termination of treatment.
*** In case of unexplained liver dysfunction donepezil hydrochloride
treatment should be considered to be terminated.
4.9. Dose aging and treatment
Animal study data
Donepezil hydrochloride, taken as a single oral dose in mice, rats and dogs
the estimated mean lethal dose is 45, 32 and 15 mg / kg, respectively
the maximum recommended daily dose of 10 mg for human is approximately 225,
160 and 75 times. Dosage-related statements of cholinergic stimulation in animals
and they are characterized by sudden decrease in motion, prone position,
walking sagging, tear secretion, clonic convulsions, difficulty in breathing,
saliva secretion, myosin, fasciculation and drop in body surface temperature
It is included.
Symptoms of Dose Aging / Cholinergic crisis
With cholinesterase inhibitors, dose-dependent, severe nausea, vomiting, salivation,
sweating, bradycardia, hypotension, respiratory distress, collapse and convulsions
character can result in a cholinergic crisis. A possible increase in muscle weakness
If respiratory muscles are involved, it can result in death.
Treatment
General support measures should be used, as is the case for each dose.
Donepezil hydrochloride may be administered as an antidote to atropine (1 to 2 mg
The initial dose of intravenous is followed by subsequent doses depending on the clinical response
(tertiary) anticholinergics can be used. glycopyrrolate
when taken together with anticholinergics in a quaternary (quaternary) structure such as
Atypical responses have been reported with cholinomimetics in blood pressure and heart rate.
Donepezil hydrochloride and / or its metabolites may be dialysed (hemodialysis, peritoneal
dialysis or hemofiltration) is not known.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Cholinesterase inhibitors
ATC code: N06DA02
Acetylcholinesterase, the predominant cholinesterase in the donepezil hydrochloride brain
specific and reversible (reversible) inhibitor. Donepezil hydrochloride
which is an enzyme located in the center of the central nervous system,
is 1000 times more potent inhibitor of this enzyme in vitro.
Clinical studies
Alzheimer's disease of mild to moderate severity
In clinical trials involving patients with Alzheimer type dementia, 5 mg or 10 mg
taking donepezil hydrochloride as a single dose per day, followed by dozen
In the measurements, 63.6% and 77.3% of acetylcholinesterase activity (erythrocyte
steady state inhibition, measured on the membranes.
Inhibition of AChE in red blood cells by donepezil hydrochloride induced cognitive
ADAS-COG, which is a sensitive scale that examines the selected properties of the function
are shown to be compatible with variations. Donepezil hydrochloride in the underlying
the potential for alteration in the course of neuropathology has not been investigated. Therefore,
donepezil hydrochloride is not considered to be an effect on the progression of the disease.
The efficacy of donepezil in the treatment of Alzheimer type dementia was assessed by four placebo-controlled
(2 studies for 6 months and 2 studies for 1 year).
In clinical trials, an analysis was performed as a result of 6 months of donepezil treatment.
In this analysis, 3 efficacy criteria were used together. ADAS-cog, near the patient
the opinion of the clinician based on interviews (CIBIC + -
global functions), the daily life of the Clinical Dementia Measurement Scale
Activities Subtype (CDR - social, home, mobile and personal
measures skills in care).
Patients compliant with the features listed below are accepted to have received treatment
have been.
Answer = At ​​least 4 points improvement in ADAS-Cog
No worsening in CIBIC +
Daily Living Activities of the Clinical Dementia Measurement Scale
There is no worsening in Altshalka.

Donepezil, dozza in the percentage of patients who were determined to respond to treatment
it is a statistically significant increase in dependence.
5.2. Pharmacokinetic properties
General features
Absorption: Approximately 3 to 4 hours after oral intake to maximum plasma levels
Reached. Plasma concentrations and area under the curve (EAA) were dose-proportional
. Since the half-life is about 70 hours,
taking a single dose per day results in a steady state approach.
Approximately stable condition is reached within 2-3 weeks after treatment has started. One
Once steady state has been achieved, plasma donepezil hydrochloride
concentrations and the pharmacodynamic activity associated with it are very low throughout the day
change.
The absorption of donepezil hydrochloride is not affected by food.
Distribution: Donepezil hydrochloride accounts for approximately 95% of plasma proteins
Connected. The active metabolite, 6-O-desmethyldonepeziline,
is unknown. Donepezil hydrochloride can be applied to various body tissues
has not been analyzed strictly. However, healthy men
C14-labeled donepezil in a volumetric balance study of volunteers
After a single dose of 5 mg of hydrochloride was taken 240 hours later,
28% did not come out. This is because the donepezil hydrochloride and / or its metabolites
10 days long can be permanent.
Biotransformation: Donepezil hydrochloride cytochrome P450 system (especially
CYP3A4 and less than CYP2D6 isoenzymes)
many uncharacterized metabolites are translated. 14C-labeled donepezil
hydrochloride product after taking a single dose of 5 mg,
of the plasma radioactivity expressed as a percentage
donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11% - donepezil hydrochloride
), donepezil-cis-N-oxide (9%), 5-
O-desmethyl donepezil (7%), 5-O-desmethyl donepezil glucuronide conjugate (3%),
It is determined.
Elimination: The plasma half-life is about 70 hours. Recep
about 57% of the hydrochloride dose was excreted in urine (not changed by 17%
donepezildir), 14.5% was discarded with dısk, which is biotransformation and urine

it shows that it is the way to go. Donepezil hydrochloride and / or
of any of its metabolites will enter enterohepatic circulation
There is no evidence.
Special groups:
Gender, race and smoking habits donepezil hydrochloride plasma
there is no clinical effect that can be considered significant. Donepezil
pharmacokinetics in healthy elderly, Alzheimer patients or vascular dementia
have not been thoroughly examined in patients. However, the average plasma
levels closer to healthy young volunteers.
In patients with mild to moderate hepatic insufficiency, donepezil
an increase in the state concentration is observed; The mean EAA was 48%, Cmax
averaging 39% (see Section 4.2 Posology and practice).
5.3. Preclinical safety data
General
Comprehensive experiments on experimental animals are carried out in accordance with the intended
has little effect except for the effect of cholinergic stimulant.
mutagenicity
Donepezil, mutagenic in bacterial and mammalian cell mutation assays
It is bulunmamıs. Donepezil hydrochloride reverse bacterial mutation and mouse lymphoma
test is not genotoxic. In chromosomal alteration tests, in vitro,
toxic values ​​and steady-state plasma for cells
Some clastogenic effects at concentrations 3000 times higher than their concentrations
but in the in vivo mouse micronucleus model no clastogenic or
no other genotoxic effects were observed and in vivo / in vitro UDS tests
no DNA damage has been observed.
carcinogenicity
Donepezil hydrochloride was administered in CD-1 mice and treated with 180 mg / kg / day (mg / kg
Approximately 1100 times the highest recommended human dose or mg / m2
to about 90 times the highest recommended human dose
In a 88-week carcinogenicity study with the drug or in a Sprague-Dawley
(the highest recommended human dose of 30 mg / kg / day (mg / kg)
the recommended highest human dose of about 180 times or mg / m2
about 30 times) dose of drug given 104 weeks of carcinogenicity
there is no evidence that it may be of carcinogenic potential.
Fertility
Donepezil hydrochloride, 10 mg / kg / day (mg / m2 recommended highest
about 8 times the human dose), the fertility in rats
There is no effect on the slight extension of the twinning cycle over
It is not set. Donepezil hydrochloride is teratogenic in rats or rabbits
It is bulunmamıs. At doses up to 10 mg / kg / day to pregnant rats, stillbirths
and the mild nature of the survival of the new nature (see Chapter 4.6 -
Pregnancy and lactation).
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6.PARMACEUTICAL PROPERTIES
6.1. List of supporting materials
Lactose
Starch
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Colloidal silicon dioxide
Film coating content:
HPMC 15cP
Titanium dioxide
Talc
PEG 6000
6.2. Incompatibilities
It is invalid.
6.3. Shelf life
24 months.
6.4. Special precautions for storage
Store at room temperature below 25 ° C.
6.5. The nature and content of the packaging
14 and 28 tablets in a blister package.
6.6. Removal of remaining substances from the medicinal product and other special precautions
The unused products are replaced with the residual materials "Medical Waste Control
Regulation "and" Packaging and Packaging Waste Control Regulation "
should be destroyed as