Active ingredients: Donepezil hydrochloride (donepezil hydrochloride)
Donepezil Mylan Generics Italia 5 mg orodispersible tablets
Donepezil Mylan Generics Italia 10 mg orodispersible tablets
Why is Donepezil used - Generic Drug? What is it for?
Donepezil Mylan Generics Italia contains the active substance donepezil hydrochloride. It is used for the treatment of dementia. Donepezil Mylan Generics Italia (donepezil hydrochloride) belongs to a group of medicines called acetylcholinesterase inhibitors. It is used to treat the symptoms of mild to moderate Alzheimer's dementia. Alzheimer's dementia is a type of disease that alters the way the brain works and is common in the elderly. Symptoms include increased memory loss, increased confusion, and changes in behavior that make it more difficult to carry out normal daily activities. It should only be used in adult patients.
Contraindications When Donepezil - Generic Drug should not be used
Do not take Donepezil Mylan Generics Italia:
- If you are allergic to donepezil hydrochloride, piperidine derivatives or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Donepezil - Generic Drug
Talk to your doctor or pharmacist before taking Donepezil Mylan Generics if you have or have ever suffered from any of the following conditions.
- A heart disorder (especially if you have an irregular heartbeat, sinus node disease, or other conditions that affect the heart's rhythm). Donepezil Mylan Generics Italia can slow your heart rate.
- Stomach or duodenal ulcers or use of non-steroidal anti-inflammatory drugs (NSAIDs) (to treat pain or arthritis)
- Difficulty urinating
- Convulsions or seizures: Donepezil Mylan Generics Italia can cause seizures. Your doctor will monitor your symptoms.
- Asthma or other lung diseases
- Diseases of the liver. Tell your doctor if you are going to have surgery, as the dose of the drug used for anesthesia may need to be changed.
Children and adolescents
Children and adolescents under 18 should not take this medicine.
Interactions Which drugs or foods can change the effect of Donepezil - Generic Drug
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, especially if you are taking any of the following:
- Antidepressants (e.g. fluoxetine)
- Quinidine (for heart rhythm disorders)
- Erythromycin (an antibiotic)
- Rifampicin (to treat tuberculosis)
- Ketoconazole or itraconazole (antifungals)
- Carbamazepine or phenytoin (to control epilepsy)
- Beta blockers (medicines for heart disease)
- Non-steroidal anti-inflammatory drugs (for the treatment of pain or arthritis) Donepezil Mylan Generics Italia should not be taken with other medicines that work in the same way, that is, they increase the amount of acetylcholine in the brain, blocking its destruction by the " acetylcholinesterase enzyme (e.g. galantamine). Medicines that reduce the amount of acetylcholine may work less well when taken together with Donepezil Mylan Generics Italia. If you are not sure, talk to your doctor. Tell your doctor if you are going to have surgery because Donepezil Mylan Generics Italia may increase the effect of muscle relaxants used in anesthesia.
Donepezil Mylan Generics Italia with food, drink and alcohol
Take special care with alcohol use when taking Donepezil Mylan Generics Italia as alcohol may reduce the effect of Donepezil Mylan Generics Italia.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are planning to become pregnant, do not take Donepezil Mylan Generics Italia until you have talked to your doctor. Donepezil Mylan Generics Italia should not be used during pregnancy unless clearly necessary. Women who take Donepezil Mylan Generics Italia should not breastfeed.
Ask your doctor or pharmacist before taking any medicine.
Driving and using machines
Do not drive or use machines if you feel dizzy or sleepy or if you have muscle cramps while taking Donepezil Mylan Generics Italia. Alzheimer's disease can in turn impair your ability to drive or use machines. You should not do these activities unless your doctor has told you that you can do it safely.
Dose, Method and Time of Administration How to use Donepezil - Generic Drug: Posology
Always take this medicine exactly as your doctor has told you. If you are not sure, ask your doctor or pharmacist.
Tell your doctor the name of the person who cares for you. This person will help you take your medicine as it was prescribed for you.
Adults
The recommended starting dose is 5 mg of Donepezil Mylan Generics Italia taken once a day for at least one month. Your doctor may then increase the dose to 10 mg of Donepezil Mylan Generics Italia once a day. The maximum recommended daily dose is 10 mg per day. If you experience an increase in side effects by taking 10 mg every day, talk to your doctor or pharmacist.
Use in patients with liver and kidney disease
In adults with mild to moderate liver disease, the doctor may want to change the dose. No dose adjustment is required if you have kidney problems.
Use in children and adolescents
Donepezil Mylan Generics Italy is only recommended for adults.
Method of administration:
The tablet should be kept on the tongue until completely disintegrated before swallowing with or without water, depending on the patient's preference. Your doctor will tell you how long to continue taking these tablets. You will need to see your doctor regularly to review your treatment and evaluate your symptoms.
If you forget to take Donepezil Mylan Generics Italia
If you have forgotten to take your tablet, take one tablet the next day at the usual time. Never take a double dose to make up for a forgotten one.
If you forget to take your medicine for more than a week, contact your doctor before taking the medicine again.
If you stop taking Donepezil Mylan Generics Italia
When the treatment is stopped, the beneficial effects of Donepezil Mylan Generics Italia will gradually diminish. Do not stop taking the tablets without first talking to your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken an overdose of Donepezil - Generic Drug
If you take more Donepezil Mylan Generics than you should
Do not take more than one tablet per day. Contact your doctor or the emergency room of the nearest hospital immediately. Take the box and any remaining tablets with you.
If you have taken more Donepezil Mylan Generics than you should, you may have symptoms such as severe nausea, vomiting, salivation, sweating, slow heart rate (bradycardia), low blood pressure (hypotension), difficulty breathing (respiratory depression), muscle weakness. (collapse) and involuntary contractions of the muscles (convulsions). In addition, he may suffer from "increased muscle weakness which can be life-threatening if respiratory muscles are involved."
Side Effects What are the side effects of Donepezil - Generic Drug
Like all medicines, this medicine can cause side effects, although not everybody gets them.
You should see your doctor immediately if you experience the serious side effects mentioned below. Urgent medical treatment may be needed.
- Liver problems including hepatitis (inflammation of the liver characterized by dark urine, pale stools, jaundice, feeling sick (nausea) and fever); this effect is rare (may affect up to 1 in 1,000 people)
- Bleeding and ulcers of the stomach or intestines; this effect is uncommon (may affect up to 1 in 100 people)
- Convulsions; this effect is uncommon (may affect up to 1 in 100 people)
- Fever with muscle stiffness, sweating or a reduced level of consciousness (a disorder called "Neuroleptic Malignant Syndrome"); this effect is very rare (may affect up to 1 in 10,000 people).
Other side effects include:
Very common (may affect more than 1 in 10 patients)
Diarrhea, feeling sick (nausea), headache.
Common (may affect less than 1 in 10 patients)
Vomiting, muscle cramps, feeling tired, insomnia (difficulty falling asleep), cold, anorexia (lack of appetite), hallucinations (seeing or hearing things that are not real), unusual dreams including nightmares, agitation, aggressive behavior, fainting , lightheadedness, abdominal pain or discomfort, rash and itching, urinary incontinence, pain, accidents.
Uncommon (may affect less than 1 in 100 patients)
Slowing of the heartbeat, an increase in the blood levels of a substance called creatine kinase, which is involved in metabolism.
Rare (may affect less than 1 in 1000 patients)
Extra-pyramidal symptoms which include: involuntary movements, tremor and stiffness, motor restlessness, muscle contractions and changes in respiratory and heart rate; changes in heart rhythm.
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.
- This medicinal product does not require any special storage conditions.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other_information "> Other information
What Donepezil Mylan Generics Italia contains
- The active substance is donepezil hydrochloride.
- Donepezil Mylan Generics Italia 5 mg orodispersible tablets: each tablet contains 5 mg of donepezil hydrochloride (equivalent to 4.56 mg of donepezil).
- Donepezil 10 mg orodispersible tablets: each tablet contains 10 mg donepezil hydrochloride (equivalent to 9.12 mg donepezil).
The other ingredients are mannitol, anhydrous colloidal silica, hydroxy propyl cellulose, acesulfame potassium, wisteria, sodium starch glycolate (type A), crospovidone (type A), microcrystalline cellulose, magnesium stearate.
Donepezil Mylan Generics Italy 10 mg orodispersible tablets also contain yellow iron oxide "E172".
What Donepezil Mylan Generics Italia looks like and contents of the pack
Your medicine is in the form of orodispersible tablets.
Donepezil Mylan Generics Italia 5 mg comes as white, round tablets with beveled edges, debossed with "DL 5" on one side and "M" on the other.
Donepezil Mylan Generics Italia 10 mg is presented as yellow, round tablets with beveled edges, debossed with "DL 10" on one side and "M" on the other.
OPA / Al / PVC-Al blisters of 7, 10, 14, 28, 30, 50, 56, 60, 84, 98, 100, 120 and 180 orodispersible tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
DONEPEZIL MYALN GENERICS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each 5 mg tablet contains 5 mg donepezil hydrochloride (as monohydrate), equivalent to 4.56 mg donepezil.
Each 10 mg tablet contains 10 mg donepezil hydrochloride (as monohydrate), equivalent to 9.12 mg donepezil.
Excipient with known effects:
For the 5 mg: each orodispersible tablet contains 70.30 mg of mannitol.
For the 10 mg: each orodispersible tablet contains 140.60 mg of mannitol.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Orodispersible tablet.
Donepezil Mylan Generics Italia 5 mg is presented as white, round tablets with beveled edges, engraved with "DL 5" on one side and "M" on the other.
Donepezil Mylan Generics Italia 10 mg is presented as yellow, round tablets with beveled edges, debossed with "DL 10" on one side and "M" on the other.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Donepezil Mylan Generics Italia is indicated for the mild to moderate symptomatic treatment of Alzheimer's dementia.
04.2 Posology and method of administration -
Adults / seniors
Treatment is started with a dose of 5 mg / day (once daily). Donepezil Mylan Generics Italia should be administered orally, in the evening, before going to bed. The tablet should be kept on the tongue until completely disintegrated before swallowing with or without water depending on the patient's preference.
The dose of 5 mg / day should be maintained for at least 1 month in order to assess the early clinical response of the treatment and to allow the steady state concentrations of donepezil hydrochloride to be reached. After one month of clinical evaluation of treatment at 5 mg / day, the dose of donepezil can be increased to 10 mg / day (once daily). The maximum recommended dose is 10 mg / day. Doses greater than 10 mg / day have not been studied in clinical trials.
Treatment should be initiated under the supervision of 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). Donepezil therapy should only be initiated if a qualified person is available who can regularly monitor the patient's intake of the product. Maintenance treatment can be continued as long as there is a therapeutic benefit to the patient. Therefore the benefit clinical trial of donepezil should be evaluated regularly. Discontinuation should be considered when there is no longer evidence of a therapeutic effect. Individual response to donepezil cannot be predicted.
A gradual reduction in the beneficial effects of donepezil was observed after discontinuation of treatment.
Patients with renal or hepatic impairment
A similar posology can be followed for patients with renal impairment, since clearance of donepezil is not affected by this condition.
Due to the possible increase in exposure in mild to moderate hepatic impairment (see section 5.2), dose escalation should be performed based on individual tolerability. There are no data for patients with severe hepatic impairment.
Pediatric population
The use of Donepezil Mylan Generics Italia is not recommended in children.
04.3 Contraindications -
Hypersensitivity to the active substance, to piperidine derivatives or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use -
The use of donepezil hydrochloride in patients with severe Alzheimer's dementia, other types of dementia or other types of memory impairment (eg, age-related cognitive decline) has not been studied.
Anesthesia
Donepezil hydrochloride, as a cholinesterase inhibitor, may exaggerate succinylcholinic muscle relaxation during anesthesia.
Cardiovascular Disorders
Due to their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g. bradycardia). The effect of this mechanism may be particularly relevant in patients with "sick sinus disease" or with other supraventricular cardiac conduction disorders, such as atrioventricular or sinoatrial block.
There have been reports of syncope or convulsions. The possibility of heart block or long sinus pauses should be considered when evaluating these patients.
Gastrointestinal disorders
Patients with an increased risk of developing ulcers, eg. those with a history of ulcer or those on concomitant non-steroidal anti-inflammatory drugs (NSAIDs) should be monitored for any symptoms. However, clinical trials with donepezil hydrochloride have shown no increases compared to placebo in the incidence of peptic ulcers. or gastrointestinal bleeding.
Genitourinary disorders
Although not observed in clinical studies with donepezil hydrochloride, cholinomimetics can cause urinary obstruction.
Neurological disorders
Seizures: Cholinomimetics are thought to have the potential to cause generalized seizures. However, seizures can 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 characterized by hyperthermia, muscle stiffness, autonomic instability, impaired consciousness and elevated serum creatine phosphokinase, has been found very rarely in association with donepezil, in particular in patients taking concomitant antipsychotic medicines. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of a neuroleptic malignant syndrome or has unexplained high fever without further clinical manifestations of NMS, treatment should be discontinued.
Pulmonary disorders
Due to their cholinomimetic action, cholinesterase inhibitors should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease.
Administration of donepezil hydrochloride together with other acetylcholinesterase agonist inhibitors, agonists or antagonists of the cholinergic system should be avoided.
Severe hepatic impairment
There are no data for patients with severe hepatic impairment.
Mortality in vascular dementia studies
Three six-month clinical studies were conducted in individuals who met the NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-AIREN criteria were designed to identify patients whose dementia appears to be due solely to vascular causes and to exclude patients with Alzheimer's disease. In the first study, the mortality rate was 2/198 (1%) with donepezil hydrochloride 5 mg, 5/206 (2.4%) with donepezil hydrochloride 10 mg and 7/199 (3.5%) with placebo. In the second study, the mortality rate was 4/208 (1.9%) with donepezil hydrochloride 5 mg, 3/215 (1.4%) with donepezil hydrochloride 10 mg and 1/193 (0.5%) with placebo. In the third study, the mortality rate was 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. The mortality rate for the 3 combined VaD studies for the donepezil group hydrochloride (1.7%) was numerically greater than in the placebo group (1.1%), however this difference was not statistically significant. The majority of deaths in patients taking donepezil hydrochloride or placebo appear to be the result of various vascular causes, which may be expected in this elderly population with concomitant vascular disease. An analysis of all serious non-fatal and fatal events showed no difference in the onset rate in the donepezil group compared to the placebo group.
In the pool of Alzheimer's disease studies (n = 4146) and when these Alzheimer's disease studies were summed with other dementia studies including vascular dementia studies (n = 6888), the mortality rate in the placebo group was outnumbered that in the donepezil hydrochloride groups.
04.5 Interactions with other medicinal products and other forms of interaction -
Donepezil hydrochloride and / or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concomitant administration of digoxin or cimetidine. Studies in vitro demonstrated that cytochrome P450 isoenzyme 3A4, and to a lesser extent 2D6, are involved in the metabolism of donepezil. Drug interaction studies conducted in vitro showed that ketoconazole and quinidine, CYP3A4 and 2D6 inhibitors, 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 a study in healthy volunteers, ketoconazole resulted in an increase in mean donepezil concentrations of approximately 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol may reduce donepezil levels. As the extent of an inhibitory or inductive effect is unknown, administration of the above drug combinations should be undertaken with caution. Donepezil hydrochloride can interfere with drugs with anticholinergic activity. It is also possible a synergistic activity with concomitant treatment based on drugs such as succinylcholine, other neuromuscular blockers or cholinomimetics or with beta-blockers that act on cardiac conduction.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no adequate data on the use of donepezil hydrochloride in pregnant women.
Studies in animals have not shown teratogenic effects but have shown peri- and postnatal toxicity (see section 5.3). The potential risk is unknown.
Donepezil hydrochloride should not be used during pregnancy unless clearly needed.
Feeding time
Donepezil hydrochloride is excreted in the milk of rats. It is not known whether donepezil is excreted in human milk and there are no studies in breastfeeding women. Therefore women taking donepezil should not breastfeed.
04.7 Effects on ability to drive and use machines -
Donepezil hydrochloride has a mild or moderate influence on the ability to drive or use machines.
Dementia can cause impaired ability to drive or use machines. In addition, donepezil hydrochloride can induce fatigue, dizziness and muscle cramps, especially at the start of therapy or when the dose is increased. The treating physician should routinely assess the ability of the patient being treated with donepezil hydrochloride to continue driving or operating complex machinery.
04.8 Undesirable effects -
The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia.
Adverse reactions reported more frequently than in isolated cases are listed below, sorted by organ and system and by frequency. Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100 and
* The possibility of heart block or long sinus pauses should be considered when evaluating patients with syncope or seizures (see section 4.4).
** Cases of hallucinations, abnormal dreams and nightmares, agitation and aggressive behavior resolved with dose reduction or discontinuation of treatment.
*** In cases of unexplained hepatic dysfunction, discontinuation of donepezil hydrochloride should be considered.
04.9 Overdose -
Donepezil hydrochloride is a reversible and specific inhibitor of acetylcholinesterase.Following a single oral dose of donepezil hydrochloride administered to mice and rats, a mean lethal drug dose of 45 mg / kg and 32 mg / kg, respectively, was calculated; this dose corresponds to approximately 225 and 160 times the maximum recommended human dose, equal to 10 mg / day. Signs of dose-related cholinergic stimulation have been observed in animals, including: reduction of spontaneous movements, prone position , lame walking, lacrimation, clonic convulsions, respiratory depression, salivation, myosis, muscle fasciculation and lowering of body temperature.
Overdose with cholinesterase inhibitors can cause cholinergic crises characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. There is the possibility of an increase in muscle weakness which, in the presence of respiratory muscle involvement, can result in the patient's death.
As with all cases of overdose, general supportive measures should be used. Tertiary anticholinergics, such as atropine, can be used as an antidote in the event of an overdose of donepezil hydrochloride. Intravenous administration of atropine sulfate is recommended at the dose necessary to achieve the desired effect: an initial dose of 1.0 to 2.0 mg ev with subsequent dose adjustment based on clinical response. Alterations in blood pressure and heart rate responses have occurred with other cholinomimetics administered concomitantly with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and / or its metabolites are eliminated by dialysis (hemodialysis, peritoneal dialysis, or haemofiltration).
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
ATC code: N06DA02.
Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the most commonly found cholinesterase in the brain. Donepezil hydrochloride inhibits this enzyme with a potency in vitro equal to 1000 times that of butyrylcholinesterase, an enzyme mainly present outside the central nervous system.
Alzheimer's dementia
In patients with Alzheimer's dementia who participated in clinical trials, administration of single doses of 5 mg or 10 mg donepezil hydrochloride resulted in steady-state "inhibition of" aceticolinesterase activity (measured in erythrocyte membranes). ) equal to 63.6% and 77.3%, respectively, when detected after drug administration. Inhibition of acetylcholinesterase (AChE) in erythrocytes following use of donepezil hydrochloride has been observed to correlate with changes recorded by the ADAS-cog scale, a sensitive scale used to assess specific aspects of cognitive function. The ability of donepezil hydrochloride to alter the course of underlying neurological disease has not been studied. Therefore, it is not possible to state that donepezil hydrochloride can in any way modify the evolution of the disease.
The efficacy of donepezil treatment was evaluated in 4 placebo-controlled clinical trials, of which 2 were 6 months long and 2 were 1 year long.
In clinical trials lasting 6 months, at the conclusion of treatment with donepezil hydrochloride, an analysis was performed based on a combination of 3 efficacy criteria: ADAS-Cog (scale for the measurement of cognitive performance), Clinician Interview Based Impression of Change with Caregiver Input (scale for measuring global functions) and Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (scale for measuring interpersonal and social relationships, household activities, hobbies and personal care).
Patients who responded to treatment were defined as all those who met the criteria listed below:
Answer = Improvement of the ADAS-Cog by at least 4 points.
No deterioration of the CIBIC.
No deterioration of Activities of Daily Living Subscale of the Clinical Dementia Rating Scale.
* p
** p
Donepezil hydrochloride produced a statistically significant and dose-dependent increase in the proportion of patients who were judged "responder" to the treatment.
05.2 "Pharmacokinetic properties -
Absorption
Maximum plasma levels are reached approximately 3-4 hours after oral administration. Plasma concentrations and area under the curve increase proportionally with dose. The terminal elimination half-life is approximately 70 hours and therefore multiple dosing of single daily doses allows for a gradual achievement of steady-state. An almost comparable concentration to the "steady-state" concentration is reached within 3 weeks of starting therapy. Once "steady-state" is reached, the plasma concentrations of donepezil hydrochloride and related pharmacological activity exhibit minimal change in "span of the day.
Food intake does not alter the absorption of donepezil hydrochloride.
Distribution
Donepezil hydrochloride is 95% bound to plasma proteins. Plasma protein binding of the active metabolite 6-O-desmethyldonepezil is unknown. The distribution of donepezil hydrochloride in different body tissues has not been definitively studied. However, in a body mass distribution study conducted in healthy male volunteers, it was observed that 240 hours after administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the drug is not eliminated. . This finding suggests that donepezil hydrochloride and / or its metabolites can remain in the body for over 10 days.
Metabolism / Excretion
Donepezil hydrochloride is excreted unchanged in the urine and is metabolised by the cytochrome P450 system into several metabolites, some of which have not been identified. Following administration of a single 5 mg dose of C-labeled donepezil hydrochloride, plasma radioactivity, expressed as a percentage of the administered dose, was mainly present as unchanged donepezil hydrochloride (30%), 6-O-desmethyl donepezil ( 11% - the only metabolite with similar activity to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the 5-O glucuronide conjugate -desmethyl donepezil (3%). About 57% of the total administered radioactivity was eliminated in the urine (17% as unchanged drug) and 14.5% in the faeces; this fact suggests that biotransformation and urinary excretion are the main routes of elimination.
There is no evidence to suggest that donepezil hydrochloride and / or its metabolites re-enter the circulation at the entero-hepatic level.
Plasma concentrations of donepezil hydrochloride decrease with a half-life of approximately 70 hours.
Gender, race and smoking do not cause clinically significant changes in the plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil have not been specifically studied in healthy elderly subjects or in Alzheimer's or vascular dementia patients. However, the mean plasma concentrations in these patients closely match those found in healthy young volunteers.
Patients with mild to moderate hepatic impairment have increased concentrations of donepezil hydrochloride: mean AUC increase of 48% and mean Cmax increase of 39% (see section 4.2).
05.3 Preclinical safety data -
Extensive animal studies have shown that donepezil hydrochloride causes a small number of effects other than those within the drug's own pharmacological effects, consistent with its cholinergic stimulatory action (see section 4.9). Donepezil did not produce mutagenic effects in mutation tests conducted on bacterial and mammalian cells. Some clastogenic effects have been observed in vitro at concentrations clearly toxic to cells and 3000 times greater than plasma concentrations at steady-state. No clastogenic or genotoxic effects were observed in the in vivo mouse micronucleus model. Long-term carcinogenicity studies, conducted in both rats and mice, did not reveal any oncogenic potential.
Donepezil hydrochloride had no adverse effects on the fertility of rats and no teratogenic effects were detected in rats or rabbits, but had a slight effect on stillbirths and survival of premature infants when administered to pregnant rats at 50 dosages. times higher than the maximum dose used in humans (see section 4.6).
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Mannitol
Anhydrous colloidal silica
Hydroxy propyl cellulose
Acesulfame potassium
Wisteria
Sodium starch glycolate (type A)
Crospovidone (type A)
Microcrystalline cellulose
Magnesium stearate
Yellow iron oxide E172 (only for 10 mg)
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
This medicinal product does not require any special storage precautions.
06.5 Nature of the immediate packaging and contents of the package -
5 mg and 10 mg tablets
OPA / Al / PVC-Al blisters of 7, 10, 14, 28, 30, 50, 56, 60, 84, 98, 100, 120 and 180 orodispersible tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Mylan S.p.A.
Via Vittor Pisani, 20
20124 Milan
08.0 MARKETING AUTHORIZATION NUMBER -
041088016 - "5 Mg Orodispersible Tablets" 7 Tablets In Blister Opa / Al / Pvc-Al
041088028 - "5 Mg Orodispersible Tablets" 10 Tablets In Blister Opa / Al / Pvc-Al
041088030 - "5 Mg Orodispersible Tablets" 14 Tablets In Blister Opa / Al / Pvc-Al
041088042 - "5 Mg Orodispersible Tablets" 28 Tablets In Blister Opa / Al / Pvc-Al
041088055 - "5 Mg Orodispersible Tablets" 30 Tablets In Blister Opa / Al / Pvc-Al
041088067 - "5 Mg Orodispersible Tablets" 50 Tablets In Blister Opa / Al / Pvc-Al
041088079 - "5 Mg Orodispersible Tablets" 56 Tablets In Blister Opa / Al / Pvc-Al
041088081 - "5 Mg Orodispersible Tablets" 60 Tablets In Blister Opa / Al / Pvc-Al
041088093 - "5 Mg Orodispersible Tablets" 84 Tablets In Blister Opa / Al / Pvc-Al
041088105 - "5 Mg Orodispersible Tablets" 98 Tablets In Blister Opa / Al / Pvc-Al
041088117 - "5 Mg Orodispersible Tablets" 100 Tablets In Blister Opa / Al / Pvc-Al
041088129 - "5 Mg Orodispersible Tablets" 120 Tablets In Blister Opa / Al / Pvc-Al
041088131 - "5 Mg Orodispersible Tablets" 180 Tablets In Blister Opa / Al / Pvc-Al
041088143 - "10 Mg Orodispersible Tablets" 7 Tablets In Blister Opa / Al / Pvc-Al
041088156 - "10 Mg Orodispersible Tablets" 10 Tablets In Blister Opa / Al / Pvc-Al
041088168 - "10 Mg Orodispersible Tablets" 14 Tablets In Blister Opa / Al / Pvc-Al
041088170 - "10 Mg Orodispersible Tablets" 28 Tablets In Blister Opa / Al / Pvc-Al
041088182 - "10 Mg Orodispersible Tablets" 30 Tablets In Blister Opa / Al / Pvc-Al
041088194 - "10 Mg Orodispersible Tablets" 50 Tablets In Blister Opa / Al / Pvc-Al
041088206 - "10 Mg Orodispersible Tablets" 56 Tablets In Blister Opa / Al / Pvc-Al
041088218 - "10 Mg Orodispersible Tablets" 60 Tablets In Blister Opa / Al / Pvc-Al
041088220 - "10 Mg Orodispersible Tablets" 84 Tablets In Blister Opa / Al / Pvc-Al
041088232 - "10 Mg Orodispersible Tablets" 98 Tablets In Blister Opa / Al / Pvc-Al
041088244 - "10 Mg Orodispersible Tablets" 100 Tablets In Blister Opa / Al / Pvc-Al
041088257 - "10 Mg Orodispersible Tablets" 120 Tablets In Blister Opa / Al / Pvc-Al
041088269 - "10 Mg Orodispersible Tablets" 180 Tablets In Blister Opa / Al / Pvc-Al
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
December 2011
10.0 DATE OF REVISION OF THE TEXT -
September 2013
