Active ingredients: Donepezil (Donepezil hydrochloride)
Memac 5 mg film-coated tablets
Memac package inserts are available for packs:- Memac 5 mg film-coated tablets
- Memac 10 mg film-coated tablets
Indications Why is Memac used? What is it for?
Memac tablets belongs to a group of medicines called acetylcholinesterase inhibitors.
It is used to treat the symptoms of dementia in patients diagnosed with mild or moderately severe Alzheimer's disease. Symptoms include increasing memory loss, confusion, and behavioral changes. The consequence is that people with Alzheimer's disease find it more difficult to carry out daily activities.
Memac tablets are for use by adult patients only.
Contraindications When Memac should not be used
DO NOT take Memac tablets
- If you are allergic (hypersensitive) to donepezil hydrochloride or to derivatives of piperidine, or to any of the other ingredients of Memac tablets listed in section 6.
Precautions for use What you need to know before taking Memac
Tell your doctor or pharmacist before you start taking Memac tablets if you have or have had:
- Gastric or duodenal ulcers
- Seizures (paroxysms) or convulsions
- A heart disorder (irregular or very slow heartbeat)
- Asthma or other long-term lung disease
- Liver problems or hepatitis
- Difficulty urinating or mild kidney disease
- Extrapyramidal symptoms (tremors, stiffness or uncontrolled movement, especially of the face and tongue, but also of the limbs). Memac tablets can induce or aggravate extrapyramidal symptoms.
- Memac tablets can be used in patients with kidney disease or mild to moderate liver disease. Tell your doctor if you have ever had kidney or liver disease. Patients with severe liver disease should not take Memac tablets.
Also tell your doctor if you are pregnant or plan to become pregnant.
Interactions Which drugs or foods can modify the effect of Memac
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines. These include medicines not prescribed by your doctor, but purchased on your own initiative from a chemist / pharmacist. This also applies to any medicines you may take in the future if you continue to take Memac tablets. This is because these medicines can weaken or enhance the effects of Memac tablets.
Especially tell your doctor if you are taking any of the following medicines:
- Other medicines for Alzheimer's disease, eg. galantamine
- Pain relievers or medicines to treat arthritis, such as aspirin, or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or diclofenac sodium
- Anticholinergic medicines, eg. tolterodine
- Antibiotics, eg. erythromycin or rifampicin
- Antifungal medicines, eg. ketoconazole
- Antidepressants, eg. fluoxetine
- Anticonvulsants, eg. phenytoin, carbamazepine
- Medicines to treat a heart disorder, eg. quinidine, beta blockers (propanolol and atenolol)
- Muscle relaxants, eg. diazepam, succinylcholine
- General anesthetics
- Medicines obtained without a prescription, e.g. herbal remedies.
If you are about to have an operation under general anesthesia, tell your doctor and anesthetist that you are taking Memac tablets. This is because the medicine can affect the amount of anesthetic needed.
Tell your doctor or pharmacist the name of the person who cares for you. This person will help you take the medicine as prescribed.
Taking Memac tablets with food and drink
Food does not influence the effect of Memac tablets.
Memac tablets should not be taken with alcoholic beverages as alcohol can alter their effect.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use Memac tablets while breastfeeding.
If you are pregnant or planning to become pregnant, ask your doctor for advice before taking any medicine.
Driving and using machines
Alzheimer's disease can decrease your ability to drive and use machines, so you should not do these activities unless your doctor tells you that you can still do them with some degree of safety.
In addition, the medicine can cause tiredness, dizziness and muscle cramps. If these effects occur, avoid driving or using machines.
Important information about the ingredients of Memac tablets
This medicinal product contains lactose.If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking Memac tablets.
Dose, Method and Time of Administration How to use Memac: Posology
How much Memac tablets should you take?
Dosage
Usually, you start taking 5 mg (one white tablet) every night. After one month, your doctor will tell you to take 10 mg (one yellow tablet) every evening.
Swallow Memac with a sip of water in the evening before going to bed.
The strength of the tablets you need to take may change depending on when you started taking the medicine and according to your doctor's recommendations. The maximum recommended dose is 10 mg each evening.
Always follow your doctor or pharmacist's instructions on how and when to take your medicine.
Do not change the dose without consulting your doctor.
How long should you take Memac tablets for?
Your doctor or pharmacist will advise you on how long to continue taking the tablets. You will need to go back to your doctor periodically to review your treatment and evaluate your symptoms.
If you stop taking Memac tablets
Do not stop taking the tablets unless your doctor tells you to. If you stop taking Memac tablets, the benefits of the treatment will gradually disappear.
If you forget to take Memac tablets
If you forget to take a tablet, just take one tablet the following day at the usual time. Do not take a double dose to make up for a forgotten tablet.
If you forget to take your medicine for more than a week, call your doctor before taking any other medicine.
Overdose What to do if you have taken too much Memac
DO NOT take more than one tablet per day. If you take more than you should, contact your doctor immediately. If you cannot contact your doctor, go to the emergency room of the nearest hospital immediately. Always take your tablets and the cardboard box with you to the hospital, so that the doctor knows which product you have taken.
Symptoms of overdose include nausea and vomiting, excessive sweating, sweating, slow heart rate, low blood pressure (slight lightheadedness or dizziness while standing), trouble breathing, loss of consciousness and fits (paroxysms) or convulsions.
Side Effects What are the side effects of Memac
Like all medicines, Memac tablets can cause side effects, although not everybody gets them.
These are the side effects reported by patients who have taken Memac tablets.
Tell your doctor if you experience any of these effects while taking Memac tablets.
Serious side effects:
Tell your doctor immediately if you notice these serious side effects mentioned. You may need urgent clinical treatment.
- Liver damage, eg. hepatitis. Symptoms of hepatitis are nausea and vomiting, loss of appetite, generally feeling unwell, fever, itching, yellowing of the skin and eyes, dark colored urine (affects 1-10 users in 10,000).
- Gastric and duodenal ulcers. Symptoms of ulcers are stomach pain and discomfort (indigestion) felt between the navel and the breastbone (affects 1 to 10 users in 1,000).
- Bleeding in the stomach and intestines. This can cause carbon-black stools or noticeable blood to come out of the rectum (affects 1 to 10 users in 1,000).
- Seizures (paroxysms) or convulsions (affects 1 to 10 users in 1,000
- Fever with muscle stiffness, sweating and a decreased level of consciousness (a disorder called "Neuroleptic Malignant Syndrome").
- Muscle weakness, tenderness or pain and particularly, if you are also unwell, you may have a high fever or have dark urine. These symptoms can be caused by abnormal breakdown of muscle tissue which can be life-threatening and lead to kidney problems (a condition called rhabdomyolysis).
Very common side effects (affects more than 1 user in 10):
- Diarrhea
- Nausea or vomiting
- Headache
Common side effects (affects 1 -10 in 100 users):
- Muscle cramps
- Tiredness
- Difficulty sleeping (insomnia)
- Flu-like symptoms
- Loss of appetite
- Hallucinations (visual or auditory perception of non-existent things)
- Agitation
- Aggressive behavior
- Fainting
- Dizziness
- Stomach discomfort
- Rash
- Itching
- Uncontrolled urination
- Ache
- Accidents (patients may tend to fall and cause accidental injuries)
- Unusual dreams including nightmares
Uncommon side effects (affects 1 to 10 users in 1,000):
- Slow heartbeat
Rare side effects (affects 1-10 users in 10,000):
- Stiffness, tremors or uncontrolled movement, especially of the face and tongue, but also of the limbs
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Do not store above 30C.
Keep out of the reach and sight of children.
DO NOT use Memac tablets after the expiry date which is stated on the label. The expiry date refers to the last day of the month.
If your doctor asks you to stop taking the medicine, return any unused tablets to your pharmacist.
Other information
What does Memac tablets contain?
The active ingredient is donepezil hydrochloride. The 5 mg tablet contains 5 mg donepezil hydrochloride.
The excipients are
- Core: lactose monohydrate, colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch and magnesium stearate.
- Coating: lpromellose (E464), talc (E553b), propylene glycol (E1520) and titanium dioxide (E171).
What does Memac tablets look like?
5 mg tablets: white to off-white, round, biconvex, gastro-resistant coated tablets, debossed "ML 89" on one side and flat on the other.
What is in a pack of Memac tablets?
The tablets are supplied in packs of 28 units.
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
MEMAC 5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 5 mg donepezil hydrochloride, equivalent to 4.56 mg donepezil as the free base, and 87.9 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Donepezil 5 mg tablets are white to off-white, round, biconvex, film-coated tablets debossed with "ML 89" on one side and flat on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Memac tablets are indicated for the symptomatic treatment of mild or moderately severe Alzheimer's dementia.
04.2 Posology and method of administration
Adult / senior
Treatment is started at 5 mg / day (single daily dosage). Memac tablets should be taken orally in the evening just before bedtime. The 5 mg / day dose should be maintained for at least one month to allow for assessment of initial clinical responses to treatment and to obtain steady-state concentrations of donepezil hydrochloride. Following clinical evaluation one month after treatment with 5 mg / day, the dose of Memac tablets can be increased to 10 mg / day (once daily dosing). The maximum recommended daily dose is 10 mg. Doses above 10 mg / day have not been analyzed in clinical studies.
Therapy should be initiated and supervised by a physician who specializes in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made following accepted guidelines (eg DSM IV, ICD 10). Donepezil therapy should only be initiated if a person is available to assist the patient and who regularly monitors the patient's intake of the medicinal product. Maintenance treatment can be continued as long as there is a therapeutic benefit for the patient. Therefore, the clinical benefit of donepezil should be reassessed on a regular basis. In the event that a therapeutic effect is no longer observed, treatment discontinuation should be considered. Individual response to donepezil is unpredictable.
After discontinuation of treatment, a gradual decline in the beneficial effects of Memac is observed.
Reduced kidney and liver function
A similar dosing schedule can be followed in patients with impaired renal function as clearance of donepezil hydrochloride is not affected by this condition.
Given the possible increased exposure in mild or moderate hepatic function (see section 5.2), dose escalation should be made based on individual tolerability. There are no data in patients with severe hepatic impairment.
Children and adolescents
Memac tablets are not recommended for use in children and adolescents under 18 years of age.
04.3 Contraindications
Memac is contraindicated in patients with known hypersensitivity to donepezil hydrochloride, to piperidine derivatives or to any of the excipients used in the formulation.
04.4 Special warnings and appropriate precautions for use
The use of Memac in patients with severe Alzheimer's dementia, other types of dementia or memory impairment (eg, age-related cognitive decline) has not been investigated.
Anesthesia: Donepezil hydrochloride, being a cholinesterase inhibitor, is likely to increase 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 possibility of this action may be particularly important in patients with "sick sinus syndrome" or other supraventricular cardiac conduction disorders, such as sino-atrial or atrio-ventricular block.
There have been reports of syncope and seizures. When evaluating these patients, consider the possibility of heart block or long sinus pauses.
Gastrointestinal disorders: Patients at increased risk for developing ulcers, eg. those with a history of ulcer disease, or who are receiving non-steroidal anti-inflammatory drugs (NSAIDs) at the same time, should be monitored for symptoms. However, clinical trials with Memac have shown no increase, compared with placebo, in the incidence of peptic ulcer or gastrointestinal bleeding.
Genitourinary disorders: Although the effect was not observed in clinical studies with Memac, cholinomimetics may cause obstruction of bladder outflow.
Neurological disorders: cholinomimetics are believed to be capable of causing generalized convulsions. However, seizure activity can also be a manifestation of Alzheimer's disease.
Cholinomimetics can aggravate or induce extrapyramidal symptoms.
Neuroleptic Malignant Syndrome (NMS): NMS, a life-threatening disease characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been found very rarely in association with donepezil, particularly in patients being treated concomitantly with antipsychotics. Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms typical of NMS, or has unexplained high fever without further clinical manifestations of NMS, treatment should be discontinued.
Pulmonary disorders: Due to their cholinomimetic actions, cholinesterase inhibitors should be prescribed with caution in patients with a history of asthma or obstructive pulmonary disease.
Avoid co-administration of Memac with other acetylcholinesterase inhibitors or agonists / antagonists of the cholinergic system.
Severe impairment of liver function: there are no data in patients with severe hepatic impairment.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, i.e. the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Mortality in vascular dementia clinical trials
Three 6-month clinical trials were conducted to study subjects who met the NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-AIREN criteria are designed to identify patients whose dementia appears to be due solely to vascular causes, excluding patients with Alzheimer's disease. In the first study, mortality rates were 2/198 (1.0%) in the donepezil hydrochloride 5 mg group, 5/206 (2.4%) in the donepezil hydrochloride 10 mg group, and 7/199 (3 , 5%) in the placebo group. In the second study, mortality rates were 4/208 (1.9%) in the donepezil hydrochloride 5 mg group, 3/215 (1.4%) in the donepezil hydrochloride 10 mg group, and 1/193 (0 , 5%) in the placebo group. In the third study, mortality rates were 11/648 (1.7%) in the donepezil hydrochloride 5 mg group and 0/326 (0%) in the placebo group. The mortality rate for the three combined VaD studies in the donepezil hydrochloride group (1.7%) was numerically higher than in the placebo group (1.1%) and, however, this difference was not statistically significant. Most deaths in patients taking donepezil hydrochloride or placebo appear to result from various vascular causes, a predictable fact in this elderly population with pre-existing vascular disease. An analysis of all fatal and non-fatal vascular events showed no difference in the relapse rate for the donepezil hydrochloride group versus placebo.
In pooled Alzheimer's disease studies (n = 4146) and when Alzheimer's disease studies were pooled with other dementia studies, including vascular dementia studies (total n = 6888), the death rate in the placebo groups exceeded numerically that of the groups with donepezil hydrochloride.
04.5 Interactions with other medicinal products and other forms of interaction
Memac and / or any of 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 showed that cytochrome P450 3A4 and to a lesser extent 2D6 isoenzymes are involved in the metabolism of donepezil. Interaction studies with other medicines conducted in vitro show that ketoconazole and quinidine, inhibitors of CYP-3A4 and CYP-2D6, respectively, inhibit the metabolism of donepezil. For this reason, these and other CYP-3A4 inhibitors, such as itraconazole and erythromycin, as well as CYP-2D6 inhibitors such as fluoxetine, may inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by approximately 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol can reduce donepezil levels. Since the extent of the inhibiting or inducing effect is unknown, these drug combinations should be used with caution. donepezil hydrochloride may interfere with medicinal products having anticholinergic activity. There is also a possible synergistic activity in the case of concomitant treatment involving medicinal products such as succinylcholine, other neuromuscular blocking agents, cholinergic agonists or beta-blocking agents that affect cardiac conduction.
04.6 Pregnancy and breastfeeding
Fertility
In non-clinical studies, donepezil had no effect on fertility (see section 5.3). It is not known whether donepezil affects fertility in humans.
Pregnancy
There are no adequate data from the use of donepezil in pregnant women.
Animal studies did not show teratogenic effects, but peri- and postnatal toxicity (see section 5.3 Preclinical safety data). The potential risk for humans is unknown.
Memac tablets should not be used during pregnancy unless absolutely necessary.
Feeding time
Donepezil is excreted in breast milk in rats. It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Therefore, women treated with donepezil should not breastfeed.
04.7 Effects on ability to drive and use machines
Donepezil has minor or moderate effects on the ability to drive or use machines.
Dementia can impair the ability to drive or use machines. Furthermore, donepezil can induce fatigue, dizziness and muscle cramps, mainly in the initial phase of treatment or by increasing the dosage. The treating physician should periodically evaluate the ability of patients treated with donepezil to continue driving or using machines.
04.8 Undesirable effects
The most common side effects are diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia.
Adverse reactions reported as more than one isolated case are listed below by system organ class and frequency. In terms of frequency, the effects are defined as: very common (≥1 / 10), common (≥1 / 100,
* When evaluating patients for syncope or seizures, consider the possibility of heart block or long sinus pauses (see section 4.4)
** Reports of hallucinations, abnormal dreams, nightmares, agitation and aggressive behavior have seen resolution of the problem with dose reduction or discontinuation of treatment.
*** In cases of unexplained hepatic dysfunction, consider discontinuing Memac.
**** Rhabdomyolysis has been observed regardless of neuroleptic malignant syndrome and in close temporal association with initiation of donepezil treatment or following dose escalation.
04.9 Overdose
The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice and rats is 45 and 32 mg / kg, respectively, i.e. approximately 225 and 160 times the maximum recommended human dose of 10 mg / day. Dose related signs of cholinergic stimulation were observed in animals, including reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic seizures, respiratory depression, salivation, miosis, fasciculation and lowering of body temperature.
Overdose with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increased muscle weakness is a possible occurrence that can cause death if it involves the respiratory muscles.
As in all cases of overdose, general supportive measures are used. In overdose of Donepezil hydrochloride, tertiary anticholinergics such as atropine can be used as antidote. Intravenous atropine sulfate is recommended at the dose needed to achieve the desired effect: a starting dose of 1.0-2.0 mg IV, with subsequent dose adjustment based on clinical response Atypical responses in terms of blood pressure and heart rate have been reported with other cholinomimetics when administered concomitantly with quaternary anticholinergics such as glycopyrrolate.
It is not known whether donepezil hydrochloride and / or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or haemofiltration).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-dementia drugs, anticholinesterases.
ATC code N06DA02.
Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is, in vitro, over 1000 times more potent as an inhibitor of this enzyme than butyrylcholinesterase, an enzyme found mainly outside the central nervous system.
Alzheimer's dementia
In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg donepezil hydrochloride produced a "steady-state inhibition in" acetylcholinesterase activity (measured in erythrocyte membranes) of 63, 6% and 77.3%, respectively, when measured after dosing. Inhibition of acetylcholinesterase (AChE) in red blood cells caused by donepezil hydrochloride was correlated with changes in ADAS-cog, a sensitive scale that analyzes selected aspects of the cognitive state. The potential ability of donepezil hydrochloride to alter the course of pre-existing neuropathology has not been studied. Memac tablets cannot be said to affect the progress of the disease.
The efficacy of treatment with donepezil hydrochloride was investigated in four placebo-controlled studies, 2 studies of 6 months duration and 2 of 1 year duration.
In the 6-month clinical study, an analysis was performed at the conclusion of treatment with donepezil using a combination of three efficacy criteria: the ADAS-Cog scale (a measure of cognitive ability), 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 met the criteria listed below were considered treatment responders.
Response = Improvement of the ADAS-Cog (cognitive component of the Scale for the assessment of Alzheimer's disease) by at least 4 points.
No worsening of CIBIC + (Clinician Interview Based Impression of Change with Caregiver Input).
No worsening of the Activities of Daily Living Subscale component of the Clinical Dementia Rating Scale (CDR-ADL).
* p
** p
Donepezil hydrochloride produced a statistically significant dose-dependent increase in the proportion of patients who were judged to be treatment responders.
05.2 Pharmacokinetic properties
Absorption: Maximum plasma levels were reached approximately 3-4 hours after oral administration. Plasma concentrations and area under the curve increased in proportion to dose. The terminal elimination half-life is approximately 70 hours, so administration of multiple single daily doses results in a gradual approach to steady state. Approximate steady state is achieved within 3 weeks of initiation of therapy. Once steady state is achieved, the plasma concentrations of donepezil hydrochloride and its pharmacodynamic activity show limited variability throughout the day.
Food did not affect the absorption of donepezil hydrochloride.
Distribution: donepezil hydrochloride is approximately 95% bound to human plasma proteins. Plasma protein binding of the active metabolite 6-O-desmethyl-donepezil is unknown. The distribution of donepezil hydrochloride in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 hours after administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the marker escaped detection. This suggests that donepezil hydrochloride and / or its metabolites may persist in the body for more than 10 days.
Metabolism / excretion: donepezil hydrochloride is both excreted unchanged in the urine and metabolised by the cytochrome P450 system to form multiple metabolites, some of which still escape identification. Following administration of a single 5 mg dose of C-labeled donepezil, plasma radioactivity, expressed as a percentage of the administered dose, was mainly present as unchanged donepezil (30%), 6-O-desmethyl-donepezil (11%, only the metabolite showing "donepezil hydrochloride-like activity), donepezil-cis-N-oxide (9%), 5-O-desmethyl-donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl-donepezil (3 %). Approximately 57% of total administered radioactivity was detected in urine (17% as unmodified donepezil), while 14.5% was detected in faeces, suggesting that biotransformation and urinary excretion are the major pathways. There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and / or any of its metabolites.
Plasma concentrations of donepezil decrease with a half-life of approximately 70 hours.
Gender, race and smoking history have no clinically significant influence on the plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil have not been officially studied in healthy elderly subjects or in patients with Alzheimer's dementia or vascular dementia. However, plasma levels in patients did not deviate from those of healthy young volunteers.
Patients with mild or moderate hepatic impairment saw steady-state concentrations of donepezil increase: mean AUC by 48% and C by 39% (see section 4.2).
05.3 Preclinical safety data
Extensive studies in experimental animals have shown that this compound causes fewer effects, apart from the intended pharmacological effects, consistent with its cholinergic stimulator action (see section 4.9). Donepezil was not mutagenic in bacterial and mammalian cell mutation studies. Clastogenic effects were observed in vitro at concentrations clearly toxic to cells and over 3,000 times the steady-state plasma concentrations. No clastogenic or other genotoxic effects were observed in the micronucleus test in vivo in the mouse. There is no evidence of oncogenic potential in long-term carcinogenicity studies in rats or mice.
Donepezil hydrochloride had no effect on fertility in rats and was not teratogenic in rats or rabbits, but had a slight effect on stillbirth and early neonatal survival when administered to pregnant rats at doses 50 times that of humans (see section 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate.
Film coating: titanium dioxide (E171), hypromellose 5cP (E464), talc (E553b), propylene glycol (E1520).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Thick transparent PVC (coated with 40 gsm of PVdC) and aluminum foil in a cardboard box.
Pack of 28 film-coated tablets.
06.6 Instructions for use and handling
No special instructions.
Unused product and other waste materials must be disposed of according to local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bracco s.p.a. Via E. Folli, 50 - Milan
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 042613012
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
17/04/2014
10.0 DATE OF REVISION OF THE TEXT
June 2016
