Aripil 5mg & 10mg Film-coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Aripil 5 mg Film-coated Tablets: Each 5 mg film-coated tablet contains 5 mg donepezil hydrochloride (equivalent to 4.56 mg of donepezil).

Aripil 10 mg Film-coated Tablets: Each 10 mg film-coated tablet contains 10 mg donepezil hydrochloride (equivalent to 9.12 mg of donepezil).

Excipient with known effect:

Aripil 5 mg Film-coated Tablets: Each 5 mg film-coated tablet contains 87.15 mg lactose.

Aripil 10 mg Film-coated Tablets: Each 10 mg film-coated tablet contains 174.3 mg lactose.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Aripil 5 mg Film-coated Tablet: are white, film-coated, round tablets embossed with “DL” over “5” on one side and “G” on the reverse, approximately 7 mm in diameter.

Aripil 10 mg Film-coated Tablet: are white, film-coated, round tablets embossed with “DL” over “10” on one side and “G” on the reverse, approximately 9 mm in diameter


4. CLINICAL PARTICULARS

4.2 Posology and method of administration

Posology

Adults / Elderly:
Treatment is initiated at 5 mg/day (once-a-day dosing). The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of donepezil hydrochloride Aripil can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.

Treatment should be initiated and supervised by 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). Therapy with donepezil hydrochloride Aripil should only be started if a caregiver is available who will regularly monitor drug intake of the medicinal product by for the patient. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil hydrochloride Aripil should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil hydrochloride Aripil cannot be predicted.

Upon discontinuation of the treatment, a gradual abatement of the beneficial effects of donepezil hydrochloride Aripil is seen.

Paediatric population

Donepezil hydrochloride is not recommended for use in children and adolescents below 18 years of age.

Patients with rRenal or hepatic impairment:
A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil hydrochloride is not affected by this condition.

Due to possible increased exposure in mild to moderate hepatic impairment (see section 5.2), dose escalation should be performed according to individual tolerability. There are no data for patients with severe hepatic impairment.

Paediatric population:
Aripil is not recommended for use in paediatric patients.

Method of administration

For oral use.

4.4        Special warnings and precautions for use

Cardiovascular conditions

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g. bradycardia). The potential for this action may be particularly important forto patients with “sick sinus syndrome”

Neurological conditions:
Seizures: cholinomimeticsCholinomimetics are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer’s disease.

Severe hepatic impairment:
There are no data for patients with severe hepatic impairment.

This medicinal product contains lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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This medicinal product contains lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine.

In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezilhydrochloride. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezilhydrochloride metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezilhydrochloride.

In a study in healthy volunteers, ketoconazole increased mean donepezil hydrochloride concentrations by about 30%.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil hydrochloride.

Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care.

Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta-blocking agents which that have effects on cardiac conduction.

4.7        Effects on ability to drive and use machines

 

Donepezil hydrochloride has minor or moderate influence on the ability to drive and use machines.

 

Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil hydrochloride can induce fatigue, dizziness and muscle cramps mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil hydrochloride to continue driving or operating complex machines.

4.8        Undesirable effects

 

The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.

 

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

 

System Organ Class	Very Common	Common	Uncommon	Rare	Very Rare
Infections and infestations		Common cold
Metabolism and nutrition disorders		Anorexia
Psychiatric disorders		Hallucinations**   Agitation **   Aggressive behaviour**   Abnormal dreams and Nightmares**
Nervous system disorders		Syncope* Dizziness   Insomnia	Seizure*	Extrapyramidal symptoms	Neuroleptic Malignant Syndrome
Cardiac disorders			Bradycardia	Sino-atrial block   Atrioventricular block
Gastrointestinal disorders	Diarrhoea   Nausea	Vomiting   Abdominal disturbance	Gastrointestinal haemorrhage   Gastric and duodenal ulcers   Salivary hypersecretion
Hepatobiliary disorders				Liver dysfunction including hepatitis***
Skin and subcutaneous tissue disorders		Rash Pruritus
Musculoskeletal and connective tissue disorders		Muscle cramps			Rhabdomyolysis ****
Renal and urinary disorders		Urinary incontinence
General disorders and administration site conditions	Headache	Fatigue   Pain
Investigations			Minor increase in serum concentration of muscle creatine kinase
Injury, and poisoning and procedural complications		Accident

4.9        Overdose

 

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterised by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. IncreasedIncreasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-dementia drugs, anticholinesterases, ATC code: N06DA02

Mechanism of action

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 an inhibitor of this enzyme than of butylcholinesterase, an enzyme that which is present 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 of donepezil hydrochloride produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6 % and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AchE) in red blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog, a sensitive scale which examines selected aspects of cognition.,

tThe potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus donepezil hydrochloride cannot be considered to have any effect on the progress of the disease.

Efficacy of treatment of Alzheimer’s Dementia with donepezil hydrochloride has been investigated in four placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.

In the 6 monthsmonths’ clinical trial, an analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria: the ADAS-cogCog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (a measure of capabilities in community affairs, home and hobbies and personal care).

Patients who fulfilled the criteria listed below were considered treatment responders.

Response = Improvement of ADAS-Cog of at least 4 points.
No deterioration of CIBIC
No deterioration of Activities of Daily Living Schedule Subscale of the Clinical Dementia Rating Scale.

5.2        Pharmacokinetic properties

 

Absorption

Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve rise in proportion to theof dose.

Biotransformation/Elimination

Patients with mild to moderate hepatic impairment had increased donepezil hydrochloride steady state concentrations: mean AUC by 48% and mean C_max by 39% (see section 4.2).

5.3        Preclinical safety data

 

Extensive testing in experimental animals has demonstrated that this compound causes few effects other than the intended pharmacological effects consistent with its action as a cholinergic stimulator (see section 4.9). Donepezil hydrochlorideis not mutagenic in bacterial and mammalian cell mutation assays. Some clastogenic effects were observed in vitro at concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma concentrations.

10. DATE OF REVISION OF THE TEXT

January 2016July 2017



4.2 Posology and method of administration    

Posology 

 

Adults / Elderly: 

Aripil should be taken orally, in the evening, just prior to retiring.

Treatment is initiated at 5 mg/day (once-a-day dosing). The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of

 

Aripil donepezil to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of Aripil can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.

Paediatric population:
There is no relevant use of donepezil in the paediatric populationAripil is not recommended for use in paediatric patients.Aripil is only recommended for use in adults. 

Method of administration 

 

Donepezil Mylan should be taken orally, in the evening just prior to retiring. 
   

4.5 Interaction with other medicinal products and other forms of interaction

 

 

 

Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine.

 

 

 

 

 

 

 

In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil hydrochloride. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil hydrochloride metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole itroconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil hydrochloride. In a study in healthy volunteers, ketoconazole increased mean donepezil hydrochloride concentrations by about 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil hydrochloride. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta-blocking agents which have effects on cardiac conduction.

 

 

4.7 Effects on ability to drive and use machines

 

 

 

 

Donepezil hydrochloride has minor or moderate influence on the ability to drive and use machines.

Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil hydrochloride can induce fatigue, dizziness and muscle cramps mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil

 

hydrochloride to continue driving or operating complex machines.

 

 

 

 

4.8 Undesirable effects

 

The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.
Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data).

System Organ Class	Very Common	Common	Uncommon	Rare	Very Rare
Infections and infestations		Common cold
Metabolism and nutrition disorders		Anorexia
Psychiatric disorders		Hallucinations**   Agitation **   Aggressive behaviour**   Abnormal dreams and Nightmares**
Nervous system disorders		Syncope* Dizziness   Insomnia	Seizure*	Extrapyramidal symptoms	Neuroleptic Malignant Syndrome
Cardiac disorders			Bradycardia	Sino-atrial block   Atrioventricular block
Gastrointestinal disorders	Diarrhoea   Nausea	Vomiting   Abdominal disturbance	Gastrointestinal haemorrhage   Gastric and duodenal ulcers
Hepatobiliary disorders				Liver dysfunction including hepatitis***
Skin and subcutaneous tissue disorders		Rash Pruritis
Musculoskeletal and connective tissue disorders		Muscle cramps			Rhabdomyolysis ****
Renal and urinary disorders		Urinary incontinence

 

**** Rhabdomyolysis has been reported to occur independently of neuroleptic malignant syndrome and in close temporal

 

associatedassociation with donepezil initiation or dose increase.  

Reporting or suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie.

Metabolism/Excretion

 

Biotransformation/Elimination:
Donepezil hydrochloride is both excreted in the urine intact and metabolised by the cytochrome P450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of 14C-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percentage of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the glucuronide glucorinide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil) and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites. 

6.1 List of excipients

Tablet core:

Lactose monohydrate
Maize starch
Hydroxypropylcellulose
Cellulose, microcrystalline
Magnesium Sstearate

Film coating:

Hypromellose
Titanium dioxide E171
Macrogol 400  

In Section 3, the scoreline has been removed and the product description is updated accordingly

4.4 Special warnings and precautions for use

New text added:

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially life-threatening condition characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur very rarely in association with donepezil, particularly in patients also receiving concomitant antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, treatment should be discontinued.

4.8 Undesirable effects

New side effect added:

Nervous system disorders
Very Rare: Neuroleptic Malignant Syndrome

10. DATE OF REVISION OF THE TEXT

Date changed to January 2013

(internal ref: SE/H/0723/IB/014)

shelf-life increased from 2 to 3 years

Section 4.8 Undesirable effects updated.

Additional side effects added under category Psychiatric disorders:

Abnormal dreams and Nightmares**

** Reports of hallucinations, abnormal dreams, nightmares, agitation and aggressive behaviour have resolved on dose-reduction or discontinuation of treatment.