Alzime

Alzime

donepezil

Manufacturer:

Berlin Pharm

Distributor:

Berlin Pharm

Marketer:

Berlin Pharm
Full Prescribing Info
Contents
Donepezil HCl.
Description
Each tablet contains donepezil hydrochloride (monohydrate) 10 mg.
Film coated tablet for oral use.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible inhibitor of acetylchlolinesterase. The drug is structurally unrelated to other cholinesterase agents (e.g. tacrine, physostigmine).
The precise mechanism of action of donepezil in patients with dementia of the Alzheimer's type (Alzheimer's disease) has not been fully elucidated. The drug is an anticholinesterase agent that binds reversibly with and inactivates cholinesterase (e.g. acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. In vitro data and data in animals indicate that the anticholinesterase activity of donepezil is relatively specific for acetylchlolinesterase in the brain compared with butyrylcholinesterase inhibition in peripheral tissues.
A deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits. Because the resultant cortical deficiency of this neurotransmitter is believed to account for some of the clinical manifestations of mild to moderate dementia, enhancement of cholinergic function with an anticholinesterase agent, such as tacrine or donepezil, is one of the pharmacologic approaches to treatment.
Alzheimer's disease: Donepezil hydrochloride is used for the palliative treatment of mild to moderate dementia of the Alzheimer's disease, presenile or senile dementia. The rationale for use of donepezil in this condition is to potentially increase CNS acetylcholine concentrations, which can be deficient in patients with Alzheimer's disease. The current indication is based principally on 2 short-term (15 or 30 weeks), double-blind, placebo-controlled studies in patients with a diagnosis of Alzheimer's disease of mild to moderate severity. Both studies demonstrated clinically important but modest and variable improvement in cognitive function and clinician-rated global assessment of observed clinical change.
The specific role of donepezil in the management of Alzheimer's disease, particularly long-term or in patients with severe disease remains to be fully elucidated. In patients who received therapy with donepezil for at least 2 years in uncontrolled studies following their participation in placebo-controlled studies of the drug, improvement in cognitive function was maintained for an average of at least 40 weeks, with some benefit still evident after 2 years of follow-up.
In the 15 and 30 week, placebo-controlled studies upon which the current indication principally is based, donepezil therapy was associated with improvement in cognitive and overall functioning (e.g. as assessed by results of neuropsychological tests and clinicians impression of change, respectively). Age, race, or gender did not predict response to donepezil therapy in this study. Cognitive function was evaluated with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), a multiple-item instrument that has been extensively validated in longitudinal cohort of patients with Alzheimer's disease. ADAS cog measures elements of memory, orientation, attention, reasoning, language and praxis. Scores on the ADAS cog range from 0-70, with increasing scores being indicative of increasing cognitive impairment. Although normal geriatric adults may have scores of 0 or 1, slightly higher scores are not unusual in adults without dementia. Patients recruited into the 2 controlled studies of donepezil had initial scores of approximately 26 (range 4-61) on the ADAS cog. Longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggest that scores on the ADAS cog will increase (i.e. indicating a decline in cognitive function) by 6-12 points each year in such patients. A smaller annual change in score is observed in patients with either very mild or very advanced Alzheimer's disease because the ADAS cog does not uniformly reflect cognitive change over the course of the disease. In clinical trials of donepezil, ADAS cog scores increases by approximately 2-4 points per year in patients who received placebo.
Overall clinical change in patients receiving donepezil or placebo was evaluated with a Clinician's Interview Based Impression of Change (CIBIC) that required use of information from caregivers (CIBIC plus). A variety of CIBIC formats have been used in clinical studies, and the various CIBIC formats may differ in terms of depth and structure. The CIBIC plus used in the studies of donepezil was a subjective, semistructured instrument intended to measure the patient's ability to function generally, cognitively , behaviorally, and in activities of daily living. Scores of 1, 4, or 7 on the CIBIC plus denote marked improvement, no change, or markedly worse, respectively.
In the 15- and 30-week controlled studies of donepezil, the treatments were administerd for 12 or 24 weeks, respectively, followed by placebo washout periods of 3 or 6 weeks, respectively,to determine whether rebound effects would occur following discontinuance of the drug . Patients received 5 or 10 mg of donepezil hydrochloride or placebo once daily in these studies; patients who were assigned to receive the 10-mg dosage of donepezil hydrochloride initially received 5 mg daily for 7 days to minimize the likelihood of adverse cholinergic effects. In the 15-week study, the improvement from baseline in the ADAS cog scores with donepezil compared with placebo averaged 2.7 or 3 points after 12 weeks of treatment with donepezil hydrochloride 5 or 10 mg daily, respectively; the difference in ADAS cog scores for the 2 dosages was not statistically significant. In this study, and improvement of 7 points in the ADAS cog scores was attained at 12 weeks by a cumulative 14, 21, or 36% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively, while an improvement of 4 points was attained at 12 weeks by a cumulative 30, 49, or 57% of patients in these respective groups. Cognitive function was maintained (i.e., no change in ADAS cog scores from baseline) at 12 weeks in a cumulative 72, 83, or 87% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. In the 30-week study, improvement from baseline in ADAS cog scores with donepezil compared with placebo averaged 2.8 or 3.1 points after 24 weeks of treatment with 5 or 10mg daily, respectively, of donepezil hydrochloride; the difference in ADAS cog scores for the 2 dosages was not statistically significant. An improvement of 7 points from baseline in the ADAS cog scores was attained at 24 weeks by a cumulative 8, 15, or 26% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Improvement of 4 points from baseline in the ADAS cog scores was attained at 24 weeks by a cumulative 28, 40, or 58% of patients who received placebo. 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Cognitive function was maintained (i.e., no change in ADAS cog scores from baseline) at 24 weeks in a cumulative 59, 83, or 82% of patients who received placebo, donepezil hydrochloride 5 mg, or donepzil hydrochloride 10 mg once daily, respectively.
Overall clinical improvement (as determined by the CIBIC plus assessment) also was observed in patients treated with donepezil in these 2 controlled studies. CIBIC plus scores attained in patients receiving 5 or 10 mg of donepezil hydrochloride once daily differed from placebo by 0.36 or 0.38 points, respectively, after 12 weeks of treatment in the 15-week study and by 0.35 or 0.39 points, respectively, after 24 weeks of treatment in the 30-week study. As with the ADAS cog scores, a dose-related effect of donepezil on overall clinical change in these studies was not established. Following the 6-week placebo washout period in the 30-week study, scores on the ADAS cog scores for patients treated with donepezil or placebo were indistinguishable, indicating no evidence of an effect of donepezil on the underlying disease process in dementia. Results of neuropsychologic test (i.e., ADAS cog scores, CIBIC plus, Mini-Mental State Examination [MMSE], and Clinical Dementia Rating {CDR}) performed 6 weeks after discontinuance of donepezil therapy did not show evidence of a rebound deterioration in cognitive symptoms.
Vascular dementia: Donepezil may be effective in treatment of vascular dementia. Results from a randomized, controlled study have shown an improvement in cognition and global function in patients with probably or possible vascular dementia. A systemic review also concluded that donepezil improved mild to moderate vascular cognitive impairment in the short term (treatment for 6 months). The manufacturer has reported that out of a total of 3 studies of donepezil in vascular dementia, one (Study 319) showed an apparently increased mortality compared with placebo: 1.7% and 0%, respectively. In a combined analysis of the other 2 studies, the mortality rate was1.7% in the donepezil group and 2 % in the placebo group. Combined analysis of all 3 studies showed no statistically significant difference in the mortality rates between the donepezil (1.7%) and placebo (1.1%) groups; the risk of vascular events such as stroke and myocardial infarction was also similar for each group. The unexpected low mortality rate with placebo in Study 319 was unusual given the age and pathology of the subjects. An increased risk of death has also been reported with another acetylcholinesterase inhibitors, galantamine, when used in patients who did not have Alzheimer's diseased.
Dementia with Lewy bodies (DLB): DLB is a common form of dementia in the elderly, and is the second largest group of dementia after AD. Donepezil hydrochloride was recommended as a first-line therapy in people with mild to moderate dementia with Lewy bodies and to consider its use for people with severe dementia with Lewy bodies. (See Table 1.)

Click on icon to see table/diagram/image

More recently, Mori et al. (2012) reported a randomized, placebo-controlled trial of 140 DLB patients who received placebo or 3, 5 or 10 mg of donepezil daily for 12 weeks. This exploratory study had no prespecified primary endpoint but rather examined a variety of cognitive, behavioral, global function, and caregiver outcomes. Efficacy was assessed at baseline and at weeks 4, 8, and 12. At the final evaluation, 5 or 10 mg donepezil treated patients benefited from a 2.0 to 3.8 points on the Min Mental State Examination (MMSE), which is a larger difference than that reported in other studies of cholinesterase inhibitors (ChEIs) in DLB, Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). The Neuropsychiatric Inventory (NPI) scores were significantly more improved over the course of the study in the 5 mg and 10 mg donepezil groups compared with placebo. Significant improvements were also seen in several neuropsychiatric domains affected by DLB, especially delusions, hallucinations and cognitive fluctuations, for patients receiving donepezil. Global function scores also were significantly higher in all active treatment groups compared with placebo. Caregiver scores were improved in the 10-mg group only compared with placebo, and that difference was not significant after baseline adjustments. Furthermore, the same research group reported the safety and efficacy of long-term administration of donepezil in patients with DLB 108 patients enrolled in the 52-week, multicenter, open-label extension study, showed improvements in cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks.
Most of the treatment-related AEs were mild or moderate and only parkinsonism had an incidence of 5% or more. None of the reported parkinsonian symptoms was severe or serious. No major concerns exist regarding the safety or tolerability profile of long-term administration of donepezil at up to 10 mg. The safety results in DLB studies were consistent with the known profile of donepezil reported in AD studies except for parkinsonism.
Pharmacokinetics: Pharmacokinetics parameters: Absorption: Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1 to 10 mg given once daily. Neither food nor time of administration (morning vs evening dosing) influences the rate or extent of absorption.
Distribution: Following multiple-dose administration, donepezil accumulates in plasma by 4-to 7-fold and steady state is reached within 15 days. The steady-state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (approximately 75%) and alpha-1 acid glycoprotein (approximately 21%) over the concentration range of 2 to 1,000 ng/mL.
Metabolism: Donepezil is excreted in the urine intact and extensively metabolized to 4 major metabolites (2 of which are known to be active) and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by the CYP-450 isoenzymes 2D6 and 3A4, and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to approximately 20% of donepezil.
Excretion: The elimination half-life of donepezil is approximately 70 hours and the mean apparent plasma is 0.13 L/h/kg. Approximately 57% and 15% of the total dose was recovered in urine and faces, respectively, over a period of 10 days, while 28% remained unrecovered, with approximately 17% of the donepezil dose recovered in the urine as unchanged drug.
Indications/Uses
Alzheimer's disease: For the treatment of mild to moderate dementia of the Alzheimer's type as well as severe dementia.
For treatment in patients with vascular dementia. (Dementia associated with cerebrovascular disease).
For treatment in patients with Dementia with Lewy Bodies (DLB).
Dosage/Direction for Use
Mild to moderate Alzheimer disease: 5 or 10 mg once daily.
The higher dose of 10 mg did not provide a statistically significant clinical benefit greater than that of the 5 mg dose. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trial, that a daily dose of donepezil 10 mg might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
Severe Alzheimer's disease: 10 mg administered once daily.
Dose titration-Evidence from the controlled trials in mild to moderate Alzheimer's disease indicated that the 10 mg dose, with a 1-week titration, is likely to be associated with a higher incidence of cholinergic adverse reactions than the 5 mg dose. In open-label trials using a 6-week titration, the frequency of these same adverse reactions was similar between the 5 and 10 mg dose groups. Therefore, because steady state is not achieved for 15 days and the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be achieved until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
Vascular dementia: 5 or 10 mg administered once daily. Doses greater than 10 mg/day have not been studied in clinical trials in vascular dementia.
Dementia with Lewy bodies (DLB): 5 or 10 mg administered once daily. Doses greater than 10 mg/day have not been studied in clinical trials in DLB.
Dosage in renal impairment: Limited data in a few patients with moderate to severe renal impairment (creatinine clearance less than 22 mL/minute per 1.73 m2) indicate no difference in the clearance of donepezil compared with that in healthy individuals matched for age and gender and the manufacture makes no specific recommendation for dosage adjustment in patients with renal impairment.
Dosage in hepatic impairment: Clearance of donepezil in a limited number of patients with stable alcoholic cirrhosis was reduced by 20% compared with that in healthy age and gender matched individuals; however, the manufacturer makes no specific recommendation for dosage adjustment in patient with hepatic disease.
Children: There are no adequate and well-controlled trials to document the safety and efficacy of donepezil in any illness occurring in children.
Mode of Administration: Donepezil hydrochloride is administered orally. The drug is administered once daily in the evening at bedtime. Because food does not affect the rate or extent of absorption of donepezil when administered as conventional film-coated tablets, the drug can be administered with or without food.
Overdosage
Overdose: Overdose with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Treatment: Tertiary anticholinergics such as atropine may be used as an antidote for donepezil overdosage. Intravenous (IV) atropine titrated to effect is recommended: an initial dose of 1 to 2 mg IV with subsequent dose based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quarternary anticholinergics such as glycopyrrolate. It is not known whether donepezil and/or its metabolites can be removed by dialysis (e.g., hemodialysis, peritoneal dialysis, hemofiltration).
Contraindications
Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation.
Warnings
Cholinesterase inhibitors may cause bradycardia and/or heart block with or without a history of cardiac disease; syncopal episodes have been associated with donepezil. Alzheimer's treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors.
Use with caution with sick sinus syndrome or other supraventricular cardiac conduction abnormalities, COPD, or asthma.
Use with caution in patients with a history of seizure disorder; cholinomimetics may potentially cause generalized seizures, although seizure activity may also result from Alzheimer's disease.
Use with caution in patients at risk of ulcer disease (e.g., previous history or NSAID use), or in patients with bladder outlet obstruction.
May cause dose-related diarrhea, nausea, and/or vomiting, which usually resolves in 1-3 weeks.
May cause anorexia and/or weight loss (dose-related).
May exaggerate neuromuscular blockade effects of depolarizing neuromuscular-blocking agents (e.g., succinylcholine).
Special Precautions
Anesthesia: Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Cadiovascular effects: Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil.
GI effects: Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion because of increased cholinergic activity. Therefore, monitor patients closely for symptoms of active or occult GI bleeding, especially those at increased risk for developing ulcers (e.g., those with a history of ulcer disease or those receiving concurrent non-steroidal anti-inflammatory drugs [NSAIDs]). Clinical studies of donepezil have shown no increase relative to placebo in the incidence of peptic ulcer disease or GI bleeding.
Donepezil, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting 1 to 3 weeks, and have resolved during continued use of donepezil.
Genitourinary effects: Although not observed in clinical trials, cholinomimetics may cause bladder outflow obstruction.
Pulmonary effects: Because of their cholinomimetic actions, prescribe cholinesterase inhibitors with care to patients with a history of asthma or obstructive pulmonary disease.
Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer disease.
Hepatic function impairment: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decrease 20% relative to 10 healthy age and sex-matched subjects.
Mutagenesis: In the chromosome aberration test in cultures of Chinese hamster lung cells, some clastogenic effects were observed.
Monitoring: Monitor patients closely for symptoms of active or occult (GI bleeding, especially those at increased risk for developing ulcers (e.g., those with a history of ulcer disease or those receiving NSAIDs).
Use In Pregnancy & Lactation
Pregnancy: In a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the MRHD on a mg/m2 basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through postpartum day 4 at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant woman. Use donepezil during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Lactation: It is not known whether donepezil is excreted in breast milk. Donepezil has no indication for use in breast-feeding mother.
Adverse Reactions
Central nervous system: >10%: Insomnia (2% to 14%).
1% to 10%: Headache (3% to 10%), pain (3% to 9%), fatigue (1% to 8%), dizziness (2% to 8%), abnormal dreams (3%), hostility (3%), nervousness (1% to 3%), hallucinations (3%), depression (2% to 3%), emotional lability (2%), personality disorder (2%), confusion (2%), fever (2%), somnolence (2%), abnormal crying, aggression, agitation, anxiety, aphasia, delusions, irritability, restlessness, seizure, vertigo.
Gastrointestinal: >10%: Nausea (3% to 19%; dose related), diarrhea (5% to 15%; dose related).
1% to 10%: Anorexia (2% to 8%), vomiting (3% to 9%: dose related), weight loss (3% to 5%: dose related), abdominal pain, bloating, constipation, dyspepsia, epigastric pain, fecal incontinence, gastroenteritis, GI bleeding, toothache.
Cardiovascular: 1% to 10%: Hypertension (3%), chest pain (2%), hemorrhage (2%), syncope (2%), hypotension, atrial fibrillation, bradycardia, ECG abnormal, edema, peripheral edema, heart failure, hot flashes, vasodilation.
Dermatologic: 1% to 10%: Bruising (4% to 5%), eczema (3%), pruritus, rash, skin ulcer, urticaria.
Endocrine & metabolic: 1% to 10%: Dehydration (1% to 2%), hyper-lipemia (2%), libido increased.
Genitourinary: 1% to 10%: Urinary frequency (2%), urinary incontinence (1% to 3%), cystitis, hematuria, glycosuria, nocturia, UTI.
Hematologic: 1% to 10%: Contusion (<2%), anemia.
Hepatic: 1% to 10%: Alkaline phosphatase increased.
Neuromuscular & skeletal: 1% to 10%: Muscle cramps (3% to 8%), back pain (3%), CPK increased (3%), arthritis (1% to 2%), ataxia, bone fracture, gait abnormal, lactate dehydrogenase increased, paresthesia, tremor, weakness (1% to 2%).
Ocular: 1% to 10%: Blurred vision, cataract, eye irritation.
Respiratory: 1% to 10%: Bronchitis, cough increased, dyspnea, pharyngitis, pneumonia, sore throat.
Miscellaneous: >10%: Accident (7% to 13%), infection (11%).
1% to 10%: Diaphoresis, fungal infection, flu symptoms.
<1% (Limited to important or life-threatening): Angina, cardiomegaly, cerebrovascular accident, cholecystitis, conjunctival hemorrhage, deep vein thrombosis, diabetes mellitus, diverticulitis, gastrointestinal ulcer, glaucoma, heart block, heart failure, hemolytic anemia, hepatitis, hyperglycemia, hypertonia, hypokalemia, hypokinesia, hyponatremia, hypoxia, intracranial hemorrhage, jaundice, LFTs increased, MI, neuroleptic malignant syndrome, pancreatitis, pleurisy, pulmonary collapse, pulmonary congestion, pyelonephritis, renal failure, retinal hemorrhage, SVT, thrombocythemia, thrombocytopenia, tongue edema, transient ischemic attack.
Drug Interactions
See Table 2.

Click on icon to see table/diagram/image
Storage
Store below 30°C.
ATC Classification
N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Presentation/Packing
FC tab 10 mg (yellow, round biconvex, with "ALM" on one side and "10" beyond the half scored on other side) x 3 x 10's.
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