Donepezil

N06D - Anti-dementia drugs ATC N06DA02 Small molecule approved 1996 Oral Topical Natural product

JFDA label: Donazet 5mg

Mechanism of Action

Alzheimer's disease is characterized by cholinergic deficiency in the cortex and basal forebrain, which contributes to cognitive deficits. Donepezil reversibly and noncompetitively inhibits centrally-active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system.

Indications

Approved

Alzheimer disease

Off-label

Dementia associated with Parkinson disease
Lewy body dementia
Traumatic brain injury
Vascular dementia

Contraindications

Source: Lexicomp

Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (11)

Common atrial fibrillation · bradycardia · cardiac failure · chest pain · ECG abnormality · edema · Hypertension · hypotension · peripheral edema · syncope · vasodilation

Nervous system disorders (27)

Very Common Insomnia

Common abnormal dreams · abnormal gait · aggressive behavior · agitation · anxiety · aphasia · ataxia · confusion · convulsions · delusions · depression · dizziness · drowsiness · emotional lability · fatigue · hallucination · Headache · hostility · irritability · nervousness · pain · paresthesia · personality disorder · restlessness · vertigo · wandering

Hepatobiliary disorders (1)

Common Increased serum alkaline phosphatase

Renal and urinary disorders (6)

Common cystitis · hematuria · nocturia · urinary frequency · Urinary incontinence · urinary tract infection

Blood and lymphatic system disorders (3)

Common anemia · Bruise · hemorrhage

Metabolism and nutrition disorders (7)

Common dehydration · glycosuria · hot flash · hyperlipidemia · increased lactate dehydrogenase · increased libido · Weight loss

Gastrointestinal disorders (14)

Very Common diarrhea · Nausea

Common abdominal pain · anorexia · bloating · constipation · dyspepsia · epigastric pain · fecal incontinence · gastroenteritis · gastrointestinal hemorrhage · sore throat · toothache · Vomiting

Skin and subcutaneous tissue disorders (7)

Common dermal ulcer · diaphoresis · Ecchymosis · eczema · pruritus · skin rash · urticaria

Musculoskeletal and connective tissue disorders (7)

Common arthritis · back pain · bone fracture · increased creatine phosphokinase · Muscle cramps · tremor · weakness

Eye disorders (3)

Common Blurred vision · cataract · eye irritation

Infections and infestations (3)

Very Common Infection

Common Fungal infection · influenza

General disorders and administration site conditions (2)

Very Common Accidental injury

Common Fever

Respiratory, thoracic and mediastinal disorders (6)

Common Bronchitis · dyspnea · flu-like symptoms · increased cough · pharyngitis · pneumonia

Other (169)

Not Known Abnormal hepatic function tests · abnormal lacrimation · abnormal vision · abscess · acute rhinitis · albuminuria · alopecia · angina pectoris · apathy · arteritis · arthralgia · arthropathy · asthma · atelectasis · atrophic striae · benign prostatic hypertrophy · blepharitis · breast fibroadenosis · cachexia · cardiomegaly · cellulitis · cerebral hemorrhage · cerebral infarction · cerebral ischemia · cerebrovascular accident · chills · cholecystitis · cholelithiasis · conjunctival hemorrhage · conjunctivitis · decreased libido · deep vein thrombosis · dementia · dermatitis · diabetes mellitus · diverticulitis · duodenal ulcer · dysarthria · dysgeusia · dysphagia · dysphoria · dysuria · emotional disturbance · eosinophilia · epigastric distress · epistaxis · eructation · erythema · erythrocytopenia · esophagitis · euphoria · extrapyramidal reaction · facial edema · fasciculations · fibrocystic breast changes · first degree atrioventricular block · flatulence · fungal dermatitis · gastric ulcer · gastritis · gingivitis · glaucoma · goiter · gout · hearing loss · heart block · hemiplegia · hemolytic anemia · hemorrhoids · hepatitis · hernia · herpes zoster · hiatal hernia · hirsutism · hyperbilirubinemia · hyperglycemia · hyperkeratosis · hypersensitivity reaction · hypertonia · hypokalemia · hypokinesia · hyponatremia · hypoproteinemia · hypoxia · increased appetite · increased blood urea nitrogen · increased gamma-glutamyl transferase · increased post-void residual urine volume · increased serum ALT · increased serum AST · increased serum creatinine · increased serum transaminases · increased thirst · intestinal obstruction · intracranial hemorrhage · iron deficiency anemia · irritable bowel syndrome · jaundice · leg cramps · leukocytosis · localized coldness · malaise · mastitis · melena · motion sickness · muscle spasm · myalgia · myasthenia · myocardial infarction · neuralgia · neurodermatitis · neuroleptic malignant syndrome · night sweats · nystagmus · orthostatic hypotension · osteoporosis · otalgia · otitis externa · otitis media · pacing · pancreatitis · paranoia · peptic ulcer disease · periodontal abscess · periodontitis · periorbital edema · peripheral vascular disease · pernicious anemia · pleurisy · polydipsia · post nasal drip · prolonged Q-T interval on ECG · psoriasis · pulmonary congestion · pyelonephritis · pyuria · rectal hemorrhage · renal failure · retinal hemorrhage · rhabdomyolysis · rhinitis · seeing spots · sensation of cold · sepsis · severe depression · sialorrhea · skin discoloration · sleep apnea · snoring · supraventricular extrasystole · supraventricular tachycardia · thrombocythemia · thrombocytopenia · tinnitus · tongue edema · tonic-clonic seizures · torsades de pointes · transient ischemic attacks · urinary urgency · uterine hemorrhage · vaginitis · ventricular premature contractions · ventricular tachycardia · vesiculobullous dermatitis · weight gain · wheezing · xeroderma · xerophthalmia · xerostomia

Dosing

Source: Lexicomp

Alzheimer disease: Oral: Mild-to-moderate: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; effective dosage range in clinical studies: 5 to 10 mg/day Moderate-to-severe: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; may increase further to 23 mg once daily after ≥3 months; effective dosage range in clinical studies: 10 to 23 mg/day Dementia associated with Parkinson disease (off-label use): 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; may increase further to 23 mg once daily after the use of 10 mg once daily ≥3 months (APA [Rabins 2007]); Dubois 2012) Lewy body dementia (off-label use): Initial: 2.5 mg once daily for 2 weeks, then increase to 5 mg once daily. After 4 weeks may further increase dose based on response and tolerability up to 10 mg once daily (Ikeda 2013; Mori 2012) Traumatic brain injury (off- label use): Initial: 5 mg once daily for 2 to 3 weeks, then increase to 10 mg once daily (Kim 2009; Zhang 2004). Vascular dementia (with comorbid Alzheimer disease) (off-label use): See Alzheimer disease dosing.

Refer to adult dosing. Note: The Canadian labeling recommends a maximum dose of 5 mg once daily in elderly women (≥85 years of age) of low body weight.

There are no dosage adjustments provided in the manufacturer’s labeling. Limited data suggest severe renal impairment does not adversely affect donepezil clearance.

There are no dosage adjustments provided in the manufacturer’s labeling.

Warnings & Precautions

Source: Lexicomp

Altered cardiac conduction

Donepezil may be associated with QT prolongation and torsades de pointes; use with caution in patients at risk of prolonged cardiac repolarization (Howes 2014). Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block in patients with or without a history of cardiac disease; syncopal episodes have been associated with donepezil. Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally active cholinesterase inhibitors (APA [Rabins 2007]).

Anorexia/weight loss

May cause anorexia and/or weight loss (dose-related).

GI effects

May cause dose-related diarrhea, nausea, and/or vomiting; usually resolves in 1 to 3 weeks.

Neuroleptic malignant syndrome

Rare cases of neuroleptic malignant syndrome (NMS) have been reported (Matsumoto 2004; Warwick 2008). Discontinuation of donepezil therapy may be necessary in patients presenting with symptoms of NMS (eg, hyperthermia, irregular pulse or blood pressure, cardiac arrhythmia, diaphoresis, muscle rigidity, mental status changes, elevated creatine phosphokinase [CPK], or unexplained high fever without additional symptoms).

Rhabdomyolysis

Rare cases of rhabdomyolysis (including acute renal failure) have been reported after a few months of therapy (Sahin 2014) or in the days following therapy initiation and dose increase (Aricept Canadian product monograph 2014). Use with caution in patients with risk factors for rhabdomyolysis (eg, concomitant medications associated with rhabdomyolysis, history of muscular disorders, uncontrolled hypothyroidism, renal/hepatic impairment). Discontinuation of therapy may be necessary for marked elevation of CPK levels and/or symptoms (eg, muscle pain, tenderness or weakness, malaise, fever, dark urine) suggesting rhabdomyolysis. Disease-related concerns:

Peptic ulcer disease

Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); cholinesterase inhibitors may increase gastric acid secretion. Monitor for symptoms of bleeding.

Respiratory disease

Use with caution in patients with COPD and/or asthma.

Seizure disorder

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 disease.

Urinary tract obstruction

Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms (APA [Rabins 2007]). Special populations:

Low-weight patients

Patients weighing Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Aspartame

Some products may contain aspartame, which is metabolized to phenylalanine and must be avoided (or used with caution) in patients with phenylketonuria.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in some animal reproduction studies.

Lactation

It is not known if donepezil is excreted in breast milk. The manufacturer recommends that caution be used if administered to a nursing woman.

Monitoring

Clinical pearl	Mental status, weight, symptoms of GI intolerance, symptoms of active or occult GI bleeding.

Chemistry & Properties

Formula	C24H29NO3
Molecular weight	379.5 g/mol
IUPAC name	2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one
CAS	120014-06-4
PubChem CID	3152
InChIKey	`ADEBPBSSDYVVLD-UHFFFAOYSA-N`
logP	4.36 (XLogP 4.3)
Polar surface area	38.77 Å²
H-bond acceptors / donors	4 / 0
Drug-likeness (QED)	0.75
Lipinski violations	0

SMILES

COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB 0.89)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 54.67999999999996 µM
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Bupropion	major
Iohexol	major
Iopamidol	major
Ozanimod	major
Siponimod	major
Abarelix	moderate
Acrivastine	moderate
Alectinib	moderate
Alimemazine	moderate
Aminoglutethimide	moderate
Anagrelide	moderate
Apalutamide	moderate
Arsenic trioxide	moderate
Astemizole	moderate
Atropine	moderate
Atropine (ophthalmic)	moderate
Azatadine	moderate
Bexarotene	moderate
Bosutinib	moderate
Brigatinib	moderate
Brompheniramine	moderate
Cabozantinib	moderate
Carbinoxamine	moderate
Ceritinib	moderate
Chlorcyclizine	moderate
Chloroquine	moderate
Chlorpheniramine	moderate
Cilostazol	moderate
Cimetidine	moderate
Cisapride	moderate
Clemastine	moderate
Clidinium	moderate
Cyclizine	moderate
Cyproheptadine	moderate
Dabrafenib	moderate
Daunorubicin	moderate
Daunorubicin (liposomal)	moderate
Deferasirox	moderate
Degarelix	moderate
Dexamethasone	moderate

Showing 40 of 100+.

Registered Products (26)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Alzancer Easytab 5 mg Oradispersible Tablet	Tablet 5 mg	28 tab	Ibn Rushd Drug Store	8.640
Arimac	Tablet 10 mg	30 tab	Sahar Drug Store	13.170
Alzancer Easytab 10 mg Orodispersible Tablet	Tablet 10 mg	28 tab	Ibn Rushd Drug Store	14.170
Donagen	Tablet 5 mg	28 tab	Orient Montreal Drug Store	15.070
Dementile	Tablet 5 mg	30 tab	Sukhtian Group	15.270
DONEX 5 mg ODT	Tablet 5 mg	30 tab	AL-TAQADDOM PHARMACEUTICAL INDUSTRIES/JORDAN	17.510
Dozile	Tablet 5 mg	28 tab	Itqan Pharmaceutical Industries/Jordan	18.140
Donazet	Tablet 5 mg	30 tab	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	19.430
Donagen	Tablet 10 mg	28 tab	Orient Montreal Drug Store	19.490
Dementile	Tablet 10 mg	30 tab	Sukhtian Group	20.540
Arcada 5mg Oral Dispersible Tablets	Tablet 5 mg	30 tab	United Pharmaceutical	22.770
Donex 10mg ODT	Tablet 10 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	23.200
Dozile	Tablet 10 mg	28 tab	Itqan Pharmaceutical Industries/Jordan	24.390
Doxera	Tablet 5 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	24.980
Joswe Demenza 5mg ODS	Tablet 5 mg	30 tab	Jordan Sweden Medical & Sterilization Co.	24.980
Zapiden	Tablet (Hcl) 5 mg	30 tab	Pharma International Company/ Jordan	24.980
Aricept Tab.	Tablet 5 mg	28 tab	Nairoukh Drug Store	25.270
Donazet	Tablet 10 mg	30 tab	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	26.770
Arcada 10mg Disp tab	Tablet 10 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	33.600
Doxera	Tablet 10 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	33.600
Joswe Demenza 10mg ODS	Tablet 10 mg	30 tab	Jordan Sweden Medical & Sterilization Co.	33.600
Zapiden	Tablet (Hcl) 10 mg	30 tab	Pharma International Company/ Jordan	33.600
Aricept Tab.	Tablet 10 mg	28 tab	Nairoukh Drug Store	33.740
Menzotel 14mg/10 mg Extended Release Capsule	Capsule 10 mg, 14 mg	28 tab	United Pharmaceutical Manufacturing Co. Ltd.	50.240
Menzotel 28mg/10 mg Extended Release Capsule	Capsule 10 mg, 28 mg	28 tab	الشركة المتحدة لصناعة الأدوية / United Pharmaceutical Manufacturing Co. Ltd. / Drug	64.320
Doxera 23 mg SR Tab	Tablet 23 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	—