Donepezil

From Pubdrug

Jump to: navigation, search

Contents
image:pdgreen.GIF This page has been completed and reviewed for accuracy.
You are reading a certified PubDrug document. This document is complete and accurate to the best of the knowledge of the author and reviewer. This document cannot be edited without being unlocked by a PubDrug admin. Edits or updates may be recommended under the Discussion tab.

Authored by: Km39 20:45, 13 March 2007 (PDT)
Certified by: Rlweber 11:06, 19 April 2007 (PDT)

Donepezil quick reference

Donepezil
Donepezil general drug information
 Pronunciation doe NEP e zil (.wav file)
 Trade Name(s) Aricept, Aricept ODT
 How Supplied Tablets: 5 mg, 10 mg
Oral solution: 1 mg/mL
Orally disintegrating tablets (ODT): 5 mg, 10 mg
 Generic Availability No generics available
 Patent Expiry Date 11/2010
 Classification Cholinesterase (ChE) inhibitor
 Schedule Rx
 Pregnancy Category C
 Breast-feeding Safety is unclear. Unknown if donepezil is excreted in breast milk.
Donepezil chemical information
 IUPAC Name 2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
 Empirical Formula C24H29NO3
 Molecular Weight 379.492 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Alzheimer’s disease causes a progressive dementia leading to a steady decline in cognitive function which adversely affects functional abilities required for activities of daily living.[1] Approximately 5% of the population over the age of 65 is affected by Alzheimer’s and the prevalence doubles every 5 years after the age of 65.[2] It appears that synaptic loss is the primary factor in the creation of dementia symptoms. The synaptic neurotransmitters include acetylcholine, glutamate and serotonin. Donepezil is a cholinesterase inhibitor which inhibits the breakdown of acetylcholine.[3]

Donepezil is the first piperidine-type reversible cholinesterase inhibitor.[4] Donepezil is thought to prolong a patient’s ability to perform activities of daily living by facilitating improvement in cognition, memory, behavior and mood. It is not a cure for Alzheimer’s disease.[3] Some studies suggest donepezil may have neuroprotective effects, however further studies are needed to confirm this.[5]

Donepezil is given once a day because of its long half life of 70 hours. It is as efficacious as rivastigmine and galantamine[6][7] and is well-tolerated when titrated over four to six weeks.[8]

Mechanism of Action

Donepezil is the first piperidine-type reversible cholinesterase inhibitor. Cholinesterase inhibition is aimed at increasing the acetylcholine in synaptic terminals. It reversibly obstructs the hydrolysis of acetylcholine in the synapse, allowing for more acetylcholine at the muscarinic and nicotinic receptors.[3][8]

Muscarinic and nicotinic receptors make up the cholinergic receptors. It is the synaptic dysfunction that seems to be responsible for the dementia symptoms of donepezil.[3] Donepezil does not affect the production of acetylcholine.[9]

Time Required for Therapeutic Response

  • Initial: type initial response time
  • Maximum: type maximum response time

Pharmacokinetics

Absorption
The absorption of donepezil is complete with a 100% bioavailability. Donepezil exhibits linear pharmacokinetics in doses up to and including 10 mg daily.[10] The Tmax is 3-4 hours. Food does not affect bioavailability.[8]

Distribution
Steady state is reached in 15 days and donepezil accumulates in the plasma up to 4-7 fold after multiple doses are administered.[8] The volume of distribution is 12 L/kg and and it is 96% bound to proteins. The protein binding is delineated as 75% bound to albumin and 21% bound to alpha-1-acid glycoprotein.

Metabolism
Donepezil is metabolized by CYP2D6, CYP3A4, and undergoes glucuronidation. There are four major metabolites produced, one of which is active.[8] The major metabolite which is produced is 6-O-desmethyl-donepezil. This is present in 20% of the plasma concentration.[10]

Excretion
The half-life of donepezil is 70 hours, allowing for its once-daily dosing. The mean plasma clearance is 0.13 L/hr/kg. About 57% of the drug is recovered in the urine and 15% is recovered in the feces. 17% of the drug is found unchanged in the urine.[8]

Back to top

Special Population Pharmacokinetics

  • Renal insufficiency: Dosage adjustment does not appear necessary. In 11 patients with a creatinine clearance of less than 18 mL/min, the clearance of donepezil did not differ when compared with subjects of normal renal function.[8]
  • Hepatic insufficiency: In patients with alcoholic cirrhosis, it was found that the clearance of donepezil was lowered by 20% when compared to healthy patients.[8] It appears that no dosage adjustment is needed, however. Monitoring of side effects is warranted.[10]
  • Hemodialysis: Insufficient data.[8]
  • Geriatric: It appears that there is no difference in pharmacokinetics between older and younger patients.[8] The AUC and clearance do not between the two populations.[10]
  • Pediatric: Insufficient data.[8]
  • Gender: Gender does not seem to impact PK.[8]

Indications and Dosages

FDA Approved Indications

Alzheimer’s disease (mild, moderate and severe) [8][11][12][13][14][15]

  • Starting dose:
    • 5 mg once a day
  • Maintenance dose:
    • 10 mg once a day
  • Titration schedule:
    • Increase dose after patient is stabilized on 5 mg/day for 4 to 6 weeks.
    • Faster titration leads to a greater likelihood of adverse effects.
    • There was no statistical difference between the 5 mg and 10 mg dose for mild to moderate Alzheimer’s disease. The 10mg dose should be titrated to for severe Alzheimer’s disease.

Dementia [8][16][17]

  • Starting dose:
    • 5 mg once a day
  • Maintenance dose:
    • 10 mg once a day
  • Titration schedule:
    • Increase dose after patient is stabilized on 5 mg/day for 4 to 6 weeks.
    • Faster titration leads to a greater likelihood of adverse effects.

Non-FDA Approved Indications

  • Tourette's syndrome[18]
  • Poststroke aphasia (PSA)[19]
  • Multiple sclerosis[20]

Dosage Adjustment

Hepatic insufficiency: No dosage adjustment needed. Monitor for side effects in patients with severe hepatic disease.[8]
Hemodialysis: Unknown.[8]

Dosage Limits

  • Adults: 10 mg/day[8]
  • Elderly: 10 mg/day[8]
  • Adolescents and children: no data


Back to top

Administration

  • Route: Oral (tablet)
  • Method:
    • Aricept tablets should be taken in the evening with a drink of water. They can be taken with or without food.[8]
  • Route: Oral (orally disintegrating tablet)
  • Method:
    • Aricept ODT should be placed on the tongue to dissolve and then the patient should have a drink of water.[8]

Monitoring Parameters

  • Neurological function[8]
  • Weight[8]

Contraindications/Precautions

Contraindications

  • Patients with hypersensitivity to donepezil or piperidine derivatives.[8]

Precautions

  • Caution with succinylcholine-type anesthetics
  • Bradycardia or heart block
  • Gastrointestinal bleeding or patients who are at risk for the development of ulcers
  • Bladder outlet obstruction
  • Seizure disorder
  • COPD or asthma
    • A recent study found that acetylcholinesterase inhibitors can be used safely in elderly patients with chronic airway disease.[21]

Pregnancy indications

Category C [8]

There was a slight increase in the number of still births in pregnant rats, and a decrease in pup survival. There have been no well-controlled studies in humans.[8]

Breast-feeding indications

Donepezil is not indicated for breast feeding mothers. It is unknown if donepezil is excreted in breast milk.[8]

Back to top

Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Aricept is generally well tolerated. In phase III trials, 12% of patients in the treatment group discontinued use of donepezil (7% of patients in the placebo group stopped treatment). The most prevalent adverse effects include anorexia, nausea, diarrhea and urinary tract infection.[8] The adverse effects usually go away with continued treatment. The adverse effects are also lessened with slow titration.[3] Typically, patients experience more adverse effects at higher doses of donepezil, or in patients who are of low body weight.[3]

Donepezil Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Nausea (5-19%), insomnia (6-14%)
1-10% CNS Fatigue (3-8%), headache (>2%), dizziness (>2%), depression (>2%), abnormal dreams (>2%), somnolence (>2%), confusion (>2%)
Cardiovascular Syncope (>2%),[22] hypertension (>2%), hemorrhage (>2%), hyperlipidemia (>2%)
Dermatologic Eczema (>2%)
GI Diarrhea (8-15%), vomiting (3-8%), anorexia (3-7%), weight decrease (>2%)
Genitourinary Frequent urination (>2%), urinary tract infection (2%)
Neuromuscular/skeletal Muscle cramps (3-8%), pain (>2%)[23]
Miscellaneous Ecchymosis (>2%), dehydration (>2%)
<1% All Influenza, chest pain, toothache, vasodilatation, atrial fibrillation,[24] hot flashes, hypotension, fecal incontinence, gastrointestinal bleeding,[25] epigastric pain, delusions, tremor, irritability, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia, dyspnea, sore throat, bronchitis, pruritis, urticaria, cataract, eye irritation, vision blurred, nocturia

Overdosage Measures

An overdosage is marked by a characteristic set of cholinergic symptoms. These symptoms include nausea and vomiting, increased production of saliva, sweating, slow heart beat, low blood pressure, respiratory depression, collapse and convulsions. The respiratory depression results from muscle weakness.
Treatment:[8]

  • Atropine or another tertiary amine may be given in cases of donepezil overdosage. The recommended dosage of atropine sulfate is 1 to 2 mg intravenously.
  • Additional doses may be given based on clinical status of the patient.
  • It is unknown if donepezil is removed by hemodialysis.
Back to top

Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
5 mg tablet white round 5/ARICEPT
10 mg tablet yellow round 10/ARICEPT
5 mg orally disintegrating tablet yellow round 5/ARICEPT
10 mg orally disintegrating tablet yellow round 10/ARICEPT
1 mg/mL solution clear to light yellow - strawberry flavor
  • Inactive ingredients for tablets: corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide, yellow iron oxide (synthetic, 10 mg tablet only)
  • Inactive ingredients for orally disintegrating tablets: carrageenan, colloidal silicon dioxide, mannitol, polyvinyl alcohol, yellow ferric oxide (10 mg tablet only)
  • Inactive ingredients for solution: citric acid anhydrous, methylparaben, povidone K-30, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate, sodium metabisulfite, sorbitol solution 70%, strawberry flavor

Patient Information

  • Donepezil is typically given at bedtime. If donepezil causes abnormal dreams, it may be taken in the morning.
  • Donepezil tablets should be taken with a drink of water
  • Donepezil orally-disintegrating tablets should be placed in the mouth and allowed to dissolve, and then swallowed. It may be taken with water but this is not needed.
  • Donepezil solution should be measured using a special dosage spoon.
  • Ask your prescriber or pharmacist before you take any over the counter medications for pain, cough, cold or allergies.
  • Call your prescriber or pharmacist right away if you experience dizziness, rash, stomach pain, vomiting, or weight loss.
  • Other side effects that you may notice from taking donepezil include diarrhea, drowsiness, and nausea
  • Do not drive until you find out how this medication affects you.


Back to top

References

  1. ↑ Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.
  2. ↑ Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129(Pt 11):2840-55.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 2001;61(1):41-52.
  4. ↑ Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer's disease. Drugs. 2001;61(1):41-52.
  5. ↑ Mori E, Hashimoto M, Krishnan KR, Doraiswamy PM, Mori E, Hashimoto M, et al. What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors? Alzheimer Disease & Associated Disorders. 2006 Apr-Jun;20(2 Suppl 1):S19-26.
  6. ↑ Wilkinson DG, Passmore AP, Bullock R, Hopker SW, Smith R, Potocnik FC, et al. A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. International journal of clinical practice. 2002 Jul-Aug;56(6):441-6.
  7. ↑ Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease. Drugs Aging. 2003;20(10):777-89
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 8.19 8.20 8.21 8.22 8.23 8.24 8.25 8.26 8.27 Aricept (Donepezil hydrochloride) package insert, New York, NY; Pfizer:2006 October http:/ www.pfizer.com/pfizer/download/uspi_aricept.pdf.
  9. ↑ Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 2004;21(7):453-78.
  10. ↑ 10.0 10.1 10.2 10.3 Jann MW, Shirley KL, Small GW, Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clinical Pharmacokinetics. 2002;41(10):719-39.
  11. ↑ Marder K, Marder K. Donepezil in patients with severe Alzheimer's disease: double-blind parallel-group, placebo controlled study. Current Neurology & Neuroscience Reports. 2006 Sep;6(5):364-3.
  12. ↑ Birks J, Flicker L, Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database of Systematic Reviews. 2006;3:CD006104.
  13. ↑ Winblad B, Wimo A, Engedal K, Soininen H, Verhey F, Waldemar G, et al. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy. Dementia & Geriatric Cognitive Disorders. 2006;21(5-6):353-63.
  14. ↑ Johannsen P, Salmon E, Hampel H, Xu Y, Richardson S, Qvitzau S, et al. Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer's disease.[erratum appears in CNS Drugs. 2006;20(10):866]. CNS Drugs. 2006;20(4):311-25.
  15. ↑ Winblad B, Kilander L, Eriksson S, Minthon L, Batsman S, Wetterholm AL, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study.[see comment][erratum appears in Lancet. 2006 Jun 17;367(9527):1980]. Lancet. 2006 Apr 1;367(9516):1057-65.
  16. ↑ Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R, et al. Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology.[erratum appears in Curr Med Res Opin. 2006 Aug;22(8):1451]. Current Medical Research & Opinion. 2006 Jan;22(1):49-59.
  17. ↑ Goldsmith DR, Scott LJ. Donepezil: in vascular dementia. Drugs Aging 2003;20(15):1127-36.
  18. ↑ Niederhofer H, Niederhofer H. Donepezil also effective in the treatment of Tourette's syndrome? Movement Disorders. 2006 Nov;21(11):2027.
  19. ↑ Berthier ML, Green C, Higueras C, Fernandez I, Hinojosa J, Martin MC, et al. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Neurology. 2006 Nov 14;67(9):1687-9.
  20. ↑ Christodoulou C, Melville P, Scherl WF, Macallister WS, Elkins LE, Krupp LB, et al. Effects of donepezil on memory and cognition in multiple sclerosis. Journal of the Neurological Sciences. 2006 Jun 15;245(1-2):127-36.
  21. ↑ Thacker EL, Schneeweiss S, Thacker EL, Schneeweiss S. Initiation of acetylcholinesterase inhibitors and complications of chronic airways disorders in elderly patients. Drug Safety. 2006;29(11):1077-85.
  22. ↑ Bordier P, Garrigue S, Lanusse S, Margaine J, Robert F, Gencel L, et al. Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's disease. CNS Drugs. 2006;20(5):411-7.
  23. ↑ Kuloor CB, Puranik A, Kuloor CB, Puranik A. Pain with donepezil. Age & Ageing. 2006 Nov;35(6):639-40.
  24. ↑ Suleyman T, Tevfik P, Abdulkadir G, Ozlem S, Suleyman T, Tevfik P, et al. Complete atrioventricular block and ventricular tachyarrhythmia associated with donepezil. Emergency Medicine Journal. 2006 Aug;23(8):641-2.
  25. ↑ Cholongitas E, Pipili C, Dasenaki M, Cholongitas E, Pipili C, Dasenaki M. Recurrence of upper gastrointestinal bleeding after donepezil administration. Alzheimer Disease & Associated Disorders. 2006 Oct-Dec;20(4):326.

PUBMED References

Efficacy Trial Articles

  1. Goldsmith DR, Scott LJ. Donepezil: in vascular dementia. Drugs Aging 2003;20(15):1127-36
  2. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 2004;21(7):453-78.
  3. Mori E, Hashimoto M, Krishnan KR, Doraiswamy PM, Mori E, Hashimoto M, et al. What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors? Alzheimer Disease & Associated Disorders. 2006 Apr-Jun;20(2 Suppl 1):S19-26.
  4. Marder K. Donepezil in patients with severe Alzheimer's disease: double-blind parallel-group, placebo controlled study. Current Neurology & Neuroscience Reports. 2006 Sep;6(5):364-3.
  5. Birks J, Flicker L, Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database of Systematic Reviews. 2006;3:CD006104.
  6. Winblad B, Wimo A, Engedal K, Soininen H, Verhey F, Waldemar G, et al. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy. Dementia & Geriatric Cognitive Disorders. 2006;21(5-6):353-63.
  7. Johannsen P, Salmon E, Hampel H, Xu Y, Richardson S, Qvitzau S, et al. Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer's disease.erratum appears in CNS Drugs. 2006;20(10):866. CNS Drugs. 2006;20(4):311-25.
  8. Winblad B, Kilander L, Eriksson S, Minthon L, Batsman S, Wetterholm AL, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study.see comment; erratum appears in Lancet. 2006 Jun 17;367(9527):1980. Lancet. 2006 Apr 1;367(9516):1057-65.
Back to top

Therapeutic Class Comparison Articles

  1. Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 2001;61(1):41-52.
  2. Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R, et al. Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology.erratum appears in Curr Med Res Opin. 2006 Aug;22(8):1451. Current Medical Research & Opinion. 2006 Jan;22(1):49-59.
  3. Grossberg GT, Edwards KR, Zhao Q. Rationale for combination therapy with galantamine and memantine in Alzheimer's disease. Journal of Clinical Pharmacology. 2006 Jul;46(7 Suppl 1):17S-26S.
  4. Preskorn SH, Borges S, Flockhart D. Clinically relevant pharmacology of neuropsychiatric drugs approved over the last three years: part I. Journal of Psychiatric Practice. 2006 Jul;12(4):244-9.
  5. Rabins PV, Lyketsos CG. Cholinesterase inhibitors and memantine have a role in the treatment of Alzheimer's disease. Nature Clinical Practice Neurology. 2006 Nov;2(11):578-9.
  6. Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs. 2006;66(11):1515-34.

Pharmacokinetics Articles

  1. Jann MW, Shirley KL, Small GW, Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clinical Pharmacokinetics. 2002;41(10):719-39.
Back to top

Drug Interaction Articles

  1. Bentue-Ferrer D, Tribut O, Polard E, Allain H, Bentue-Ferrer D, Tribut O, et al. Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. CNS Drugs. 2003;17(13):947-63.
  2. Nagy CF, Kumar D, Perdomo CA, Wason S, Cullen EI, Pratt RD, et al. Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses. British Journal of Clinical Pharmacology. 2004 Nov;58 Suppl 1:25-33.
  3. Alzheimer's disease: beware of interactions with cholinesterase inhibitors. Prescrire Int. 2006 Jun;15(83):103-6.

Adverse Effects Articles

  1. Bordier P, Garrigue S, Lanusse S, Margaine J, Robert F, Gencel L, et al. Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's disease. CNS Drugs. 2006;20(5):411-7.
  2. Kuloor CB, Puranik A, Kuloor CB, Puranik A. Pain with donepezil. Age & Ageing. 2006 Nov;35(6):639-40.
  3. Suleyman T, Tevfik P, Abdulkadir G, Ozlem S, Suleyman T, Tevfik P, et al. Complete atrioventricular block and ventricular tachyarrhythmia associated with donepezil. Emergency Medicine Journal. 2006 Aug;23(8):641-2.
  4. Cholongitas E, Pipili C, Dasenaki M, Cholongitas E, Pipili C, Dasenaki M. Recurrence of upper gastrointestinal bleeding after donepezil administration. Alzheimer Disease & Associated Disorders. 2006 Oct-Dec;20(4):326.
Back to top

Compliance Articles

Pharmacoeconomic Articles

Back to top

External Links

Clinical treatment guidelines

Patient information pages

Other resources

Back to top
Retrieved from "http://www.smbrower.com/mediawiki/index.php/Donepezil"
Personal tools