Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Rivastigmine: Difference between pages

{{Short description|Chemical compound}}

{{Use dmy dates|date=August 2024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 464382904

| image = Rivastigmine chemical structure.svg

| alt =

| image2 = Rivastigmine ball-and-stick.png

| alt2 =

<!-- Clinical data -->

| pronounce =

| tradename = Exelon, others

| DailyMedID = Rivastigmine

| pregnancy_AU = B2

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]], [[transdermal patch]]

| class =

| ATC_prefix = N06

| ATC_suffix = DA03

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024 | archive-date=6 July 2023 | archive-url=https://web.archive.org/web/20230706023149/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | url-status=live }}</ref>

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=[[Health Canada]] | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=1 April 2024 | archive-date=29 March 2024 | archive-url=https://web.archive.org/web/20240329200203/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | url-status=live }}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US_comment = <ref name="Exelon FDA label">{{cite web | title=Exelon- rivastigmine patch, extended release | website=DailyMed | date=8 May 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=07c12e14-bbd5-4ec8-84e4-fbe7b5ba10e0 | access-date=16 August 2024}}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Prometax EPAR">{{cite web | title=Prometax EPAR | website=European Medicines Agency (EMA) | date=4 December 1998 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/prometax | access-date=16 August 2024 | archive-date=22 June 2021 | archive-url=https://web.archive.org/web/20210622043749/https://www.ema.europa.eu/en/medicines/human/EPAR/prometax | url-status=live }}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = 60 to 72%

| metabolism = [[Liver]], via [[Cholinesterase enzyme|pseudocholinesterase]]

| metabolites =

| onset =

| duration_of_action =

| excretion = 97% in urine

<!-- Identifiers -->

| IUPHAR_ligand = 6602

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 8874

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = (''S'')-3-[1-(dimethylamino)ethyl]phenyl ''N''-ethyl-''N''-methylcarbamate

| C=14 | H=22 | N=2 | O=2

| SMILES = O=C(Oc1cc(ccc1)[C@@H](N(C)C)C)N(CC)C

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Rivastigmine''', sold under the brand name '''Exelon''' among others, is an [[acetylcholinesterase inhibitor]] used for the treatment of dementia associated with [[Alzheimer's disease]] and with [[Parkinson's disease]].<ref name="Exelon FDA label" /><ref name="Khoury Rajamanickam Grossberg 2018 pp. 171–178">{{cite journal | vauthors = Khoury R, Rajamanickam J, Grossberg GT | title = An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine | journal = Therapeutic Advances in Drug Safety | volume = 9 | issue = 3 | pages = 171–178 | date = March 2018 | pmid = 29492246 | pmc = 5810854 | doi = 10.1177/2042098617750555 | publisher = SAGE Publications }}</ref><ref name="Tanner 2024">{{cite journal | vauthors = Tanner CM, Ostrem JL | title = Parkinson's Disease | journal = The New England Journal of Medicine | volume = 391 | issue = 5 | pages = 442–452 | date = August 2024 | pmid = 39083773 | doi = 10.1056/NEJMra2401857 }}</ref> Rivastigmine can be administered orally or via a [[transdermal patch]]; the latter form reduces the prevalence of side effects,<ref name=Winblad/> which typically include nausea and vomiting.<ref name=Inglis/>

Rivastigmine is eliminated through the urine, and appears to have relatively few drug-drug interactions.<ref name="Inglis" />

<!-- Society and culture -->

It was patented in 1985 and came into medical use in 1997.<ref name=Fis2006>{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=540 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA540 |language=en |access-date=2 June 2020 |archive-date=11 January 2023 |archive-url=https://web.archive.org/web/20230111091216/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA540 |url-status=live }}</ref>

==Medical uses==

Rivastigmine is [[indicated]] for the treatment of dementia of the Alzheimer's type;<ref name="Exelon FDA label" /> and for the treatment of dementia associated with Parkinson's disease.<ref name="Exelon FDA label" />

Rivastigmine capsules, liquid solution and patches are used for the treatment of mild to moderate dementia of the [[Alzheimer's]] type, and for mild to moderate [[Parkinson's disease dementia]].<ref>{{cite web |url=https://www.nice.org.uk/guidance/ng71/chapter/Recommendations |title=Recommendations - Parkinson's disease in adults |publisher=[[National Institute for Health and Care Excellence]] |date=2017-07-19 |access-date=2023-01-02 |archive-date=18 January 2024 |archive-url=https://web.archive.org/web/20240118155232/https://www.nice.org.uk/guidance/ng71/chapter/Recommendations |url-status=live }}</ref>

Rivastigmine has demonstrated treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer's.<ref>{{cite journal |vauthors=Corey-Bloom J, Anand R, Veach J |year=1998 |title=A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease |journal=International Journal of Geriatric Psychopharmacology |volume=1 |issue=2 |pages=55–65 |url=https://www.researchgate.net/publication/284814323 |access-date=25 December 2015 |archive-date=29 August 2021 |archive-url=https://web.archive.org/web/20210829041052/https://www.researchgate.net/publication/284814323_A_randomized_trial_evaluating_the_efficacy_and_safety_of_ENA_713_rivastigmine_tartrate_a_new_acetylcholinesterase_inhibitor_in_patients_with_mild_to_moderately_severe_Alzheimer%27s_disease |url-status=live }}</ref><ref>{{cite journal | vauthors = Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stähelin HB, Hartman R, Gharabawi M | title = Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial | journal = BMJ | volume = 318 | issue = 7184 | pages = 633–638 | date = March 1999 | pmid = 10066203 | pmc = 27767 | doi = 10.1136/bmj.318.7184.633 }}</ref><ref>{{cite journal | vauthors = Finkel SI | title = Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease | journal = Clinical Therapeutics | volume = 26 | issue = 7 | pages = 980–990 | date = July 2004 | pmid = 15336465 | doi = 10.1016/S0149-2918(04)90172-5 }}</ref><ref>{{cite journal | vauthors = Rösler M, Retz W, Retz-Junginger P, Dennler HJ | title = Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease | journal = Behavioural Neurology | volume = 11 | issue = 4 | pages = 211–216 | year = 1998 | pmid = 11568422 | doi = 10.1155/1999/168023 | doi-access = free }}</ref>

===Efficacy===

In people with either type of dementia, rivastigmine has been shown to provide meaningful symptomatic effects that may allow patients to remain independent and ‘be themselves’ for longer. In particular, it appears to show marked treatment effects in patients showing a more aggressive course of disease, such as those with younger onset ages, poor nutritional status, or those experiencing symptoms such as delusions or hallucinations.<ref name="ReferenceA">{{cite journal | vauthors = Gauthier S, Vellas B, Farlow M, Burn D | title = Aggressive course of disease in dementia | journal = Alzheimer's & Dementia | volume = 2 | issue = 3 | pages = 210–217 | date = July 2006 | pmid = 19595889 | doi = 10.1016/j.jalz.2006.03.002 | s2cid = 30562189 }}</ref> For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer's and Parkinson's patients.<ref name="ReferenceB">{{cite journal | vauthors = Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R | title = Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology | journal = Current Medical Research and Opinion | volume = 22 | issue = 1 | pages = 49–59 | date = January 2006 | pmid = 16393430 | doi = 10.1185/030079906X80279 | s2cid = 29977831 }}</ref><ref>{{cite journal | vauthors = Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, Lane R | title = Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease | journal = Movement Disorders | volume = 21 | issue = 11 | pages = 1899–1907 | date = November 2006 | pmid = 16960863 | doi = 10.1002/mds.21077 | s2cid = 24621350 }}</ref> These effects might reflect the additional inhibition of butyrylcholinesterase, which is implicated in symptom progression and might provide added benefits over acetylcholinesterase-selective drugs in some patients.<ref name="ReferenceA"/><ref name="ReferenceB"/> Multiple-infarct dementia patients may show slight improvement in executive functions and behaviour. No firm evidence supports usage in schizophrenia patients.

Its efficacy is similar to [[donepezil]] and [[tacrine]]. Doses below 6&nbsp;mg/d may be ineffective. The effects of this kind of drug in different kinds of dementia (including Alzheimer's dementia) are modest, and it is still unclear which AChE (BChE) esterase inhibitor is better in Parkinson's dementia, though rivastigmine is well-studied.

==Side effects==

Side effects may include nausea and vomiting, decreased appetite and weight loss.<ref name=Inglis/>

The strong potency of rivastigmine, provided by its dual inhibitory mechanism, has been postulated to lead to more nausea and vomiting during the titration phase of oral rivastigmine treatment.<ref name=Inglis/>

In a large clinical trial of the rivastigmine patch in 1,195 patients with Alzheimer's disease, the target dose of 9.5&nbsp;mg/24-hour patch provided similar clinical effects (e.g. memory and thinking, activities of daily living, concentration) as the highest doses of rivastigmine capsules, but with one-third fewer reports of nausea and vomiting.<ref name=Winblad>{{cite journal | vauthors = Winblad B, Grossberg G, Frölich L, Farlow M, Zechner S, Nagel J, Lane R | title = IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease | journal = Neurology | volume = 69 | issue = 4 Suppl 1 | pages = S14–S22 | date = July 2007 | pmid = 17646619 | doi = 10.1212/01.wnl.0000281847.17519.e0 | s2cid = 38846813 }}</ref>

Usage of rivastigmine was associated with a higher frequency of reports of death as an adverse event in the Food and Drug Administration Adverse Event Reporting System database compared to the other acetylcholinesterase inhibiting drugs donepezil and galantamine; this increase could be related to improper application of the transdermal patch, or because rivastigmine is more often used during advanced illness.<ref>{{cite journal | vauthors = Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R | title = Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada | journal = PLOS ONE | volume = 10 | issue = 12 | pages = e0144337 | year = 2015 | pmid = 26642212 | pmc = 4671709 | doi = 10.1371/journal.pone.0144337 | doi-access = free | bibcode = 2015PLoSO..1044337A }}</ref>

Rivastigmine can increase gastric acid; it is discontinued if there are signs of gastrointestinal bleeding, particularly in individuals using [[nonsteroidal anti-inflammatory drug]]s (NSAIDs) or who have a history of [[peptic ulcer disease]].<ref>{{cite web |url= https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-2294?p |publisher= Elsevier |title= Drug monograph: Rivastigmine |work= Clinical Key database |access-date= May 31, 2023 |page= 8 |archive-date= 15 July 2020 |archive-url= https://web.archive.org/web/20200715003558/https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-2294?p |url-status= live }}</ref>

==Administration==

Rivastigmine [[tartrate]] is a white to off-white, fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). It comes in a variety of administrations including a capsule, solution and a [[transdermal patch]]. Like other [[Cholinesterase#Inhibitors|cholinesterase inhibitors]], it requires doses to be increased gradually over several weeks; this is usually referred to as the titration phase.<ref name=Inglis>{{cite journal | vauthors = Inglis F | title = The tolerability and safety of cholinesterase inhibitors in the treatment of dementia | journal = International Journal of Clinical Practice. Supplement | issue = 127 | pages = 45–63 | date = June 2002 | pmid = 12139367 }}</ref>

==Pharmacology==

===Pharmacodynamics===

Rivastigmine, a [[cholinesterase inhibitor]], inhibits both [[butyrylcholinesterase]] and [[acetylcholinesterase]] (unlike [[donepezil]], which selectively inhibits acetylcholinesterase). It is thought to work by inhibiting these cholinesterase enzymes, which would otherwise break down the brain [[neurotransmitter]] acetylcholine.<ref>{{cite journal | vauthors = Camps P, Muñoz-Torrero D | title = Cholinergic drugs in pharmacotherapy of Alzheimer's disease | journal = Mini Reviews in Medicinal Chemistry | volume = 2 | issue = 1 | pages = 11–25 | date = February 2002 | pmid = 12369954 | doi = 10.2174/1389557023406638 }}</ref>

===Pharmacokinetics===

When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3&nbsp;mg twice daily, but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.<ref name= Cummings>{{cite journal | vauthors = Cummings J, Lefèvre G, Small G, Appel-Dingemanse S | title = Pharmacokinetic rationale for the rivastigmine patch | journal = Neurology | volume = 69 | issue = 4 Suppl 1 | pages = S10–S13 | date = July 2007 | pmid = 17646618 | doi = 10.1212/01.wnl.0000281846.40390.50 | s2cid = 21290898 }}</ref> The 9.5&nbsp;mg/24 h rivastigmine patch provides comparable exposure to 12&nbsp;mg/day capsules (the highest recommended oral dose).<ref name=Cummings />

The compound does cross the [[blood–brain barrier]]. Plasma protein binding is 40%.<ref>{{cite journal | vauthors = Jann MW, Shirley KL, Small GW | title = Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors | journal = Clinical Pharmacokinetics | volume = 41 | issue = 10 | pages = 719–739 | year = 2002 | pmid = 12162759 | doi = 10.2165/00003088-200241100-00003 | s2cid = 22768375 }}</ref> The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.<ref>{{cite journal | vauthors = Jann MW | title = Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease | journal = Pharmacotherapy | volume = 20 | issue = 1 | pages = 1–12 | date = January 2000 | pmid = 10641971 | doi = 10.1592/phco.20.1.1.34664 | s2cid = 25007829 }}</ref> The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.<ref name=Inglis/>

A QbD driven HPLC method was developed for the quantification of rivastigmine in rat plasma and brain for its pharmacokinetics study [<ref>{{Cite journal |vauthors=Gopalan D, Patil PH, Jagadish PC, Kini SG, Alex AT, Udupa N, Mutalik S |date=2022-06-05 |title=QbD-driven HPLC method for the quantification of rivastigmine in rat plasma and brain for pharmacokinetics study |url=https://japsonline.com/abstract.php?article_id=3665&sts=2 |journal=Journal of Applied Pharmaceutical Science |volume=12 |issue=6 |pages=056–067 |doi=10.7324/JAPS.2022.120606 |eissn=2231-3354 |doi-access=free |access-date=6 March 2024 |archive-date=23 May 2024 |archive-url=https://web.archive.org/web/20240523001939/https://japsonline.com/abstract.php?article_id=3665&sts=2 |url-status=live }}</ref>].

==History==

Rivastigmine was developed by [[Marta Weinstock-Rosin]] of the Department of Pharmacology at the [[Hebrew University of Jerusalem]]<ref>{{cite web|title=Exelon|url=http://www.yissum.co.il/success.php?cat=12&in=0|publisher=Yissum Technology Transfer|access-date=7 October 2010|archive-date=26 October 2011|archive-url=https://web.archive.org/web/20111026071525/http://www.yissum.co.il/success.php?cat=12&in=0|url-status=dead}}</ref> and sold to [[Novartis]] by [[Yissum Research Development Company of the Hebrew University|Yissum]] for commercial development. It is a semi-synthetic derivative of [[physostigmine]].<ref>{{cite journal | vauthors = Kumar V | title = Potential medicinal plants for CNS disorders: an overview | journal = Phytotherapy Research | volume = 20 | issue = 12 | pages = 1023–1035 | date = December 2006 | pmid = 16909441 | doi = 10.1002/ptr.1970 | s2cid = 25213417 }}</ref>

== References ==

{{Reflist}}

{{Anti-dementia drugs}}

{{Acetylcholine metabolism and transport modulators}}

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[[Category:Acetylcholinesterase inhibitors]]

[[Category:Antidementia agents]]

[[Category:Drugs developed by Novartis]]

[[Category:Aromatic carbamates]]

[[Category:Israeli inventions]]

[[Category:Treatment of Alzheimer's disease]]