Sertindole Explained

Watchedfields:changed
Verifiedrevid:464389408
Width:250
Tradename:Serdolect, Serlect
Pregnancy Au:C
Routes Of Administration:By mouth
Atc Prefix:N05
Atc Suffix:AE03
Legal Au:S4
Legal Status:Rx-only
Bioavailability:75%[1]
Protein Bound:99.5%
Metabolism:Liver (mostly via CYP2D6 and CYP3A4)[2]
Elimination Half-Life:3 days
Excretion:Faecal (the majority), Kidney (4% metabolites; 1% unchanged)
Cas Number:106516-24-9
Pubchem:60149
Iuphar Ligand:98
Drugbank:DB06144
Chemspiderid:54229
Unii:GVV4Z879SP
Kegg:D00561
Chebi:9122
Chembl:12713
Iupac Name:1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
C:24
H:26
Cl:1
F:1
N:4
O:1
Smiles:Fc1ccc(cc1)n3c2ccc(Cl)cc2c(c3)C5CCN(CCN4C(=O)NCC4)CC5
Stdinchi:1S/C24H26ClFN4O/c25-18-1-6-23-21(15-18)22(16-30(23)20-4-2-19(26)3-5-20)17-7-10-28(11-8-17)13-14-29-12-9-27-24(29)31/h1-6,15-17H,7-14H2,(H,27,31)
Stdinchikey:GZKLJWGUPQBVJQ-UHFFFAOYSA-N

Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States and was discontinued in Australia in January 2014.

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.[3] In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, sertindole was found to be slightly less effective than haloperidol, quetiapine, and aripiprazole, as effective as ziprasidone, approximately as effective as chlorpromazine and asenapine, and slightly more effective than lurasidone and iloperidone.[4]

Adverse effects

Very common (>10% incidence) adverse effects include:[5]

Common (1–10% incidence) adverse effects include:

Uncommon (0.1–1% incidence) adverse effects include:

Rare (<0.1% incidence) adverse effects include:

Unknown frequency adverse events include:

Pharmacology

Biologic protein Binding affinity (Ki[nM])[7] Notes
280
60
96
430
360
0.39 The receptor believed to mediate the atypicality of atypical antipsychotics.[8]
0.9 Likely responsible for its propensity for causing weight gain.
5.4
28
1.8 Likely responsible for the orthostatic hypotension seen in patients on sertindole.
640
450
450
5000
5000
>10000
2692
2.35 Believed to be responsible for the drug's efficacy against positive symptoms.
2.30
4.92
3 Responsible for the QT interval prolongation and torsade de pointes
130
1000

Sertindole is metabolized in the body to dehydrosertindole.[9]

Safety and status

United States

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.[13] Nevertheless, in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.[14], the drug has not been approved by the FDA for use in the USA.[15]

European Union

In the European Union, sertindole was approved and marketed in 19 countries from 1996,[12] but its marketing authorization was suspended by the European Medicines Agency in 1998[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.[17] [18], sertindole is authorized in several states of the European Union.[19]

Notes and References

  1. Karamatskos E, Lambert M, Mulert C, Naber D . Drug safety and efficacy evaluation of sertindole for schizophrenia . Expert Opinion on Drug Safety . 11 . 6 . 1047–62 . November 2012 . 22992213 . 10.1517/14740338.2012.726984 . 11339387 .
  2. Juruena MF, de Sena EP, de Oliveira IR . Sertindole in the management of schizophrenia . Journal of Central Nervous System Disease . 3 . 75–85 . May 2011 . 23861640 . 3663609 . 10.4137/JCNSD.S5729 .
  3. Lewis R, Bagnall AM, Leitner M . Sertindole for schizophrenia . The Cochrane Database of Systematic Reviews . 3 . CD001715 . July 2005 . 2005 . 16034864 . 10.1002/14651858.CD001715.pub2 . 7025766 .
  4. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM . 6 . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis . Lancet . 382 . 9896 . 951–62 . September 2013 . 23810019 . 10.1016/S0140-6736(13)60733-3 . 32085212 .
  5. Web site: PRODUCT INFORMATION SERDOLECT TABLETS. TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. 27 October 2013. PDF.
  6. Book: 978-0-470-97948-8 . The Maudsley prescribing guidelines in psychiatry . Taylor D, Paton C, Shitij K . 2012 . Wiley-Blackwell . West Sussex .
  7. Web site: PDSP Ki Database . Psychoactive Drug Screening Program (PDSP). Bryan Roth . Roth BL, Driscol J . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 27 October 2013 . 12 January 2011 . dead . https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php . 8 November 2013 .
  8. Book: 978-0-07-162442-8 . Goodman and Gilman's The Pharmacological Basis of Therapeutics . 12th . Brunton L, Chabner B, Knollman B . 2010 . McGraw-Hill Professional . New York . Goodman and Gilman's The Pharmacological Basis of Therapeutics .
  9. Web site: TRC Details of CAS = 173294-84-3, ChemicalName = Dehydrosertindole, synonym = 1-[2-[4-[5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-Imidazol-2-one; Lu 28-092, MolFormula = . 20 April 2015 . 27 April 2015 . https://web.archive.org/web/20150427111632/http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092 . dead .
  10. http://www.thepharmaletter.com/file/57165/zenecas-seroquel-nears-market-approval.html Zeneca's Seroquel Nears Market Approval
  11. http://www.thepharmaletter.com/file/65187/abbott-labs-withdraws-sertindole-nda.html Abbott Labs Withdraws Sertindole NDA Sertindole
  12. Web site: WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn . https://web.archive.org/web/20110622124240/http://apps.who.int/medicinedocs/en/d/Js2256e/1.12.html#Js2256e.1.12 . dead . 22 June 2011 .
  13. http://sweden.lundbeck.com/investor/releases/ReleaseDetails/Release_1304142_EN.asp FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia
  14. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM198218.pdf Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
  15. Web site: Welcome to Lundbeck's global site.
  16. http://www.nelm.nhs.uk/en/NeLM-Area/News/483119/483386/483398/ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole)
  17. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Sertindole_36/WC500011855.pdf COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE
  18. http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019523 Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect)
  19. Sertindole: List of nationally authorised medicinal products - PSUSA/00002695/202001 . 3 September 2020 . EMA/270645/2015 . European Medicines Agency (EMA) .

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