Sertindole

Sertindole
Clinical data
Trade namesSerdolect, Serlect
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability75%[1]
Protein binding99.5%[1]
MetabolismLiver (mostly via CYP2D6 and CYP3A4)[2][3]
Elimination half-life3 days[2]
ExcretionFaecal (the majority), Kidney (4% metabolites; 1% unchanged)[2]
Identifiers
IUPAC name
  • 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.162.562
Edit this at Wikidata
Chemical and physical data
FormulaC24H26ClFN4O
Molar mass440.95 g·mol−1
3D model (JSmol)
SMILES
  • Fc1ccc(cc1)n3c2ccc(Cl)cc2c(c3)C5CCN(CCN4C(=O)NCC4)CC5
InChI
  • InChI=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) checkY
  • Key:GZKLJWGUPQBVJQ-UHFFFAOYSA-N checkY
  (verify)

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.[4] 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.[5]

Adverse effects

Very common (>10% incidence) adverse effects include:[2]

  • Headache
  • Ejaculation failure
  • Insomnia
  • Dizziness

Common (1–10% incidence) adverse effects include:[2]

  • Urine that tests positive for red and/or white blood cells
  • Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly [and non-significantly] more sedation than amisulpride and paliperidone)[5][6]
  • Ejaculation disorder
  • Erectile dysfunction
  • Orthostatic hypotension[6]
  • Weight gain (which it seems to possess a similar propensity for causing as quetiapine)[5]

Uncommon (0.1–1% incidence) adverse effects include:[2]

  • Substernal chest pain
  • Face oedema
  • Influenza-like illness
  • Neck rigidity
  • Pallor
  • Peripheral vascular disorder
  • syncope
  • Torsades de pointes
  • Vasodilation
  • Suicide attempt
  • Amnesia
  • Anxiety
  • Ataxia
  • Confusion
  • Incoordination
  • Libido decreased
  • Libido increased
  • Miosis
  • Nystagmus
  • Personality disorder
  • Psychosis
  • Reflexes decreased
  • Reflexes increased
  • Stupor
  • Suicidal tendency
  • Urinary retention
  • Vertigo
  • Diabetes mellitus
  • Abnormal stools
  • Gastritis
  • Gingivitis
  • Glossitis
  • Increased appetite
  • Mouth ulceration
  • Rectal disorder
  • Rectal haemorrhage
  • Stomatitis
  • Tongue disorder
  • Ulcerative stomatitis
  • Anaemia
  • Ecchymosis
  • Hypochromic anaemia
  • Leukopenia
  • Hyperglycaemia
  • Hyperlipemia
  • Oedema
  • Bone pain
  • Myasthenia
  • Twitching
  • Bronchitis
  • Hyperventilation
  • Pneumonia
  • Sinusitis
  • Furunculosis
  • Herpes simplex
  • Nail disorder
  • Psoriasis
  • Pustular Rash
  • Skin discolouration
  • Skin hypertrophy
  • Skin ulcer
  • Abnormal vision
  • Keratoconjunctivitis
  • Lacrimation disorder
  • Otitis externa
  • Pupillary disorder
  • Taste perversion
  • Anorgasmia
  • Penis disorder (gs)
  • Urinary urgency
  • Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do)[5]
  • Seizures
  • Galactorrhoea

Rare (<0.1% incidence) adverse effects include:[2]

Unknown frequency adverse events include:[2]

  • Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE)[5]
  • Venous thromboembolism
  • QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation)[5]

Pharmacology

Biologic proteinBinding affinity (Ki[nM])[7]Notes
5-HT1A280
5-HT1B60
5-HT1D96
5-HT1E430
5-HT1F360
5-HT2A0.39The receptor believed to mediate the atypicality of atypical antipsychotics.[8]
5-HT2C0.9Likely responsible for its propensity for causing weight gain.[8]
5-HT65.4
5-HT728
α1A1.8Likely responsible for the orthostatic hypotension seen in patients on sertindole.[8]
α2A640
α2B450
α2C450
β15000
β25000
M1>10000[8]
M32692
D22.35Believed to be responsible for the drug's efficacy against positive symptoms.[8]
D32.30
D44.92
hERG3Responsible for the QT interval prolongation and torsade de pointes
H1130
NK11000

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] As of October 2010, 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] As of September 2020, sertindole is authorized in several states of the European Union.[19]

References

  1. 1 2 Karamatskos E, Lambert M, Mulert C, Naber D (November 2012). "Drug safety and efficacy evaluation of sertindole for schizophrenia". Expert Opinion on Drug Safety. 11 (6): 1047–62. doi:10.1517/14740338.2012.726984. PMID 22992213. S2CID 11339387.
  2. 1 2 3 4 5 6 7 8 "PRODUCT INFORMATION SERDOLECT TABLETS" (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013.
  3. ↑ Juruena MF, de Sena EP, de Oliveira IR (May 2011). "Sertindole in the management of schizophrenia". Journal of Central Nervous System Disease. 3: 75–85. doi:10.4137/JCNSD.S5729. PMC 3663609. PMID 23861640.
  4. ↑ Lewis R, Bagnall AM, Leitner M (July 2005). "Sertindole for schizophrenia". The Cochrane Database of Systematic Reviews (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMC 7025766. PMID 16034864.
  5. 1 2 3 4 5 6 Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
  6. 1 2 Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
  7. ↑ Roth BL, Driscol J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 27 October 2013.
  8. 1 2 3 4 5 Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  9. ↑ {{Cite web | url=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 | title=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 = C24H24ClFn4O
  10. ↑ Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
  11. ↑ Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 Jan 1998
  12. 1 2 "WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn". Archived from the original on June 22, 2011.
  13. ↑ FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia Archived 2011-07-14 at the Wayback Machine - Lundbeck press release, 8 Apr 2009
  14. ↑ Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
  15. ↑ "Welcome to Lundbeck's global site".
  16. ↑ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) Archived 2011-10-02 at the Wayback Machine - National electronic Library for Medicines, NHS
  17. ↑ COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE - European Medicines Agency, 13 Sep 2002
  18. ↑ Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) Archived 2010-11-17 at the Wayback Machine - MHRA, 2002
  19. ↑ Sertindole: List of nationally authorised medicinal products - PSUSA/00002695/202001 (PDF) (Report). European Medicines Agency (EMA). 3 September 2020. EMA/270645/2015.
  • "Sertindole". Drug Information Portal. U.S. National Library of Medicine.
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