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Clotiazepam structure.svg
Clinical data
Trade namesVeratran, Rize, Clozan
AHFS/Drugs.comInternational Drug Names
Routes of
Oral, sublingual, liquid drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life6–18 hours
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.046.920 Edit this at Wikidata
Chemical and physical data
Molar mass318.8 g/mol g·mol−1
3D model (JSmol)
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Clotiazepam[1] (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[2] It possesses anxiolytic,[3] skeletal muscle relaxant,[4] anticonvulsant, sedative properties.[5] Stage 2 NREM sleep is significantly increased by clotiazepam.[6]


Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.[7] Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively.[8][9]


A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.[10]


Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.[5] Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam.[11]

Clotiazepam has a relatively short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.[12] Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.[13] The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein.[13] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.[14] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam.[15]

Side effects

Drowsiness and asthenia are common side effects.[16] There has been a report of hepatitis caused by clotiazepam.[17]


Clotiazepam is a recognised drug of abuse.[18]

See also


  1. ^ DE Patent 2107356
  2. ^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.
  3. ^ Klicpera, C.; Strian, F. (May 1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatr Neuropsychopharmakol. 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828.
  4. ^ Fukuda, T.; Tsumagari, T. (Aug 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats" (PDF). Jpn J Pharmacol. 33 (4): 885–90. doi:10.1254/jjp.33.885. PMID 6632385.
  5. ^ a b Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective". Curr Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
  6. ^ Nakazawa Y; Kotorii M; Oshima M; Horikawa S; Tachibana H. (October 31, 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives". Psychopharmacologia. 44 (2): 165–71. doi:10.1007/BF00421005. PMID 709.
  7. ^ Martucci, N.; Manna, V.; Agnoli, A. (Apr 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". Int Clin Psychopharmacol. 2 (2): 121–8. doi:10.1097/00004850-198704000-00005. PMID 2885366.
  8. ^ Official Japanese Drug Information Sheet (Kusuri-no-Shiori)
  9. ^ French Guide to Medicines - Clotiazepam (Veratran)
  10. ^ C. Benvenuti; V. Bottà; M. Broggini; V. Gambaro; F. Lodi; M. Valenti (1989). "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. doi:10.1007/BF00562556 (inactive 2019-08-20). PMID 2575522.
  11. ^ Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (Nov 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". Br J Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.
  12. ^ Greenblatt, DJ.; Divoll, M.; Abernethy, DR.; Ochs, HR.; Shader, RI. (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clin Pharmacokinet. 8 (3): 233–52. doi:10.2165/00003088-198308030-00003. PMID 6133664.
  13. ^ a b Arendt, R.; Ochs, HR.; Greenblatt, DJ. (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittelforschung. 32 (4): 453–5. PMID 6125154.
  14. ^ Ochs, HR.; Greenblatt, DJ.; Verburg-Ochs, B.; Harmatz, JS.; Grehl, H. (1984). "Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol". Eur J Clin Pharmacol. 26 (1): 55–9. doi:10.1007/BF00546709. PMID 6143670.
  15. ^ Ochs, HR.; Greenblatt, DJ.; Knüchel, M. (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". Eur J Clin Pharmacol. 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061.
  16. ^ Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol. 38 (1–2): 45–9. PMID 1971433.
  17. ^ Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (Sep 1989). "Clotiazepam-induced acute hepatitis". J Hepatol. 9 (2): 256–9. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.
  18. ^ Shimamine, M.; Masunari, T.; Nakahara, Y. (1993). "[Studies on identification of drugs of abuse by diode array detection. I. Screening-test and identification of benzodiazepines by HPLC-DAD with ICOS software system]". Eisei Shikenjo Hokoku (111): 47–56. PMID 7920567.

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