996 and

Etifoxine Hydrochloride (BANM, rINNM) Profile Etifoxin Hydrochloride; Étifoxine, Chlorhydrate d’; Etifoxini Hy- is a with general properties similar to those of (p.961). It has been used in the management H C O drochloridum; Hidrocloruro de etifoxina; Hoe-36801. 6-Chloro- 3 of , insomnia, and withdrawal symptoms. How- N 4-methyl-4-phenyl-3,1-benzoxazin-2-yl(ethyl)amine hydrochlo- ever, are no longer considered appropriate in the ride. management of these conditions. Этифоксина Гидрохлорид Tetrabamate, a complex of febarbamate, , and N C17H17ClN2O,HCl = 337.2. , has been used similarly but was associated with CAS — 21715-46-8 (); 56776-32-0 (etifoxine hy- the development of hepatitis. O N drochloride). 2 F ATC — N05BX03. Preparations ATC Vet — QN05BX03. Proprietary Preparations (details are given in Part 3) Multi-ingredient: Hung.: Atrium†.

NOTE. The following terms have been used as ‘street names’ (see (BAN, rINN) p.vi) or slang names for various forms of : Fluanisone Benzo; Circles; Date rape drug; Forget me drug; Forget pill; For- H Fluanison; Fluanisona; Fluanisoni; Fluanisonum; Haloanisone; MD- get-me pill; Forget-Me-Pill; Getting roached; La Rocha; La Ro- O N CH3 2028; R-2028; R-2167. 4′-Fluoro-4-[4-(2-methoxyphenyl)piper- che; Lunch money drug; Mexican valium; Pingus; R2; R-2; Rey- H3C azin-1-yl]butyrophenone. nolds; Rib; Rick James Biatch; Roach 2; Roach-2; Roaches; N Roachies; Roapies; Robutal; Rochas dos; Roche; Roches; Флуанизон Rolpes; Roofie; Roofies; Roopies; Rope; Rophies; Rophy; Rop- C21H25FN2O2 = 356.4. ies; Roples; Ropples; Row-shay; Ruffies; Ruffles; Sedexes; CAS — 1480-19-9. Wolfies. Cl ATC — N05AD09. Pharmacopoeias. In Eur. (see p.vii) and Jpn. ATC Vet — QN05AD09. (etifoxine) Ph. Eur. 6.2 (Flunitrazepam). A white or yellowish crystalline powder. Practically insoluble in water; slightly soluble in alco- hol; soluble in . Protect from light. Profile Etifoxine hydrochloride is an anxiolytic used for the short-term treatment of anxiety (p.952). It is given in usual oral doses of 150 Dependence and Withdrawal or 200 mg daily in 2 or 3 divided doses. O N As for , p.987. Preparations N OCH3 Proprietary Preparations (details are given in Part 3) Adverse Effects, Treatment, and Precau- Fr.: Stresam. tions As for Diazepam, p.987. F Abuse. A WHO review1 concluded that flunitrazepam had a (rINN) Pharmacopoeias. In BP(Vet). moderate abuse potential that might be higher than that of other AHR-3219; Étizolam; Etizolamum; Y-7131. 4-(2-Chlorophenyl)- BP(Vet) 2008 (Fluanisone). White or almost white to buff-col- . It was reported that there was current evidence 2-ethyl-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine. oured, odourless or almost odourless crystals or powder. It exhib- of widespread abuse of flunitrazepam among drug abusers, par- Этизолам its polymorphism. M.p. 72° to 76°. Practically insoluble in water; ticularly among those who used or cocaine. freely soluble in alcohol, in , in ether, and in dilute so- C17H15ClN4S = 342.8. Flunitrazepam is tasteless and odourless and has been misused to CAS — 40054-69-1. lutions of organic acids. Protect from light. incapacitate the victim and produce amnesia in sexual assaults2 ATC — N05BA19. and drug-facilitated rape (‘date rape’).3 A 1-mg dose may pro- Profile 4 ATC Vet — QN05BA19. Fluanisone is a butyrophenone with general properties similar to duce impairment for 8 to 12 hours. Some manufacturers have those of haloperidol (p.1000). It has been used in the manage- incorporated a blue dye into flunitrazepam tablets to increase vis- ment of agitated states in psychiatric patients and as anaesthetic ibility when placed into drinks but caution is still necessary as it N has been reported that blue tropical drinks and punches are being H C premedication. 3 N used to overcome this.3 Fluanisone is used in veterinary medicine for neuroleptanalgesia. N 1. WHO expert committee on drug dependence: twenty-ninth re- port. WHO Tech Rep Ser 856 1995. Available at: http:// S libdoc.who.int/trs/WHO_TRS_856.pdf (accessed 21/08/08) 2. Simmons MM, Cupp MJ. Use and abuse of flunitrazepam. Ann N (rINN) Pharmacother 1998; 32: 117–19. Fludiazépam; Fludiazepamum; ID-540. 7-Chloro-5-(2-fluorophe- 3. National Institute on Drug Abuse. Rohypnol and GHB (issued H3C May 2006). Available at: http://www.nida.nih.gov/PDF/ Cl nyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one. Infofacts/Rohypnol06.pdf (accessed 21/08/08) Флудиазепам 4. Smith KM, et al. Club drugs: methylenedioxymethampheta- C H ClFN O = 302.7. mine, flunitrazepam, ketamine hydrochloride, and γ-hydroxybu- 16 12 2 tyrate. Am J Health-Syst Pharm 2002; 59: 1067–76. CAS — 3900-31-0. ATC — N05BA17. Breast feeding. Concentrations in breast milk the morning af- Pharmacopoeias. In Jpn. ATC Vet — QN05BA17. ter a single evening 2-mg dose of flunitrazepam were considered Profile to be too low to produce clinical effects in breast-fed infants, al- Etizolam is a short-acting derivative with gener- though accumulation in the milk might occur after repeated use.1 al properties similar to those of diazepam (p.986). It is given for O 1. Kanto J, et al. Placental transfer and breast milk levels of fluni- the short-term treatment of insomnia (p.957) and anxiety disor- trazepam. Curr Ther Res 1979; 26: 539–46. ders (p.952) in oral doses of up to 3 mg daily in divided doses or Local reactions. Of 43 patients given a single intravenous dose CH3 as a single dose at night. N N of flunitrazepam 1 to 2 mg, two had local thrombosis 7 to 10 Preparations days later.1 The incidence was lower than in those given di- azepam [in solution]. However, there was little difference in the Proprietary Preparations (details are given in Part 3) Ital.: Depas; Pasaden; Jpn: Depas. incidence of local reactions after intravenous use of fluni- trazepam and diazepam in another study.2 F 1. Hegarty JE, Dundee JW. Sequelae after the intravenous injection of three benzodiazepines—diazepam, , and fluni- Febarbamate (rINN) Cl trazepam. BMJ 1977; 2: 1384–5. Fébarbamate; Febarbamato; Febarbamatum; Go-560. 1-(3-Bu- 2. Mikkelsen H, et al. Local reactions after iv injections of di- Pharmacopoeias. In Jpn. azepam, flunitrazepam and isotonic saline. Br J Anaesth 1980; toxy-2-carbamoyloxypropyl)-5-ethyl-5-phenylbarbituric acid. 52: 817–19. Фебарбамат Profile Porphyria. Flunitrazepam has been associated with acute at- Fludiazepam is a short-acting benzodiazepine with general prop- C20H27N3O6 = 405.4. tacks of porphyria and is considered unsafe in porphyric patients. CAS — 13246-02-1. erties similar to those of diazepam (p.986). It has been used in the ATC — M03BA05. short-term treatment of anxiety disorders. ATC Vet — QM03BA05. Interactions As for Diazepam, p.989.

O Flunitrazepam (BAN, USAN, rINN) Pharmacokinetics H3C HN Flunitratsepaami; Flunitrazépam; Flunitrazepám; Flunitrazepamas; Flunitrazepam is readily absorbed from the gastroin- CH O 3 Flunitrazepamum; Ro-5-4200. 5-(2-Fluorophenyl)-1,3-dihydro- testinal tract. About 77 to 80% is bound to plasma pro- 1-methyl-7-nitro-1,4-benzodiazepin-2-one. teins. It is extensively metabolised in the liver and ex- O N Флунитразепам creted mainly in the urine as metabolites (free or O O C16H12FN3O3 = 313.3. conjugated). Its principal metabolites are 7-aminoflu- O CAS — 1622-62-4. and N-; N-des- H2N ATC — N05CD03. methylflunitrazepam is reported to be pharmacologi- ATC Vet — QN05CD03. cally active. The elimination half-life of flunitrazepam Etifoxine Hydrochloride/Flupentixol 997 is reported to be between 16 and 35 hours. Fluni- Flupentixol Hydrochloride (BANM, rINNM) phrenia (p.955) and other psychoses. Unlike chlorpro- trazepam crosses the placental barrier and is distributed Flupenthixol Dihydrochloride; Flupenthixol Hydrochloride; Flu- mazine, an activating effect has been ascribed to flu- into breast milk. pentiksol Dihidroklorür; Flupentiksolidihydrokloridi; Flupentikso- pentixol, and it is not indicated in overactive or manic ◊ References. lio dihidrochloridas; Flupentixol, Chlorhydrate de; Flupentixol, patients. Flupentixol has also been used for its antide- dichlorhydrate de; Flupentixol-dihidroklorid; Flupentixol-dihy- 1. Davis PJ, Cook DR. Clinical pharmacokinetics of the newer in- pressant properties. travenous anaesthetic agents. Clin Pharmacokinet 1986; 11: drochlorid; Flupentixoldihydroklorid; Flupentixoli dihydrochlori- 18–35. dum; Flupentixoli Hydrochloridum; Hidrocloruro de flupentixol. Flupentixol is given orally as the hydrochloride al- 2. Pariente-Khayat A, et al. Pharmacokinetics and tolerance of flu- Флупентиксола Гидрохлорид though doses are expressed in terms of the base; flu- nitrazepam in neonates and in infants. Clin Pharmacol Ther pentixol hydrochloride 3.5 mg is equivalent to about 1999; 66: 136–9. C H F N OS,2HCl = 507.4. 23 25 3 2 3 mg of flupentixol. Flupentixol is also given as the CAS — 2413-38-9. Pregnancy. Concentrations of flunitrazepam in umbilical-vein longer-acting decanoate ester by deep intramuscular and umbilical-artery plasma were lower than those in maternal ATC — N05AF01. injection. The long-acting preparation available in the venous plasma about 11 to 15 hours after a dose of flunitrazepam ATC Vet — QN05AF01. 1 mg in 14 pregnant women; concentrations in amniotic fluid UK contains flupentixol decanoate as the cis(Z)-iso- were lower still.1 Pharmacopoeias. In Eur. (see p.vii). mer (see Action, below) and doses are expressed in Ph. Eur. 6.2 (Flupentixol Dihydrochloride; Flupentixol Hydro- 1. Kanto J, et al. Placental transfer and breast milk levels of fluni- terms of the amount of cis(Z)-flupentixol decanoate. trazepam. Curr Ther Res 1979; 26: 539–46. chloride BP 2008). A white or almost white powder. Very soluble in water; soluble in alcohol; practically insoluble in dichlo- The usual initial oral dose for the treatment of psycho- romethane. A 1% solution in water has a pH of 2.0 to 3.0. Protect Uses and Administration from light. ses is the equivalent of 3 to 9 mg of flupentixol twice Flunitrazepam is a short-acting benzodiazepine with daily adjusted according to response; the maximum general properties similar to those of diazepam (p.992). Stability. References. recommended daily dose is 18 mg. The initial dose in It is used in the short-term management of insomnia 1. Enever RP, et al. Flupenthixol dihydrochloride decomposition in elderly and debilitated patients may need to be reduced (p.957), as a premedicant in surgical procedures, and aqueous solution. J Pharm Sci 1979; 68: 169–71. to a quarter or a half of the usual starting dose. If given 2. Li Wan Po A, Irwin WJ. The photochemical stability of cis- and for induction of anaesthesia (p.1780). trans-isomers of tricyclic neuroleptic drugs. J Pharm Pharmacol by deep intramuscular injection, an initial test dose of A usual oral dose for insomnia is 0.5 to 1 mg at night; 1980; 32: 25–9. 20 mg of the decanoate, as 1 mL of a 2% oily solution, up to 2 mg may be given if necessary. In elderly or de- is used. Then after at least 7 days and according to re- bilitated patients the initial dose should not exceed Adverse Effects and Treatment sponse, this may be followed by doses of 20 to 40 mg 0.5 mg at night; up to 1 mg may be given if necessary. As for , p.969. Flupentixol is less like- every 2 to 4 weeks. Shorter dosage intervals or greater ly to cause sedation, but extrapyramidal effects are amounts may be required according to the patient’s re- A dose of 1 to 2 mg (15 to 30 micrograms/kg) has been more frequent. given intramuscularly or orally for premedication or sponse. The initial dose in elderly and debilitated pa- by slow intravenous injection for induction of general Sudden death. There has been a report of sudden death in 3 tients may need to be reduced to a quarter or a half of 1 anaesthesia. patients given depot injections of flupentixol decanoate. the usual starting dose. If doses greater than 40 mg 1. Turbott J, Smeeton WMI. Sudden death and flupenthixol de- (2 mL) are considered necessary they should be divid- Preparations canoate. Aust N Z J Psychiatry 1984; 18: 91–4. ed between 2 separate injection sites. Another means Proprietary Preparations (details are given in Part 3) of reducing the volume of fluid to be injected in pa- Arg.: Nervocuril; Parsimonil†; Primum; Rohypnol; Austral.: Hypnodorm; Precautions tients requiring high-dose therapy with flupentixol de- Austria: Guttanotte; Rohypnol; Somnubene; Belg.: Rohypnol; Braz.: Ro- As for Chlorpromazine, p.972. Flupentixol is not rec- hydorm; Rohypnol; Chile: Ipnopen; Rohypnol†; Cz.: Rohypnol†; Denm.: canoate is to give an injection containing 100 or Flunipam; Rohypnol†; Ronal; Fr.: Narcozep; Rohypnol; Ger.: Fluni†; Flunibe- ommended in states of excitement or overactivity, in- 200 mg/mL of the decanoate (10 or 20%). The usual ta; Flunimerck†; Fluninoc; Rohypnol; Gr.: Hipnosedon; Ilman; Neo Nifalium; cluding mania. Nilium†; Vulbegal; Hong Kong: Absint†; Flunita; Rohypnol; Irl.: Rohypnol; maintenance dose is between 50 mg every 4 weeks and Israel: Hypnodorm; Ital.: Darkene; Roipnol; Valsera; Mex.: Rohypnol; 300 mg every 2 weeks but doses of up to 400 mg Neth.: Rohypnol; Norw.: Flunipam; Rohypnol†; Pol.: Rohypnol; Port.: Ro- Porphyria. Flupentixol is considered to be unsafe in patients hypnol; Sedex†; S.Afr.: Hypnor†; Insom; Rohypnol; Spain: Rohipnol; with porphyria because it has been shown to be porphyrinogenic weekly have been given in severe or resistant cases. Swed.: Fluscand; Rohypnol†; Switz.: Rohypnol; Thai.: Rohypnol; UK: Ro- in animals. hypnol†. Flupentixol has also been given as the hydrochloride Interactions for the treatment of mild to moderate depression, with As for Chlorpromazine, p.973. or without anxiety (p.373). The usual initial oral dose, expressed in terms of the equivalent amount of flupen- Flupentixol (BAN, rINN) tixol, is 1 mg (0.5 mg in the elderly) daily, increased Pharmacokinetics Flupenthixol; Flupentiksoli; Flupentixolum; LC-44; N-7009. (Z)-2- after 1 week to 2 mg (1 mg in the elderly) and then to a Flupentixol is readily absorbed from the gastrointesti- {4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]piperazin- maximum of 3 mg (2 mg in the elderly) daily. Doses nal tract and is probably subject to first-pass metabo- 1-yl}ethanol. above 2 mg (1 mg in the elderly) should be given in 2 lism in the gut wall. It is also extensively metabolised Флупентиксол divided doses. The last dose of the day should be given in the liver and is excreted in the urine and faeces in the C H F N OS = 434.5. no later than 4 p.m. and if no effect has been noted 23 25 3 2 form of numerous metabolites; there is evidence of en- CAS — 2709-56-0. within 1 week of reaching the maximum dose, treat- terohepatic recycling. Owing to the first-pass effect, ment should be withdrawn. ATC — N05AF01. plasma concentrations after oral doses are much lower ATC Vet — QN05AF01. than those after estimated equivalent doses of the intra- Action. Patients with acute schizophrenic illnesses taking α-flu- muscular depot preparation. Moreover, there is very pentixol [(Z)-flupentixol or cis-flupentixol] improved more after wide intersubject variation in plasma concentrations of 3 weeks than patients who were taking equal doses of β-flupen- OH 1 N flupentixol, but, in practice, no simple correlation has tixol [(E)-flupentixol or trans-flupentixol] or a placebo. The α- isomer had more effect on the positive symptoms of the disease; N been found between the therapeutic effect and plasma this difference was less apparent for the negative symptoms. The concentrations of flupentixol and its metabolites. After difference in activity between the isomers was attributed to the greater dopamine-receptor blocking activity of the α-isomer CF oral doses, peak plasma concentrations occur in about 3 4 hours and the biological half-life is about 35 hours. rather than to differences in distribution.2 Paths of metabolism of flupentixol include sulfoxida- 1. Johnstone EC, et al. Mechanism of the effect in the S tion, side-chain N-dealkylation, and glucuronic acid treatment of acute schizophrenia. Lancet 1978; i: 848–51. conjugation. Flupentixol is more than 95% bound to 2. Crow TJ, Johnstone EC. Mechanism of action of neuroleptic cis-form plasma proteins. It is widely distributed in the body and drugs. Lancet 1978; i: 1050. crosses the blood-brain barrier. Flupentixol crosses the Preparations Flupentixol Decanoate (BANM, rINNM) placental barrier and small amounts have been detected Decanoato de flupentixol; Flupenthixol Decanoate; (Z)-Flupen- in breast milk. BP 2008: Flupentixol Injection. thixol Decanoate; cis-Flupenthixol Decanoate; Flupentiksol The decanoate ester of flupentixol is very slowly ab- Proprietary Preparations (details are given in Part 3) Dekanoat; Flupentixol, Décanoate de; Flupentixoli Decanoas. sorbed from the site of intramuscular injection and is Austral.: Fluanxol; Austria: Fluanxol; Belg.: Fluanxol; Canad.: Fluanxol; Флупентиксола Деканоат therefore suitable for depot injection. It is gradually re- Chile: Fluanxol; Cz.: Fluanxol; Denm.: Fluanxol; Fin.: Fluanxol; Fr.: Fluanx- ol; Ger.: Fluanxol; Flupendura; Hong Kong: Fluanxol; Hung.: Fluanxol; In- C33H43F3N2O2S = 588.8. leased into the bloodstream where it is rapidly hydro- dia: Fluanxol; Irl.: Depixol; Fluanxol; Israel: Fluanxol; Malaysia: Fluanxol; CAS — 30909-51-4. lysed to flupentixol. Mex.: Fluanxol; Neth.: Fluanxol; Norw.: Fluanxol; NZ: Fluanxol; Psytixol†; ATC — N05AF01. Philipp.: Fluanxol; Pol.: Fluanxol; Port.: Fluanxol; Rus.: Fluanxol (Флюанксол); S.Afr.: Fluanxol; Singapore: Fluanxol; Swed.: Fluanxol; ATC Vet — QN05AF01. Uses and Administration Switz.: Fluanxol; Thai.: Fluanxol; Turk.: Fluanxol; UK: Depixol; Fluanxol. Pharmacopoeias. In Br. Flupentixol is a thioxanthene antipsychotic with gener- Multi-ingredient: Austria: Deanxit; Belg.: Deanxit; Hong Kong: An- BP 2008 (Flupentixol Decanoate). A yellow viscous oil. Very al properties similar to those of the phenothiazine, free; Deanxit; Ital.: Deanxit†; Singapore: Deanxit; Spain: Deanxit; slightly soluble in water; soluble in alcohol; freely soluble in Switz.: Deanxit; Thai.: Deanxit. chloroform and in ether. Store at a temperature below −15° and chlorpromazine (p.975). It has a piperazine side-chain. protect from light. Flupentixol is used mainly in the treatment of schizo- The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)