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Clemastine Fumarate 573 Profile of 3 to 6 Hours

Clemastine Fumarate 573 Profile of 3 to 6 Hours

Hydrochloride/ Fumarate 573 Profile of 3 to 6 hours. is excreted in the faeces methyl . A 10% suspension in water has a pH of 3.2 to Chlorphenoxamine, a congener of (p.577), has mainly as unchanged drug, and in the urine predomi- 4.2. antimuscarinic and antihistaminic properties. It has been used in USP 31 (Clemastine Fumarate). A colourless to faintly yellow, nausea, vomiting, and vertigo, and was formerly used in the nantly as metabolites. odourless, crystalline powder. Very slightly soluble in water; symptomatic treatment of . Chlorphenoxamine has very slightly soluble in ; slightly soluble in methyl al- also been used in hypersensitivity reactions. Uses and Administration cohol. pH of a 10% suspension in water is between 3.2 to 4.2. Preparations Cinnarizine is a derivative with antihista- Store in airtight containers at a temperature not exceeding 25°. Protect from light. Proprietary Preparations (details are given in Part 3) mine, , and calcium-channel blocking activity. Ger.: Systral; Hong Kong: Systral†; Indon.: Systral; Philipp.: Systral; It is used for the symptomatic treatment of nausea and Port.: Systral; Thai.: Systral; Turk.: Sistral; Systral. vertigo caused by Ménière’s disease and other vestibu- Adverse Effects and Precautions Multi-ingredient: Austria: Spirbon; Ger.: Systral C†; S.Afr.: Analgen- As for the sedating in general, p.561. SA†. lar disorders (see Vertigo, p.565) and for the prevention and treatment of motion sickness (p.564). It is also Breast feeding. The American Academy of Pediatrics1 consid- used in the management of various peripheral and cer- ers that clemastine should be given with caution to breast-feed- ebral vascular disorders. ing mothers, since it has been associated with adverse effects in Cinnarizine (BAN, USAN, rINN) the infant. Drowsiness, irritability, a high-pitched cry, neck stiff- In the UK, the usual oral dose for vertigo and vestibular ness, and refusal to feed in a 10-week-old breast-fed baby oc- Cinarizin; Cinarizina; Cinarizinas; Cinnarizin; Cinnarizinum; Cy- disorders is 30 mg three times daily. For motion sick- curred 12 hours after her mother started treatment with clemas- naryzyna; 516-MD; R-516; R-1575; Sinarizin; Sinnaritsiini. 1-Ben- ness a dose of 30 mg is taken 2 hours before the start of tine.2 Clemastine was detected in the mother’s breast milk. The zhydryl-4-cinnamylpiperazine; (E)-1-(Diphenylmethyl)-4-(3-phe- the journey and 15 mg every 8 hours during the jour- baby recovered and was feeding normally on the day after the nylprop-2-enyl)piperazine. drug was stopped. ney if necessary. Children aged 5 to 12 years are given Циннаризин 1. American Academy of Pediatrics. The transfer of drugs and oth- half the adult dose for both indications. In other Euro- er chemicals into human milk. Pediatrics 2001; 108: 776–89. C H N = 368.5. 26 28 2 pean countries, a dose of 75 mg once or twice daily has Correction. ibid.; 1029. Also available at: CAS — 298-57-7. http://aappolicy.aappublications.org/cgi/content/full/ ATC — N07CA02. been given for vertigo and vestibular disorders. Doses pediatrics%3b108/3/776 (accessed 08/04/04) 2. Kok THHG, et al. Drowsiness due to clemastine transmitted in ATC Vet — QN07CA02. of 75 mg have also been given 1 to 3 times daily for cerebrovascular disorders and 2 or 3 times daily for pe- breast milk. Lancet 1982; i: 914–15. ripheral vascular disorders. Porphyria. Clemastine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients. N ◊ References. 1. Shupak A, et al. Cinnarizine in the prophylaxis of seasickness: Interactions N laboratory vestibular evaluation and sea study. Clin Pharmacol Ther 1994; 55: 670–80. As for the sedating antihistamines in general, p.563. Preparations Proprietary Preparations (details are given in Part 3) Arg.: Dismaren; Fabracin; Folcodal; Iroplex†; Natropas; Stugeron; Austria: Clemastine fumarate is rapidly and almost completely Cinnabene; Pericephal; Stutgeron; Belg.: Stugeron; Braz.: Antigeron; Ci- absorbed from the ; peak plasma naran; Cinarivert†; Cinarix†; Cinazin†; Cinazon; Civertim; Cronogeron; Fluxon; Laberitin†; Labigeron; Nerizina†; Stugerina†; Stugeron; Vertigeron; concentrations are achieved in 2 to 4 hours. Unchanged Pharmacopoeias. In Chin. and Eur. (see p.vii). Verzum; Vessel†; Chile: Cinergil; Siridone; Stugeron; Cz.: Cinedil†; Cinna- drug and metabolites are excreted principally in the Ph. Eur. 6.2 (Cinnarizine). A white or almost white powder. bene; Stugeron; Denm.: Sepan; Gr.: Derozin; Stugeron; Hong Kong: Ce- urine. An elimination half-life of about 21 hours has Practically insoluble in water; slightly soluble in alcohol and in lenid†; Medozine; Stugeron; Hung.: Stugeron; India: Avidazine; Cintigo; Diziron; Stugeron; Vertiron; Indon.: Merron; Nariz; Perifas; Stugeron; Ver- been reported. Clemastine is distributed into breast methyl alcohol; soluble in acetone; freely soluble in dichlo- tizine; Irl.: Stugeron; Israel: Stunarone; Ital.: Cinazyn; Stugeron; Toliman; romethane. Protect from light. Malaysia: Celenid†; Cereron†; Cinna; Cinnaron; Stugeron; Uphageron; milk. Mex.: Bulasan; Cisaken; Dilateron-F; Dilper-INA; Karilex; Oblant; Stugeron; ◊ References. Venoxil; Winpar; Philipp.: Dizzinon; Niziran; Stugeron; Vertisin; Port.: Adverse Effects and Precautions Cinon; Stugeron; Rus.: Phezam (Фезам); Stugeron (Структум); S.Afr.: 1. Schran HF, et al. The pharmacokinetics and of As for the sedating antihistamines in general, p.561. Purazine; Stugeron; Singapore: Celenid; Cinna; Cinnar; Cinnaron; clemastine and phenylpropanolamine in single-component and Stugeron†; Urizine†; Spain: Stugeron; Switz.: Cerepar; Cinnageron; Cin- combination formulations. J Clin Pharmacol 1996; 36: 911–22. There have been rare reports of extrapyramidal symp- named†; Stugeron; Thai.: C-Pela†; Celenid; Cenai; Cerebroad; Ceremin; toms after taking cinnarizine, sometimes associated Cinerine; Cinna; Cinnar; Cinnaza; Cinrizine; CN-25†; Linazine; Manoron; Med-Circuron†; Medozine; Siarizine; Silicin; Sorebral; Stugeron; Stugin; Stu- Uses and Administration with depressive feelings. no; Urizine; Vernarin; Turk.: Sefal; UK: Arlevert; Cinaziere†; Stugeron; Ven- Clemastine fumarate, a monoethanolamine derivative, High doses of cinnarizine should be used with caution ez.: Cinaren; Cinarin; Sinver; Stugeron; Vericin. is a sedating with antimuscarinic and Multi-ingredient: Arg.: Cadencial Plus; Cinacris; Difusil; Ribex; Vasodu- in patients with hypotension because of the possibility al†; Austria: Cinnarplus; Belg.: To u r i s t i l ; Braz.: Coldrin; Exit; Forgrip†; moderate sedative properties. It has been reported to of decreasing blood pressure further. Sureptil; Cz.: Arlevert; Fin.: Rinomar; Ger.: Arlevert; Hong Kong: C-Sik†; have a duration of action of about 10 to 12 hours. It is Hung.: Arlevert; India: Vertigil; Neth.: Primatour; Rus.: Omaron Extrapyramidal disorders. For reference to extrapyramidal (Омарон); Piracezine (Пирацезин); Spain: Clinadil; Clinadil Compositum; used for the symptomatic relief of allergic conditions disorders associated with the use of cinnarizine, see , Diclamina; Swed.: Rinomar. including urticaria and angioedema (p.565), rhinitis p.580. (p.565) and conjunctivitis (p.564), and in pruritic skin Hypersensitivity. Immunologically-defined lichen planus disorders (p.565). pemphigoides has been reported1 in a 72-year-old woman taking Clemastine Fumarate Clemastine is given as the fumarate although doses are cinnarizine. Lesions began to clear when treatment was stopped expressed in terms of the base. Clemastine fumarate but challenge with cinnarizine provoked severe itching and reac- (BANM, USAN, rINNM) tivation of pigmented lesions. Another case2 has also been de- 1.34 mg is equivalent to about 1 mg of clemastine Clémastine, fumarate de; Clemastini fumaras; Fumarato de clem- base. The usual oral dose is 1 mg twice daily. Up to scribed. astina; HS-592 (clemastine); Klemastiinifumaraatti; Klemastin fu- 1. Miyagawa S, et al. Lichen planus pemphigoides-like lesions in- marát; Klemastin Hidrojen Fumarat; Klemastinfumarat; Klemasti- 6 mg daily has been given, particularly for urticaria and duced by cinnarizine. Br J Dermatol 1985; 112: 607–13. angioedema. Children aged 1 to 3 years may be given 2. Ramallal M, et al. Lichenoid eruption associated with cinnar- no fumaratas; Klemastyny fumaran; Klemasztin-fumarát; Meclas- izine use. Pharm World Sci 2002; 24: 215–16. tine Fumarate; Mecloprodine Fumarate. (+)-(2R)-2-{2-[(R)-4- 250 to 500 micrograms twice daily; those aged 3 to 6 Porphyria. Cinnarizine is considered to be unsafe in patients Chloro-α-methylbenzhydryloxy]ethyl}-1-methylpyrrolidine hy- years, 500 micrograms twice daily; and those aged 6 to with porphyria because it has been shown to be porphyrinogenic drogen fumarate. 12 years, 0.5 to 1 mg twice daily. in animals. Клемастина Фумарат Clemastine fumarate may be given by intramuscular or C H ClNO,C H O = 460.0. Tinnitus. The Spanish System of Pharmacovigilance had re- 21 26 4 4 4 slow intravenous injection in a total daily dose equiva- ceived reports1 of tinnitus associated with calcium-channel CAS — 15686-51-8 (clemastine); 14976-57-9 (clemas- lent to 4 mg of clemastine for acute allergic reactions; blockers; some of the reports, including the one relating to cin- tine fumarate). for prophylaxis 2 mg is given by intravenous injection. narizine, were in patients also receiving other ototoxic drugs. ATC — D04AA14; R06AA04. WHO was said to have additional reports of tinnitus associated ATC Vet — QD04AA14; QR06AA04. The dose for children is 25 micrograms/kg daily in two with calcium-channel blockers including cinnarizine. divided doses by intramuscular injection. 1. Narváez M, et al. Tinnitus with calcium-channel blockers. Lan- Clemastine fumarate has also been used topically, al- cet 1994; 343: 1229–30. Cl CH3 though as with other antihistamines, there is a risk of Weight gain. There has been a report1 of weight gain in 4 pa- sensitisation. tients who had taken cinnarizine for 1 to 2 years; in all cases the N O weight gain was associated with increased appetite. Preparations 1. Navarro-Badenes J, et al. Weight-gain associated with cinnar- CH BP 2008: Clemastine Oral Solution; Clemastine Tablets; izine. Ann Pharmacother 1992; 26: 928–30. 3 USP 31: Clemastine Fumarate Tablets. Proprietary Preparations (details are given in Part 3) Interactions Austria: Tavegyl; Braz.: Agasten; Canad.: Tavist; Cz.: Tavegyl; Denm.: Tav - As for the sedating antihistamines in general, p.563. egyl; Ger.: Tavegil; India: Clamist; Indon.: Tavegyl; Ital.: Tavegil†; Mex.: (clemastine) Tavist; Neth.: Tavegil; Philipp.: Marsthine; Tavegyl; Tavist; Port.: Tavegyl; Tavist; Rus.: Tavegyl (Тавегил); S.Afr.: Tavegyl; Spain: Tavegil; Swed.: Tav - Pharmacokinetics egyl; Switz.: Tavegyl; Turk.: Tavegyl; UK: Tavegil; USA: Contac 12 Hour Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. ; Dayhist-1; Tavist Allergy. Cinnarizine is absorbed from the gastrointestinal tract, Ph. Eur. 6.2 (Clemastine Fumarate). A white or almost white, Multi-ingredient: Braz.: Emistin; Ger.: Corto-Tavegil†; Mex.: Tavist-D†; peak plasma concentrations occurring 2 to 4 hours after crystalline powder. Very slightly soluble in water; sparingly sol- Spain: Dexa Tavegil. oral doses. It undergoes metabolism and has a half-life uble in alcohol (70%); slightly soluble in alcohol (50%) and in 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) 574 Antihistamines

Clemizole Hydrochloride (BANM, rINNM) (BAN, rINN) Effects on the blood. Agranulocytosis occurred in a patient after 6 weeks of treatment with cyclizine 50 mg three times dai- AL-20; Clémizole, Chlorhydrate de; Clemizoli Hydrochloridum; Ciclizina; Cyclizinum; Cyklizin; Siklizin; Syklitsiini. 1-Benzhydryl-4- ly.1 The blood count returned to normal once cyclizine was with- Hidrocloruro de clemizol. 1-(4-Chlorobenzyl)-2-(pyrrolidin-1-yl- methylpiperazine. drawn. methyl) hydrochloride. Циклизин 1. Collier PM. Agranulocytosis associated with oral cyclizine. BMJ 1986; 292: 174. C H N = 266.4. Клемизола Гидрохлорид 18 22 2 1 CAS — 82-92-8. Effects on the heart. In a study of 11 patients with severe C H ClN ,HCl = 362.3. 19 20 3 ATC — R06AE03. heart failure, cyclizine produced detrimental haemodynamic ef- fects including increased systemic and pulmonary artery pres- CAS — 442-52-4 (); 1163-36-6 (clemizole hy- ATC Vet — QR06AE03. drochloride). sures and ventricular filling pressures, and negated the vasodila- tor effects of diamorphine. It was suggested that the use of cyclizine should be avoided in patients with acute myocardial in- farction or severe heart failure. Cl 1. Tan LB, et al. Detrimental haemodynamic effects of cyclizine in heart failure. Lancet 1988; i: 560–1. Effects on the . An 8-year-old girl developed jaundice on NN CH3 2 occasions after taking cyclizine hydrochloride 25 mg daily by 1 N mouth. ‘Hypersensitivity hepatitis’ was considered responsible. 1. Kew MC, et al. “Hypersensitivity hepatitis” associated with ad- ministration of cyclizine. BMJ 1973; 2: 307. N N Pregnancy. For discussion of the use of antihistamines in preg- Pharmacopoeias. In Br. nancy, including studies involving cyclizine, see p.563. BP 2008 (Cyclizine). A white or creamy white, crystalline pow- der. Practically insoluble in water. It dissolves in most organic Interactions (clemizole) solvents and in dilute acids. M.p. about 107°. A saturated solu- As for the sedating antihistamines in general, p.563. tion in water has a pH of 7.6 to 8.6. Cyclizine may counteract the haemodynamic benefits Profile of (see Effects on the Heart, above) and this Clemizole hydrochloride is a sedating antihistamine (p.561). It Cyclizine Hydrochloride (BANM, rINNM) should be considered before using preparations that has been used for the symptomatic relief of allergic conditions, Ciklizin-hidroklorid; Ciklizino hidrochloridas; Cyclizine, chlorhy- contain a combination of cyclizine and an anal- in pruritic skin disorders, and in combination preparations for the drate de; Cyclizini hydrochloridum; Cyklizin hydrochlorid; Cykliz- gesic. treatment of symptoms of the common cold. Clemizole has also inhydroklorid; Hidrocloruro de ciclizina; Syklitsiinihydrokloridi. been applied topically as the hexachlorophene, the sodium sul- Циклизина Гидрохлорид General anaesthetics. For a possible interaction between cy- fate, and the undecylate derivatives in topical and rectal prepara- clizine premedication and anaesthetics see under C18H22N2,HCl = 302.8. Thiopental, p.1795. tions combined with and local anaesthetics, al- CAS — 303-25-3. though as with other antihistamines, there is a risk of ATC — R06AE03. sensitisation. ATC Vet — QR06AE03. Pharmacokinetics See p.251 for the use of clemizole penicillin. Pharmacopoeias. In Eur. (see p.vii) and US. Cyclizine is absorbed from the gastrointestinal tract Ph. Eur. 6.2 (Cyclizine Hydrochloride). A white or almost white, and has an onset of action within 2 hours. The duration Preparations crystalline powder. Slightly soluble in water and in alcohol. A of action is reported to be about 4 hours. Cyclizine is Proprietary Preparations (details are given in Part 3) 2% solution in alcohol 2 vol. and water 3 vol. has a pH of 4.5 to metabolised in the liver to the relatively inactive me- 5.5. Protect from light. tabolite, norcyclizine. Both cyclizine and norcyclizine Multi-ingredient: Arg.: Apracur†; Braz.: Ultraproct; Hong Kong: Ul- USP 31 (Cyclizine Hydrochloride). A white, odourless, crystal- traproct†; Indon.: Ultraproct; Thai.: Apracur; Scheriproct†. line powder or small colourless crystals. Soluble 1 in 115 of wa- have plasma elimination half-lives of 20 hours. Less ter and of alcohol and 1 in 75 of chloroform; insoluble in . than 1% of the total oral dose is eliminated in the urine pH of a 2% solution in alcohol 2 vol. and water 3 vol. is between in 24 hours. 4.5 and 5.5. Store in airtight containers. Protect from light. Hydrochloride (rINNM) Uses and Administration Chlorcinnazine Dihydrochloride; Clocinizine, Chlorhydrate de; Cyclizine Lactate (BANM, rINNM) Cyclizine, a piperazine derivative, is a sedating antihis- Clocinizini Hydrochloridum; Hidrocloruro de clonizina. 1-(4- Cyclizine, Lactate de; Cyclizini Lactas; Lactato de ciclizina. tamine with antimuscarinic activity, although the seda- Chlorobenzhydryl)-4-cinnamylpiperazine dihydrochloride. Циклизина Лактат tive effects are not marked. Клоцинизина Гидрохлорид C18H22N2,C3H6O3 = 356.5. It is used as an antiemetic in the management of nausea CAS — 5897-19-8. and vomiting (p.564) including motion sickness, post- C26H27ClN2,2HCl = 475.9. ATC — R06AE03. CAS — 298-55-5 (clocinizine). ATC Vet — QR06AE03. operative nausea and vomiting, after radiotherapy, and Pharmacopoeias. Br. includes an injection of cyclizine lac- in drug-induced nausea and vomiting. It is included as tate. an antiemetic with some opioids, and in combination Cl Incompatibility. Cyclizine lactate is reported to be incompati- preparations for the treatment of migraine attacks ble with oxytetracycline hydrochloride, chlortetracycline hydro- (p.616). Cyclizine is also used for the symptomatic chloride, benzylpenicillin, and solutions with a pH of 6.8 or treatment of vertigo (p.565) caused by Ménière’s dis- more. ease and other vestibular disturbances.

Cyclizine Tartrate (BANM, rINNM) In the management of nausea and vomiting, cyclizine Cyclizine, Tartrate de; Cyclizini Tartras; Tartrato de ciclizina. hydrochloride is given in a usual oral dose of 50 mg up to three times daily, although up to 200 mg may be giv- N Циклизина Тартрат en in 24 hours if necessary. For the prevention of mo- C18H22N2,C4H6O6 = 416.5. ATC — R06AE03. tion sickness, the first dose should be given about 30 N ATC Vet — QR06AE03. minutes before travelling. Children aged 6 to 12 years may be given 25 mg up to three times daily. Although Adverse Effects and Precautions not licensed in the UK, the BNFC suggests that those As for the sedating antihistamines in general, p.561. aged 1 month to 6 years may be given 0.5 to 1 mg/kg Cyclizine may aggravate severe heart failure. Hypo- (maximum of 25 mg) up to 3 times daily. tension may occur on injection. Cyclizine is given intramuscularly or intravenously as Abuse. Cyclizine tablets have been abused either alone or with the lactate. Doses of cyclizine lactate are similar to opioids for their euphoric effects.1-7 They have been taken by those of cyclizine hydrochloride given orally. For the mouth or used to make injections. It has been suggested that cy- (clocinizine) clizine dependence may occur when it is used with opioids in the prevention of postoperative nausea and vomiting the treatment of chronic pain.8 first dose of cyclizine lactate should be given about 20 1. Gott PH. Cyclizine toxicity—intentional drug abuse of a propri- minutes before the anticipated end of surgery. Profile etary antihistamine. N Engl J Med 1968; 279: 596. Clocinizine hydrochloride, a piperazine derivative, is an antihis- 2. Kahn A, Harvey GJ. Increasing misuse of cyclizine. Pharm J Although not licensed in the UK, cyclizine is also tamine (p.561) given by mouth in combination preparations for 1985; 235: 706. available as suppositories on a named-patient basis. the symptomatic treatment of upper respiratory-tract disorders, 3. Atkinson MK. Misuse of cyclizine. Pharm J 1985; 235: 773. The BNFC suggests that children aged 2 to 6 years may often with a decongestant. 4. Halpin D. Misuse of cyclizine. Pharm J 1985; 235: 773. 5. Council of the Pharmaceutical Society of Great Britain. Sales of be given rectal doses of 12.5 mg; those aged 6 to 12 Preparations preparations containing cyclizine. Pharm J 1985; 235: 797. years, 25 mg; and those aged 12 to 18 years, 50 mg. 6. Ruben SM, et al. Cyclizine abuse among a group of opiate de- Doses may be given up to 3 times daily. Proprietary Preparations (details are given in Part 3) pendents receiving . Br J Addict 1989; 84: 929–34. 7. Bassett KE, et al. Cyclizine abuse by teenagers in Utah. Am J Cyclizine salts are used as antiemetics in combination Multi-ingredient: Fr.: Denoral†; Ital.: Denoral†; Spain: Senioral. Emerg Med 1996; 14: 472–4. 8. Hughes AM, Coote J. Cyclizine dependence. Pharm J 1986; with or dipipanone; the use of such fixed- 236: 130. combination opioid preparations is considered to be

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