574

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 liver. 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 opioids (see Effects on the Heart, above) and this Clemizole hydrochloride is a sedating (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 opioid 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 barbiturate anaesthetics see under C18H22N2,HCl = 302.8. Thiopental, p.1795. tions combined with corticosteroids 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 ether. 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. Clocinizine Hydrochloride (rINNM) Uses and Administration Chlorcinnazine Dihydrochloride; Clocinizine, Chlorhydrate de; Cyclizine Lactate (BANM, rINNM) Cyclizine, a 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 methadone. 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 morphine or dipipanone; the use of such fixed- 236: 130. combination opioid preparations is considered to be Clemizole Hydrochloride/ Citrate 575 unsuitable for the prolonged treatment that may be re- UK licensed product information states that may embolisation, a procedure sometimes used to relieve the symp- quired in palliative care. See also under Interactions, cause a false positive test result for in toms of carcinoid syndrome.2 There have been a few reports of urine. tumour regression, in addition to symptomatic control, after above. 3,4 1. Bivens CH, et al. Inhibition of hypoglycaemia-induced growth treatment of carcinoid tumours with cyproheptadine. Preparations hormone secretion by the serotonin antagonists cyproheptadine 1. Caplin ME, et al. Carcinoid tumour. Lancet 1998; 352: 799–805. and methysergide. N Engl J Med 1973; 289: 236–9. 2. Maton PN, et al. Role of hepatic arterial embolisation in the car- BP 2008: Cyclizine Injection; Cyclizine Tablets; Dipipanone and Cyclizine cinoid syndrome. BMJ 1983; 287: 932–5. Correction to dosage. Ta bl e t s ; Interactions ibid.; 1664. USP 31: Cyclizine Hydrochloride Tablets. 3. Harris AL, Smith IE. Regression of carcinoid tumour with cy- As for the sedating antihistamines in general, p.563. Proprietary Preparations (details are given in Part 3) proheptadine. BMJ 1982; 285: 475. 4. Leitner SP, et al. Partial remission of carcinoid tumor in response Austria: Echnatol; Denm.: Marzine; Fin.: Marzine; Hong Kong: Marzine†; Antidepressants. For reports suggesting that cyproheptadine to cyproheptadine. Ann Intern Med 1989; 111: 760–1. Valoid†; India: Medazine; Irl.: Valoid; Neth.: Kruidvat Reistabletten; can reduce the effectiveness of SSRIs, see under Fluoxetine, Norw.: Marzine; NZ: Marzine; Nausicalm; Valoid; S.Afr.: Aculoid; Cov- p.396. Serotonin syndrome. Cyproheptadine has been successfully amet; Emitex†; Medazine; Nauzine; Norizine†; Triazine; Valoid; Singapore: used to treat the serotonin syndrome (p.416) in patients who have Marzine†; Swed.: Marzine†; Switz.: Marzine; UK: Valoid; USA: Bonine for Kids; Marezine. developed the syndrome after overdoses involving serotonergic Pharmacokinetics drugs or who have had their therapy changed Multi-ingredient: Austria: Echnatol B ; Migril; Fin.: Vertipam; Hong After absorption from the gastrointestinal tract, cypro- without an adequate wash-out period.1,2 Kong: Migril†; Wellconal†; Irl.: Cyclimorph; Diconal†; Migril†; Neth.: Ercy- cof†; S.Afr.: Cyclimorph; Migril; Wellconal; UK: Cyclimorph; Diconal; Migril. heptadine hydrochloride undergoes almost complete 1. Lappin RI, Auchincloss EL. Treatment of the serotonin syn- metabolism. Metabolites are excreted principally in the drome with cyproheptadine. N Engl J Med 1994; 331: 1021–2. 2. McDaniel WW. Serotonin syndrome: early management with cy- urine as conjugates, and also in the faeces. proheptadine. Ann Pharmacother 2001; 35: 870–3. Sexual dysfunction. Cyproheptadine has been tried in the

Cyproheptadine Hydrochloride Uses and Administration management of sexual dysfunction induced by SSRIs (see Ef- (BANM, rINNM) Cyproheptadine, a piperidine derivative, is a sedating fects on Sexual Function under Fluoxetine, p.393) but may pos- antihistamine with antimuscarinic, serotonin-antago- sibly reduce the effectiveness of the SSRI. Ciproheptadin-hidroklorid; Ciproheptadino hidrocloridas; Cy- proheptadine, chlorhydrate de; Cyproheptadin-hydrochlorid nist, and calcium-channel blocking actions. It is used as Preparations seskvihydrát; Cyproheptadinhydroklorid; Cyproheptadini hydro- the hydrochloride for the symptomatic relief of allergic BP 2008: Cyproheptadine Tablets; chloridum; Cyproheptadini Hydrochloridum Sesquihydricum; conditions including urticaria and angioedema (p.565), USP 31: Cyproheptadine Hydrochloride Syrup; Cyproheptadine Hydro- Hidrocloruro de ciproheptadina; Siproheptadin Hidroklorür; rhinitis (p.565) and conjunctivitis (p.564), and in pru- chloride Tablets. Syproheptadiinihydrokloridi. 4-(5H-Dibenzo[a,d]cyclohepten-5- ritic skin disorders (p.565). Other uses include the Proprietary Preparations (details are given in Part 3) Austral.: Periactin; Austria: Periactin; Belg.: Periactin; Braz.: Periatin; ylidene)-1-methylpiperidine hydrochloride sesquihydrate. management of migraine (p.564). Cyproheptadine hy- Preptin†; Chile: Viternum; Cz.: Peritol; Denm.: Periactin†; Fr.: Periactine; Ципрогептадина Гидрохлорид drochloride is given as the sesquihydrate although dos- Ger.: Peritol; Hong Kong: Cyprogin; Hung.: Peritol; India: Apenorm†; Ciplactin; Peritol; Practin; Indon.: Alphahist; Apeton; Cydifar; Cylat; En- es are expressed in terms of the anhydrous substance. C21H21N,HCl,1 ⁄ H2O = 350.9. namax; Esprocy; Glocyp; Heptasan; Lexahist; Poncohist; Profut; Prohessen; Anhydrous cyproheptadine hydrochloride 10 mg is Pronicy; Sinapdin; Irl.: Periactin; Ital.: Periactin; Mex.: Viternum; Neth.: CAS — 129-03-3 (cyproheptadine); 969-33-5 (anhydrous Periactin; NZ: Periactin; Pol.: Peritol; Port.: Trimetabol†; Viternum; Rus.: cyproheptadine hydrochloride); 41354-29-4 (cyprohepta- equivalent to about 11 mg of cyproheptadine hydro- Peritol (Перитол); S.Afr.: Cipla-Actin; Periactin; Singapore: Cyprotin; chloride sesquihydrate. Spain: Klarivitina†; Periactin; Viternum; Swed.: Periactin; Switz.: Periactin†; dine hydrochloride sesquihydrate). Thai.: Cyheptine; Cyprogin; Cyprono; Cyprosian; Cyprotec; Hepdine; Peri- ATC — R06AX02. For allergic conditions and pruritus the oral dose in actin; Polytab; Turk.: Prakten; Sipraktin; UK: Periactin; Venez.: Cyprodin; Eptacor†; Periactin†. ATC Vet — QR06AX02. adults is initially 4 mg three times daily, adjusted as Multi-ingredient: Arg.: Apeplus; Apetitol Forte; Ciprocort; Ciprovit Cal- necessary. The average dose requirement is 12 to cio; Ciprovit Energizante; Ciprovit Magnesico; Mikesan; Nipiol†; Potencil; 16 mg daily in three or four divided doses, but up to Sudevil Vita; Braz.: Apetivit BC; Apetiviton BC; Apevitin BC; Apmed; Bona- petit†; Cobactin; Cobaglobal; Cobavit; Cobavital; Polivitam†; Trimetabol; 32 mg daily may occasionally be necessary. The dose Chile: Apetrol; Grisetin Con Carnitina†; Orodina; Peracon; Revil; Rodepan; for children aged 2 to 6 years is 2 mg two or three times Viternum Vitaminado; Hong Kong: Petina Compound; Tres Orix Forte; Ital.: Carpantin†; Mex.: Cipro-Dexol†; Ciprolisina; Pangavit Pediatrico; Ro- daily increasing to a maximum of 12 mg daily and for cavit; Spain: Anti Anorex Triple; Childrevit†; Covitasa B12; Desarrol; children aged 7 to 14 years, 4 mg two or three times Enoton; Glotone; Medenorex; Pantobamin; Pranzo; Stolina; Tonico Juven- tus; Tres Orix Forte†; Trimetabol; Troforex Pepsico; Vita Menal; Venez.: daily up to a maximum of 16 mg daily. Cyprohepta- Cipromet†; Cyprodex. dine is not recommended in debilitated elderly pa- tients. N A dose of 4 mg is used for both prophylaxis and treat- Deptropine Citrate (BANM, rINNM) CH ment of migraine and other vascular headaches and Citrato de deptropina; Deptropiinisitraatti; Deptropincitrat; 3 may be repeated after 30 minutes; patients who re- Deptropin-citrát; Deptropine, citrate de; Deptropini citras; Dep- (cyproheptadine) spond usually obtain relief with 8 mg, and this dose tropino citratas; Dibenzheptropine Citrate. (1R,3r,5S)-3-(10,11- should not be exceeded within a 4- to 6-hour period. A Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)tropane dihydro- maintenance dose of 4 mg may be given every 4 to 6 gen citrate. Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. Дептропина Цитрат Ph. Eur. 6.2 (Cyproheptadine Hydrochloride). A white or slight- hours. C H NO,C H O = 525.6. ly yellow, crystalline powder. Slightly soluble in water; sparingly Other cyproheptadine salts that have been given orally 23 27 6 8 7 soluble in alcohol; freely soluble in methyl alcohol. Protect from CAS — 604-51-3 (deptropine); 2169-75-7 (deptropine ci- include the acetylaspartate, aspartate, cyclamate, oro- trate). light. USP 31 (Cyproheptadine Hydrochloride). A white to slightly tate, acefyllinate (7-theophyllineacetate), and the pyri- ATC — R06AX16. yellow, odourless or practically odourless, crystalline powder. doxal phosphate salt (dihexazine). ATC Vet — QR06AX16. Soluble 1 in 275 of water, 1 in 35 of alcohol, 1 in 26 of chloro- form, and 1 in 1.5 of methyl alcohol; practically insoluble in Abdominal migraine. Cyproheptadine has been tried in the prophylactic treatment of children with abdominal migraine (see ether. H3C , p.624). N Adverse Effects and Precautions Angina pectoris. Cyproheptadine was used successfully to treat 2 patients with Prinzmetal’s angina (p.1157) refractory to As for the sedating antihistamines in general, p.561. In- standard treatment with calcium-channel blockers and nitrates.1 creased appetite and weight gain may occur with cy- Serotonin is an important endocrine mediator of coronary vasos- H proheptadine. pasm and the beneficial effects of cyproheptadine were attributed to its activity as a serotonin antagonist. O Abuse. Dependence developed in a patient who took about 1 1. Schecter AD, et al. Refractory Prinzmetal angina treated with 180 mg of cyproheptadine daily by mouth for 5 years. cyproheptadine. Ann Intern Med 1994; 121: 113–14. 1. Craven JL, Rodin GM. Cyproheptadine dependence associated with an atypical somatoform disorder. Can J Psychiatry 1987; Appetite disorders. Cyproheptadine has been widely used as 32: 143–5. an appetite stimulant, including for anorexia nervosa and cachex- ia (see under Megestrol, p.2115), but in the long-term appears to Effects on the nervous system. Antimuscarinic toxicity have little value in producing weight gain and such use is no (deptropine) manifest by hallucinations and agitation developed in a 9-year- longer generally recommended. There has been concern that cy- old child taking cyproheptadine 4 mg twice daily for migraine proheptadine was being promoted and used inappropriately as an In Eur. (see p.vii). prophylaxis.1 1 Pharmacopoeias. appetite stimulant in some developing countries. Ph. Eur. 6.2 (Deptropine Citrate). A white or almost white, mi- 1. Watemberg NM, et al. Central anticholinergic syndrome on ther- 1. Anonymous. Cyproheptadine: no longer promoted as an appetite crocrystalline powder. Very slightly soluble in water and in dehy- apeutic doses of cyproheptadine. Pediatrics 1999; 103: 158–60. stimulant. WHO Drug Inf 1994; 8: 66. drated alcohol; practically insoluble in dichloromethane. A satu- Interference with diagnostic tests. Cyproheptadine re- Carcinoid syndrome. The management of carcinoid tumours rated solution in water has a pH of 3.7 to 4.5. Protect from light. duced hypoglycaemia-induced growth hormone secretion by be- (p.643) is largely symptomatic. Cyproheptadine hydrochloride, a 1 Profile tween 5 and 97% in 8 healthy subjects. It was suggested that if serotonin antagonist, has had limited success in relieving symp- Deptropine citrate is a sedating antihistamine (p.561) with a patients receiving cyproheptadine were given a pituitary function toms such as diarrhoea but somatostatin analogues may now be 1 marked antimuscarinic action. It was given by mouth mainly in test that used growth hormone response to insulin-induced hy- preferred. It has been used successfully with fenclonine, apro- the treatment of respiratory-tract disorders. poglycaemia, then cyproheptadine therapy should be stopped be- tinin, methylprednisolone, and antibacterials to prevent compli- fore the test. cations arising from release of tumour metabolites during hepatic 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)