678 Antimigraine Dru s

Migraine. For comparison of the relative benefits of differ­ Migraine and clusterheadache. Pizotifen has been widely ent triptans in migraine, see under Sumatriptan, p. 680.1. �.���.��!��.�S...... used for the prophylaxis of migraine (p. 670.3) but evi­ (details are given in Volume B) Further references. ProprietaryPreparations dence for its efficacy is limited. It has also been tried in the 1. Ashcroft DM, Millson D. Naratriptan for the treatment of acute Single-ingrecfJent Preparations. Belg.: Nocertonet; Fr.: Nocer­ management of cluster headache (p. 670.1) to prevent migraine: meta-analysis of randomised controlled trials. Pharmacoepide­ tOne; Gr.: Nocertone. headache attacks during a cluster period. miol Drug Safety 2004; 11: 73-82. 2. Tfelt-Hansen PC. Published and not fully published double-blind, References. randomised, controlled trials with oral naratriptan in the treatment of I. Cleland PG, et al. Studies to assess if pizotifen prophylaxis improves migraine: a review based on the GSK Trial Register. J Headache Pain tBAN, riNN! migraine beyond the benefit offered by acute sumatriptan therapy 2011; 12: 399-403. Pizotifen alone. Bur Neuro/ 1997; 38: 31-8. 2. Barnes N, Millman G. Do pizotifen or propranolol reduce the frequency Adverse Effectsand Precautions of migraine headache? Arch DisChild 2004; 89: 684-5. As for Sumatriptan, p. 680.2 and p. 681.2. Adverse Effectsand Precautions Naratriptan should not be used in patients with severe As 'for the sedating antihistamines in general, see p. 613.1 hepatic (Child-Pugh class C) or renal (creatinine clearance and p. 613.3. less than 15 mL/minute) impairment. Naratriptan should be Increased appetite and weight gain may occur with used with caution in mild or moderate renal or hepatic pizotifen. Drowsiness may be troublesome. impairment. Patients with hypersensitivity to sulfonarnides may theoretically show a similar reaction to naratriptan. Incidence of adverse effects. Adverse effects were noted (For discussion of cross-reactivity in sulfonamides and sulfa in 22 of 47 patients with severe migraine given pizotifen drugs see Hypersensitivity under Sulfamethoxazole, l to 2 mg daily.1 These reactions included weight increase p. 365.3.) (15 patients), muscle pain or cramps (3 patients), heavy or restless legs (3 patients), fluid retention (3 patients), drow­ Medication-overuse headache. For a report of an associa­ siness (2 patients), more frequent milder headaches (2 tion between naratriptan and medication-overuse head­ patients), facial flushing (1 patient), reduced libido ache, see under Adverse Effects of Sumatriptan, p. 681.2. patient), exacerbation of epilepsy (l patient), and dream­(l ing (2 patients). Adverse effects necessitating withdrawal The Drug Database for Acute Porphyria, com­ Porphyria. occurred in 11 patients. piled by the Norwegian Porphyria Centre (NAPOS) and 1. Peet KMS. Use of pizotifen in severe migraine: a long·term study. Curr the Porphyria Centre Sweden, classifies naratriptan as pos­ Med Res bpin 1977; 5: 192-9. sibly porphyrinogenic; it should be used only when no safer alternative is available and precautions should be Pharmacopoeias. In Br. Porphyria. The Drug Database for Acute Porphyria, com­ considered in vulnerable patients.1 BP 2014: (Pizotifen Malate). A white or slightly yellowish­ piled by the Norwegian Porphyria Centre (NAPOS) and 1. The Drug Database for Acute Porphyria. Available at: http://www. white, odourless or almost odourless, crystalline powder. the Porphyria Centre Sweden, classifies pizotifen as possi­ drugs-porphyria.org (accessed 11/04/11) Very slightly soluble in water; slightly soluble in alcohol and bly porphyrinogenic; it should be used only when no safer in chloroform; sparingly soluble in methyl alcohol. Protect alternative is available and precautions should be consid­ Interactions from light. ered in vulnerable patients. 1 As for Sumatriptan, p. 681.3. 1. The Drug Database for Acute Porphyria. Available at: http:l/www. Uses and Administration drugs·porphyria.org (accessed 11/04/11) Pharmacokinetics Pizotifen is a sedating antihistamine (p. 610.1) that has strong serotonin antagonist and weak antimuscarinic Interactions After oral doses, peak plasma-naratriptan concentrations properties. It also antagonises the action of tryptamine. As for the sedating antihistamines in general, see p. 614.3. occur at 2 to 3 hours, and bioavailability is reported to be Pizotifen is used, usually as the malate, for the prophylaxis 63% in men and 74% in women. Plasma protein binding is of migraine and for the prevention of headache attacks Antihypertensives. After a report1 of loss of blood pressure about 29%. Naratriptan undergoes some hepatic metab­ during cluster periods. It is not effective in treating an acute control when treatment with pizotifen was started in a olism via a wide range of cytochrome P450 isoenzymes. It is attack. Doses of pizotifen malate are expressed in terms of patient receiving debrisoquine the manufacturer suggested mainly excreted in the urine with 50% of a dose being the base; pizotifen malate 1.45 mg is equivalent to about that since pizotifen had a similar chemical structure to the recovered as unchanged drug and 30% as inactive l mg of pizotifen. Pizotifen hydrochloride has also been used tricyclic antidepressants it might antagonise the actions of metabolites. The elimination half-life is 6 hours, and is in the management of migraine. adrenergic neurone blockers in a similar manner. significantly prolonged in patients with renal or hepatic The usual oral dose is the equivalent of 1.5 mg of I. Bailey RR. Antagonism of debrisoquine sulphate by pizotifen impairment. pizotifen daily either in three divided doses or as a single (Sandomigran). N Z Med J 1976; 1: 449. Distribution into milk has been found in studies in rats. dose at night. Gradual increase from an initial dose of 500 micrograms may help to avoid undue drowsiness. Doses Pharmacokinetics ����.��.!��.n.s...... may vary from 500 micrograms up to a maximum of 4.5 mg Pizotifen is well absorbed from the gastrointestinal tract and ProprietaryPreparations (details are given in Volume B) daily; not more than 3 mg should be given as a single dose. For details of doses in children, see below. peak plasma concentrations occur about 5 hours after a Single-ingredient Preparations. Arg.: Naramig; Austral.: Nata­ single oral dose. Over 90% is bound to plasma proteins. mig; Austria: Antimigrint; Naramig; Belg.: Naramig; Braz.: Administration in children. For the prophylaxis of Pizotifen undergoes extensive metabolism. Over half of a Naramig; Naratrin; Amerge; Bagomigral; Migtal; Canad.: Chile: migraine and for the prevention of headache attacks dur­ dose is excreted in the urine, mainly as metabolites; a Miragran; Naramig; Cz.: Naramig; Denm.: Naragran; Naramig; ing cluster periods, children aged over 2 years may be significant proportion is excreted in the faeces. The primary Fin.: Naramig; Fr.: Naramig; Ger.: Formigran; Naramig; Gr.: given up to 1.5 mg daily of pizotifen orally, although the metabolite of pizotifen (N-glucuronide conjugate) has a Naramig; India: Naratrex; Irl. : Naramergt; Naramig; Naraverg; long elimination half-life of about 23 hours. Israel: Naramig; Mex.: Naramigt; Neth.: Migatane; Naramig; maximum single dose (at night) should not exceed l mg. Gradual increase from an initial dose of 500 micrograms Distribution into milk has been found in animal studies. Norw.: Naramig; NZ: Naramig; Port.: Naramig; Rus.: Naramig may help to avoid undue drowsiness. (Hapi!MHI'); S.Afr.: Naramig; Singapore: Naramig; Spain: Nara­ r mig; Swed.: Naramig; Switz.: Naramig; Turk. : Naramig; UK: ����. �.!���S...... Naramig; USA: Amerge. Abdominal migraine. Abdominal migraine is a recurrent ProprietaryPreparations (details are given in Volume B) disorder seen mainly in children and characterised by epi­ PharmacopoeialPreparations sodic midline abdominal pain lasting for up to 72 hours. Single-ingredient Preparations. Arg. : Sandomigran; Austral.: USP 36: Naratriptan Hydrochloride Oral Suspension; Naratriptan The pain is severe enough to disrupt normal activities and Sandomigran; Belg.: Sandomigran; Braz.: Sandomigran; Tablets. may be associated with pallor, anorexia, nausea, and Canad.: Sandomigran; Cz.: Sandomigran; Denm.: Sandomigrin; vomiting.1•2 Sleep, and sometimes vomiting, terminate the Fr.: Sanmigran; Gr.: Mosegor; Hong Kong: Sandomigran; Indon.: Lysagor; Ir1.: Sanomigran; Ital.: Sandomigran; Malay­ attack. Oxetorone Fumarate (USAN, riNNM) sia: Sandomigran; Neth.: Sandomigran; NZ: Sandomigran; Phi­ In one small study pizotifen was found to be effective for lipp.: Litec; Mor- Vita; Mosegor; Pol.: Polomigran; S.Afr.: San­ the prophylaxis of abdominal pain in children with domigran; Spain: Mosegor; Sandomigran; Swed.: Sandomigrin; abdominal migraine;3 however, a systematic review Switz.: Mosegort; Thai.: Anorsia; Bozo; Manzofen; Migrin; concluded that there was only weak evidence in favour of Mosegor; Moselar; Mozifen-EF; Pizomed; Zofen; Turk.: Sando­ such use in recurrent abdominal pain and suggested that migran; UK: Sanomigran. pizotifen should only be used in the context of clinical trials or in children with severe problems refractory to Multi-ingredient Preparations.Philip p.: Appetens; Mosegor Vita. conventional management.• Prophylactic treatment with PharmacopoeialPreparations propranolol or cyproheptadine may also be of benefit.' BP 2014: Pizotifen Tablets. I. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia 2004; 24 (suppl 1): 9-160. Also available at: http:/1 onlinelibrary. wiley .com/ doi/1 0.1 111/cha.2004.24.issue·s 1 /issuetoc Rizatriptan Benzoate (accessed 12/08/10) 2. Russell G, et al. The child with recurrent abdominal pain: is it abdominal (BANM, USAN, p/NNM) migraine? Br J Hosp Med2007; 68: M1 10-M113. Profile 3. Symon DNK, Russell G. Double blind placebo controlled trialofpizotifen syrup in the treatment of abdominal migraine. Arch Dis Child 1995; 72: Oxetorone fumarate is an antihistamine and serotonin 48-50. antagonist used orally in the treatment of migraine 4. Huertas·Ceballos A. et al. Pharmacological interventions for recurrent (p. 670.3) and cluster headache (p. 670.1) in doses of up to abdominal pain (RAP)and irritable bowel syndrome (ffiS)in childhood. l80mg daily. Oxetorone was reported to have induced Available in The Cochrane Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2008 (accessed 14112/10). hyperplastic changes in breast tissue and the uterine 5. Worawattanakul M, et al. Abdominal migraine: prophylactic treatment endometrium of rodents. and follow·up. J Pediatr Gastroenterol Nutr 1999; 28: 37-40.

All cross-references refer to entries in Volume A Oxetorone 679

- . safer alternative is available and precautions should be USP 36: (Sumatriptan Succinate). A white or almost white CAS M4034.S0-0 (riza Wpton): 14:5202-66-0 :{r!za trfptitn considered in vulnerable patients.1 powder. Freely soluble in water; sparingly soluble in methyl l. The Drug Database for Acute Porphyria. Available at: http:/l"www. alcohol; practically insoluble in dichloromethane. Store in benzoate),_:_ ATC N02CC04 , drugs-porphyria.org {accessed 11/04/11) airtight containers at a temperature not exceeding 30 A TC - degrees. Do not allow to freeze. Protect from light. Vet�. QN02CC04. UNit WR97857QHH. Interactions Pharmacopoeias. In Bur. (see p. vii) and US. Oral liquid preparations of sumatriptan 5 mg/mL As for Sumatriptan, p. 681.3. Stability. Ph, Eur, 8: (Rizatriptan Benzoate). A white or almost white Propranolol increases plasma-rizatriptan concentrations prepared from crushed sumatriptan succinate tablets in 3 different syrups were stable for at least 21 days when powder or crystals. Soluble in water; sparingly soluble in and it is recommended that lower doses of rizatriptan should 1 alcohol; slightly soluble in dichloromethane, It shows be used in patients receiving both drugs (see Uses and stored at 4 degrees and protected from light. polymorphism. Administration, above). I. Fish DN, et a!. Stability of sumatriptan succinate in extemporaneously prepared oral liquids. Am J Health·Syst Pharm 1997; 54: 1619-22. USP 36: (Rizatriptan Benzoate). A white to almost white crystalline powder. Soluble in water; sparingly soluble in Pharmacokinetics alcohol; slightly soluble in dichloromethane, Uses and Administration After oral doses, peak plasma-rizatriptan concentrations occur in about 1 to 2.5 hours depending on the formulation. Sumatriptan is a selective serotonin agonist that acts at 5- Uses and Administration Bioavailability is about 40 to 45%. Food may delay the time HT1 receptors and produces vasoconstriction of cranial to peak plasma concentrations of the tablet formulation by arteries. Drugs such as sumatriptan, which are commonly Rizatriptan is a selective serotonin (5-HT ) agonist with known as triptans, are believed to act mainly at 5-HT B and I about 1 hour. Plasma protein binding is low (14%). l actions and uses similar to those of sumatriptan (below). It is Rizatriptan ismetabolised mainly by monoamine oxidase 5-HTm subtype receptors and are therefore sometimes used for the acute treatment of the headache phase of type A to the inactive indole acetic acid derivative. The referred to as 5HT1B11n-receptor agonists. migraine attacks, It should not be used lor prophylaxis. active metabolite N-monodesmethyl-rizatriptan is formed Sumatriptan is used for the acute treatment of migraine Rizatriptan is given as the benzoate, and doses are expressed to a minor degree; other minor metabolites are also attacks and of cluster headache. It should not be used for in terms of the base; rizatriptan benzoate 14.5 mg is produced, About 14% of an oral dose is excreted in the prophylaxis. It may be given orally, subcutaneously, or equivalent to about lO mg of rizatriptan. urine as unchanged rizatriptan, 51% as the indole acetic transdermally as the succinate and intranasally as the base. The licensed dose in the UK of rizatriptan is the acid metabolite, and no more than 1% as N-mono­ Doses are expressed in terms of the base; sumatriptan equivalent of lO mg orally, If this is ineffective, a second desmethyl-rizatriptan. The plasma half-life is about 2 to 3 succinate 70 mg is equivalent to about 50 mg of sumatrip­ dose should not be taken for the same attack. If symptoms hours. tan. recur after an initial response, a further dose of I 0 mg may Distribution into milk has been found in studies in rats. For the acute treatment of migraine sumatriptan should be taken after an interval of at least 2 hours. In the USA be used as soon as possible after the onset of the headache licensed doses of 5 or lO mg are used. The recommended l. Lee Y, et al. Pharmacokinetics and tolerability of oral rizatriptan in phase, but efficacy is independent of the duration of the maximum dose in 24 hours is 20mg in the UK and 30mg in healthy male and female volunteers. Br Clin Pharmacol i999; 47: 373-8. attack before starting treatment. If no response is obtained 1 the USA. A reduced dose of 5 mg is recommended in 2. Goldberg MR, et a!. Rir.atriptan, a novel 5-IIT1n1m agonist for migraine: with the initial dose by any route, a second dose should not patients also receiving propranolol (see Interactions, single- and multiple-dose tolerability and pharmacokinetics in healthy be given lor the same attack. subjects. J Clin Pharmacal 2000; 40: 74-83. below), with the maximum dose in 24 hours reduced to orally 3. Vyas KP, et al. Disposition and pharmacokinetics of the antimigraine • It is given to adults aged 18 years and over; the lOmg in the UK and l5mg in the USA. It is also drug, rizatriptan, in humans. Drug Metab Dispos 2000; 28: 89-95. recommended dose in the UK is 50 mg, although some recommended that doses of the 2 drugs should be separated 4. Swan SK, et al. Pharmacokinetic profile of rizatriptan IO-mg tablet and patients may require 100 mg. A clinical response can be by at least 2 hours. 10-mg orally disintegrating tablet administered with or without water in expected after about 30 minutes. If symptoms recur after For doses in children and in hepatic or renal impairment, healthy subjects: an open-label, randomized, single-dose, 3-period Clin Pharmacol 2006; 46: 172-8. an initial response, further doses may be given provided crossover study. 1 see below. that there is a minimum interval of 2 hours between r r i doses and that not more than 300 mg is taken in any 24- P.. �p()_ ()_l ?.n.�...... hour period. US licensed product information recom­ Administration in children. In the USA, rizatriptan is (details are given in Volume B) licensed for the treatment of acute migraine in children ProprietaryPreparations mends that a lower dose o£ 25 mg may be used, although and adolescents aged 6 to 17 years. A single oral dose of Single-ingredient Prepara�ons. Austral.: Maxalt; Austria: Max­ some patients require 50 or 100 mg. This may be 5 mg may be given to children weighing less than 40 kg alt; Belg.: Maxalt; Braz.: Maxalt; Canad.: Maxalt; Chile: Maxalt; followed by a second dose of up to 100 mg if the and lO mg to those weighing 40 kg or more, In children China; Ouliting ShanQing Xin Qu (Jil:Jll); headache returns or the patient has a partial response Maxalt; Maxalt; Maxalt; Maxaltlyo; also receiving propranolol (see Interactions, below), a sin­ Denm.: Fin.:(i!X.lz:1 'l'); Fr.: ('if.if!i); Ger.: provided that the total daily dose does not exceed the Maxalt; Gr.: Maxalt; Modinol; India: Rizact; Israel: Rizalt; Ital. : gle dose of rizatriptan 5 mg is recommended in those who recommended maximum of 200mg. A minimum Maxalt; Rizaliv; Trizadol; Mex. : Maxaltt; Neth.: Latariz; Maxalt; interval of 2 hours is recommended between doses. A weigh 40 kg or more; however, it should not be given to Rizatan; Triptosig; Norw.: Maxalt; NZ: Maxalt; Pol.: Maxalt; those who weigh less than 40 kg. The safety and efficacy tablet supplying a dose equivalent to 85 mg of Port,: Maxalt; Migroft; S.Afr. : Maxalt; Spain: Maxalt; Swed.: sumatriptan, as a fixed-dose combination with 500 mg of a second dose have not been established. Maxalt; Maxalt; Maxalt; Maxalt; Max­ Switz.: Turk.: UK: USA: of naproxen sodium, is also available in the USA; a single alt; Venez.: Maxalt. dose may be taken, repeated once within 24 hours if Administration in hepatic or renal impairment. UK necessary, with a minimum interval of 2 hours. licensed product information recommends that in patients • When used intranasally a clinical response can be with mild to moderate hepatic or renal impairment, the Sumatriptan (BAN. riNNJ expected in 15 minutes. UK licensed product information oral dose of rizatriptan should be reduced to 5 mg. If the Sumatriptaat\!; · Sum�trlpttm; Sumatli tanum; recommends that patients aged 18 years and over may be headache recurs after an initial response, a further dose of . p Sumatryptan; CyMaip.,n'raH. given a single dose of 20 mg into one nostril, although 5 mg may be taken after an interval of at least 2 hours. Gf\,43175X; 3- (2-Dimethylarnlnoethyllindoi:S-xlcN·methylmethanesuffo- lOmg may be effective in some patients. US licensed The recommended maximum dose in 24 hours in these product information recommends that a dose of 5, 10, or namlde. .. patients is 10 mg. It is also recommended that rizatriptan 20 mg may be used. If symptoms recur, a second dose C,4Hl,N,Q/i""295.4 should not be used in patients with severe hepatic or renal may be given at least 2 hours after the first dose. Not CAS impairment. -- more than 40 mg should be used in a 24-hour period. !0362lF46 ·2. In patients aged 18 years and over sumatriptan may be NOZa:o r.· • Migraine. For comparison of the relative benefits of differ­ self-administered by subcutaneous injection in a single dose QNOlCCO I. ent triptans in migraine, see under Sumatriptan, p. 680.1. � of 6 mg; a clinical response may be expected after 10 to 15 8Rl8F6L9VO. Further references. Pharmacopoeias. In Br. and US. minutes. If symptoms recur, a second dose of 6 mg may be injected at least one hour alter the first dose; not more l. Wellington K, Plosker GL. Rizatriptan: an update of its use in the BP 2014: (Sumatriptan). A white to pale yellow powder. management of migraine. Drugs 2002; 62: 1539-74. than 12 mg should be given in a 24-hour period. US Very slightly soluble in water. Protect from light. 2. Pascual J. A review of rizatriptan, a quick and consistent 5-HTlB/lD licensed product information recommends that it may agonist for the acute treatment of migraine. Expert Opin Pharmacother USP 36: (Sumatriptan). A white to pale yellow powder. also be used in single doses ol l to 5 mg if adverse effects 2004; 5: 669-77. Very slightly soluble in water. Store in airtight containers at are dose-limiting, A needle-freesubcutaneous deliverysystem 3. Ahonen K, et al. A randomized trial of rizatriptan in migraine attacks in children. Neurology 2006; 67: 1135-40. below 30 degrees. Do not allow to freeze. Protect from light. is also available for the delivery of 6-mg doses. 4. Mannix LK. A review of the 5-HTlB/lD agonist rizatriptan: update on • An iontophoretic transderrnal delivery system, supplying recent research and implications for the future. Expert Opin Pharmacother Sumatriptan Succinate (BANM, USAN, r!NNM) 6. 5 mg of sumatriptan over 4 hours, may also be used by 2008; 9: 1001-ll. et al. patients aged 18 years and over. It should be applied to 5. Hargreaves RJ, Ten years of rizatriptan: from development to SN-3Q, ;S i:<;:inato surnatript�h;Sum succinate}, to those used for migraine. Rizatriptan should be given with caution to patients with � A1C NOXCOQN02CC0I: 1. For doses in children and in hepatic impairment, see mild or moderate hepatic or renal impairment; UK licensed : below and p. 680.1, respectively. product information contra-indicates its use in more severe A TC Vet - impairment. UNII - J8BDZ68989. Pharmacopoeias. In Bur. (see p. vii) and US. Administration in children. Sumatriptan may be given for Ph. Eur. 8: (Sumatriptan Succinate). A white or almost the treatment of acute migraine in children and adoles­ Porphyria. The Drug Database for Acute Porphyria, com- white powder. Freely soluble in water; practically insoluble cents. Although not licensed for oral paediatric use in the piled by the Norwegian Porphyria Centre (NAPOS) and , in dichloromethane; sparingly soluble in methyl alcohol. A UK, the BNFC suggests that a single oral dose of 25 mg the Porphyria Centre Sweden, classifies rizatriptan as pos- i 1% solution in water has a pH of 4.5 to 5.3. Protect from may be given to children aged 6 to lO years, 50 mg to sibly porphyrinogenic; it should be used only when no i light. those aged 10 to 12 years, and 50 to lOOmg to those aged

The symbol t denotes a preparation no longer actively marketed