Doxofylline/Formoterol Fumarate 1209 only significant when they were given by nebulisation. 9 ··· • .· . Interactions • ·· .· · Also a working pany of the UK CSM considered10 that a <C�A.t��.ci,ili�¢1t-f.4o4�804:9 ... �� •13�73-87-2 '(formotero l); .43229.-80-7 (formorerol causal link between asthma mortality and beta-agonist use As for Salbutamol, p. 1223.1. .CAS: · frlrpai:G te}. ; . · . could neither be confirmed nor refuted. < . ATC ....... f/03Ati3.·• · • • \• · . · Not surprisingly there are different views on the cause of Pharmacokinetics .. · A ' . • • •.• the increased asthma monality. The cardiotoxidty of the 'It Fenoterol is incompletely absorbed from the gastrointestinal Vel:.,_;;;i(.)/lt)3AC13. ·· W34SHF8.12K beta agonist ntight have to be considered, although UN/I . :- .· F'3]5()A S1?N <fo.rm.oterol ftlmatate);· · tract and is also subject to extensive first-pass metabolism by evidence for such an effect is considered by some to be i:J;hycfrqte): · sulfate conjugation. It is excreted in the urine and bile (fo(rpbr�rclfilrrarate slight.11 The severity of the asthma might have been a factor Pharmacopoeias. Bur. (see p. vii), Jpn, and US include the almost entirely as the inactive sulfate conjugate. Fenoterol is in two different ways. One hypothesis is that patients used dihydrate, (C H ,.N 0 ),,C.JI.0 ,2H 0 840. 9. distributed into breast ntilk. 1 9 2 2 4 4 2 = more fenoterol because they had severe asthma and were Ph_ Bur. 8: (Formoterol Fumarate Dihydrate; Formoteroli already at increased risk of dying.12 Another proposes that References. I. Warnke K, et al. The pharmacokinetics of the beta 2-adrenoceptor Fumaras Dihydricus). A white or almost white or slightly heavy beta-agonist use led to an increase in asthma agonist fenoterol in healthy women. Bur J Clin Pharmarol 1992; 43: 663- yellow powder. Slightly soluble in water and in isopropyl severity13 which could be explained by a down regulation of 5. alcohol; practically insoluble in acetonitrile; soluble in beta receptors.14 2. Hochhaus G, M61lmann H. Pharmacokinetic/pharmacodynamic methyl alcohol. A 0.1% solution in water has a pH of 5.5 to This may appear to be only of historical interest since characteristics of the beta-2-agonists terbutaline, salbutamol and fenoterol. Int J Clin Pharmacal Ther Toxicol 1992; 30: 342-62. 6.5. Protect from light. monality rates have fallen and current recommendations 3. Hildebrandt R, et al. Pharmacokinetics of fenoterol in pregnant and USP 36: (Formoterol Fumarate). A white or almost white or for the use of shon-acting beta agonists, which are nonpregnant women. Bur J Clin Pharmacol 1993; 45: 275-7. 2 slightly yellow powder. Slightly soluble in water and in generally more selective than fenoterol, are for them to be isopropyl alcohol; soluble in methyl alcohol; freely soluble taken as required rather than on a regular basis; indeed P..r�P.�.rc:'ti().".� .......................................................................... .. in acetic acid and in dimethyl sulfoxide; practically insoluble increasing use of such drugs is seen as an indication to Proprieklry Preparations (details are given in Volume B) in acetonitrile and in ether. A 0.1% solution in water has a amend the treatment schedule. Moreover, the dose of pH of 5.5 to 6.5. Protect from light. fenoterol has been reduced in recent years. However, Single-ingredient Preparations. Arg. : Alveofen; Asmopul; Berotec; Austria: Berotec; Belg. : Berotect; Braz.: Berotec; Bro­ controversy over regular use of short-acting beta2 agonists rnifen; Bromotec; Fenatec; Fenozant; Cz. : Berotec; Denm.: Stability. Nebuliser solution containing formoterol fumar­ continues to be fed by conflicting studies of their benefit. l Berotect; Ger.: Berotec; Partusisten; Gr. : Berotec; Ftagirol; ate 0 nticrograms/mL was found to be physically and che­ More recently 2 further observational studies have reported Hung. : Berotect; Indon.: Berotec; Irl.: Berotect; Ital.: Dosbero­ mically stable when ntixedwith the following solutions:1 an association between use of short-acting betaz agonists budesonide inhalation suspension 250 micrograms/mL tec; Jpn: Berotec; Malaysia: Berotec; Ferro; Mex. : Partusisten; • and adverse effects on mortality.I5•16 A cohort study, !' Neth.: Philipp. : Pol.: acetylcysteine solution 100 mg/mL Berotect; Partusisten; Berotect; Berotec; • designed to evaluate the effect of respiratory medications on Port. : Berotect; Rus.: Berotec (EeporeK); Partusisten ipratropium bromide inhalation solution 200 micro- • asthma death, found an association between the excessive (IIaprycHcTeH); S.Afr. : Berotec; Singapore: Berotec; Switz. : grams/mL use of short-acting beta2 agonists and an increased risk of Berotec; Thai. : Berotect; Iperol; Ukr. : Berotec (EeporeK); sodium cromoglicate inhalation solution 10 mg/mL • asthma death; no additional risk was found with fenoterol Venez. : Segamol. The authors of this study noted that when these solutions beyond the risk associated with beta agonists as a class. It 2 Multi-ingredient Preparations. Arg. : Berodual; Ipradual; Austria: were mixed and nebulised, or given sequentially, the was unknown whether excessive use was a symptom or a Berodual; Berodualin; Belg.: Duovent; Braz. : Duovent; Canad.: amount of drug delivered in vitro was increased compared cause of worsening asthma. A case-control study16 similarly Duovent; Chile: Berodual; Cz. : Berodual; Denm.: Berodual; with single-drug nebulisation. Additionally, sequential found a modestly increased risk of mortality associated with Duovent; Fin.: Atrovent Camp; Fr.: Bronchodual; Ger.: Bero­ nebulisation led to higher delivery of the first drug given. use of short -acting beta2 agonists in the previous l to 5 dual; Gr. : Berodual; Hung. : Berodual; India: Fenovent; Indon.: The clinical implications of these results were unclear. years. However, the study had insufficient power to come to Berodual; Irl.: Duoventt; Ital.: Duovent; Malaysia: Berodual; I. Akapo S, et a!. Compatibility and aerosol characteristics of formoterol any conclusions regarding the effects of fenoterol, which Duovent; Mex. : Berodual; Berosolvon; Neth.: Berodual; Phi­ fumarate mixed with other nebulizing solutions. Ann Phannacother was rarely prescribed alone, and concluded that evidence lipp.: Berodual; Pol. : Berodual; Port. : Berodual; Rus.: Berodual 2008; 42: 1416-24. (Eepo;zyaJI); Ditec ( eK)t; S.Afr. : Atrovent Beta; Berodualt; for a direct adverse effect of beta2 agonists was inconclusive; ):1m' other explanations might include lack of more appropriate Duovent; Sabax Nebrafen; Singapore: Berodual; Duovent; Uses and Administration Switz.: Thai.: asthma care, more severe disease or increasing severity of Berodual; Aeroduol; Berodual; Inhalex; Iprateral; Punol; UK: Duoventt; Ukr. : Berodual (Eepo;zyaJI); Venez : Hero­ Formoterol is a direct-acting sympathomimetic with mainly disease, or a tendency for patients whose disease was not dual; Duovent; Respidual. beta-adrenoceptor stimulant activity specific to beta responding to receive a wider range of treatments. 2 receptors (a beta agonist) . It has properties sintilar to For discussion of sintilar concerns about the use of long­ Pharmacopoeial Preparations 2 those of salbutamol (p. 1220.2), but like salmeterol acting beta agonists in asthma, see Salmeterol, p. 1224.3. BP 2014: Fenoterol Pressurised Inhalation. 2 (p. 1224.1) it has a prolonged duration of action of up to 12 1. Pearce N, et al. Beta agonists and asthma mortality: deja vu. Clin Exp hours; it is therefore not considered suitable for the Allergy 1991; 21: 401-10. 2. Crane J, et a!. Prescribed fenoterol and death from asthma in New Fenspiride Hydrochloride {USAN, r/NNM) symptomatic relief of acute attacks of bronchospasm. It is Zealand, 1981-83: case-control study. Lancet 1989; i: 917-22. used with regular inhaled corticosteroid when a regular 3. Pearce N, et al. Case-control study of prescribed fenoterol and death from .•. · .• •. long-acting beta2 agonist is needed for management of asthma in New Zealand, 1977-81. Thorax 1990; 45: 170-5. •1qidrq�iq(��.P �;�� �·��nspJr,i�e chronic asthma (p. 1195.2), or for prevention of exercise­ 4. Grainger J, et al. Prescribed fenoterol and death from asthma in New liltl£<l"l9!4f(). JJ:>;42.8; induced asthma. It is also used in chronic obstructive Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105- · . $A; �ti.d!\1P'!AA 111. f14).1 p®1bp1i!.f!.· · i ....... ....... .. (i .... .. ..... .. ; ( . pulmonary disease (p. 1199.1). 5. Pearce N, et al. End of the New Zealand asthma mortality epidemic. �Ptt�ii�thYf<l"c)j(��.��aspl�· . (!@.�d�an����·. Formoterol is given by inhalation as the fumarate but Lancet 1995; 345: 41-4. ttydrc)s . .. •··· how the dose is expressed may depend on the formulation. 6. Sears MR, et al. Regular inhaled beta-agonist treatment in bronchial > • • •• !0•• > ••.. • , • · �h!<;lr!d!)... ..... ••••• A usual dose for asthma is l inhalational capsule of asthma. Lancet 1990; 336: 139 1-6. ; · .· • , · . · . ... · > •· C,s!:J2o!'l202,8CI=�96,S . 7. Spitzer WO, et al. The use of � -agonists and the risk of death and near 9\,9.:; :�o/J�� ;f��sfl(��.. );.. SIJS!.�Z:.·'·(fr!?s�lr!1Je •b�rp- formoterol fumarate 12 micrograms twice daily. In the death from asthma. N Bngl J Med 1992; 316: 501-6. UK, this may be increased to 2 inhalational capsules 8. Beasley R, et al. � -agonist therapy and asthma mortality in Japan. Lancet , ..•. • •••· . •• •• ,> , :cl'lton«li!J·• . (24micrograms) twice daily if necessary for severe 1998; 351: 1406-7. · .·