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Formoterol Fumarate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: BD-40A; CGP-25827A; Eformoterol Fumarate; Formoterol, fumarato de; Formoterol-fumarát; Formoterolfumarat; Formoteroli Fumaras; Formoterolifumaraatti; Formoterolio fumaratas; YM-08316
BAN: Formoterol Fumarate [BANM]
USAN: Formoterol Fumarate
INN: Formoterol Fumarate [rINNM (en)]
INN: Fumarato de formoterol [rINNM (es)]
INN: Formotérol, Fumarate de [rINNM (fr)]
INN: Formoteroli Fumaras [rINNM (la)]
INN: Формотерола Фумарат [rINNM (ru)]
Chemical name: (±)-2´-Hydroxy-5´-[(RS)-1-hydroxy-2-{[(RS)-p-methoxy-αmethylphenethyl]amino}ethyl]formanilide fumarate
Molecular formula: (C19H24N2O4)2,C4H4O4 =804.9
CAS: 73573-87-2 (formoterol); 43229-80-7 (formoterol fumarate)
ATC code: R03AC13

Pharmacopoeias. In Japan, Europe includes the dihydrate.

European Pharmacopoeia, 6th ed. (Formoterol Fumarate Dihydrate Formoteroli Fumaras Dihydricus). A white or almost white or slightly yellow powder. Slightly soluble in water and in isopropyl alcohol practically insoluble in acetonitrile soluble in methyl alcohol. A 0.1% solution in water has apH of 5.5 to 6.5. Protect from light.

Formoterol_Fumarate

Adverse Effects and Precautions

As for Salbutamol. Inhalation of formoterol may be associated with paradoxical bronchospasm, and high doses have been associated with an increase in severe exacerbations of asthma. It should not be used in patients who are not also receiving an inhaled cortico steroid.

Long-acting beta2 agonists such as formoterol are not appropriate for the treatment of acute bronchospasm. Conjunctival irritation and eyelid oedema have been reported in isolated cases.

Asthma. A review of 3 controlled studies comparing inhaled formoterol with placebo, concluded that regular use of high-dose formoterol (48 micrograms daily) may be associated with more frequent serious asthma exacerbations. The concomitant use of inhaled corticosteroids was allowed but not mandatory, and was not reported in the review, which led to debate on whether the results of the study would be applicable when current prescribing guidelines for asthma were followed.

In contrast to this, a subsequent study, designed to test the hypothesis of a dose-related increase in serious asthma exacerbations with formoterol therapy, did not show any increase in serious asthma exacerbations between different formoterol doses and placebo. Again, inhaled corticosteroid use was allowed but not mandatory, with 62.4% of patients reported as receiving regular anti-inflammatory therapy.

A systematic review firmly concluded that the addition of a long-acting beta2 agonist (such as formoterol) to low or high doses of inhaled corticosteroids reduced the risk of asthma exacerbations compared with ongoing treatment with similar doses of inhaled corticosteroids alone. The addition of a long-acting beta2 agonist reduced by 19% the relative risk and by 5% the absolute risk of patients requiring systemic corticosteroids for an asthma exacerbation, over 4 to 54 weeks.

For discussion of serious adverse effects associated with long-acting beta2 agonists in asthma, see Increased Mortality, under Salmeterol.

Effects on skeletal muscle. Myalgia and muscle weakness associated with elevated creatine kinase has been reported during formoterol therapy. Subsequent muscle biopsy suggested mitochondrial dysfunction. No inflammatory changes were seen and symptoms resolved on withdrawal of formoterol.

Tolerance. Regular use of formoterol produced bronchodilator desensitisation, and tachyphylaxis to bronchoprotection against methacholine, effects that have been noted with other long-acting beta2 agonists (see Salmeterol) and short-acting beta2 agonists (see Salbutamol).

Interactions

As for Salbutamol.

Pharmacokinetics

Inhaled formoterol is rapidly absorbed. It is largely metabolised by glucuronidation and O-demethylation, with about 10% being excreted in the urine as unchanged drug. The mean terminal elimination half-life after inhalation is estimated to be 10 hours.

Stereoselectivity. Formoterol occurs as a racemic mixture, of which arformoterol is the R,R -enantiomer. Only the R,R-enantiomer is active. It has been suggested that stereoselective metabolism and excretion may account for the individual variation in duration of effect seen with formoterol, although the exact mechanism remains unclear.

Uses and Administration

Formoterol is a direct-acting sympathomimetic with mainly beta-adrenoceptor stimulant activity specific to beta2 receptors (a beta2 agonist). It has properties similar to those of salbutamol, but like salmeterol it has a prolonged duration of action of up to 12 hours it is therefore not considered suitable for the symptomatic relief of acute attacks of bronchospasm. It is used when the regular use of a long-acting beta2 agonist is needed for management of reversible airways obstruction, as in chronic asthma or in some patients with chronic obstructive pulmonary disease.

Formoterol is given by inhalation as the fumarate but how the dose is expressed may depend on the formulation.

• A usual dose is 12 micrograms of formoterol fumarate twice daily from inhalational capsules, increased to 24 micrograms twice daily if necessary in severe disease.

• Metered doses from a dry powder inhaler may be expressed as the amount delivered into the mouthpiece (multiples of 6 micrograms per inhalation) or the amount delivered/rom the mouthpiece (corresponding to multiples of 4.5 micrograms per inhalation). Usual doses, expressed as the amount delivered into the mouthpiece, are 6 or 12 micrograms once or twice daily, increased if necessary in severe disease to 24 micrograms twice daily.

• Metered doses from an aerosol inhaler may also be expressed as the amount delivered into the mouthpiece (12 micrograms per inhalation) or the amount delivered from the mouthpiece (corresponding to 10.1 micrograms per inhalation). Usual doses are 1 or 2 inhalations twice daily.

Treatment should be reassessed if this proves inadequate in the UK, some preparations are licensed for additional short-term symptom relief, but such use is contrary to current asthma guidelines. Formoterol fumarate may also be inhaled via a nebulis-er in a dose of 20 micrograms twice daily. Oral doses of 80 micrograms have been given twice daily in adults.

For doses of formoterol fumarate used in children, see Administration in Children, below.

Administration in children. Doses of formoterol fumarate inhaled from inhalational capsules in children aged 5 years or older are the same as those for adults, see Uses and Administration, above.

Formoterol fumarate may be given by metered-dose dry powder inhaler to children 6 years of age and over. The usual dose, expressed as the amount delivered into the mouthpiece, is 6 to 12micrograms once or twice daily. Occasionally up to 48 micrograms daily may be required (maximum single dose should not exceed 12 micrograms).

In some countries, such as Japan, formoterol fumarate has been given orally to children from the age of 6 months at a dose of 4 micrograms/kg daily, in 2 or 3 divided doses.

Asthma. Formoterol is a long-acting beta2 agonist (duration of action about 12 hours). Guidelines on the management of asthma, generally recommend that the use of long-acting beta2 agonists be reserved for patients with chronic asthma who have already progressed to inhaled corticosteroids it is not a substitute for corticosteroids. The exact dose of inhaled corticoster-oid at which to add additional therapy, such as a long-acting beta2 agonist, has yet to be determined. There is some evidence to suggest that, apart from in severe exacerbations, adding a long-acting beta2 agonist to standard dose inhaled corticosteroid therapy may be more effective than increasing the dose of corticosteroid, or than combining a corticosteroid and an anti-leukotriene drug. Combinations of formoterol with an inhaled corticosteroid, used as both maintenance and reliever therapy, have also been studied. Results are seemingly encouraging, although what role such combinations should play in therapy is not yet clearly defined. Some asthma guidelines include this regimen as an option for adults at treatment step 3. Formoterol may also be useful in controlling persistent nocturnal asthma or preventing exercise-induced attacks. There is some evidence that after prolonged use, protection against broncho constriction is reduced (see Tolerance, above), and high-dose therapy may be associated with an increased rate of severe exacerbations (see Asthma under Adverse Effects and Precautions, above).

Stuttering. Inhaled formoterol 12 micrograms daily was reported to improve stuttering in 3 children between 14 and 20 years old. In 2 males, the onset of effect was about 6 weeks, but long-term follow-up was not possible. In the female patient there was early improvement that persisted during 45 weeks of treatment.

Preparations

Proprietary Preparations

 

Argentina: Fordilen Oxis Xanol

Australia:: Foradile Oxis

Austria: Foradil Oxis

Belgium: Foradii Oxis

Brazil: Fluir Foradil Formocaps Oxis

Canada: Foradil Oxeze

Czech Republic: Atimos Foradil Forair Formano Formovent Oxis

Denmark: Delnil Foradil Oxis

Finland: Foradil Oxis

France: Foradil

Germany: Foradil Forair Formatris FormoLich Formotop Oxis

Greece: Broncoteril Foradil Forair Forcap Formopen Formotil Imotec Oxez

Hong Kong: Foradil Oxis

Hungary: Atimos Diffumax Foradil Fortofan Oxis

India: Foratec

Ireland: Foradil Oxis

Israel: Foradil Oxis

Italy: Atimos Eolus Foradil Liferol Oxis

Japan: Atock

Malaysia: Foradil Oxis

Mexico: Foradil Oxis

The Netherlands: Foradil Oxis

Norway: Foradil Oxis

New Zealand: Foradil Oxis

Philippines: Atock Foradil Oxis

Poland: Atimos Diffumax Foradil Forastmin Oxis Oxodil Zafiron

Portugal: Asmatec Atimos Eformax Foradil Forair Formaxa Oxis

Russia: Atimos Foradil Oxis

South Africa: Foradil Foratec Oxis

Singapore: Foradil Oxis

Spain: Broncoral Foradil Neblik Oxis

Sweden: Foradil Oxis

Switzerland: Foradil Oxis

Thailand: Oxis

Turkey: Foradil Oxis

UK: Atimos Modulite Foradil Oxis

USA: Foradil Perforomist

Venezuela: Fluir Foradil Formotec Oxis-F.

Multi-ingredient

Argentina: Neumoterol Symbicort

Australia:: Symbicort

Austria: Symbicort

Belgium: Symbicort

Brazil: Alenia Foraseq Symbicort

Canada: Symbicort

Chile: Symbicort

Czech Republic: Combair Formodual Symbicort

Denmark: Symbicort

Finland: Symbicort

France: Innovair Symbicort

Germany: Symbicort

Greece: Symbicort

Hong Kong: Symbicort

Hungary: Symbicort

India: Duova Foracort

Indonesia: Symbicort

Ireland: Symbicort

Israel: Symbicort

Italy: Assieme Sinestic Symbicort

Malaysia: Foracort Symbicort

Mexico: Symbicort

The Netherlands: Assieme Sinestic Symbicort

Norway: Symbicort

New Zealand: Symbicort

Philippines: Symbicort

Poland: Symbicort

Portugal: Assieme Formodual Foster Symbicort

Russia: Simbicort

South Africa: Symbi-cord

Singapore: Symbicort

Spain: Rilast Symbicort

Sweden: Symbicort

Switzerland: Symbicort

Thailand: Symbicort

Turkey: Symbicort

UK: Fostair Symbicort

USA: Symbicort

Venezuela: Foraseq Symbicort

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