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Salmeterol Xinafoate

 

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

Drug Nomenclature

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

Synonyms: GR-33343G; Salmaterol Xinafoate; Salmeterol 1-Hydroxy-2-naphthoate; Salmeterol, xinafoato de; Salmeterol-xinafoát; Salmeteroli Xinafoas; Salmeteroliksinafoaatti; Salmeterolio ksinafoatas; Sameterolxinafoat
BAN: Salmeterol Xinafoate [BANM]
USAN: Salmeterol Xinafoate
INN: Salmeterol Xinafoate [rINNM (en)]
INN: Xinafoato de Salmeterol [rINNM (es)]
INN: Salmétérol, Xinafoate de [rINNM (fr)]
INN: Salmeteroli Xinafoas [rINNM (la)]
INN: Салметерола Ксинафоат [rINNM (ru)]
Chemical name: (RS)-5-{1-Hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}salicyl alcohol 1-hydroxy-2-naphthoate
Molecular formula: C25H37NO4,C11H8O3 =603.7
CAS: 89365-50-4 (salmeterol); 94749-08-3 (salmeterol xinafoate)
ATC code: R03AC12

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Salmeterol Xinafoate). A white or almost white powder. Practically insoluble in water slightly soluble in dehydrated alcohol soluble in methyl alcohol. Protect from light.

Adverse Effects and Precautions

As for Salbutamol. Inhalation of salmeterol may be associated with paradoxical bronchospasm, and it should not be used in patients who are not also receiving an inhaled corticosteroid.

Salmeterol is not appropriate for the treatment of acute bronchospasm or for patients whose asthma is deteriorating.

Effects on the cardiovascular system. A pooled analysis of safety data from 7 studies of salmeterol in chronic obstructive pulmonary disease found no evidence of an increased risk of cardiovascular adverse effects. The duration of these studies had ranged from 12 weeks to 1 year.

Effects on the respiratory system. Transient paradoxical bronchoconstriction with breathlessness, wheeze, or cough has been reported in 6 asthmatic patients after inhalation of salmeterol from a metered-dose aerosol but not after inhalation of the dry powder formulation by diskhaler. The fluorocarbon propellants in the metered-dose aerosol were suspected as the irritants causing bronchoconstriction.

Effects on the skin. Urticarial rash associated with inhaled salmeterol, of which the propellant was not the cause, has been reported. Although many urticarial reactions and a variety of rashes had been attributed to beta-agonist therapy their reproducibility had not always been documented.

Salmeterol_Xinafoate

Increased mortality. Interim results from a large controlled study (SMART) designed to evaluate the safety of salmeterol compared with placebo, found a small but statistically significant increase in respiratory-related and asthma-related deaths or life-threatening episodes in the total population receiving salmeterol compared with placebo. This imbalance occurred mainly in the African-American subpopulation, and combined with difficulties in enrolment, led to early termination of the study. Various factors may have influenced the differences in outcomes seen with salmeterol greater disease severity was noted at baseline in the African-American subgroup compared to Caucasian subjects, and nearly half of all participants were not receiving inhaled corticosteroids.

A subsequent meta-analysis of 19 placebo-controlled studies of patients with asthma who were taking the long-acting beta2 agonists salmeterol or formoterol, reported an increased risk of hospitalisation for an asthma exacerbation, life-threatening asthma attacks, and asthma-related deaths compared with placebo. A sub-group analysis that examined studies in which more than 75% of patients were also receiving inhaled corticosteroids also found an increased risk of hospital admission. The applicability of this review to therapy as recommended by current guidelines has been questioned, as many of the studies included in the primary analysis did not require inhaled corticosteroids to be used, and studies which compared different asthma maintenance regimens were excluded because they were not placebo-controlled. Concomitant asthma treatments and adherence to treatment, differences in baseline disease severity, racial or genetic factors, polymorphism, tolerance, and masking of underlying airway inflammation by long-acting beta2 agonists have all been proposed as possible explanations for the increased risk of adverse outcomes reported with long-acting beta2 agonists.

In contrast to the above studies, a case-control study that included 532 patients under age 65 who had died from asthma, matched with 532 controls with a hospital admission for asthma, found no evidence of adverse effects on mortality with medium to long-term use of inhaled long-acting beta2 agonists. An earlier observational cohort study also found no evidence that salmeterol contributed to deaths reported from asthma.

Current guidelines advocate use of a long-acting beta2 agonist in addition to inhaled corticosteroids, and not as monotherapy, see Management of Asthma

A recent review by the UK MHRA concluded that:

• epidemiological data indicated that since the introduction of long-acting beta-agonists there had been a reduction in asthma-related hospitalisations in adolescents and a decrease in asthma related-mortality in all ages.

• data from controlled clinical study did not reflect the safety concern from postmarketing studies, possibly due to more consistent use of corticosteroids in controlled settings

• the data supported the use of long-acting beta-agonists with inhaled corticosteroids consistent with the UK guidelines on the management of asthma and that to aid compliance in the concomitant use of a corticosteroid, a combination inhaler should be used when appropriate

Tolerance. As with short-acting beta2 agonists (see Salbutamol), there is evidence that regular use of long-acting beta2 agonists such as salmeterol produces tachyphylaxis to their protective effect against bronchoconstriction, as provoked by stimuli such as allergen, methacholine, or exercise. The authors of a study of the long-term effect of salmeterol on exercise-induced asthma concluded that the decreased bronchoprotective effect over time was due to a decrease in duration of action (to less than 9 hours) rather than tachyphylaxis, but this interpretation was criticised.

There is also some evidence to suggest that symptomatic relief by short-acting beta2 agonists is significantly reduced by regular use of long-acting beta2 agonists. Receptor downregulation, induced by regular use of a long-acting beta2 agonist, has been suggested as the mechanism for this reduction in response and may lead to patients requiring higher doses of beta2 agonists to attain relief from an acute asthma attack. One study suggested that the greater tachyphylaxis to short-acting beta2 agonists seen with salmeterol compared with formoterol might represent the expression of partial antagonism by salmeterol at beta2 receptors. Whatever the mechanism, the reduced bronchoprotective effect is perhaps more of a concern with long-acting beta2 agonists, since, unlike the short-acting beta2 agonists, their use on a regular basis is recommended. See also Beta2 Agonists, under Interactions of Salbutamol.

Interactions

As for Salbutamol.

For a study suggesting a decreased effect of salbutamol in patients receiving salmeterol, as well as a report of additive effects, see Beta2 Agonists under Interactions of Salbutamol.

Pharmacokinetics

Plasma concentrations of salmeterol are negligible after inhalation of therapeutic doses.

Uses and Administration

Salmeterol is a direct-acting sympathomimetic with beta-adrenoceptor stimulant activity and a selective action on beta2 receptors (a beta2 agonist). When given by inhalation, salmeterol acts as a bronchodilator. The onset of action is about 10 to 20 minutes but the full effect may not be apparent until after several doses. Unlike short-acting beta2 agonists (see Salbutamol), salmeterol is therefore not suitable for the symptomatic relief of an acute attack of bronchospasm. However, it is long-acting with a duration of action of about 12 hours and is indicated where the regular use of a long-acting beta2 agonist is required for persistent reversible airways obstruction, as in chronic asthma or in some patients with chronic obstructive pulmonary disease. It may be useful in protecting against nocturnal and exercise-induced asthma attacks. Short-acting beta2 agonists (on an as-required basis) and regular anti-inflammatory therapy should continue to be used. Salmeterol is used in the form of the xinafoate doses are expressed in terms of the equivalent amount of salmeterol salmeterol xinafoate 1.45 micrograms is equivalentto about 1 microgram of salmeterol. The usual dose is 50 micrograms of salmeterol twice daily from a metered-dose aerosol or dry powder inhaler if necessary, up to 100 micrograms may be inhaled twice daily. For doses of salmeterol used in children, see Administration in Children, below.

Administration in children. For persistent reversible airways obstruction which requires regular bronchodilatation, including nocturnal asthma and prevention of exercise-induced asthma, children aged 4 to 12 years may be given 50 micrograms of salmeterol twice daily by inhalation.

Asthma. Salmeterol is a long-acting beta2 agonist (duration of action about 12 hours). Guidelines on the management of asthma, generally recommend that salmeterol should be reserved for use in patients with chronic asthma who have already progressed to inhaled corticosteroids it is not a substitute for corticosteroids. Evidence suggests 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. Salmeterol may also be useful in controlling persistent nocturnal asthma or preventing exercise-induced attacks. There is some evidence that after prolonged use, duration of protection against exercise-induced bron-choconstriction is reduced (see Tolerance, above).

Chronic obstructive pulmonary disease. Short-acting beta2 agonists are used as bronchodilators in patients with chronic obstructive pulmonary disease, although there is some evidence to suggest that an antimuscarinic might be preferable. Guidelines indicate that long-acting beta2 agonists such as salmeterol may be used for maintenance therapy in moderate and more severe disease. Improvement in lung function and symptoms has been seen in such patients after regular treatment with inhaled salmeterol a reduction in exacerbations has also been seen. Additional benefit has been reported from the use of salmeterol with inhaled corticosteroids.

Preparations

Proprietary Preparations

 

Argentina: Abrilar Serevent

Australia:: Serevent

Austria: Serevent

Belgium: Serevent

Brazil: Serevent

Canada: Serevent

Chile: Kolpovent Serevent Xemos

Czech Republic: Serevent

Denmark: Serevent

Finland: Serevent

France: Serevent

Germany: Aeromax Serevent

Greece: Serevent

Hong Kong: Serevent

Hungary: Serevent

India: Salmeter Serobid

Indonesia: Serevent

Ireland: Serevent

Israel: Serevent

Italy: Arial Salmetedur Serevent

Japan: Serevent

Malaysia: Serevent

Mexico: Serevent

The Netherlands: Serevent

Norway: Serevent

New Zealand: Serevent

Philippines: Serevent

Poland: Serevent

Portugal: Dilamax Serevent Ultrabeta

Russia: Seretide Serevent

South Africa: Serevent

Singapore Serevent

Spain: Beglan Betamican Inaspir Serevent

Sweden: Serevent

Switzerland: Serevent

Thailand: Serevent

Turkey: Astmerole Serevent

UK: Serevent

USA: Serevent

Venezuela: Salmeter Salspray Serevent

Multi-ingredient

Argentina: Flutivent Neumotide Seretide

Australia: Seretide

Austria: Seretide Viani

Belgium: Seretide

Brazil: Seretide

Canada: Advair

Chile: Aero metro I Plus Aurituss Brexotide Seretide

Czech Republic: Duaspir Seretide

Denmark: Seretide

Finland: Seretide

France: Seretide

Germany: Atmadisc Viani

Greece: Seretide Viani

Hong Kong: Seretide

Hungary: Seretide Thoreus

India: Forair Seretide Seroflo

Indonesia: Seretide

Ireland: Seretide

Israel: Seretide

Italy: Aliflus Seretide

Malaysia: Seretide

Mexico: Seretide

The Netherlands: Seretide Viani

Norway: Seretide

New Zealand: Seretide

Philippines: Seretide

Poland: Seretide

Portugal: Brisomax Maizar Seretaide Veraspir

South Africa: Seretide

Singapore: Seretide

Spain: Anasma Brisair Inaladuo Plusvent Seretide

Sweden: Seretide

Switzerland: Seretide

Thailand: Seretide

Turkey: Seretide

UK: Seretide

USA: Advair

Venezuela: Seretide.

 

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