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flutiform® (fluticasone propionate/formoterol): growing evidence for effective asthma management

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ADVERTISEMENT FEATURE FUNDED AND EDITED BY NAPP PHARMACEUTICALS LTD

Fflux

Fflux

 

flutiform

flutiform is the first pressurised metered-dose inhaler to combine the ICS, fluticasone propionate, with the fast-acting inhaled LABA, formoterol.2

flutiform is licensed for asthma maintenance therapy for patients 12 years and older (low and medium strengths), adults (all strengths).2

Guidelines from the British Thoracic Society / Scottish Intercollegiate Guidelines Network (BTS/SIGN) recommend inhaled corticosteroids (ICS) in combination with long-acting β2-agonists (LABA) in patients with asthma that is not controlled with an ICS alone.3 Once asthma is under control, the dose of ICS can be stepped down to avoid potential side effects. The guidelines recommend that in stable patients it is reasonable to attempt to halve the dose of ICS every three months.3

Recent data from a trial named FFLUX, (a pragmatic open-label, randomised controlled, non-inferiority trial in adult patients with asthma) have shown that:

  • Switching from Seretide® Evohaler® 250/25 μg to flutiform 250/10 μg can maintain patient outcomes4
  • Patients on flutiform 250 μg can be stepped down to 125 μg and maintain good asthma control5

Switching from Seretide Evohaler to flutiform

In phase I of the FFLUX study of 225 patients with controlled or partially controlled asthma on Seretide Evohaler 250 μg, subjects were randomised 2:1 to switch to flutiform 250 μg or remain on Seretide Evohaler 250 μg.4

Patients switched to flutiform 250 μg had non-inferior asthma control (assessed using the 7-item Asthma Control Questionnaire (mean difference [95%CI] -0.11[-0.31,0.09])

However in this study flutiform 250 μg patients had significantly higher odds of being more controlled (according to Global Initiative for Asthma [GINA] criteria) than with Seretide Evohaler 250 μg (odds ratio [95% CI]2.04 [1.16, 3.59], p=0.01).4

A previous retrospective study, effectiveness, showed that 88.4% of 164 patients were switched successfully to flutiform from Seretide Evohaler.

Primary endpoint, change success, defined as ≥70% of patients receiving ≥1 prescriptions of flutiform in the 6 months following therapy change (not including first prescription).6

Furthermore, in phase 2 of the effectiveness study, which was a 2 year retrospective database study in 153 asthma patients 12-80 years, flutiform was a non-inferior to Seretide Evohaler in terms of “no severe exacerbations”.*

Patients switching to flutiform from Seretide Evohaler did not experience an increase in severe exacerbations, defined as asthma-related inpatient or emergency room attendance, or acute courses of oral corticosteroids.

The secondary endpoint of the study showed that patients had a 22% mean relative reduction in asthma-related GP consultations (mean consultations with or without prescription of oral steroids
(1.4 vs 1.8; p = 0.001)7

 

*Lower limit of non-inferiority set at -12.5%, lower 95% CI of mean treatment difference = -4.5%, demonstrating non-inferiority.

Stepping down effectively with flutiform

In Phase II of the FFLUX study, 116 adults who had been stable on flutiform 250/10 μg for 12 weeks, were randomised 1:1 to remain on flutiform 250/10 μg or step down to flutiform 125/5 μg.5

At 12 weeks, patients continued to maintain good asthma control. flutiform 125/5 μg was non-inferior to flutiform 250/10 μg in terms of asthma control when assessed by ACQ7 (mean difference [95% CI],0.01 [-0.20, 0.22]) non-inferiority limit on AcQ7 was set at 0.03.

There was no evidence of significant differences between groups in other measures, including asthma-related exacerbations, quality of life, and forced expiratory volume in the first second (FEV1) % predicted.5

Further evidence also shows that in long-term studies patients on flutiform had a low rate of severe exacerbations.8

Dr Omar Usmani, Clinical Senior Lecturer and Consultant Physician in Respiratory Medicine at the National Heart and Lung Institute (NHLI), Imperial College London & Royal Brompton Hospital (RBH) and a member of the steering group for the study, comments on phase II of the FFLUX trial:

“These data show that stepping down to flutiform treatment based on the BTS/SIGN guidelines is a safe and appropriate way to manage asthma. This evidence is crucial to making good decisions regarding asthma management and provides reassurance on stepping down patients successfully”

Implications for clinical practice

  • Switching from Seretide Evohaler to flutiform and stepping down can maintain patient outcomes4,5
  • flutiform can offer drug cost savings compared with Seretide Evohaler across all three doses.9

References

  1. Asthma UK. Time to take action on asthma. 2014.
  2. flutiform® Summary of Product Characteristics. Available at: www.medicines.org.uk/emc/medicine/26954. Accessed November 2016.
  3. British Thoracic Society / Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma: A national clinical guideline. 2016. Available at: https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2016/. Accessed November 2016.
  4. Kemppinen A, Gardener E, Thomas V et al. Pragmatic trial comparing continuing Seretide MDI with changing to flutiform in asthma. J Thorac Dis 2016;8(Suppl 5):AB038.
  5. Kemppinen A, Gardener E, Thomas V et al. Pragmatic trial stepping down flutiform in patients maintained on high dose ICS. J Thorac Dis 2016;8(Suppl 5):AB039.
  6. Lim D, Small I, Wolfe S, et al. Real world effectiveness of changing fixed-dose combination therapy from Seretide MDI to flutiform in UK asthma patients. Late breaking abstract presented at the 7th World Conference of the International Primary Care Respiratory Group; May 21–24, 2014; Athens, Greece.
  7. Lim D, Small I, Wolfe S, et al. Effectiveness of fluticasone-propionate/salmeterol versus fluticasone-propionate/formoterol in UK patients with asthma. Pragmatic and Observational Research Journal 2015;6:34–35. Abstract 22.
  8. Papi A, Mansur AH, Dissanayake S, Pertseva T, Kaiser K, McIver T, Grothe B, Dissanayake S. Long-term fluticasone propionate/formoterol fumarate combination therapy is associated with a low incidence of severe asthma exacerbations. J Aerosol Med Pulm Drug Deliv. 2016;online ahead of print. DOI: 10.1089/jamp.2015.1255. 
  9. Monthly Index of Medical Specialities (MIMS). Available at: www.mims.co.uk/drugs/respiratory-system/asthma-copd. Accessed November 2016.

 

flutiform® (fluticasone propionate and formoterol fumarate) pressurised inhalation suspension

Prescribing Information United Kingdom

Please read the Summary of Product Characteristics before prescribing.

Presentation

Pressurised inhalation suspension, in a pressurised metered dose inhaler (pMDI), containing
fluticasone propionate and formoterol fumarate dihydrate at strengths of 50 µg/5 µg,
125 µg/5 µg or 250 µg/10 µg per actuation.

Indications

Regular treatment of asthma where the use of a combination product (inhaled corticosteroid and
long-acting β2-agonist)is appropriate: For patients not adequately controlled with inhaled
corticosteroids and ‘as required’ inhaled short-acting β2- agonist (SABA), or for patients already
adequately controlled on both an inhaled corticosteroid and a long-acting β2-agonist (LABA). 
flutiform 50 µg/5 µg and 125 µg/5 µg per actuation are indicated for use in adults and adolescents
12 years and above. flutiform 250 µg/10 µg per actuation is only indicated for use in adults.

Dosage and administration For inhalation use. The patient should be shown how to use the
inhaler correctly by a physician or other healthcare professional.

Patients should be given the strength of flutiform containing the appropriate fluticasone propionate
dose for their disease severity (note that flutiform 50 µg/5 µg per actuation is not appropriate in
patients with severe asthma). The appropriate strength should be taken as two inhalations,
twice-daily (normally in the morning and evening) and used every day, even when asymptomatic.

flutiform should not be used in children under 12 years. Prescribers should be aware that in
asthmatics, fluticasone propionate is as effective as some other inhaled steroids when administered
at approximately half the total daily microgram dose. Total daily dose can be increased if asthma
remains poorly controlled by administering a higher strength inhaler. Appropriate doses of the 
β2-agonist and inhaled corticosteroid (ICS) in separate inhalers, or the ICS alone, should be 
prescribed if a patient requires doses outside the recommended dose regimens. Patients should be
assessed regularly and once asthma is controlled, treatment should be reviewed and stepped down
to the lowest effective dose, or an ICS alone. It is extremely important to regularly review 
patients as their treatment is stepped down. ICSs alone are first line treatment for most patients.
flutiform is not intended for initial treatment of mild asthma. For patients with severe asthma the
ICS therapy should be established before prescribing a fixed- dose combination product. 
Patients on flutiform must not use an additional LABA. An inhaled SABA should be taken for 
immediate relief of asthma symptoms arising between doses. The AeroChamber Plus® spacer device
is recommended in patients who find it difficult to use inhalers; re-titration should always follow
the introduction of a spacer device. Patients should be advised to contact their prescriber when
the flutiform dose counter is getting near zero.

Contra-indications Hypersensitivity to the active substances or to any of the excipients.

Precautions and warnings

flutiform should not be used for the first treatment of asthma, to treat acute asthma symptoms or
for prophylaxis of exercise-induced asthma. It should not be initiated during an exacerbation,
during significantly worsening or acutely deteriorating asthma, and should not be stopped abruptly.
Patients should use their flutiform maintenance treatment as prescribed, even when asymptomatic.
If a patient experiences serious asthma-related adverse events or exacerbations, they should
continue treatment but also seek medical advice. Patients should be reviewed as soon as possible
if there is any indication of deteriorating asthma control. In the case of sudden and progressive
deterioration, which is potentially life-threatening, an urgent medical assessment should be
carried out. Use with caution in patients with: pulmonary tuberculosis; quiescent tuberculosis;
fungal, viral or other infections of the airway; thyrotoxicosis; pheochromocytoma; diabetes
mellitus (consider additional blood sugar controls); uncorrected hypokalaemia; predisposition to
low levels of serum potassium; impaired adrenal function (monitor HPA axis function regularly);
hypertrophic obstructive cardiomyopathy; idiopathic subvalvular aortic stenosis; severe
hypertension; aneurysm or other severe cardiovascular disorders. There is risk of potentially
serious hypokalaemia with high doses of β2-agonists or concomitant treatment with β2-agonists and
drugs that can induce or potentiate a hypokalaemic effect. Particular caution is recommended in
unstable or acute severe asthma and other conditions when the likelihood for hypokalemia adverse
effects is increased. Monitoring of serum potassium levels is recommended during these
circumstances. Formoterol may induce prolongation of the QTc interval. Caution must be observed
when treating patients with existing prolongation of QTc interval.

flutiform should be discontinued immediately if there is evidence of paradoxical bronchospasm.
Systemic effects with an ICS may occur, particularly at high doses for prolonged periods or when
combined with potent CYP3A4 inhibitors, but are less likely than with oral corticosteroids. Use of
a spacer device may also cause an increased systemic exposure. Increased exposure can be expected
in patients with severe hepatic impairment. Prolonged treatment with high doses of corticosteroids
may result in adrenal suppression and acute adrenal crisis, particularly in adolescents and
children or potentially as a result of trauma, surgery, infection or rapid dose reduction. Patients
should be advised that flutiform contains a small amount of ethanol; however this negligible amount
does not pose a risk to patients. flutiform is not recommended in children under 12 years of age.

Interactions

Caution is advised in long-term co-administration with strong CYP3A4 inhibitors (e.g. ritonavir,
atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole and
telithromycin); co-administration should be avoided if possible.

Ritonavir in particular should be avoided, unless the benefits outweigh the risks of systemic
side-effects.

Caution is advised with use of non-potassium sparing diuretics (e.g. loop or thiazide), xanthine
derivatives, glucocorticosteroids, L-Dopa, L-thyroxine, oxytocin, alcohol or other adrenergic
drugs. There is an increased risk of arrhythmias in patients receiving concomitant anaesthesia with
halogenated hydrocarbons. Hypokalaemia may increase the risk of arrhythmias in patients being
treated with digitalis glycosides.

Concomitant use of β-adrenergic drugs can have a potentially additive effect.
Caution should be taken when using formoterol fumarate with drugs known to prolong the QTc
interval, such as tricyclic antidepressants or MAOIs (and for two weeks following their
discontinuation), as well as antipsychotics (including phenothiazines), quinidine, disopyramide,
procainamide and antihistamines. Concomitant use of an MAOI or a similar agent, such as
furazolidone or procarbazine, may precipitate hypertensive reactions. β-blockers and formoterol
fumarate may inhibit the effect of each other.

β-blockers may produce severe bronchospasm in asthma patients, and they should not normally be
treated with β-blockers including those that are used as eye drops to treat glaucoma. Under certain
circumstances, e.g. as prophylaxis after myocardial infarction, cardioselective β-blockers could be
considered with caution.

Pregnancy and lactation

flutiform is not recommended during pregnancy. It should only be considered if benefits to the
mother outweigh risks to the foetus. It is not known whether fluticasone propionate or formoterol
are excreted in breast milk; a risk to the breast feeding infant cannot be excluded. A decision
should be made on whether to discontinue breastfeeding or discontinue/abstain from flutiform.

Side-effects Potentially serious side-effects: hyperglycaemia; depression; aggression; behavioural
changes (predominantly in children); paradoxical bronchospasm; agitation; vertigo; palpitations;
ventricular extrasystoles; angina pectoris; tachycardia; hypertension; dyspnoea; peripheral oedema;
Cushings Syndrome; adrenal suppression; growth retardation; cataract and glaucoma; hypersensitivity
reactions and QTc interval prolongation. Please consult the SPC for details of non-serious side-
effects and those reported for the individual molecules.

Legal category POM

Package quantities and price

One inhaler containing 120 actuations

50 µg/5 µg - £14.40

125 µg/5 µg - £28.00

250 µg/10 µg - £45.56

Marketing Authorisation numbers

PL 16950/0167 PL 16950/0168 PL16950/0169

Marketing Authorisation holder

Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0GW, UK, Tel: 01223 424444. Member of the Napp Pharmaceutical Group

For medical information enquiries, please contact medicalinformationuk@napp.co.uk

Date of preparation July 2015

Date effective August 2015 UK/FLUT-15085

® FLUTIFORM is a registered trademark of Jagotec AG, and is used under licence.

® The ‘lung’ device (logo) is a registered trademark of Mundipharma AG.

® AEROCHAMBER and AEROCHAMBER PLUS are registered trademarks of Trudell Medical International.

® SERETIDE and ® EVOHALER are registered trademarks of the GlaxoSmithKline group of companies.

 Adverse events should be reported. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Napp Pharmaceuticals Limited on 01223 424444.

UK/FLUT-16075a Date of preparation February 2017

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