New Medicines Committee Briefing January 2014
Fluticasone furoate (Avamys®) nasal spray suspension
Fluticasone furoate to be reviewed for use within:
Primary Care Secondary Care
Summary:
Avamys® is licensed for the treatment of the symptoms of allergic rhinitis in adults and children aged 6 years and over.
Fluticasone furoate is a synthetic corticosteroid with a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action.
The SMC accepted fluticasone furoate for the treatment of the symptoms of allergic rhinitis in adults, adolescents (12 years and over) and children (6 to 11 years). However, prescribers should be aware that the recommended doses of fluticasone furoate are not equivalent to fluticasone propionate nasal sprays. In addition other intranasal steroids are available at a lower cost.
An active-comparator study randomised adult patients with seasonal allergic rhinitis to fluticasone furoate, fluticasone propionate or placebo. Fluticasone furoate was found to be non-inferior to fluticasone propionate in reducing the reflective Total Nasal Symptom Score (rTNSS).
In perennial allergic rhinitis, one open-label, active-controlled study in adults showed there to be no significant difference in fluticasone furoate and mometasone furoate reducing the rTNSS.
Caution is recommended when co-administering fluticasone furoate with potent CYP3A4 inhibitors (as it may increase systemic exposure of fluticasone furoate).
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Formulary application:
Ears, Nose and Throat:
Consultant & Clinical Director submitting application: Mr Gareth Rowlands (Consultant Surgeon ENT)
Mr Rowlands has requested that Avamys® (fluticasone furoate) be considered for inclusion in the North Staffordshire Joint Formulary (NSJF) for the treatment of allergic rhinitis, chronic rhinosinusitis and maintenance treatment in patients with nasal polyps. In the application Mr Rowlands explains that from his experience, patients who have been previously taking Flixonase® have switched to Avamys® and have found this preparation to be more effective and easier to tolerate. He adds that patients comment on the ease of the spray mechanism, the fine mist and the lack of smell and taste in the mouth following use. It is estimated that 7 patients per week will be commenced on this drug on a long-term basis. He has indicated that the cost of this drug per patient will be £36.12 per year.
Please note: an application for the addition of Avamys® (fluticasone furoate) to the NSJF was submitted to the New Medicines Committee in January 2010. The addition was rejected on the grounds that the patient treatment group was small. The non-formulary route was suggested for Avamys® prescribing if needed.
Background:
Allergic rhinitis is an inflammatory disorder of the nose which occurs when the membranes lining the nose become sensitised to allergens. Although not classed as a life-threatening disease, allergic rhinitis can reduce the patient’s quality of life.
It is characterised by nasal symptoms including: anterior or posterior rhinorrhoea, sneezing, nasal blockage and/or itching of the nose. It is often accompanied with symptoms involving the eyes (allergic conjunctivitis), throat and ears. 1,2,3
Chronic rhinosinusitis with nasal polyps is a condition represented with inflammatory changes throughout the nose and sinuses from a group of disorders which all lead to swelling and overgrowth of the nasal mucosa.9
Allergen avoidance is essential in the management of allergic rhinitis. Drug treatment may be necessary to prevent and control frequent or persistent symptoms, especially if nasal obstruction/polyps are present.1 Intranasal corticosteroids are considered more effective than oral antihistamines at relieving most nasal symptoms. They provide potent anti-inflammatory activity locally at the nasal mucosa while limiting systemic corticosteroid effects.3,4 They may be used with or without nasal surgery in the treatment of chronic rhinosinusitis with nasal polyps.9
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Several corticosteroids are formulated for intranasal use, including beclometasone, budesonide, flunisolide, fluticasone, mometasone furoate and triamcinolone. Spray preparations are preferred as drops may have an increased risk of systemic side effects.4,5
Fluticasone furoate is a synthetic, lipophilic, trifluorinated glucocorticoid receptor agonist. Although the exact mechanism of action in allergic rhinitis is not known, it is claimed that this steroid has potent anti- inflammatory actions though its high affinity and selectivity for the glucocorticoid receptor.3, 5
Current formulary status:
The North Staffordshire Joint Formulary currently lists the following:
12.2 DRUGS ACTING ON THE NOSE
12.2.1 Drugs used in nasal allergy Antihistamines Azelastine Corticosteroids Beclometasone 1st line for the treatment and prophylaxis of allergic perennial rhinitis (beclomethasone) Budesonide Recommendation: Licensed for the treatment of nasal polyps 2nd line for the treatment and prophylaxis of allergic perennial rhinitis Mometasone Recommendation: Licensed for the treatment of nasal polyps Cromoglicate Sodium cromoglicate (sodium cromoglycate)
Licensed indication6
Avamys® is indicated in adults, adolescents and children (six years and over) for the treatment of the symptoms of allergic rhinitis.
Dosage and administration4,6
Avamys® nasal spray is for administration by the intranasal route only.
Adults and adolescents (12 years and over) The recommended starting dose is two spray actuations (27.5 micrograms of fluticasone furoate per spray actuation) in each nostril once daily (total daily dose, 110 micrograms). Once adequate control of symptoms is achieved, dose reduction to one spray actuation in each nostril (total daily dose 55 micrograms) may be effective for maintenance.
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The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
Children (6 to 11 years of age) The recommended starting dose is one spray actuation (27.5 micrograms of fluticasone furoate per spray actuation) in each nostril once daily (total daily dose, 55 micrograms). Patients not adequately responding to one spray actuation in each nostril once daily (total daily dose, 55 micrograms) may use two spray actuations in each nostril once daily (total daily dose, 110 micrograms). Once adequate control of symptoms is achieved, dose reduction to one spray actuation in each nostril once daily (total daily dose, 55 micrograms) is recommended.
Elderly Patients & Renally Impaired Patients: No dose adjustment is required
Hepatic Impaired Patients: No dose adjustment is required in mild to moderate hepatic impairment. The manufacturer states that that they have no data in patients with severe hepatic impairment.
The intranasal device should be shaken before use. The device is primed by pressing the mist release button for at least six spray actuations (until a fine mist is seen), whilst holding the device upright. Re-priming (approximately 6 sprays until a fine mist is seen) is only necessary if the cap is left off for 5 days or the intranasal device has not been used for 30 days or more.
The device should be cleaned after each use and the cap replaced.
Guidance:
NICE Guidance published No
Scottish Medicines Consortium7
SMC recommend Fluticasone furoate (Avamys®) use within NHS Scotland: Yes
Fluticasone furoate (Avamys®) has been accepted for use in NHS Scotland for the treatment of the symptoms of allergic rhinitis in adults, adolescents (12 years and over) and children (6 to 11 years). Evidence to support its efficacy comes from a number of comparator and placebo-controlled studies conducted in adults and children with seasonal and perennial allergic rhinitis. Prescribers should be aware that the recommended doses of fluticasone furoate are not equivalent, on a microgram per microgram basis, to other fluticasone nasal sprays currently available. The SMC noted that although they accept the use within NHS Scotland, other intranasal steroids are available at a lower cost.7
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All Wales Medicines Strategy Group (AWMSG) No
MTRAC
MTRAC Reviewed No
Cochrane:8,9 Yes
In 2009, Cochrane reviewed the therapeutic effectiveness and adverse event profiles of topical nasal steroids for intermittent and persistent allergic rhinitis in children. In the review, after assessment of trial quality, only three trials involving a total of 79 participants were included in the review (trials were excluded due to the use of ‘rescue’ medication which the authors state may have confounded the results). All three trials compared topical nasal steroids (Beconase® and flunisolide) against placebo. Cochrane concluded that the included trials provided weak and unreliable evidence for the effectiveness of Beconase® and flunisolide for the treatment of allergic rhinitis in children. Until more research is available, decisions on the use of topical steroids should be guided by the physician’s clinical experience and patients’ individual circumstances and preferences.8
Another Cochrane review was published in 2012 assessing the effects of corticosteroids delivered into the nose by spray (topical delivery) on chronic rhinosinusitis with nasal polyps. In the review, forty studies were included (total of 3624 patients). The primary outcomes were sino-nasal symptoms, poly size and polyp recurrence after surgery. Cochrane concluded that when compared to placebo, topical corticosteroids were overall beneficial in the treatment of nasal polyps. They were found to be effective in reducing symptoms, nasal obstruction and the size of the polyps. Cochrane added that topical corticosteroids also prevented polyp recurrence after surgery. There was no difference in the reported side-effects between topical corticosteroids and placebo and the benefits definitely outweigh the risks.9
Efficacy:
The manufacturer states that compared to placebo, Avamys® has been shown to significantly improve nasal (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) and ocular symptoms (comprising itching/burning, tearing/watering and redness of the eyes) associated with seasonal allergic rhinitis and perennial allergic rhinitis in adults.6,10
The Scottish Medicines Consortium reviewed efficacy data provided from 15 randomised double-blind studies. Nine efficacy studies recruited adult patients with seasonal allergic rhinitis, of which six were
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placebo-controlled (two with an active control arm), and three had active comparators (two versus an oral antihistamine and one versus fluticasone propionate nasal spray). Four efficacy studies (one of which included an active comparator arm, mometasone furoate) recruited adult patients with perennial allergic rhinitis. Paediatric data were provided from one placebo-controlled trial in seasonal allergic rhinitis and one in perennial allergic rhinitis. All patients were allocated to fluticasone furoate nasal spray at licensed doses.7
All patients were required to have a documented history of seasonal allergic rhinitis or perennial allergic rhinitis, based on clinical history of nasal allergy symptoms and immunological evidence, to have adequate exposure to relevant antigen(s) and to be symptomatic at the time of randomisation according to symptom- score criteria which differed between studies. The primary efficacy outcome was based on patients’ assessment of nasal symptoms in all studies comparing change from baseline between treatment arms. Ocular symptoms and disease-specific quality of life measures were also assessed in most studies.7
One active-comparator study randomised adult seasonal allergic rhinitis Japanese patients in the cedar pollen season to fluticasone furoate nasal spray 110micrograms daily (n = 151) or matching placebo (n = 72) and to fluticasone propionate nasal spray 100micrograms twice daily (n = 148) or matching placebo (n = 75) for two weeks. The design was double-blind for the active-placebo comparisons but allocation between the active treatment arms was blinded to investigators only (because of practical dosing concerns). The primary outcome was change from baseline in a Total Nasal Symptom Score defined as the sum of three individual 4-point symptom scores for sneezing, rhinorrhoea and nasal congestion (3TNSS). Each was scored from 0 = no symptom to 3 = severe, giving a maximum score of 9.4 Most other trials used a four-item score (4TNSS) which also assessed nasal itching and gave a maximum score of 12. As in other trials the primary assessment of TNSS was reflective (rTNSS - reflecting symptoms over the previous 12 hours) rather than instantaneous (iTNSS - at the time of assessment).7
In the active-comparator trial non-inferiority would be concluded if the upper limit of the 97.5% one-sided confidence interval in the per-protocol population did not exceed 0.75 for the difference in change from baseline in r3TNSS comparing fluticasone furoate nasal spray and fluticasone propionate nasal spray. The adjusted mean reduction from baseline was 1.06 for fluticasone propionate nasal spray and 1.23 for fluticasone furoate nasal spray representing a difference of 0.173 (95% confidence intervals: -0.51 to 0.17), verifying the non-inferiority of fluticasone furoate nasal spray. No baseline values were given. A significant reduction from placebo was observed at day 1 with fluticasone furoate nasal spray and at day 2 with fluticasone propionate nasal spray. Changes in 4TNSS were similar to those in 3TNSS. No outcomes relating to ocular symptoms or quality of life were reported in this trial.11
The problem with this comparative study of fluticasone furoate nasal spray versus fluticasone propionate nasal spray in seasonal allergic rhinitis is that the primary analysis of the trial was a non-inferiority analysis and the European Medicines Agency (EMEA) notes that non-inferiority trials are not possible in seasonal allergic / perennial allergic rhinitis due to lack of sensitivity in outcome measures.7
Two active-controlled seasonal allergic rhinitis trials showed significantly greater reductions in reflective and
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instantaneous nasal symptom scores for fluticasone furoate nasal spray compared with oral fexofenadine 180mg once daily as well as greater improvements in overall scores from the Rhinitis Quality of Life Questionnaire and ocular symptom scores. Fluticasone furoate nasal spray was also significantly superior to placebo for these measures across a range of trials.7
In perennial allergic rhinitis, one open-label, active-controlled 52-week study was primarily a safety trial investigating the nasal morphology and cytology of patients receiving fluticasone furoate nasal spray 110micrograms daily and mometasone furoate nasal spray 200micrograms daily. Daily rTNSS (assessed primarily as a measure of compliance) was reduced with fluticasone furoate nasal spray by 3.6 from a baseline of 6.2 and with mometasone furoate nasal spray by 3.8 from a baseline of 6.6 representing a treatment difference of 0.2. No other efficacy or quality of life outcomes were reported. The problem with this comparative study versus mometasone furoate nasal spray is that it was primarily a safety study and was not designed to detect treatment differences in efficacy outcomes.7
In two patient-preference studies with the same design a significantly greater proportion of patients with seasonal allergic rhinitis expressed preference for fluticasone furoate nasal spray than for fluticasone propionate nasal spray for the primary endpoint of scent/odour sensory attribute as well as for secondary endpoints of leaking out of nose/down throat, gentleness of mist, and reduced aftertaste. For both studies there were no significant differences between fluticasone furoate nasal spray and fluticasone propionate nasal spray for delivery of consistent amount of medication and comfort of the nose tip.2 In one of the studies, 52% of patients replied that they were very likely to comply with fluticasone furoate nasal spray treatment versus 38% likely compliance with fluticasone propionate nasal spray treatment (P = 0.02) if these medications were to be prescribed.12
Two placebo-controlled studies were conducted in children less than 12 years of age. In a two-week study including patients with seasonal allergic rhinitis (n = 554) there was a significant difference (P = 0.025) for fluticasone furoate nasal spray 110micrograms daily but not fluticasone furoate nasal spray 55micrograms daily versus placebo for the primary endpoint of rTNSS.6 In a 12-week study of perennial allergic rhinitis patients (n = 558), both fluticasone furoate nasal spray 55micrograms daily (P < 0.001) and fluticasone furoate nasal spray 110micrograms daily (P = 0.004) were significantly superior to placebo for iTNSS. For the primary outcome, rTNSS, the difference was significant for 55micrograms daily (P = 0.003) but not 110micrograms daily (P = 0.073).7 There were no significant differences for ocular symptoms in the study of seasonal allergic rhinitis patients.7
A review was undertaken of 35 randomised, placebo-controlled trials of intranasal corticosteroids and seasonal allergic rhinitis published between 1990 and May 2009. It revealed conflicting, inconsistent or even negative effects for most intranasal corticosteroids including mometasone furoate and fluticasone propionate, in managing the ocular symptoms of allergic rhinitis. Only fluticasone furoate nasal spray demonstrated a consistent positive effect on ocular symptoms of seasonal allergic rhinitis compared with placebo in a large number of patients across all of its prospective studies.13
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It is important to note that fluticasone furoate nasal spray has been studied at starting doses but not at the lower maintenance doses. This factor, along with the other problems mentioned above, may influence the generalisability of these studies.7
The SMC also noted that the EMEA’s European Public Assessment Report of fluticasone furoate does not present evidence from any head to head or active comparator efficacy trials, suggesting that the efficacy of fluticasone furoate nasal spray was concluded on the basis of placebo-controlled trials. This is also stated in a review of fluticasone furoate by Kumar R at al.14 Instead, the pharmacodynamics and pharmacokinetic profiles of the available inhaled corticosteroids were compared (fluticasone furoate was found to have a longer half-life and relative receptor affinity compared to fluticasone propionate, mometasone, budesonide and ciclesonide).14
The EMEA comments that treatment effects relating to nasal symptoms in seasonal allergic rhinitis were in the range expected with marketed products that are effective for allergic rhinitis and that those relating to ocular symptoms were in the range expected for oral antihistamines used in clinical practice. In perennial allergic rhinitis, the nasal treatment effects were considered within the range expected for an intranasal corticosteroid currently used in clinical practice.7, 10
Safety and adverse effects:6
Contraindications: Hypersensitivity to active substances or excipients.
Renal & hepatic impairment: The SPC states that no dose adjustments are required in renal impairment and in mild to moderate hepatic impairment. There is no data for use in patients with severe hepatic impairment and the manufacturers advise caution in these patients.
Undesirable effects: Adverse events associated with fluticasone furoate include: epistaxis (Very common ≥1/10 patients), nasal ulceration (Common ≥1/100 patients), headaches (Common ≥1/100 patients) and hypersensitivity reactions (anaphylaxis is stated as rare: less than 1 case per 1000 patients).
The manufacturer also stated that systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. Growth retardation has been reported in children receiving nasal corticosteroids.
For a comprehensive list of adverse effects, refer to the Summary of Product Characteristics (SPC).
Drug Interactions:6
The manufacturer states that fluticasone furoate is rapidly cleared by extensive first pass metabolism mediated by the cytochrome P450 3A4. Caution is recommended when co-administering fluticasone furoate
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with potent CYP3A4 inhibitors (e.g. ketoconazole) as it may increase systemic exposure of fluticasone furoate. Avamys® should not be co-administered with ritonavir for this reason.6,14
For additional information, please refer to the Summaries of Product Characteristics.
Other considerations:6
Dosage Forms: Avamys® nasal spray is a white suspension that delivers 27.5 micrograms of fluticasone furoate per each spray actuation. It is contained in a predominantly off-white plastic device with a dose indicator window, light blue side actuated lever and lid which contains a stopper. The device design is claimed as easy to use (See Figure 1).2 The nasal spray device has a side-actuation (comfortable to hold and easy to operate), a viewing window (allowing the patient to see how much medication is left) and low volume spray delivery (the steroid is delivered as a fine mist), minimising the amount of liquid running down the back of the patient’s throat or dripping from the 2, 3 nostrils. Fig. 1- Design characteristics of the 3 fluticasone furoate nasal spray device
Storage: fluticasone furoate does not require any special storage conditions. The product should be stored upright with the cap on and should not be refrigerated or frozen.
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Cost analysis:
Current Expenditure of fluticasone furoate and other commonly used intranasal steroids across the Health Economy from October 2012 – September 2013 UHNS, Lloyds & STOKE CCG NORTH STAFF CCG Drug ePACT Spend Spend Spend Beconase® (beclometasone dipropionate) £272.54 50 micrograms/ spray Rhinocort Aqua® (budesonide) £23.05 64 micrograms/ spray DATA Syntaris ® (flunisolide) £0 25 micrograms/ spray AWAITED Avamys®(fluticasone furoate) £476.73 27.5 micrograms / spray Flixonase® (fluticasone propionate) £1,385.10 50 micrograms/ spray Nasonex® (mometasone furoate) £2,991.57 50 micrograms/ spray Nasacort® (triamcinolone) £23.46 55 micrograms/ spray
Cost of intranasal steroids:
Dose (as No. of Cost at UHNS Cost in primary Intranasal steroid Strength sprays per sprays per pack care per pack* nostril) per pack (exc VAT) (exc VAT)
Beconase® 50 micrograms/ (beclometasone 2 sprays BD 200 £0.95 £2.12 (generic) spray dipropionate) Rhinocort Aqua® 64 micrograms/ 2 sprays OD 120 £3.07 £3.85 (generic) (budesonide) spray
25 micrograms/ Syntaris® (flunisolide) 2 sprays BD 240 £5.05 £5.05** spray 27.5 Avamys® micrograms / 2 sprays OD 120 £6.44 £6.44 (fluticasone furoate) spray Flixonase® £4.40 50 micrograms/ (fluticasone 2 sprays OD 150 £11.01 spray (generic) propionate) Nasonex® 50 micrograms/ 2 sprays OD 140 £6.59 £7.68 (mometasone furoate) spray
Nasacort® 55 micrograms/ 2 sprays OD 120 £7.39 £7.39 (triamcinolone) spray
*Primary care costs were obtained Drug Tariff December 2013.15 **Costs unavailable in the Drug Tariff. Costs obtained from the C&D.16
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References
1 Clinical Knowledge Summaries. Allergic rhinitis. November 2012. Available at: http://cks.nice.org.uk/allergic- rhinitis#azTab
Produced by Monjur Rahman Ali Specialist Rotational Pharmacist Medicines Management University Hospital of North Staffordshire Telephone: 01782 674542 e-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.
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