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FLIXOVATE - FLIXOVATE - CT 9987 - English version

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Introduction FLIXOVATE 0.05% cream 30 g tube (CIP code: 336 839-6) FLIXOVATE 0.005% ointment 30 g tube (CIP code: 336 841-0) Posted on May 25 2011 Active substance (DCI) fluticasone propionate Dermatologie - Nouvelle indication Pas d’avantage clinique démontré dans la prise en charge de la dermatite atopique chez le nourrisson de 3 à 12 mois FLIXOVATE 0,05 %, crème et 0,005 %, pommade est désormais indiqué dans la dermatite atopique du nourrisson de 3 à 12 mois.La fluticasone, comme les autres dermocorticoïdes d’activité forte, ne doit être utilisée chez le nourrisson que de façon exceptionnelle, en deuxième intention, c'est-à-dire en cas de dermatite atopique sévère résistante aux émollients et aux dermocorticoïdes d’activité modérée.Le traitement doit être de courte durée, appliqué sur de petites surfaces en évitant les plis et les zones génitales. Il ne doit pas être appliqué sur le visage. Pour en savoir plus, téléchargez la synthèse ou l'avis complet de FLIXOVATE. ATC Code D07AC17 Laboratory / Manufacturer GLAXOSMITHKLINE FLIXOVATE 0.05% cream 30 g tube (CIP code: 336 839-6) FLIXOVATE 0.005% ointment 30 g tube (CIP code: 336 841-0) Posted on May 25 2011
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The legally binding text is the original French version  TRANSPARENCY COMMITTEE
 OPINION  25 May 2011   FLIXOVATE 0.05% cream 30 g tube (CIP code: 336 839-6)  FLIXOVATE 0.005% ointment 30 g tube (CIP code: 336 841-0)   Applicant: GLAXOSMITHKLINE  fluticasone propionate ATC code: D07AC17  List I  Date of Marketing Authorisation: 06/12/1993 Corrections:  - 24/05/2000: extension of indication to children aged 1 year and older, and amendment of dosage schedule - extension of  25/06/2001:indication to prevention of recurrence of atopic dermatitis in adults and children aged 1 year and older. - 03/07/2003: to the indication "prevention of recurrence of atopic dermatitis in adults and children aged 1 year and older", clarification concerning method of administration using the fingertip unit. -atopic dermatitis in infants aged 3 months and 13/07/2010: extension of indication to older   Reason for request: on the list of medicines refundable by National Health Inclusion Insurance and approved for hospital use in the extension of indication to atopic dermatitis in infants aged 3 months and older.          Medical, Economic and Public Health Assessment Division
 
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1
CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Fluticasone propionate  
1.2. Indication "Infants aged 3 months and over: -atopic dermatitis.  Adults, children aged 12 months and over: 1. Indications in which topical corticosteroid therapy is agreed to be the best treatment: - contact dermatitis; - dermatitis (for curative treatment and prevention of recurrence); atopic - lichenification.  2. Indications in which topical corticosteroid therapy is one of the usual treatments: - stasis dermatitis; - psoriasis (except if there are very extensive plaques); - lichen; - prurigo; non-parasitic - dyshidrosis; - genital lichen sclerosus; - granuloma annulare; - discoid lupus erythematosus; - dermatitis, except on the face; seborrheic - treatment of pruritus caused by mycosis fungoides. symptomatic  3. Indications for a brief course of treatment: - insect bites and prurigo caused by parasites following treatment of the aetiology.  The ointment form is especially appropriate for dry or scaly lesions " .  
1.3. Dosage “ osage D  Infants aged 3 months and over: One application per day.  Adults and children from 1 year of age: One or two applications per day.  943 patients aged between 3 months and 14 years were treated with fluticasone propionate (cream, lotion or ointment), of whom 63 were children aged between 3 months and 1 year who were treated for atopic dermatitis. The duration of treatment was less than or equal to four weeks. The efficacy and tolerance of a longer course of treatment and of treatment for other dermatological conditions are not well understood. An increase in the number of daily applications carries a risk of increasing adverse effects without improving the therapeutic effect.
 
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Some skin diseases (e.g. psoriasis, atopic dermatitis) require gradual tapering of treatment. This can be done by reducing the frequency of application and/or by using a less potent or less concentrated corticosteroid.  Prevention of recurrence of atopic dermatitis: One application per day, on two days per week. After effective treatment of the acute episode, Flixovate should be applied to zones in which lesions have previously occurred or which are at risk of recurrence.  Patients are advised to use emollient products daily while using this product. Efficacy and tolerance have been evaluated using clinical trials with treatment periods of between 16 and 20 weeks.  Method of administration For adults, children and infants aged 3 months and over, the fingertip unit method can be used in order to apply the appropriate quantity of cream to a given surface area. The fingertip unit corresponds to the quantity of cream squeezed out along the length of the first finger joint of an adult's index finger. This quantity is enough to treat a surface area equivalent to the flat of 2 adult hands (around 250-300 cm2). A fingertip unit corresponds to 0.5 of the g product. A 30 g tube contains 60 fingertip units.  Treatment of large surface areas requires monitoring of the number of tubes that are used.  The advice is to apply the product sparingly, and then to spread it by rubbing gently until it is fully absorbed."    
 
2 SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification (2011) D Dermatologicals D07 Corticosteroids, derm D07A Corticosteroids, plain D07AC Corticosteroids, pote D07AC17 Fluticasone  
atological preparations  nt (group III)
2.2. Medicines in the same therapeutic category 2.2.1. Strictly comparable medicines Potent topical corticosteroids in the form of creams or ointments, indicated in the treatment of atopic dermatitis (see table 1).  
The indications for these proprietary medicinal products make no mention of age limits for use, but in the SPC (special warnings and precautions for use) it is stated that it is preferable to avoid potent corticosteroids in infants: "In infants, potent corticosteroids should preferably be avoided. In particular, care must be taken to avoid occlusion, which can occur in skin folds or under nappies." "Because corticosteroids pass into the general circulation, treatment of  large areas or areas that are occluded can lead to systemic effects of corticosteroid therapy, particularly in infants and young children. consist of Cushingoid features and growth These
 
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retardation; these effects are reversible once treatment is stopped, but sudden cessation of treatment may be followed by acute adrenal suppression."
 Table 1: potent topical corticosteroids  
INN
Amcinonide Betamethasone dipropionate Betamethasone valerate Desonide Diflucortolone Difluprednate Hydrocortisone-17-butyrate
Hydrocortisone aceponate
Betamethasone dipropionate Betamethasone valerate Diflucortolone
Proprietary medicinal product Creams PENTICORT DIPROSONE BETNEVAL LOCATOP NERISONE EPITOPIC LOCOID
EFFICORT
Ointments DIPROSONE BETNEVAL NERISONE NERISONE GRAS LOCOID
Concentration
0.1% cream 0.05% cream 0.1% cream 0.1% cream 0.1% cream 0.05% cream 0.1% cream Thick cream 0.127% Hydrophilic cream Lipophilic cream
0.05% 0.1% 0.1% 0.1% 0.1%
Hydrocortisone-17-butyrate    2.2.2. Medicines that are not strictly comparable  Topical corticosteroids with moderate potency in the form of creams or ointments, indicated in the treatment of atopic dermatitis (see table 2).  As for potent topical corticosteroids, the indication for these proprietary medicinal products do not mention age limits for use, but in the SPC (precautions for use) it is stated that it is preferable to avoid topical corticosteroids of moderate potency in infants aged under 12 months.  Table 2:topical corticosteroids with moderate activity 
Desonide Desonide
Fluocortolone  
INN
Proprietary medicinal products
Creams LOCAPRED TRIDESONIT Ointment ULTRALAN
Concentration
0.1% 0.05%
0.05%
2.3. Medicines with a similar therapeutic aim The other treatments that are used in atopic dermatitis in infants aged under 1 year are emollient agents (DEXERYL, cold cream)  Other products used to treat atopic dermatitis are not authorised in infants aged 1 year or under: % tacrolimus (PROTOPIC): asecond-line for treatmentsevere atopic dermatitis in adults who are resistant or intolerant to conventional treatments (0.1% and 0.03% presentations) and for severe atopic dermatitis in children (2 years and over) who are resistant to conventional treatments (0.03% presentation)
 
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% ciclosporin: severe forms in which other therapies have failed, to be used in adults only.    
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ANALYSIS OF AVAILABLE DATA
  3.1. Efficacy Efficacy data for the extension of indication are drawn from results involving patients aged between 3 months and 1 year who were included in the studies on which FLIXOVATE's MA for the cream, ointment and lotion forms is based: five efficacy studies (FLT001, FLT002, PFC40002, PFL30003, PFL30004) and three tolerance studies with efficacy as a secondary endpoint (PFC40001, PFO40003 and PFL10005).  Study FLT001: Comparison: fluticasone propionate (FP) 0.05% cream once daily versus twice daily in the treatment of patients with eczema. Method: randomised double-blind study lasting four weeks. Patients included: 270 patients with moderate to severe eczema aged between 4 months and 62 years, of whom one was aged between 4 and 12 months. Primary endpoint: physician global assessment1(PGA) and assessment of signs and 2 symptoms by the doctor .  Results: Just one patient was in the age range that is relevant to this MA extension (between 3 and 12 months). This patient received two applications of FP per day. In this child, the investigator considered the improvement to be excellent (at least a 75% improvement) after one week of treatment. total symptom score fell from 9.0 to 0.5.The    Study FLT002: Comparison: fluticasone propionate (FP) 0.005% ointment once daily versus twice daily in the treatment of patients with atopic eczema. Method: randomised double-blind study lasting four weeks. Patients included: 248 patients with moderate to severe eczema aged between 8 months and 65 years, of whom one was aged between 8 and 12 months. Primary efficacy endpoint: physician global assessment3(PGA) Secondary endpoint: assessment of signs and symptoms by investigator.4  Results: Just one patient was in the age range that is relevant to this MA extension (between 3 and 12 months), and this patient received 2 applications of FP per day. In this child, the
                                            1lesions), excellent result (70-100%), good result (50-75%), limited resultPGA is a six-point scale: cure (100% of atio exacerbation). 2symptomsgns and noo  fisvElaauit ( nga ,varg25%) (< sultr rep oo%0,)525-(ion, crust niheic lonticafietsilb ,tamrof rdnes: reruris, pt ihut,sni,gkcne f3e oromfr ( 0seab )tn3 otes( erevormaitno ,suni g acs.)e: cscalint n-po  PGA: a seve ure (100% of lesions), good result (marked improvement), moderate result (moderate improvement), poor result (slight improvement), aggravation (exacerbation), severe aggravation (4recaxe dekramEon).bati  valuation of signs and symptoms: redness, pruritus, thickening, lichenification, desquamation, using a score from 0 (absent) to 3 (severe).  
 
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investigator considered that the lesions were 100% cured, with the exception of a residual change in colour, after one week of treatment. The total symptom score fell from 9.5 to 1.5.  Study PFC40002: Comparison: the main objective of this study was to evaluate FP 0.05% cream versus placebo as a maintenance treatment for atopic dermatitis. This indication in infants aged 3 months and over was not in compliance with the MA, and only the results of the initial phase of the study, as a curative treatment, will be presented. Method: in the initial phase of the study, as a curative treatment, all patients were treated for four weeks with two applications of FP per day, although the validated dosage is one application per day. Patients included: 372 patients aged between 2 months and 63 years, 19 of whom were aged between 3 and 12 months, with moderate to severe atopic dermatitis.  Results: Of the 19 patients aged between 3 and 12 months who were included in the study, 17 responded to treatment of the acute episode (PGA5  2 and score 1 for each of the three signs and symptoms (redness, pruritus and papule formation/induration/oedema). Of these patients, 12 were randomised to receive FP treatment and 5 to placebo. The percentage of patients who experienced relapse was 17% in the FP arm and 40% in the placebo arm.  Study PFL30003: Comparison: FP 0.05% lotion once daily versus placebo (excipient) in patients with atopic dermatitis. Method: randomised double-blind study lasting four weeks. Patients included:220patients aged between 3 months and 87 years,18 of whom were aged between 3 and 12 months, with moderate to severe atopic dermatitis. Primary efficacy endpoint: patients with "global therapeutic success" defined by a cure of at least 50% of lesions (PGA6) in addition to improvement or no change in at least 75% of the 20 symptom assessments.  Results:  "Global therapeutic success" was obtained for 9 of the 12 patients treated with FP and for 4 of the 6 patients treated with placebo, after a mean treatment period of 23 days.   Study PFL30004: Comparison: FP 0.05% lotion once daily versus placebo (excipient) in patients with atopic dermatitis. Method: randomised double-blind study lasting four weeks. Patients included: 219 patients aged between 3 months and 87 years,10 of whom were aged between 3 and 12 months, with moderate to severe atopic dermatitis.
                                            5 Physician Global Assessment: a six-point scale (0=cure, 1=near cure, 2=marked improvement, 3=modest improvement, 4=no change, 5=exacerbation or aggravation). 6Physician Global Assessment: Atopic dermatitis was evaluated by the investigator in the four regions of the body (head/neck, trunk, upper limbs, lower limbs), with a seven-point score based on the percentage of body surface area affected. Global efficacy evaluation was based on comparison of percentage of body surface area affected at inclusion and at the end of treatment, with a six-point score where 0=cure (100% of lesions cured), 1=near cure (90-99%) 2=marked improvement (50-89%), 3=modest improvement (less than 50%), 4=no change, 5=exacerbation.  
 
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Primary efficacy endpoint: patients with "global therapeutic success" defined by a cure of at least 50% of lesions (PGA3) in addition to improvement or no change in at least 75% of the 20 symptom assessments.  Results: "Global therapeutic success" was obtained for four of the five patients treated with FP and for none of the five patients treated with placebo, after a mean treatment period of 30 days. As the protocols for studies PFL30003 and PFL30004 were identical, their results were combined, and "global therapeutic success" was therefore obtained for 13 of 17 patients who were treated with FP and for 4 of 11 patients who received placebo.  Studies FPC40001, FPO30003 and FPL10005 These were three non-comparative studies, the main objective of which was to explore the effects of FP on systemic cortisol levels. Assessment of efficacy was a secondary objective. Study FPC40001 involved 49 patients with eczema or psoriasis aged between 3 months and 6 years, of whomeight were between 3 and 12 months old. The patients were treated with FP 0.05% cream twice daily for a maximum of four weeks. Study FPO40003 involved 40 patients with atopic dermatitis aged between 4 months and 6 years, of whomseven were between 3 and 12 months old. The patients were treated with FP 0.005% ointment twice daily for a maximum of four weeks. Study FPL10005 involved 44 patients with eczema or psoriasis aged between 4 months and 6 years, of whom10 were between 3 and 12 months old. The patients were treated with FP lotion twice daily for a maximum of four weeks. In studies FPC40001 and FPL1005, redness, pruritus, papule formation, lichenification, oozing/crust formation, desquamation, induration and excoriation were evaluated on a 0-3 scale (0=absent, 1=mild, 2=moderate and 3=severe), with a maximum global signs and symptoms score of 24 points. The mean total signs and symptoms score was reduced from 13.4 to 3.3 in study FPC40001 and from 14.7 to 3.1 in the FPL10005, after a maximum treatment period of four weeks.  In study FPO40003, redness, pruritus, papule formation/infiltration, oozing/crust formation/erosion and desquamation were evaluated on a 0-3 scale (0=absent, 1=mild, 2=moderate and 3=severe), with a maximum global signs and symptoms score of 15 points. The mean total signs and symptoms score was reduced from 12.4 to 1.7 after a maximum treatment period of four weeks.  
3.2. Tolerance In the eight clinical efficacy and tolerance studies described above, 63 patients aged between 3 and 12 months were treated with FP, with a mean duration of exposure of between 7 and 30 days, and up to 126 days for the FPC40002 study of FP as a maintenance treatment. Patients received one or two applications of FP per day in the short studies, and two applications per week in study FPC40002.  Two adverse events that were attributable to the treatment were reported: one case of raised AST levels and one case of skin dryness in some of the treated areas.  No specific adjustment for infants aged 3 months and over was made to the section "Adverse effects" in the summary of product characteristics (SPC).  In the section "Special warnings and precautions for use" it is stated that because topical corticosteroids enter the general circulation, treatment of large or occluded areas (skin folds or under nappies) can cause the systemic effects of corticosteroid
 
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therapy, in particular in infants and young children. These effects are Cushingoid features and growth retardation.  Systemic tolerance studies: FPC40001, FPO40003 and FPL10005 These were three non-comparative studies, the main objective of which was to explore the effects of FP on the hypothalamic-pituitary-adrenal axis. A total of 133 patients were included in these studies, of whom 25 were aged between 3 and 12 months. Patients who were included were considered to be "at risk" of systemic adverse events following topical corticosteroid treatment, because they had extensive fissured or scaled lesions causing recurring exacerbation of moderate to severe eczema. These studies evaluated adrenal response after a simulation test using tetracosactide (a cosyntropine with an activity similar to that of ACTH) before and after treatment with FP. The results showed that FP applied twice daily for up to four weeks had a weak impact on the hypothalamic-pituitary-adrenal axis, even in infants aged between 3 and 12 months with a severe and very extensive inflammatory dermatosis.  No data are available about the effect on FP on growth and bone health.  The most recent PSUR, covering the period between 1 March 2006 and 28 February 2010, showed no new tolerance concerns.  
3.3. Conclusion The efficacy of fluticasone propionate 0.05% cream and 0.005% ointment in atopic dermatitis in infants aged 3 months and over has been shown using data from five efficacy studies and three tolerance studies, in which data from infants aged between 3 and 12 months were analysed separately (sub-group identified after the fact). This population of infants that corresponds to the population stated in the extension of the MA that was analysed by the Committee only represents between 1% and 23% of those included in these studies: a total of 74 children, 63 of whom were treated with fluticasone propionate and 11 with the excipient. In three of these studies, the patients had an inflammatory skin disease that was not atopic dermatitis (psoriasis, which is not part of the indication analysed by the Committee). Patients were treated with fluticasone propionate as a cream, ointment or lotion, applied once or (in most cases) twice daily. The latter dosage was not approved in the Marketing Authorisation. The efficacy studies were randomised, and their objective was to compare the two dosage levels applied once or twice daily (two studies), to compare two formulations applied once daily versus the excipient of the lotion (two studies), or to compare fluticasone propionate with placebo as an intermittent maintenance treatment. The main objective of the non-comparative tolerance studies was to examine systemic effects of fluticasone propionate on the hypothalamic-pituitary-adrenal axis when applied to the skin. In these studies, efficacy criteria were used as secondary endpoints. In the two patients with eczema aged between 3 and 12 months of the 518 patients included, improvement in lesions after 1 week of treatment was 75% and 100% respectively (two applications per day). In the 28 patients with eczema or psoriasis aged between 3 and 12 months of the 439 patients included, an improvement of at least 50% in lesions, associated with improvement or no change in at least 75% of the 20 symptom assessments, was observed in 13 of the 17 patients treated with fluticasone propionate, compared with 4 of the 11 patients treated with the excipient, after a mean treatment period of three-four weeks. In an open-label non-comparative study, 17/19 patients aged between 3 and 12 months with atopic dermatitis who were treated with fluticasone propionate experienced a cure, a near-cure or marked improvement in their lesions after a mean treatment period of 22 days. In the 18 patients aged between 3 and 12 months with eczema or psoriasis (indication not included in AM) of a total of 93 patients included, the total signs and symptoms score fell from 13.4 to 3.3 of a maximum of 24 points in one study, and from 14.7 to 3.1 in another study, with a maximum treatment period of four weeks. 
 
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In the 7 patients aged between 3 and 12 months with atopic dermatitis, of a total of 40 included, the mean total signs and symptoms score fell from 12.4 to 1.7 of a maximum of 15 points after a maximum treatment period of four weeks.  In the three tolerance studies that studied the effect of fluticasone propionate on the hypothalamic-pituitary-adrenal axis, cortisol levels before and after tetracosactide stimulation were similar before and after treatment with FP applied twice daily for up to four weeks in the 25 patients in the study who were aged between 3 and 12 months (of a total of 133 patients who were included). Nevertheless, the SPC states that particular attention should be paid to the risk of systemic absorption in infants, if large surface areas or occluded areas are treated, as this could cause Cushingoid symptoms and growth retardation.   4 TRANSPARENCY COMMITTEE CONCLUSIONS
 The transparency Committee has been provided with clinical data about the indications for FLIXOVATE treatment in infants aged 3 months and over. The Committee has noted these new data, which will not change the actual benefit provided by FLIXOVATE, which remains significant in infants aged between 3 and 12 months with severe atopic dermatitis that is resistant to emollient agents and moderately potent topical corticosteroids, only under the conditions of use described below.  The Committee would like to reiterate the therapeutic strategy for the treatment of atopic dermatitis in children,7 particularlythe role of FLIXOVATE in this treatment infants, and strategy: Atopic dermatitis mainly affects infants, and in more than 80% of cases it disappears before adolescence. It can have a severe effect on the quality of life of the child and his/her family. Other complications are secondary infection and lichenification.  Emollients have been shown to be effective against skin dryness and in the prevention of recurrence, and it is recommended that these be applied immediately after bathing, onto slightly damp skin, preferably twice daily.  If emollient agents fail, topical corticosteroids are used, as they are in adults.  Very potent topical corticosteroids must not be used for children. Potent topical corticosteroids can be used in exceptional cases and as short courses of treatment, in highly inflammatory or highly lichenified forms involving the extremities. Moderately potent topical corticosteroids are used on the face, skin folds and genital areas and for infants. However, it is preferable to avoid the use of potent and moderately potent topical corticosteroids in infants, because of the risk of occlusion in skin folds and under nappies, which leads to greater systemic absorption. Creams are to be preferred for oozing lesions and in skin folds, ointments on dry and lichenified lesions, and lotions on the scalp. The dosage is one application per day until the lesions clear up. There are no data to support a particular dosage of topical corticosteroids per kg of body weight that should not be exceeded. Topical corticosteroids are used to treat the acute phase and as a maintenance treatment to prevent recurrence (in children aged 1 year and older), though such use has not been subject to detailed assessment. Light therapy is not recommended for children.
                                            7 Consensus conference: Management of atopic dermatitis in children. French Society of Dermatology. Ann Dermatol Venerol 2005; 132: 1S19-33 
 
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Topical tacrolimus 0.03% is only authorised for atopic dermatitis if the following criteria are met: age > 2 years, severe form of disease that is resistant to conventional treatments. Ciclosporin is only authorised for adults who have severe forms of the condition in whom other therapies have failed. Topical or systemic antibiotic treatment can be given if secondary bacterial infection is confirmed (Staphylococcus aureus).
As a result, fluticasone propionate, like other potent topical corticosteroids, is a second-line treatment for atopic dermatitis in infants aged between 3 and 12 months, which should be used in exceptional cases of severe atopic dermatitis that is resistant to emollients and to moderately potent topical corticosteroids. It must be used as a short course of treatment on small surface areas. Skin folds and genital areas should be avoided, and it must not be used on the face.  FLIXOVATE does not provide an improvement in actual benefit (IAB V) in the therapeutic strategy for treating atopic dermatitis in infants aged between 3 and 12 months.  As FLIXOVATE can only be used in exceptional cases of atopic dermatitis in infants aged between 3 and 12 months, the target population is unlikely to alter substantially.  The Committee recommends inclusion of FLIXOVATE on the list of medicines refundable by National Insurance and on the list of medicines approved for use in hospitals and various public services in the treatment of atopic dermatitis in infants aged between 3 and 12 months, under the conditions for use described above.  Packaging: Appropriate for the prescription conditions Reimbursement rate: 65%.  The Committee wishes to receive the following information within the next two years: % changes to proportions of prescriptions of FLIXOVATE with respect to weak topical corticosteroids and other potent topical corticosteroids for children aged between 3 and 12 months between 2010 and 2012 % the conditions in which FLIXOVATE is used (second-line treatment, length of treatment courses, treatments given in combination) in this population.
 
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