Eosinophilic Esophagitis (EoE) Prof. Dr. Stephan Miehlke & Prof. Dr. Stephen Attwood

Transcription

1 Eosinophilic Esophagitis (EoE) Prof. Dr. Stephan Miehlke & Prof. Dr. Stephen Attwood

2 Eosinophilic esophagitis (EoE) The information in this brochure is intended exclusively for physicians and pharmacists. The contents are based on state-of-the-art science. Please see the current summary of product characteristics for the therapeutic indications and prescribing information. Publisher DR. FALK PHARMA GmbH Leinenweberstr Freiburg Germany Fax: / zentrale@drfalkpharma.de Dr. Falk Pharma GmbH All rights reserved. 1st edition 2018

3 Eosinophilic Esophagitis (EoE) Prof. Dr. Stephan Miehlke & Prof. Dr. Stephen Attwood 3

4 Eosinophilic esophagitis (EoE) Authors addresses: Prof. Dr. Stephan Miehlke Center for Digestive Diseases Internal Medicine Center Eppendorfer Landstraße Hamburg Germany and Center for Esophageal Diseases University Hospital Eppendorf Martinistraße Hamburg Germany Prof. Stephen E Attwood Durham University Stockton Road Durham DH1 3LE United Kingdom

5 Contents Introduction and background 4 Definition 6 Clinical picture 8 Clinical course 10 Epidemiology 12 Pathophysiology 14 Diagnosis 16 Treatment 21 Summary and outlook 36 Additional literature 37 Profile: Jorveza 38 Administration 39 References 40 3

6 Eosinophilic esophagitis (EoE) Introduction and background Eosinophilic esophagitis (EoE) is a chronic, immune-mediated, inflammatory disease of the esophagus that has received increasing attention since the early 2000s. Today, it is the second most common inflammatory disease of the esophagus after gastroesophageal reflux disease (GERD) and is a commonly underestimated cause of dysphagia and bolus obstruction in children and adults. 1,2 The disease was first described as a separate clinico-pathologic condition in ,4 Numerous epidemiological studies have found an increase in the incidence and prevalence of EoE in the past 20 years. 5 Current population-based studies reveal an incidence of 1.7 and a prevalence of 16.1 per 100,000 inhabitants in adults in Europe 2 with large geographic fluctuations. EoE is thus considered an orphan disease. In principle, EoE may occur at any age. The peak age is between 30 and 50. 6,7 Males are at a significantly higher risk both during childhood and adulthood. 2 If left untreated, EoE progresses with persistent symptoms and inflammatory processes that lead to esophageal strictures and functional disorders of the esophagus. 8 Over the long term, patients are measurably impaired in their quality of life and psychosocial adaptability, but these can be significantly alleviated with effective therapy. 9 Treatment goals with EoE include induction and maintenance of clinical and histological remission, prevention of complications, and quality-of-life improvement and/or normalization. 10 4

7 New findings from scientific studies have made it necessary to update the current clinical guidelines. The European Society of Eosinophilic Oesophagitis (EUREOS), founded in 2014, published its new consensus recommendations on eosinophilic esophagitis in These guidelines recommend treating definitively diagnosed EoE with topical corticosteroids (budesonide, fluticasone), proton-pump inhibitors (PPIs) or an elimination diet. To date, however, no medication has been officially approved for the indication. With Jorveza (active substance: budesonide), the first topical corticosteroid is now licensed and available with strong remission rates and good tolerability, as shown in large randomized and controlled clinical studies. 5

8 Eosinophilic esophagitis (EoE) Definition EoE is defined as a chronic, locally immune-mediated disease of the esophagus that is clinically characterized by esophageal dysfunction and histologically characterized by an eosinophil-rich inflammation. Other systemic and local causes associated with eosinophilia of the esophagus should be ruled out. These include, among others, gastroesophageal reflux disease (GERD), eosinophilic gastroenteritis, parasitic infections, Crohn's disease, etc. 8 In previous years, patients with abnormal ph values were defined as GERD patients and GERD and EoE were considered mutually exclusive disorders. Since 2011, EoE patients that respond to PPI therapy regardless of their ph values have been designated as PPI-responsive esophageal eosinophilia (PPI-REE) patients. However, in the subsequent years it has been found that PPI-REE and EoE do not differ in any practical sense, including clinical characteristics, ph values, endoscopic features, histological characteristics or genetic characteristics (see Table 1), with the exception of the response to PPI therapy. As a result, the current guidelines classify PPI-REE patients as a subgroup of EoE and no longer classify them along the GERD continuum. Unlike earlier definitions, EoE and GERD may also coexist with or without reciprocal influences. ph monitoring to rule out GERD is no longer required. 8 The clinical effect of PPI in EoE patients is likely based on the acid-independent eotaxin-3- blocking effect. 11 6

9 Comparison of EoE PPI-REE GERD 12 EoE PPI-responsive EoE (formerly PPI-REE) GERD Age Children + adults Children + adults Adults > children Sex Male predominance Male predominance Men = women Dominant symptom Dysphagia, bolus obstruction Dysphagia, bolus obstruction Heartburn, regurgitation Endoscopic findings Normal < 10%, edema, exudate, furrows, rings, strictures Normal < 10%, edema, exudate, furrows, rings, strictures Normal 70 80%, erosions, ulcerations, strictures, Barrett's esophagus Histology Eosinophils (> 15 eos/hpf), mast cells Eosinophils (> 15 eos/hpf), mast cells Neutrophils, lymphocytes, few eosinophils (< 5 10 eos/hpf) Acid reflux detectable with ph monitoring Rare Occasional Common Etiology Food allergens, airborne allergens Unclear Acid/Non-acid reflux Immune response/cytokines TH2 Eotaxin-3, IL-5, IL-13 TH2 Eotaxin-3, IL-5, IL-13 TH1 IL-8, MCP-1, RANTES EoE transcriptome analysis Similar gene expression to PPI-REE Similar gene expression to EoE Not available Table 1 7

10 Eosinophilic esophagitis (EoE) Clinical picture Dysphagia, bolus obstruction and chest pain unrelated to swallowing rank among the most common symptoms in adolescents and adults. Other symptoms include heartburn and regurgitation. In younger children and infants, EoE more commonly manifests as non-specific symptoms, such as reflux-related conditions, nausea, vomiting, abdominal pain, refusal to eat or growth disorders 8 (see Table 2). Many patients develop adaptive eating strategies in order to avoid symptoms: e.g. prolonged chewing, drinking copious amounts of liquids, avoiding certain foods. As a result, patients should be asked targeted questions during the medical history interview to find out whether they have experienced difficulty swallowing and any corresponding actions related to solid foods in order to grasp the extent of the patient's condition. Many patients exhibit a predisposition to atopy (hay fever, asthma, atopic eczema), but it remains unclear whether atopic diathesis predisposes for EoE. 8 In addition, there are often IgE-mediated food allergies, which are able to be confirmed in some cases through serological tests or skin tests. Elevated serum IgE is detectable in many cases. 13 However, due to the fact that EoE is not IgE-mediated in the majority of cases, an IgE-based allergy test is usually unable to identify the responsible allergens. There is no association with celiac disease. If atopy, bolus obstruction, PPI non-response, and elevated serum IgE or blood eosinophilia occur together, then there is a high likelihood of EoE. 14 8

11 Clinical manifestation of EoE 15 CHILDREN Vomiting Abdominal pain Chest pain Heartburn Cough ADULTS Dysphagia Bolus obstruction Retrosternal chest pain Heartburn Regurgitation Reduced appetite Dysphagia Refusal to eat Growth disorder Gagging Regurgitation Sleep disorders Table 2 9

12 Eosinophilic esophagitis (EoE) Clinical course The long-term prognosis of EoE is not yet completely clear. But much of the evidence suggests that EoE is a progressive disorder. Untreated EoE is usually associated with persistent symptoms and inflammation, leading to esophageal remodeling resulting in stricture formation and functional abnormalities 8 (see Fig. 1). The longer the interval without treatment, the greater the risk of esophageal stricture formation (see Fig. 2). 17 Time-dependent endoscopic progression of EoE without treatment 17 Normal esophagus Fibrosis Inflammation Inflammation + fibrosis Endoscopic features at the time of EoE diagnosis (%) > 2 5 > 5 8 > 8 11 > > > > 20 Delay in diagnosis (years) Figure 1 10

13 The progressive character of the disorder is also supported by manometric measurements that demonstrate an increase in abnormal esophageal motility with longer disease duration. 16 EoE also has a significant impact on the quality of life and psychosocial adaptability in patients themselves as well as in the familial environment of pediatric patients. Symptom improvement with therapy is accompanied by measurable improvements in the qualify of life. 9 There is currently no evidence that EoE is associated with an increased risk for malignant esophageal diseases. 8 Stricture formation rates based on time without treatment EoE patients without strictures (%) Duration of untreated EoE (in years) Figure 2 11

14 Eosinophilic esophagitis (EoE) Epidemiology As epidemiological studies in Europe have made clear, the incidence and prevalence of EoE has increased in the last 2 decades (see Fig. 3). 5 But EoE is still considered an orphan disease. However, the data on incidence are subject to broad variability, which is in part due to regional differences and differing study designs. In Europe, average incidence rates of 1.7 and prevalence rates of 16.1 per 100,000 inhabitants have been reported for EoE 2 with quite dramatic regional differences in some cases (see Fig. 3). The prevalence rate is thus well below the upper limit of 50 per 100,000 inhabitants for orphan diseases. For patients with esophageal symptoms that undergo gastroscopy, the prevalence is 7%. In patients with dysphagia and bolus obstruction, the prevalence increases to 23 50%. In children, the incidence is and the prevalence is per 100,000 inhabitants. 8 EoE can occur at any age. Peak ages include late adolescence and between the ages of 30 and 50. Males have a 2 to 3 times higher risk of developing the disease. 8 12

15 Prevalence of EoE in Europe 5 Denmark 1997 P: P: 13.8 Netherlands P: 4.1 Spain, Cáceres region 2016 P: 80 Southern Denmark P: 2.3 Switzerland, Olten District P: P: 42.8 Switzerland, Canton of Vaud 2004 P: P: 24.1 Spain, Castile-La Mancha region P: 44.6 Figure 3 P = Prevalence All values per 100,000 inhabitants 13

16 Eosinophilic esophagitis (EoE) Pathophysiology Both environmental and food allergies as well as genetic factors play a role in the pathogenesis of EoE (see Fig. 4 and 5). Other atopic disorders, such as allergic asthma, atopic eczema or allergic rhinitis frequently occur simultaneously. But whether atopy facilitates the development of EoE remains unclear Pathogenesis of EoE 21 Children Refusal to eat Vomiting Abdominal pain Dysphagia Food impaction Adults Hypertrophy and smooth muscle dysmotility 2 Remodeling and fibrosis of the lamina propria 3 Hyperplasia and reduced epithelial differentiation Organ remodeling and loss of function Figure 4 14

17 Cow's milk, wheat/gluten, eggs, soya, nuts, fish/seafood, and legumes rank among the most important food allergens. 22 In addition, airborne allergens and oral/sublingual immunotherapies have also been discussed as potential triggers of EoE. 23 Common food allergens of EoE Soya Nuts Cow's milk Wheat/Gluten Eggs Fish/Seafood Figure 5 EoE is pathophysiologically based on a TH2 immune response, involving activated eosinophils, mast cells, and the cytokines eotaxin-3, interleukin-5, and interleukin-13. Genetic susceptibility factors (TSLP, CAPN14) have also been described

18 Eosinophilic esophagitis (EoE) Diagnosis EoE is diagnosed on the basis of a combination of clinical symptoms, endoscopy, and histology. Symptoms Typical clinical symptoms in adults include dysphagia and bolus obstruction, as well as regurgitation or chest pain. More common symptoms in children include reflux-related conditions, nausea, vomiting, abdominal pain, refusal to eat or failure to thrive. 8 Validated questionnaires for both adults and children have contributed to a more objective quantification and evaluation of symptoms and disease activity and their impact on quality of life Endoscopy Endoscopic examinations have found white exudates, longitudinal furrows, edematous mucosa with loss of vascular pattern, concentric rings ("trachealization" of the esophagus), fragile esophageal mucosa (crêpe paper mucosa), strictures, and narrow-caliber esophagus (see Fig. 6). 8 A standardized endoscopic classification and grading system called the EREFS score (acronym for Exudates, Rings, Edema, Furrows, and Strictures) has existed since 2013 and can be readily used in routine clinical settings (see Table 3). 28 However, clinical symptoms and endoscopic findings inadequately reflect the disease activity of EoE; as a result, a histological examination is also necessary for diagnosis and monitoring. 29,30 16

19 Examples of endoscopic features typical of EoE Furrows and edema Rings and edema Rings (trachealization), exudate, edema Exudate Stricture formation (high-grade) Extensive narrow-caliber esophagus with secondary finding of blind-ended fistula resulting from perforation following dilation High-grade narrow-caliber esophagus High-grade rings, crêpe paper mucosa (long mucosal outline during biopsy collection) Figure 6 17

20 Eosinophilic esophagitis (EoE) Endoscopic classification of EoE (EREFS) MAJOR FEATURES CLASSIFICATION Mild Moderate Severe Exudates (E) < 10% of the surface of the esophagus > 10% of the surface of the esophagus Rings (R) Subtle circumferential rings Distinct rings, no stenosis Distinct rings, endoscope passage not possible Edema (E) Reduced visibility of mucosal vessels Mucosal vessels completely indiscernible Furrows (F) Vertical lines without visible depth Vertical lines with mucosal depth Strictures (S) Present Lacerations during passage MINOR FEATURES CLASSIFICATION Mild Moderate Severe Crêpe paper mucosa Present Reduced caliber of tubular esophagus Table 3 (modified by Hirano I et al., Gut ) A new endoluminal functional lumen imaging probe, the EndoFLIP system, has demonstrated a significant reduction in esophageal distensibility in EoE patients; but this also does not correlate with the histological inflammatory activity. 31,32 The exact significance of this procedure remains to be conclusively assessed. 18

21 Histology At least 6 biopsies should be taken from different locations of the esophagus (typically proximal, mid and distal), focusing on areas with endoscopic mucosal abnormalities, for histological examination. In justifiable cases of clinically suspected EoE, biopsies should always be taken even if the endoscopic esophageal findings are normal because no visible changes are endoscopically identified in 10 15% of EoE patients. It is also advisable to obtain duodenal and gastric mucosal biopsies upon initial diagnosis in order to exclude eosinophilic gastroenteritis. 8 Hematoxylin-eosin (HE) staining is sufficient for histological assessment of EoE in routine clinical practice. The accepted threshold for eosinophil density for the diagnosis of EoE is 15 eosinophils (eos) per high power field (hpf). Additional typical histological features that may provide evidence without being specific for EoE include eosinophil microabscesses, basal zone hyperplasia, dilated intercellular spaces, eosinophil surface layering, papillary elongation, and fibrosis of the lamina propria 8 (see Fig. 7). Histological signs of EoE Eosinophil-rich inflammatory infiltrate Eosinophil-rich microabscess Figure 7 19

22 Eosinophilic esophagitis (EoE) A validated EoE scoring system (EoEHSS) that evaluates the extent and severity of 8 histological features that are typical of EoE (eosinophil density, basal zone hyperplasia, eosinophil microabscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and fibrosis of the lamina propria) enables the standardized assessment of esophageal biopsies in cases of EoE. 33 Additional diagnostic methods No non-invasive biomarkers are currently available for the diagnosis or monitoring of EoE. Only the absolute blood eosinophil count shows an above-average correlation with esophageal eosinophil density and histological remission under treatment. 34 Minimally invasive methods, such as esophageal string or sponge tests, have produced initially promising results, but require further evaluation. 8 20

23 Treatment Therapeutic goals in the treatment of EoE include the induction of clinical and histological remission, remission maintenance, prevention of complications (bolus obstruction, emergency endoscopy, spontaneous perforation), and improved quality of life. 10 The current EUREOS guidelines recommend treating definitively diagnosed EoE with topical corticosteroids (budesonide, fluticasone), proton-pump inhibitors (PPIs) or an elimination diet (see Fig. 8). Treatment efficacy should be verified endoscopically and histologically at 6 12 weeks. 8 EUREOS algorithm EoE definitively diagnosed (clinically, endoscopically, histologically) PPI THERAPY TOPICAL CORTICOSTEROIDS ELIMINATION DIET No remission Histological remission, persistent symptoms Clinical and histological remission Review alternative options (see above) Strictures/Stenosis Yes No No remission Endoscopic dilation Reevaluation of the diagnosis, review of differential diagnoses Elemental diet Experimental therapies Long-term therapy with effective anti-inflammatory medication or diet Figure 8 (Source: Miehlke S et al., Z Gastroenterol [modified by Lucendo A et al. UEG J ]) 21

24 Eosinophilic esophagitis (EoE) Due to a lack of evidence of efficacy, other medicinal options, such as anti-allergic agents (cromoglicic acid, antihistamines) or biological agents (anti-interleukin-5 antibodies mepolizumab, reslizumab) are currently not recommended. In the case of the azathioprine and mercaptopurine immunomodulators, only isolated positive effects have been observed that were not sufficient to merit a recommendation in the guidelines. 8 Endoscopic dilation should be considered in patients with persistent dysphagia/bolus obstruction despite anti-inflammatory treatment. 8 Topical steroids The strongest scientific evidence involves the topical steroids budesonide and fluticasone. 13 randomized studies have been published to date, of which 9 were placebocontrolled, that prove the high efficacy of these topical steroids in remission induction of EoE (see Table 4). It must be borne in mind that these studies vary considerably with respect to inclusion criteria, dose and application of the active substance, treatment duration, and definition of histological remission. The highest histological remission rates have been achieved to date with budesonide in the Author, year Patients (n) Mean age (years) Konikoff F Straumann B Dohil B Alexander F Butz F Gupta B Miehlke B Dellon B Lucendo B Table 4 T s 22

25 form of an orodispersible tablet (Jorveza ) or a viscous suspension. Jorveza is an orodispersible tablet with a pharmaceutical formula specially developed for the targeted treatment of the esophagus. When taken, the tablet is pressed to the palate with the tip of the tongue and dissolves there slowly over a period of approx. 2 minutes. The tablet's mild effervescent effect stimulates salivation as it dissolves. As the patient continuously swallows the saliva during this period, the active substance is transported to the inflamed mucosa where it readily binds to the mucosa thanks to the adhesive properties of the saliva. Adult patients prefer this mode of administration over syrup. 35 Remission induction of EoE with topical steroids 12 Topical steroid Dosage form Dose/Day Duration (weeks) Histological remission (%)* Fluticasone Spray 2 x 440 μg 12 50/9 Budesonide Suspension 2 x 1 mg 2 72/11 Budesonide Suspension 1 2 mg Weight-adapted 12 87/0 Fluticasone Spray 2 x 880 μg 6 62/0 Fluticasone Spray 2 x 880 μg 12 65/0 Budesonide Budesonide Suspension Orodispersible tablet (Jorveza ), suspension mg Age-adapted 12 94/53/23/6 2 x 1 mg/2 x 2 mg 2 100/95/95/0 Budesonide Suspension 2 x 2 mg 12 39/3 Budesonide Orodispersible tablet (Jorveza ) 2 x 1 mg 6 93/0 * Topical steroid vs. placebo 23

26 Eosinophilic esophagitis (EoE) In current phase II/III studies, treatment with orodispersible budesonide yielded excellent efficacy data. In the phase II study, histological remission (primary endpoint) was achieved in 100% of cases following 2 weeks of treatment with orodispersible budesonide 2 x 1 mg daily (see Fig. 9). 35 In the phase III study, the combined primary endpoint of "clinical/histological remission" was achieved in 58% of patients following 6 weeks of treatment with orodispersible budesonide 2 x 1 mg daily (histological remis- Histological remission with the orodispersible budesonide tablet (Jorveza ) 35,36 Budesonide Placebo Histological remission: < 5 eos/hpf 120 Percentage of patients (%) * 93 * 0 0 * p < Phase II study 2 weeks Phase III study 6 weeks Phase II: Budesonide 2 x 1 mg/day, 2 weeks, n = 76 Phase III: Budesonide 2 x 1 mg/day, 6 weeks, n = 88 Figure 9 24

27 sion 93%, clinical remission 59%) The clinical remission rate increased to 85% by extending the duration of therapy to 12 weeks (see Fig. 10). 39 In addition, a significant improvement in the modified EoE Activity Index (EEsAI) endoscopic instrument score and an endoscopic remission rate of 61% were achieved following 6 weeks of treatment (see Fig. 11) Clinical/Histological remission with the orodispersible budesonide tablet (Jorveza ) Percentage of patients (%) * p < Budesonide 0 Placebo 58 * Histology: < 5 eos/hpf Dysphagia: 2 points (NRS 0 10) Odynophagia: 2 points (NRS 0 10) 85 n = 29 n = 59 n = 23 Week 6 (double-blind, db) Week 12 (db open-label) Phase III: Budesonide 2 x 1 mg/day, 6 weeks; combined, primary endpoint defined as histological and clinical remission. Open-label extension phase (6 weeks): Budesonide 2 x 1 mg/day Figure 10 25

28 Eosinophilic esophagitis (EoE) Modified EEsAI endoscopic instrument score and endoscopic remission with the orodispersible budesonide tablet (Jorveza ) 37 Total Inflammation Fibrosis Change in the modified EEsAI endoscopic instrument score from baseline to week * * -0.4 ** Budesonide Placebo * p < ; ** p = vs. baseline Percentage of patients (%) * 0 Endoscopic Remission week 6 Phase III: Budesonide 2 x 1 mg/day, 6 weeks, n = 88 Figure 11 26

29 The orodispersible dosage form of budesonide 1 mg (Jorveza ) has been approved as the only medication to date for the treatment of EoE in adults. With respect to long-term therapy, there currently only exists a small double-blind study that found that low-dose budesonide therapy of 2 x 0.25 mg/day for a year was able to maintain histological remission in 36% of cases as compared to 0% with placebo. 40 A pediatric study found that remission was maintained in 73% of cases when low-dose therapy with fluticasone (1,760 μg/day) was extended for 3 months following induction therapy. 41 A European phase III trial is currently studying the efficacy and safety of a 1-year remission maintenance therapy with orodispersible budesonide. It has been proven that an effective anti-inflammatory therapy can induce histological remission and stop the progression of the disorders. 8 However, the therapy requirement is long-term; discontinuation of treatment led to a recurrence of the symptoms in most cases (91%). 42 A current study has found that of the 33 EoE patients that achieved long-term deep remission following topical budesonide therapy, 27 patients (82%) suffered a clinical relapse after 22 weeks on average following discontinuation of the topical steroid therapy (see Fig. 12)

30 Eosinophilic esophagitis (EoE) EoE relapse rate following discontinuation of long-term therapy with topical steroids 43 Percentage of patients in deep remission % (n = 26) after 22 weeks (median) Time in weeks Figure 12 Topical steroid therapy has a favorable safety profile overall. No serious side effects have been reported to date. The rate of esophageal candidiasis is up to 10% of patients. 8 In most cases, esophageal candidiasis is asymptomatic and successfully treatable with local anti-mycotic therapy. Systemic steroids are explicitly not recommended for the treatment of EoE. While they may also be effective in short-term therapy, they are associated with a high systemic side-effect rate. 8 28

31 Swallowed nebulized topical steroids are not suitable for esophagus treatment 44 Patient 3 Patient 4 Figure 13 In the past, topical steroid sprays have been used for treating EoE but there is no measure of how much reached the esophagus. Here, patients were directed to spray the formulation into the oral cavity and then swallow instead of inhaling. Problems with using these products are that they are not designed for delivery into the esophagus, and variable amounts of spray may reach the esophagus. Also, the dose and the timing of treatments have not been identified. If nebulised steroids are used this has been clearly shown to have little esophageal steroid exposure. Scintigraphic imaging of 11 EoE patients treated under supervised study conditions revealed a considerable proportion of nebulized topical steroids in the lungs instead of the desirable esophagus (Fig. 13)

32 Eosinophilic esophagitis (EoE) Therapy with proton-pump inhibitors (PPIs) Treatment with PPIs results in a clinical and histological remission in some adult and pediatric patients. 8 The effect of PPIs in patients with EoE is presumably due, among other things, to an acid-independent inhibition of eotaxin-3, a key cytokine in the pathogenesis of EoE. 11 A meta-analysis of 33 studies found histological remission in 50.5% of patients and improved symptoms in 60.8% of patients with PPI treatment. The response tended to be higher at a higher PPI dose (2 x vs. 1 x daily standard dose) and detectable in patients with abnormal ph values. However, the authors of this meta-analysis expressly emphasize the poor quality of the evidence (e.g. no placebo-controlled studies), a significant heterogeneity, and a significant publication bias. 45 In PPI responders, long-term treatment with PPIs may lead to effective remission maintenance. 8 In a current prospective study clinical and histological remission was achieved with a high-dose PPI therapy of 2 x 40 mg omeprazole/day for 8 weeks, but only in 33% of patients. Following the step-down phase to 20 mg omeprazole/day, the remission rate dropped to 12% (see Fig. 14). 46 There are currently no placebo-controlled studies on the treatment of EoE with PPIs, such that the scale of benefit remains unclear overall. In addition, PPIs are currently not approved for the treatment of EoE. 30

33 Efficacy of the step-down therapy in adult patients with PPI-responsive EoE 46 Prospective 121 patients with EoE (therapy-naive) Omeprazole 2 x 40 mg daily 8 weeks Clinical + histological remission (< 15 eos/hpf) n = 40 (33%) 40 patients PPI-REE Omeprazole 80 mg daily 2 p Drop-out 4 p PR* 38 patients TR* Omeprazole 40 mg daily 8 weeks 3 p TR* 3 patients NR* Omeprazole 60 mg daily 31 patients TR* 13 p Drop-out 18 patients TR* Omeprazole 20 mg daily 8 weeks Clinical + histological remission following step-down n = 15 (12%) * TR = total remission, NR = no remission, PR = partial remission Figure 14 31

34 Eosinophilic esophagitis (EoE) Dietary interventions As an approach, the elimination diet represents a causal therapy and may lead to permanent, medication-free, clinical and histological remission. In principle, dietary interventions are possible either through elemental diets, empirical elimination diets or allergy-test-based elimination diets. According to a current meta-analysis that included 33 studies with a total of 1,317 patients (1,128 children, 189 adults), a remission rate of over 90% was able to be achieved with an amino-acidbased elemental diet. 47 However, this form of treatment is hardly of practical benefit due to its poor tolerability, associated restrictions on quality of life, and its often invasive nature (feeding tube). Allergy-test-based elimination diets using the results of skin prick tests, atopy patch tests or IgE blood tests to eliminate certain foods from the diet have a very low sensitivity and poor success rate Overall, the benefit of performing allergy tests to establish elimination diets appears to be rather minimal in the case of EoE patients. 8 In the case of the empirical 6-food elimination diet (6-FED), cow's milk, wheat, soya, eggs, nuts, and seafood are completely eliminated for at least 6 weeks. This approach can achieve histological remission in approx. 70% of cases and clinical improvement in up to 90% of cases (see Table 5)

35 However, an SFED involves considerable dietary restrictions and numerous endoscopic examinations during re-exposure to the eliminated foods. (Endoscopic examinations with biopsies are necessary in order to measure the impact of the diet on inflammation.) An empirical 4-food elimination diet (4-FED; no milk, wheat, eggs, legumes) achieves remission in approx. half of patients, while a 2-food elimination diet (2-FED; no milk, no wheat) achieves remission in approx. 40% of patients. 8 In addition to significant negative impacts on daily routines and quality of life, elimination diets involve an added financial burden on patients. Due to the fact that conventional grocery stores often do not carry the required foods, patients must often rely on expensive specialty suppliers. 51 Using a 3-phase step-up elimination diet (2-4-6), a current prospective multicenter study achieved remission rates of 43%, 60%, and 79% (see Fig. 15). 22 Elimination diets in EoE: meta-analysis 47 Intervention Studies (n) Histological remission (%) Children Adults Children Adults Elemental diet FED* Allergy-test-controlled Table 5 *Wheat, cow's milk, eggs, soya, nuts, seafood 33

36 Eosinophilic esophagitis (EoE) Efficacy of the step-up elimination diet (2-4-6) in EoE 22 Prospective, multicenter, n = 130 (25 children) 100 Histological remission + symptom response (%) FED 60 4-FED 79 6-FED food elimination (milk and gluten-containing grains) 6 weeks > endo + bio* NON-RESPONSE 4-food elimination (milk, gluten-containing grains, eggs, and legumes) 6 weeks > endo + bio* NON-RESPONSE 6-food elimination (milk, gluten-containing grains, eggs, legumes, nuts, and fish/seafood) 6 weeks > endo + bio* Responder > Individual re-exposure > endo + bio * Endo + bio = endoscopy and biopsy Figure 15 34

37 Endoscopic therapy According to a meta-analysis of 9 studies with 525 patients and a total of 992 dilations, symptom improvement was achieved through endoscopic dilation in 75% of cases, whereby the dilation naturally has no impact on the underlying esophageal inflammation. The duration of symptom improvement was highly variable in the analysis. 52 Endoscopic dilation is considered a safe procedure; the rate of clinically relevant complications, such as perforation or bleeding, is below 1%. 53 Chest pain immediately following the procedure was reported by 74% of patients 54 (and by only 2% upon release 52 ). Another current meta-analysis of a total of 37 studies with 977 patients and 2,034 dilations had similar results (see Table 6). 55 Endoscopic dilation in EoE 55 Adverse event (number of contributing studies) Point estimate, % of procedures 95% CI*, % of procedures Perforation (37) Bougienage (23) Balloon dilation (16) Hospitalization (22) Gastrointestinal bleeding (20) Clinically significant chest pain (20) All chest pain (7) Table 6 (modified by Dougherty M et al., Gastrointest Endosc ) * Confidence interval 35

38 Eosinophilic esophagitis (EoE) Summary and outlook EoE is a chronic, progressive, inflammatory disease with a high risk of esophageal stricture formation. Definitive diagnosis is based on the triad of clinical symptoms, endoscopic findings, and histology. Therapeutic options include topical corticosteroids, proton-pump inhibitors, and elimination diets. Therapeutic success (histological remission) requires periodic confirmation by endoscopy/biopsy. Treatment with topical steroids currently provides the broadest body of evidence and demonstrates strong response rates overall with simultaneously above-average tolerability. For the first time, the new orodispersible budesonide tablet (Jorveza ) provides a dosage form tailored specifically to the esophagus for the treatment of EoE that achieves high clinical and histological remission rates with short-term therapy. Generally with respect to long-term treatment of EoE with topical steroids, many open questions remain, which are currently being addressed by ongoing, prospective, multicenter studies with the orodispersible budesonide tablet. Various expert groups are involved in defining the optimal diagnosis and treatment of EoE, including general practitioners, gastroenterologists, pediatricians, pathologists, nutritional therapists, and allergy specialists. As a result, it is important to promote knowledge and awareness of EoE across all participating disciplines. Special attention should be paid in particular to the transition from pediatric medicine to adult medicine. 36

39 Additional available literature Patient guide on Eosinophilic Esophagitis Authors: A. Schoepfer, S. Miehlke, S. Attwood 28 pages (JO80e) We are happy to assist you personally with any further questions. Please contact us at / or Free brochures may be requested from the DR. FALK PHARMA GmbH Leinenweberstr Freiburg Germany Fax: / literaturservice@falkfoundation.de 37

40 Eosinophilic esophagitis (EoE) Profile of Jorveza 1 mg orodispersible tablets 56 Composition Each orodispersible tablet contains 1 mg of budesonide and as another excipient with known effect 26 mg sodium. Pharmaceutical form Jorveza is a round orodispersible tablet with a diameter of 7.1 mm and height of 2.2 mm. Therapeutic indications Jorveza is indicated for the treatment of eosinophilic esophagitis (EoE) in adults (older than 18 years of age). Posology The recommended daily dose is 2 mg budesonide as one 1-mg tablet in the morning and one in the evening. The usual duration of treatment is 6 weeks. For patients who do not respond appropriately during 6 weeks, the treatment can be extended to up to 12 weeks. Special patient populations Jorveza is not recommended for use in patients with hepatic impairment or severe renal impairment. The safety and efficacy of Jorveza in children and adolescents under the age of 18 years has not been established. No data is available. Safety instructions Please see the full prescribing information for contraindications, special warnings and precautions for use, potential drug interaction, information on fertility, pregnancy and lactation as well as an overview of potential side effects. 38

41 Administration Jorveza should be taken after a meal. 2. Jorveza should be placed on the tip of the tongue and gently pressed against the roof of the mouth. Jorveza should not be chewed or swallowed undissolved. 3. Jorveza usually dissolves within 2 minutes. The dissolved material mixed with saliva should be swallowed little by little while the tablet disintegrates. This ensures optimal exposure of the esophageal mucosa to the active ingredient. Approx. 2 min. 4. Jorveza should not be taken with liquid or food. There should be a period of at least 30 minutes before eating, drinking, or performing oral hygiene. 5. Using any oral medications such as liquids, sprays or chewable tablets should be avoided for 30 minutes before or after taking Jorveza. 39

42 Eosinophilic esophagitis (EoE) References 1. Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17): Arias Á, Pérez-Martínez I, Tenías JM, Lucendo AJ. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther. 2016;43(1): Attwood SE, Smyrk TC, Demeester TR, Jones JB. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci. 1993;38(1): Straumann A, Spichtin HP, Bernoulli R, Loosli J, Vögtlin J. Idiopathische eosinophile Ösophagitis: eine häufig verkannte Krankheit mit typischer Klinik und diskretem endoskopischem Bild. Schweiz Med Wochenschr. 1994;124(33): Dellon ES, Hirano I. Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology. 2018;154(2): e3. 6. Hruz P, Straumann A, Bussmann C, Heer P, Simon HU, Zwahlen M, et al. Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County, Switzerland. J Allergy Clin Immunol. 2011;128(6): e5. 7. Dellon ES, Jensen ET, Martin CF, Shaheen NJ, Kappelman MD. Prevalence of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol. 2014;12(4): e1. 8. Lucendo AJ, Molina-Infante J, Arias Á, von Arnim U, Bredenoord AJ, Bussmann C, et al. Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United European Gastroenterol J. 2017;5(3): Klinnert MD, Silveira L, Harris R, Moore W, Atkins D, Fleischer DM, et al. Health-related quality of life over time in children with eosinophilic esophagitis and their families. J Pediatr Gastroenterol Nutr. 2014;59(3): Straumann A, Katzka DA. Diagnosis and treatment of eosinophilic esophagitis. Gastroenterology. 2018;154(2): Cheng E, Zhang X, Huo X, Yu C, Zhang Q, Wang DH, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut. 2013;62(6): Miehlke S, Schlag C, Storr M, von Arnim U. Eosinophile Ösophagitis Update 2017: Neue Leitlinien der europäischen Studiengruppe EUREOS. Z Gastroenterol. 2018;56(2): Simon D, Cianferoni A, Spergel JM, Aceves S, Holbreich M, Venter C, et al. Eosinophilic esophagitis is characterized by a non-ige-mediated food hypersensitivity. Allergy. 2016;71(5): von Arnim U, Röhl FW, Miehlke S, Jechorek D, Reinhold D, Wex T, et al. Clinical symptom tool that raises the index of suspicion for eosinophilic oesophagitis in adults and drives earlier biopsy for definitive diagnosis. Aliment Pharmacol Ther. 2017;45(3): Miehlke S. Clinical features of Eosinophilic esophagitis in children and adults. Best Pract Res Clin Gastroenterol. 2015;29(5): van Rhijn BD, Oors JM, Smout AJ, Bredenoord AJ. Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis. Neurogastroenterol Motil. 2014;26(9):

43 17. Schoepfer AM, Safroneeva E, Bussmann C, Kuchen T, Portmann S, Simon HU, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology. 2013;145(6): e González-Cervera J, Arias Á, Redondo-González O, Cano-Mollinedo MM, Terreehorst I, Lucendo AJ. Association between atopic manifestations and eosinophilic esophagitis. A systematic review and metaanalysis. Ann Allergy Asthma Immunol. 2017;118(5): e Lucendo AJ, Arias Á, Tenias JM. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2014;113(6): Almansa C, Krishna M, Buchner AM, Ghabril MS, Talley N, DeVault KR, et al. Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol. 2009;104(4): O'Shea KM, Aceves SS, Dellon ES, Gupta SK, Spergel JM, Furuta GT, et al. Pathophysiology of eosinophilic esophagitis. Gastroenterology. 2018;154(2): Molina-Infante J, Arias Á, Alcedo J, Garcia-Romero R, Casabona-Frances S, Prieto-Garcia A, et al. Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The study. J Allergy Clin Immunol. 2018;141(4): Miehlke S, Alpan O, Schröder S, Straumann A. Induction of eosinophilic esophagitis by sublingual pollen immunotherapy. Case Rep Gastroenterol. 2013;7(3): Schoepfer AM, Straumann A, Panczak R, Coslovsky M, Kuehni CE, Maurer E, et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology. 2014;147(6): e Dellon ES, Irani AM, Hill MR, Hirano I. Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment Pharmacol Ther. 2013;38(6): Martin LJ, Franciosi JP, Collins MH, Abonia JP, Lee JJ, Hommel KA, et al. Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease. J Allergy Clin Immunol. 2015;135(6): e Franciosi JP, Hommel KA, Bendo CB, King EC, Collins MH, Eby MD, et al. PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity. J Pediatr Gastroenterol Nutr. 2013;57(1): Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut. 2013;62(4): Kim HP, Vance RB, Shaheen NJ, Dellon ES. The prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(9): e Safroneeva E, Straumann A, Coslovsky M, Zwahlen M, Kuehni CE, Panczak R, et al. Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis. Gastroenterology. 2016;150(3): e Kwiatek MA, Hirano I, Kahrilas PJ, Rothe J, Luger D, Pandolfino JE. Mechanical properties of the esophagus in eosinophilic esophagitis. Gastroenterology. 2011;140(1): Nicodème F, Hirano I, Chen J, Robinson K, Lin Z, Xiao Y, et al. Esophageal distensibility as a measure of disease severity in patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2013;11(9): e1. 41

44 Eosinophilic esophagitis (EoE) 33. Collins MH, Martin LJ, Alexander ES, Boyd JT, Sheridan R, He H, et al. Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Dis Esophagus. 2017;30(3): Schlag C, Miehlke S, Heiseke A, Brockow K, Krug A, von Arnim U, et al. Peripheral blood eosinophils and other non-invasive biomarkers can monitor treatment response in eosinophilic oesophagitis. Aliment Pharmacol Ther. 2015;42(9): Miehlke S, Hruz P, Vieth M, Bussmann C, von Arnim U, Bajbouj M, et al. A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis. Gut. 2016;65(3): Lucendo AJ, Miehlke S, Vieth M, Schlag C, von Arnim U, Molina-Infante J, et al. Budesonide Orodispersible Tablets are Highly Effective for Treatment of Active Eosinophilic Esophagitis: Results from a Randomized, Double-Blind, Placebo-Controlled, Pivotal Multicenter Trial (EOS-1). Gastroenterology. 2017;152(5 Suppl 1):S207 [abstract]. 37. Miehlke S, Lucendo AJ, Vieth M, Schlag C, von Arnim U, Molina-Infante J, et al. A randomized, doubleblind, placebo-controlled, pivotal multicenter trial with budesonide orodispersible tablets for treatment of active eosinophilic esophagitis (EOS-1). Oral presentation at: European Academy of Allergy and Clinical Immunology (EAACI) Congress 2017, June 17 21, 2017, Helsinki, Finland. 38. Straumann A, Lucendo AJ, Miehlke S, Vieth M, Schlag C, von Arnim U, et al. Efficacy and safety of budesonide orodispersible tablets in active eosinophilic oesophagitis: results from a randomised, doubleblind, placebo-controlled, pivotal, European multicentre trial (EOS-1). United European Gastroenterol J. 2017;5(5S):OP Lucendo A, Miehlke S, Vieth M, Schlag C, von Arnim U, Molina-Infante J, et al. Prolongation of eosinophilic esophagitis treatment with budesonide orodispersible tablets for incomplete responders is effective and safe: results from a 6-weeks open-label treatment phase of the pivotal trial EOS-1. Digestive Disease Week 2018 [abstract]. 40. Straumann A, Conus S, Degen L, Frei C, Bussmann C, Beglinger C, et al. Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2011;9(5):400 9.e Butz BK, Wen T, Gleich GJ, Furuta GT, Spergel J, King E, et al. Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology. 2014;147(2): e Helou EF, Simonson J, Arora AS. 3-yr-follow-up of topical corticosteroid treatment for eosinophilic esophagitis in adults. Am J Gastroenterol. 2008;103(9): Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, et al. Long-term treatment of eosinophilic esophagitis with swallowed topical corticosteroids: development and evaluation of a therapeutic concept. Am J Gastroenterol. 2017;112(10): Dellon ES, Sheikh A, Speck O, Woodward K, Whitlow AB, Hores JM, et al. Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. Gastroenterology. 2012;143(2):321 4.e Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14(1):13 22.e1. 42

45 46. Gómez-Torrijos E, García-Rodríguez R, Castro-Jiménez A, Rodríguez-Sanchez J, Méndez Díaz Y, Molina- Infante J. The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther. 2016;43(4): Arias Á, González-Cervera J, Tenias JM, Lucendo AJ. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology. 2014;146(7): Min JY, Ocampo CJ, Stevens WW, Price CPE, Thompson CF, Homma T, et al. Proton pump inhibitors decrease eotaxin-3/ccl26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase. J Allergy Clin Immunol Jan;139(1): e Eckmann JD, Ravi K, Katzka DA, Davis DR, See JA, Geno DR, et al. Efficacy of Atopy Patch Testing in Directed Dietary Therapy of Eosinophilic Esophagitis: A Pilot Study. Dig Dis Sci Mar;63(3): Zhan T, Ali A, Choi JG, Lee M, Leung J, Dellon ES, et al. Model to Determine the Optimal Dietary Elimination Strategy for Treatment of Eosinophilic Esophagitis. Clin Gastroenterol Hepatol May 3. pii: S (18) Asher Wolf W, Huang KZ, Durban R, Iqbal ZJ, Robey BS, Khalid FJ, et al. The six-food elimination diet for eosinophilic esophagitis increases grocery shopping cost and complexity. Dysphagia. 2016;31(6): Moawad FJ, Cheatham JG, DeZee KJ. Meta-analysis: the safety and efficacy of dilation in eosinophilic oesophagitis. Aliment Pharmacol Ther. 2013;38(7): Jung KW, Gundersen N, Kopacova J, Arora AS, Romero Y, Katzka D, et al. Occurrence of and risk factors for complications after endoscopic dilation in eosinophilic esophagitis. Gastrointest Endosc. 2011;73(1): Schoepfer AM, Gonsalves N, Bussmann C, Conus S, Simon HU, Straumann A, et al. Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol. 2010;105(5): Dougherty M, Runge TM, Eluri S, Dellon ES. Esophageal dilation with either bougie or balloon technique as a treatment for eosinophilic esophagitis: a systematic review and meta-analysis. Gastrointest Endosc. 2017;86(4): e Jorveza Prescribing Information 43

46 Eosinophilic esophagitis (EoE) Photo credits/sources: Title page: CLIPAREA l Custom media/shutterstock.com Page 9, 14: von Mende Page 9: Chombosan/Shutterstock.com (adapted by Katja Heller) Page 13: Kartoxjm/Fotolia.com Page 15, 39: Katja Heller Page 17: source: Prof. Dr. Stephan Miehlke Page 19: source: Prof. Dr. Thomas Günther, Pathologie Lademannbogen, Hamburg. Used with kind permission. Page 29: reprinted from: Dellon, S. Gastroenterology;143(2):321 4 Figure 1B, 2012, courtesy of Elsevier 44

47 SWALLOWING DIFFICULTIES due to Eosinophilic Esophagitis NEW Jorveza the first and only approved therapy for EoE Convenient orodispersible tablets with proven active ingredient budesonide 1 Innovative formulation targeting budesonide to the esophagus 2 Clinical and histological remission in 85% of patients after only 12 weeks 3 1 Jorveza Prescribing Information (PI). 2 Miehlke S et al., Gut. 2016; 65: Straumann A et al., United European Gastroenterol J. 2017;5(5S):OP348. Jorveza 1 mg orodispersible tablets. Active substance: budesonide. Composition: each orodispersible tablet contains: active substance: 1 mg budesonide. Other ingredients: disodium hydrogen citrate, docusate sodium, macrogol 6000, magnesium stearate, mannitol, anhydrous monosodium citrate, povidone K25, sodium hydrogen carbonate and sucralose. Indications: treatment of eosinophilic esophagitis (EoE) in adults (older than 18 years of age). Contraindications: hypersensitivity to the active substance or to any of the excipients. Patients with hepatic impairment. Pregnancy. Lactation (risk-benefit evaluation). Side effects: esophageal candidiasis and oral and/ or oropharyngeal candidiasis. Headache. Hypertension. Upper abdominal pain, gastroesophageal reflux disease, lip edema, nausea, oral paraesthesia. Fatigue. Blood cortisol decreased. Increased risk of infection. Cushing s syndrome, adrenal suppression, growth retardation in children. Hypokalaemia, hyperglycaemia. Depression, irritability, euphoria, psychomotor hyperactivity, anxiety, aggression. Pseudotumor cerebri including papilloedema in adolescents. Glaucoma, cataract (including subcapsular cataract), blurred vision, central serous chorioretinopathy. Increased risk of thrombosis, vasculitis (withdrawal syndrome after long-term therapy). Dyspepsia, duodenal or gastric ulcers, pancreatitis, constipation. Allergic exanthema, petechiae, delayed wound healing, contact dermatitis, ecchymosis. Muscle and joint pain, muscle weakness and twitching, osteoporosis, osteonecrosis. Malaise. Pack sizes: 20, 30, 60, 90 and 100 orodispersible tablets. Not all pack sizes may be marketed. Available on prescription only. Date of information: 1/2018.