COMMISSIONING POLICY RECOMMENDATION TREATMENT ADVISORY GROUP Policy agreed by North Lincolnshire CCG November 2012

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1 Drug, Treatment, Device name Omalizumab (Xolair; Novartis) COMMISSIONING POLICY RECOMMENDATION TREATMENT ADVISORY GROUP Policy agreed by North Lincolnshire CCG November 2012 Licensed indication Omalizumab to treat chronic urticaria is an unlicensed indication. Xolair is licensed as add-on therapy to improve asthma control in adult and adolescent patients (12 years of age and above) with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (FEV1 < 80%) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist. Xolair treatment should only be considered for patients with convincing IgE mediated asthma. Cost per patient (at recommended dose) The licensed dose is dependent on body weight and baseline serum IgE. Patients with a body weight or baseline IgE outside the tables presented in the SmPC should not be given omalizumab as there is insufficient data to allow dosage recommendations. Drug Doses SmPC Cost Omalizumab 75mg every 4 weeks 1, Omalizumab 225mg every 2 weeks 9, Omalizumab 600mg every 2 weeks 26, Resource impact on population None identified as not routinely commissioned. Recommendation to Not Routinely Commission When is funding appropriate? Omalizumab is not recommended for the management of chronic urticaria due to the limited evidence of clinical and absence of cost effectiveness for this indication. Any requests should be made to the IFR Panel. Clinical and cost effectiveness evidence Background Urticaria is a condition characterised by localized or wide spread pruritic wheals that typically exist for no more than 24 hours. By definition acute urticaria lasts no longer than six weeks, whereas chronic urticaria lasts longer, often several years. Chronic urticaria can be classified into several subtypes but these may have overlapping features. Chronic urticaria that has no detectable cause is termed chronic idiopathic urticaria. Autoimmune urticaria is not a welldefined term but it is generally recognized that those with autoimmune urticaria have anti-igg antibodies against the high-affinity IgE receptor on mast cells and basophils or directly to IgE antibodies. Autoimmune urticaria affects about one third of all patients with chronic urticaria. 1

2 Omalizumab is a recombinant humanised monoclonal antibody that blocks the high affinity Fc receptor of IgE. Omalizumab has been approved for the treatment of moderate to severe asthma. There is evidence in the form of case reports and two small phase 2 clinical trials that show omalizumab may be of benefit in some patients with chronic urticaria. This policy has been drafted following a series of individual funding requests submitted to the PCT. British Association of Dermatologists therapy guidelines Guidelines for evaluation and management of urticaria in adults and children Grattan et al. British Journal of Dermatology 2007, 157, p /urticaria%20and%20angiodema%20(2007).pdf 1 Urticaria can usually be classified on the clinical presentation without extensive investigation. The weals of physical urticaria usually last less than 1 h (except delayed pressure urticaria) whereas those of ordinary urticaria typically last from 2 to 24 h. Urticarial vasculitis should be sought by skin biopsy if weals last longer. 2 Urticaria often remains idiopathic after allergic, infectious, physical and drug-related causes have been excluded as far as possible. At least 30% of patients with the ordinary presentation of chronic urticaria appear to have an autoimmune aetiology. The autologous serum skin test is a reasonably sensitive and specific marker for histamine-releasing autoantibodies in this group. 3 Advice on general measures and information can be helpful for most patients with urticaria, especially if an avoidable physical or dietary trigger can be identified. Over 40% of hospitalized patients with urticaria show a good response to antihistamines, which are the mainstay of therapy. 4 It has become common practice to increase the dose of second- generation H1 antihistamines above the manufacturer s licensed recommendation for patients when the potential benefits are considered to outweigh any risks. 5 Combinations of nonsedating H1 antihistamines with other agents, such as H2 antihistamines, sedating antihistamines at night or the addition of antileukotrienes, can be useful for resistant cases. 6 Oral corticosteroids should be restricted to short courses for severe acute urticaria or angiooedema affecting the mouth, although more prolonged treatment may be necessary for delayed pressure urticaria or urticarial vasculitis. 7 Immunomodulating therapies for chronic autoimmune urticaria should be restricted to patients with disabling disease who have not responded to optimal conventional treatments. The guidelines only make one mention of omalizumab with reference of a successful treatment of one patient with cold urticaria. EAACI/GALEN/EDF/WAO guideline: management of urticaria Zuberbier T et al Allergy 2009: 64: (EAACI = European Academy of Allergology and clinical immunology; GALEN = Global Allergy and Asthma European Network; EDF = European Dermatology Forum; WAO = World Allergy Organisation). ttp://eaaci.net/attachments/1252_eaaci%20position%20paper%20guideline.pdf 2

3 Non sedating-antihistamine (nsah) If symptoms persist after 2 weeks nsah (up to 4x) Comments on the above algorithm If symptoms persist after 1-4 weeks Add Leukotriene antagonist or change nsah Exacerbation: Systemic steroid (for 3-7 days) If symptoms persist after 1-4 weeks Add Ciclosporin A, H2-antihistamine, dapsone, omalizumab Exacerbation: Systemic steroid (for 3-7 days) First line: High quality evidence Very good safety profile Very good evidence for efficacy Second line: Low quality of evidence Good evidence for efficacy Third Line: Very low quality evidence Low to medium cost Insufficient or no evidence for efficacy In high quality RCT Fourth Line Ciclosporin Medium to high cost Moderate safety profile Moderate level of evidence for efficacy H2-antihistamine Very low level of evidence for efficacy Dapsone 3

4 Medium level of side effects Low level of evidence for efficacy Anti-IgE (omalizumab) High cost Low level evidence for good efficacy It states that omalizumab has been shown to be effective in selected patients with chronic spontaneous urticaria, cholinergic uritcaria, cold urticaria and solar urticaria but larger double blind placebo controlled trials are needed to confirm these results. Omalizumab for Chronic Urticaria: A Case Series and Overview of the Literature Ivyansky I et al Case reports in Dermatology 2012;4: This was a case series of 19 patients (14 were female). The mean age was 36 years for females and 49 for males. The mean duration of disease at initiation of omalizumab in the sample was 21 months for females and 24 months for males. 63% of patients were classified as having chronic idiopathic urticaria, 32% of patients had chronic autoimmune urticaria and 5% had delayed pressure urticaria. Patients had been treated with anti-histamines, steroids, azathioprine and 6 with anti-tnfs. All patients received a dose of omalizumab of 150mg every 2 weeks. In total, 11 patients (58%) experienced almost complete or complete resolution of symptoms and 5 (26%) patients experienced partial resolution and 3 (16%) patients had not benefit. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase Maurer et al. Journal of allergy and Clinical immunology Vol.128 Iss1; p , July 2011 This was a multicenter, randomised, double blind, placebo controlled study patients with chronic urticaria with IgE autoantibodies against thryoperoxidase who had persistent symptoms (wheels and pruritis) despite standard antihistamine therapy. 49 Patients were randomised to receive either placebo (22) or omalizumab (27) (dose dependent on weight and IgE level) every 2 to 4 weeks for a total of 24 weeks. Patients were aged between 18 to 70 years with a clinical diagnosis of moderate to severe chronic urticaria. This was defined as persistent symptoms for more than 6 weeks despite taking maximum dose of antihistamine therapy, a total IgE level of between IU/ml within the last 3 months prior to randomization, and a weekly urticaria activity score of 10 or more. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients diaries. A total of 42 patients completed the study. At baseline the mean UAS were 24.6+/-7.4 and 21.3+/-7.6 for the omalizumab and placebo group respectively. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score of 17.8 with omalizumab and 7.9 with placebo (p=0.089). Complete protection from wheel development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in placebo group. According to patients global assessments of symptoms, 59% of those in the omalizumab group reported to be symptom free at the end of the study compared to 14% in the placebo group. 4

5 The rate of adverse events with similar in both groups. The most frequent adverse events were diarrhoea, nasopharynigitis and headache. A randomised, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. Saini S J allergy Clin Immunol Sep; 128 (3): This study aimed to evaluate the efficacy and safety of omalizumab in patients with chronic idiopathic urticaria who remain symptomatic despite concomitant H(1)- antihistamine therapy. this was a phase II, prospective, double blind, placebo-controlled, dose-ranging study to assess omalizumab in patients aged 12 to 75 years in the USA and Germany with UAS over 7 days of 12 or greater despite antihistamine therapy. Patients received either 75, 300 or 600mg of omalizumab or placebo. The primary end point was change from baseline to week 4 in UAS7. Patients were followed up for an additional 12 weeks to monitor safety. 90 patients were recruited to the study. Both the 300mg omalizumab group (-19.9 vs -6.9, p<0.001) and the 600mg group omalizumab group (-14.6 vs -6.9, p=0.047) showed greater improvement versus the placebo group in UAS7. no meaningful difference was observed for the 75mg omalizumab group. Adverse events were similar across treatment groups. Treatment of chronic autoimmune urticaria with omalizumab Kaplan et al J Allergy Clin Immunol. Vol.122;no.3; Approximately 45% of patients with chronic urticaria have an IgG autoantibody directed to the high affinity IgE receptor leading to cutaneous mast cell and basophil activation. This study aimed to investigate the efficacy of omalizumab in patients with CAU symptomatic despite antihistamine therapy. Patients with chronic urticaria were defined as having symptoms for at least 6 weeks, with hives present most days of the week despite antihistamines. A total serum IgE <700IU/ml was required to enter the study. 12 patients were recruited to the study and received placebo for 4 weeks followed by omalizumab every 2 to 4 weeks (dose dependent on weight and IgE level)for 16 weeks. Primary endpoint was change from baseline to the final 4 weeks of omalizumab in mean Urticaria activity score (scale 0-9). Changes in rescue medication and quality of life was also assessed. Mean UAS declined significantly from baseline to the end of the study (7.5+/-1.78 to 2.66+/-3.31, /-2.86, p=0.0002). 7 patients achieved complete symptom resolution. In 4 patients, mean UAS decreased but Urticaria persisted. 1 patient did not respond. Rescue medication was reduced and quality of life improved and no adverse effects were reported. It concluded that omalizumab may be useful for treatment of patients with CAU not responsive to antihistamines. Further studies should be performed to confirm these findings in CAU and to assess efficacy in other forms of chronic urticaria. Points for consideration Omalizumab is not licensed for the treatment of chronic urticaria and the published data supporting the use is limited to 2 small phase 2 clinical trials and case reports. Guidelines from the British Association of Dermatologists on the management of urticaria do not include omalizumab as part of its recommendations. 5

6 EAACI/GALEN/EDF/WAO guideline: management of urticaria 2009 does include omalizumab as a treatment option when all other standard treatments have failed. Studies have shown that omalizumab may be a useful treatment option for patients with chronic autoimmune urticaria but long term efficacy is lacking Place in therapy relative to available treatments N/A Health gains Studies have shown that omalizumab may be a useful treatment option for patients with chronic autoimmune urticaria but long term efficacy is lacking. Patient monitoring / impact Patient safety / pharmacovigilance Monitoring criteria Urticaria activity score DLQI score Adverse effects When to stop treatment Severe adverse effects Response assessed at 12 weeks and treatment discontinued in those patients who have not shown an adequate response to treatment based on a full clinical assessment. Who prescribes? It not recommended for commissioning. SPECIFICATION DATE, REVIEW DATE, AND LEAD NAME/JOB TITLE Origin Date: October 2012 Originator: TAG Review Date: November 2014 Reviewer: Christopher Ranson, Clinical TAG Recommendation Date: November 2012 Effectiveness Pharmacist Impact on individual clinical commissioning groups CCG Population Cost Impact Vale of York 337,500 Harrogate and Rural District 160,100 Scarborough & Ryedale 118,000 Hambleton, Richmondshire & Whitby 141,600 East Riding of Yorkshire 320,642 Hull 295,987 North Lincolnshire 168,400 North East Lincolnshire 167,200 6