Medical Policy



Subject: Omalizumab (Xolair®)
Document #: DRUG.00024 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses the uses of omalizumab (Xolair® ) for U.S. Food and Drug Administration (FDA) approved indications in asthma and chronic idiopathic urticaria.

Omalizumab (Xolair® ) is a monoclonal antibody that interferes with allergic response by binding to immuno-globulin E (IgE).  The drug received initial FDA approval in 2003 for individuals 12 years of age and above with moderate to severe persistent asthma, who have shown reactivity to an allergen and whose symptoms are inadequately controlled with inhaled corticosteroids.  In 2014, the FDA expanded its labeling for omalizumab to include chronic idiopathic urticaria (CIU) in adults and adolescents, 12 years of age and above, who remain symptomatic despite H1 antihistamine treatment.  In July, 2016 the FDA labeling for omalizumab was expanded to lower the age to 6 years and older for the treatment of moderate to severe persistent asthma.

Position Statement

Medically Necessary:

Omalizumab (Xolair) is considered medically necessary for individuals with moderate to severe persistent asthma (see Rationale section) who meet all of the following criteria:

Continued treatment with omalizumab beyond 12 months is considered medically necessary when the following criteria are met:

Omalizumab (Xolair) is considered medically necessary for the treatment of chronic idiopathic urticaria (CIU) as fourth-line* therapy when ALL of the following criteria are met:

* See Definitions section of this document for further information about all the lines of step-care therapy.

Investigational and Not Medically Necessary:

Omalizumab (Xolair) is considered investigational and not medically necessary for individuals who do not meet the criteria set forth in this document.

Omalizumab is considered investigational and not medically necessary for all other indications other than moderate to severe persistent asthma and refractory chronic idiopathic urticaria.

Rationale

In June 2003, the U.S. Food and Drug Administration (FDA) approved Xolair omalizumab (Genentech, Inc., South San Francisco, CA jointly marketed with Novartis Pharmaceutical Corp., East Hanover, NJ), which is a monoclonal anti-IgE antibody.  This drug forms complexes with free IgE antibodies, thus preventing interactions between free IgE and cells containing substances, such as histamines, that lead to allergic symptoms. 

Asthma

Adults and Adolescents with Asthma

Xolair was approved by the U.S. Food and Drug Administration (FDA) in 2003 for moderate to severe persistent asthmatics (age greater than or equal to 12 years old) who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids (FDA, updated 2014). 

The FDA approval was based in part on the results of three randomized, double-blind, placebo-controlled, multi-center trials, where the number of asthma exacerbations was the principal outcome.  The trials enrolled subjects 12 to 76 years old, with moderate to severe persistent asthma, (as defined by the National Heart Lung and Blood Institute [NHLBI]), a positive skin test reaction to a perennial aeroallergen and a total IgE level greater than 30 IU/ml.  The number of exacerbations was reduced in those receiving omalizumab, compared to the placebo group.  However, individuals whose FEV1 was greater than 80% predicted at enrollment did not experience a reduction in exacerbations.  The efficacy of omalizumab in moderate to severe asthma has been further demonstrated by recent meta-analysis and systematic reviews that considered reductions of steroid use and of asthma exacerbations as the primary outcomes; secondary outcome measures included lung function, use of rescue medication, asthma symptoms, and health-related quality of life (Hanania, 2011; Rodrigo, 2011). 

One of the key considerations in initiating Xolair therapy is the assessment of asthma severity.  Moderate and severe persistent asthma are defined by the National Heart, Lung, and Blood Institute (NHLBI, 2007) criteria, as detailed below.  Asthma severity should be assigned to the most severe category in which any feature occurs.  Based on symptoms, the classification of asthma severity for severe persistent and moderate persistent asthma, for individuals 12 years of age and older who are not currently taking long-term control medications, is based on the presence of some of the following features:

Severe persistent asthma:

Moderate persistent asthma:

According to this NHLBI document, the following constitute the normal ranges by age for FEV1 /FVC:

These criteria for determining asthma severity are to be applied to the situation before treatment is initiated and before adequate control is achieved.  The 2007 National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 issued Guidelines for the Diagnosis and Management of Asthma, which recommended that Xolair may be considered as adjunctive therapy in Step 5 or 6 care of individuals with allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose inhaled corticosteroids and long-acting beta2 -agonists (Level of Evidence: B NHLBI [NAEPP] Guidelines for the Diagnosis and Management of Asthma, 2007).

Note: Please see the Definitions section for an explanation of Step 5 and 6 asthma care and also definitions of the NHLBI Levels of Evidence.

In 2010, the Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention Report updated its 2007 report with the following information, (which was unchanged in the subsequent GINA, 2012 update):

Consensus Recommendation: 

For allergic patients with an elevated IgE not controlled on high dose inhaled glucocorticosteroids and a long acting B2 -agonist and who continue to have exacerbations, a trial of omalizumab can be considered.  This recommendation is based on a modest response rate for the main endpoint, exacerbations and its high cost.

Role in therapy:

Anti-IgE (omalizumab) is a treatment option limited to patients with elevated serum levels of IgE.  Its current indication is for patients with severe allergic asthma who are uncontrolled on inhaled glucocorticosteroids (ICS), although the dose of concurrent treatment has varied in different studies. Improved asthma control is reflected by fewer symptoms, less need for reliever medications and fewer exacerbations.  Further investigations will likely provide additional clarification of the role of anti-IgE in other clinical settings…Withdrawal of glucocorticosteroids facilitated by anti-IgE therapy has led to unmasking the presence of Churg Strauss syndrome in a small number of patients. Clinicians successful in initiating steroid withdrawal using anti-IgE should be aware of this side effect (Wechsler, 2009).

The GINA Report was updated in 2016 with the following information relevant to the Step-care approach to asthma treatment unchanged:  (Step-care information is located in the Definitions section of this document).

Treatment options that may be considered at Step 5 (if not already tried) include Anti-immunoglobulin E (anti-IgE) treatment (omalizumab): This is suggested for patients with moderate or severe allergic asthma that is uncontrolled on Step 4 treatment (Evidence A).

Asthma in Children

Until 2016, the FDA labeled indication for omalizumab (Xolair) in the treatment of asthma was limited to those 12 years of age and older.  In July 2016, the FDA expanded its approved labeling for Xolair as follows: 

Xolair is indicated for patients 6 years of age and older with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.  Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.  Administer Xolair 75 to 375 mg by subcutaneous injection every 2 or 4 weeks.  Determine dose (mg) and dosing frequency by serum total IgE level (IU/mL) measured before the start of treatment, and by body weight (kg). 

There have also been several studies in younger children (Lanier, 2009; Lemanske, 2002; Milgrom, 2001).  Lanier and colleagues reported on a pivotal study of 627 children with inadequately controlled, allergic (IgE-mediated) asthma who were randomized to receive either omalizumab or placebo over a period of 52 weeks (24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase).  During the 52-week period, the exacerbation rate was reduced by 43% versus placebo (p<0.001); the authors concluded that omalizumab had an acceptable safety profile with no difference in overall incidence of adverse events compared with placebo.  The following information is provided in the 2016 updated FDA labeling:

The safety and efficacy of Xolair in pediatric patients 6 to < 12 years of age with moderate to severe asthma is based on one randomized, double-blind, placebo controlled, multi-center trial (Lanier, 2009) and an additional supportive study (Milgrom, 2001).

The Milgrom study was a 28-week randomized, double blind, placebo-controlled study that primarily evaluated safety in 334 pediatric subjects, 298 of whom were 6 to less than 12 years of age, with moderate to severe asthma who were well-controlled with inhaled corticosteroids (beclomethasone dipropionate 168-420 mcg/day).  A 16-week steroid treatment period was followed by a 12-week steroid dose reduction period.  The study results found that subjects treated with Xolair had fewer asthma exacerbations, compared to placebo, during both the 16-week fixed steroid treatment period (0.18 vs. 0.32; rate ratio: 0.58; 95% confidence interval [CI]: 0.35, 0.96) and the 28-week treatment period (0.38 vs. 0.76; rate ratio: 0.50; 95% CI: 0.36, 0.71).  At the conclusion of the study, both investigators' and subjects' global evaluations of Xolair effectiveness were identical favoring omalizumab over placebo (p<0.001).

The 2010 GINA update offered the following statement about the use of Xolair in children between 6 and 12 years of age:

Anti-IgE (omalizumab) has proven efficacy in children aged 6 to 12 years with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma.

The 2016 GINA update also made the following comment about predicting responders to omalizumab:

A substantial number of children with difficult asthma will have higher IgE levels than the upper limit of IgE recommended for therapy (1,300 IU).  It is unknown if these patients will still benefit from omalizumab therapy.  There are no tests which can currently be recommended, in order to predict who will respond…The long-term (beyond one year) safety and efficacy has not yet been studied (GINA, 2016).

The 2017 updated GINA report provides the following expanded recommendations:

As Step 5, anti-immunoglobulin E (anti-IgE) treatment (omalizumab) for patients > 6 years of age with moderate or severe allergic asthma that is uncontrolled on Step 4 treatment (Evidence A).

Under phenotype-guided add-on treatment, patients with severe asthma uncontrolled on Step 4 treatment may benefit from phenotyping into categories, such as severe asthma, aspirin-exacerbated or eosinophilic asthma. Patients > 6 years with severe allergic asthma with elevated IgE levels may benefit from omalizumab (anti-IgE) therapy (Evidence A). Those > 12 years with severe eosinophilic asthma may benefit from anti-IL5 therapy (mepolizumab, reslizumab) (Evidence B) and LTRAs may be helpful for patients found to be aspirin sensitive (Evidence B) (GINA, 2017).

Dosing and Duration of Asthma

The manufacturer-recommended dose and dosing frequency for asthma are determined by body weight (kilograms) and serum IgE level (international units/milliliter) measured BEFORE the start of treatment.  Total IgE levels (unbound and complexed) are increased during omalizumab treatment and remain elevated for up to 1 year after discontinuation of treatment.  Therefore, after the first dose, serum IgE levels should not be used for dose determination unless treatment has been interrupted for more than 1 year.  Regarding optimal duration of adjunctive therapy with omalizumab, experience in the practice community has shown that if omalizumab treatment is interrupted for whatever reason, asthma symptoms and exacerbations relapse within a few months.  It has also been reported that 6 years of treatment with omalizumab has induced a durable improvement in asthma symptoms and lung function which suggests that anti-IgE therapy can induce long-term remission of the allergic state, possibly by inhibiting IgE production and depleting IgE-committed B memory cells (Chang, 2007; Nopp, 2007).  Current FDA guidance retains this statement:  "Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control." 

Safety Issues

Due to accumulating data regarding allergic reactions to Xolair, in 2007 the FDA introduced a Black Box warning and updated "Warnings, Precautions and Adverse Reactions Reporting" sections of the product labeling.  A new Medication Guide was also issued which explains the risk of anaphylaxis following Xolair administration and is to be distributed to all treated individuals with each dose of Xolair.  The Black Box Warning was reiterated in the latest prescribing information issued by the FDA (July 2016) as follows:

Anaphylaxis, presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of Xolair. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, observe patients closely for an appropriate period of time after Xolair administration. Health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur… In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006 (FDA, 2016).

On July 16, 2009, the FDA issued an "Early Communication about an Ongoing Safety Review of Omalizumab (marketed as Xolair)," which is excerpted as follows:

The FDA is evaluating interim safety findings from an ongoing study of Xolair (omalizumab) that suggests an increased number of cardiovascular and cerebrovascular adverse events in a group of patients using Xolair compared to a group of patients not given the drug (control group)… The ongoing study, titled Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS), is an observational study of approximately 5,000 Xolair treated patients and a control group of approximately 2,500 non-Xolair treated patients.  The primary objective of the EXCELS study is to assess the long-term safety profile of Xolair in patients followed for 5 years.  Study patients are 12 years of age and older with moderate to severe persistent asthma and who have a positive skin test or blood test for an aeroallergen.  The interim data, submitted by the manufacturer of Xolair (Genentech), suggests a disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic and thrombophlebitic events in patients treated with Xolair, compared to the control group of patients not given the drug. (As of 2009), the FDA had not made any conclusions regarding these data.  The Agency is working with Genentech to obtain further information and will continue to review the strengths and limitations of these interim results.  Until the evaluation of the EXCELS study is completed, healthcare providers and patients should be aware of the risks and benefits described in the prescribing information, as well as the new information from the ongoing EXCELS study that may suggest a risk of cardiovascular and cerebrovascular adverse events (FDA, 2009). 

The EXCELS study was primarily designed to assess malignancy and in March 2014, Long and colleagues reported that an increased risk of malignancy was not observed in the EXCELS study (Long, 2014).  On September 26, 2014 the FDA issued an updated Drug Safety Communication regarding risk for cardiovascular and cerebrovascular adverse events associated with Xolair.  According to the FDA, this information is provided as follow-up to the earlier safety communication issued in 2009 as follows:

A U.S. Food and Drug Administration (FDA) review of safety studies suggests a slightly increased risk of problems involving the heart and blood vessels supplying the brain among patients being treated with the asthma drug Xolair (omalizumab), than in those who were not treated with Xolair…To further evaluate the heart and brain risks noted in the 5-year safety study, we reviewed a combined analysis of 25 randomized double-blind clinical trials comparing Xolair to placebo. An increased risk of heart- and brain-related problems in patients treated with Xolair was not noted in this combined analysis, but the low number of these events, the young patient population, and the short duration of follow-up prevent us from making any definite conclusions about the absence of a risk. As a result of our review of the safety study and the combined clinical trials, we have added information about the potential risks of heart- and brain-related problems to the Adverse Reactions section of the drug label. Patients taking Xolair should continue to take the medication as prescribed and discuss any questions or concerns with their health care professionals (FDA, 2014).

This updated Drug Safety Communication also includes the following regarding cancer risk associated with Xolair:

Some previous clinical trials have shown slightly higher rates of various cancers in patients treated with Xolair compared with non-Xolair-treated patients. Our review of the 5-year safety study found no difference in the rates of cancer between those patients being treated with Xolair and those who were not being treated with Xolair. However, due to limitations in the 5-year study, we cannot rule out a potential risk of cancer with Xolair, so we have added this information to the Warnings and Precautions section of the drug label (FDA, 2014).

A Medication Guide is also available on the FDA website which was developed by Genentech, Inc. and provides details regarding possible side effects for Xolair. 

According to the latest updates to DrugPoints® (Truven Health Analytics, Greenwood Village, CO), the ratings for all non-FDA labeled (off-label) indications for the use of omalizumab are unchanged as follows:

Chronic Idiopathic Urticaria

Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria, is defined as spontaneous hives and/or angioedema with no specific cause that persists for at least 6 weeks (Zuberbier, 2009b).  In March 2014, the FDA approved Xolair for CIU which was unchanged in the 2016 FDA updated label as follows: 

Xolair is indicated for the treatment of adults and adolescents (12 years of age and above) with chronic idiopathic urticaria who remain symptomatic despite H1 antihistamine treatment.

The updated 2016 FDA prescribing information retains the following limitations of use:

The FDA approval was based, in part, on the results of two randomized, placebo-controlled, double-blind trials.  In 2013, Maurer reported results of the ASTERIA II Trial, a Phase III, multi-center, randomized, double-blind study which evaluated the safety and efficacy of omalizumab over 28 weeks in 323 subjects (aged 12 years and older) with moderate to severe CIU who had remained symptomatic despite approved doses of H1 -antihistamine therapy.  One of the goals of this trial was to determine the optimal dosage of omalizumab necessary to produce symptom improvement in CIU.  Trial participants were randomly assigned to receive 3 subcutaneous injections of omalizumab, spaced 4 weeks apart, at doses of 75 mg, 150 mg, 300 mg, or placebo, followed by a 16-week observation period.  The primary efficacy outcome was the change from baseline (at week 12) in a weekly itch-severity score (from 0 to 21 with higher scores indicating more severe itching) which was self-reported in an electronic diary.  At the start, baseline weekly itch-severity scores were approximately 14 in all groups.  The mean changes from baseline at week 12, in the weekly itch-severity scores, were significantly improved in the group receiving 150 mg of omalizumab (-8.1 ± 6.4; p=0.001) and in those receiving 300 mg of omalizumab (-9.8 ± 6.0; p<0.001) but not in the group receiving 75 mg of omalizumab (-5.9 ± 6.5; p=0.46), as compared with the placebo group (-5.1 ± 5.6).  Most pre-specified secondary outcomes showed similar dose-dependent effects at week 12.  The frequency of adverse effects was similar across all groups, although the frequency of serious adverse events was higher in the group receiving 300 mg of omalizumab (6%) than in the placebo group (3%) or in either the 75 mg or 150 mg groups (1% each).  After week 12 (follow-up period), the mean weekly itch-severity scores increased for all omalizumab-treated groups to reach values similar to those in the placebo group and did not return to baseline values for the duration of the follow-up.  The authors concluded that, although during the initial 12 week period the groups treated with 150 mg or 300 mg of omalizumab showed significantly improved outcomes in self-reported scores, the numbers of trial subjects treated with omalizumab were too small to draw any definitive safety conclusions.  Serious adverse events were more common in the group treated with the highest dose (300 mg) of omalizumab (Maurer, 2013).  

The second pivotal study was also a multicenter, randomized, double-blind, placebo-controlled study which focused on 300 mg of omalizumab in subjects aged 12 to 75 years (18-75 years in Germany) with CIU who remained symptomatic, despite treatment with H1 -antihistamines at up to 4 times the approved dose plus H2 -antihistamines, leukotriene receptor antagonists (LTRAs), or both.  Trial subjects had CIU for a minimum of 6 months duration prior to entering the trial.  The treatment period with omalizumab was 24 weeks followed by a 16 week observation period during which omalizumab was not administered.  At week 12, the mean change from baseline in weekly itch-severity score was 28.6 (95% CI, 29.3 to 27.8) in the omalizumab group compared with 24.0 (95% CI, 25.3 to 22.7) in the placebo group (p<0.001).  This improvement in itch-severity score was sustained to 24 weeks.  At week 40, after discontinuation of omalizumab, there were no statistical differences in the weekly itch-severity scores between the omalizumab-treated group and placebo group.  Serious adverse events were reported by 23 (6.9%) subjects during the total 40-week study period (18 [7.1%] in the omalizumab-treated group and 5 [6.0%] in the placebo group) (Kaplan, 2013).   

An updated 2014 practice parameter from the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology for the diagnosis and management of acute and chronic urticaria provides a step-based approach to the treatment of chronic urticaria (CU).  Within this document, omalizumab is included in the Step 4 care approach when the CU has been refractory to treatment with potent antihistamines and leukotriene receptor antagonists.  The following is excerpted:

The therapeutic utility of omalizumab for refractory CU has been supported by findings from large, double-blind, randomized controlled trials and is associated with a relatively low rate of clinically significant adverse effects. On the basis of this evidence, omalizumab should be considered for refractory CU if this is favorable from the standpoint of balancing the potential for benefit with the potential for harm/burden and cost and the decision to proceed is consistent with patients' values and preferences (Bernstein, 2014).

The use of a step-based approach to the treatment of CIU when refractory to conventional therapy with antihistamines is described in the JTFPP/AAAAI/ACAAI document as follows:

A step-care approach has been developed for the management of CU.  H1 antagonists are effective in the majority of patients with CU but might not achieve complete control in all patients.

As noted above, these parameters consider omalizumab a treatment option only when multiple prior attempts (Step-1 – 3 care) at symptomatic control with maximal FDA-approved doses of antihistamines have failed (Step-4 care which also aligns with fourth-line therapy).  Step therapy involves advanced doses, (that is, increasing doses to the maximal FDA-approved dosages) of antihistamines and combination therapy with other drugs, as described above, unless the individual has contraindications or experiences intolerable side effects.  

Other Indications

At present, there is insufficient evidence to demonstrate the safety and effectiveness of Xolair for any off-label uses (Bez, 2004; Burch, 2012; Kanu, 2008; Pinto, 2010; Pressler, 2013; Ricci, 2009; Zirbes, 2008).

Background/Overview

Asthma is a respiratory disorder characterized by increased responsiveness of the trachea and bronchi to various stimuli, resulting in the narrowing of the airways, along with mucous secretion.  This airway hyper-responsiveness is reversible either spontaneously or through therapy.  The symptom triad includes wheezing, cough, and dyspnea, which can vary widely in severity and duration, although a typical attack does not last for more than several hours.  Attacks can be triggered by a number of factors, including allergic triggers, smoke and pollution, cold air, colds and other respiratory infections, exercise, and strong emotions. 

Chronic idiopathic urticaria (CIU) is defined as itchy hives that last at least 6 weeks and have no apparent external trigger.  Non-sedating antihistamines are the current mainstay for initial treatment.  However, a majority of afflicted individuals do not achieve a therapeutic response to this therapy even when high doses are used.

Definitions

Anaphylaxis: A very severe allergic or immunologic response that leads to the constriction of the bronchial tree in the lungs, dilation of capillaries and eventually shock.

Angioedema: A skin condition that is characterized by the sudden swelling of the lower dermis and subcutaneous tissue.  It occurs in 40-50% of subjects with a diagnosis of chronic idiopathic urticaria (CIU) and may present as painful swelling of the fingers, hands, lips, and tongue.

Asthma: Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, neutrophils (especially in sudden onset, fatal exacerbations, occupational asthma, and patients who smoke), T lymphocytes, macrophages, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of coughing (particularly at night or early in the morning), wheezing, breathlessness, and chest tightness. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment (NAEPP, 2007).

Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria (CSU): A dermatologic allergic condition which is characterized by itchy hives that occur for at least 6 weeks duration with or without angioedema but have no apparent trigger (for example, allergen, physical event, or drugs).

Churg-Strauss syndrome (also known as allergic granulomatosis and allergic angiitis): A disorder marked by blood vessel inflammation. This inflammation can restrict blood flow to vital organs and tissues, sometimes permanently damaging them. It involves mainly the blood vessels of the lungs, beginning as a severe type of asthma, gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable and non-transmissible.

Dyspnea: Shortness of breath, which is also described as subjective difficulty or distress in breathing.

FEV1 (forced expiratory volume in 1 second): A measure of airway obstruction determined using spirometry. Individual FEV1 values are compared to predicted values based on age, height, sex and race.

Lines of Therapy: 

PEF (peak expiratory flow): PEF is often described as a percent of personal best measurement.  Personal best PEF is the highest PEF value attained after 2 to 3 weeks of testing when asthma is in good control.

Pulmonary function tests (PFTs): A battery of respiratory tests that include spirometry and other tests to determine lung functional parameters, such as lung capacity and forced expiratory volume in one second (FEV1 ).

Relevant to Asthma Treatment

Step 5 Care, long-term control medications (according to the updated National Asthma Education and Prevention Program [NAEPP] Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma from the National Heart Lung and Blood Institute [NHLBI], 2007):

Step 6 Care, long-term control medications (NHLBI, 2007):

Levels of Evidence: The system used to describe the levels of evidence within the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (from the National Heart Lung and Blood Institute) is as follows:

Evidence Category A: Randomized controlled trials (RCTs), rich body of data
Evidence is from end points of well-designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made.  Category A requires substantial numbers of studies involving substantial numbers of participants.

Evidence Category B: RCTs, limited body of data
Evidence is from end points of intervention studies that include only a limited number of patients, post hoc or subgroup analysis of RCTs, or meta-analysis of RCTs.  In general, category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.

Evidence Category C: Nonrandomized trials and observational studies
Evidence is from outcomes of uncontrolled or nonrandomized trials or from observational studies.

Evidence Category D: Panel consensus judgment
This category is used only in cases where the provision of some guidance was deemed valuable, but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories.  The panel consensus is based on clinical experience or knowledge that does not meet the criteria for categories A through C (Jadad, 2000).

Wheal: A transient (duration less than 24 hours) swelling of the upper and mid dermis (skin layer beneath the epidermis). Wheals vary in size, have an itching or burning sensation, and commonly appear as erythematous (pink or red) skin discoloration.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary, when criteria are met:

HCPCS  
J2357 Injection, omalizumab, 5 mg [Xolair]
   
ICD-10 Diagnosis  
J44.0-J44.9 Other chronic obstructive pulmonary disease [with asthma]
J45.20-J45.998 Asthma
L50.0-L50.9 Urticaria

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

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  18. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005; 60(3):309-316.
  19. Jadad AR, Moher M, Browman GP, et al. Systematic reviews and meta-analyses on treatment of asthma:  critical evaluation. BMJ. 2000; 320(7234):537-540.
  20. Johansson SG, Nopp A, Oman H, et al. The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair) treatment. Allergy. 2009; 64(10):1472-1477.
  21. Kamin W, Kopp MV, Erdnuess F, et al. Safety of anti-IgE treatment with omalizumab in children with seasonal allergic rhinitis undergoing specific immunotherapy simultaneously. Pediatr Allergy Immunol. 2010; 21(1 Pt 2):e160-165.
  22. Kanu A, Patel K. Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti-IgE antibody (omalizumab). Pediatr Pulmonol. 2008; 43(12):1249-1251.
  23. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol. 2013; 132(1):101-109.
  24. Kulus M, Hébert J, Garcia E, et al. Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma. Curr Med Res Opin. 2010; 26(6):1285-1293.
  25. Lanier B, Bridges T, Kulus M, et al. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009; 124(6):1210-1216.
  26. Lanier BQ, Corren J, Lumry W, et al. Omalizumab is effective in the long-term control of severe allergic asthma. Ann Allergy Asthma Immunol. 2003; 91(2):154-159.
  27. Lemanske RF Jr, Nayak A, McAlary M, et al. Omalizumab improves asthma-related quality of life in children with allergic asthma. Pediatrics. 2002; 110(5):e55-e59.
  28. Long A, Rahmaoui A, Rothman KJ, et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. J Allergy Clin Immunol. 2014; 134(3):560-567.
  29. Mathias SD, Crosby RD, Zazzali JL, et al. Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012; 108(1):20-24.
  30. Maurer M, Altrichter S, Bieber T, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol. 2011; 128(1):202-209.
  31. Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013; 368(10):924-935.
  32. Metz M, Altrichter S, Ardelean E, et al. Anti-immunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol. 2011; 154(2):177-180.
  33. Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001; 108(2):E36-E45.
  34. Milgrom H, Fowler-Taylor A, Vidaurre CF, Jayawardene S. Safety and tolerability of omalizumab in children with allergic (IgE-mediated) asthma. Curr Med Res Opin. 2011; 27(1):163-169.
  35. Nopp A, Johansson SG, Ankerst J, et al. CD-sens and clinical changes during withdrawal of Xolair after 6 years of treatment. Allergy. 2007; 62(10):1175-1181.
  36. Pelaia G, Gallelli L, Renda T, et al. Update on optimal use of omalizumab in management of asthma.  J Asthma Allergy. 2011; (4):49-59. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140296/. Accessed on July 6, 2017.
  37. Pinto JM, Mehta N, DiTineo M, et al. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010; 48(3):318-324.
  38. Poole JA, Matangkasombut P, Rosenwasser LJ. Targeting the IgE molecule in allergic and asthmatic diseases: review of the IgE molecule and clinical efficacy. J Allergy Clin Immunol. 2005; 115(3):S376-S385.
  39. Pressler A, Grosber M, Halle M, et al. Failure of omalizumab and successful control with ketotifen in a patient with vibratory angio-oedema. Clin Exp Dermatol. 2013; 38(2):151-153.
  40. Ricci G, Dondi A, Patrizi A, Masi M. Systemic therapy of atopic dermatitis in children. Drugs. 2009; 69(3):297-306.
  41. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs. placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2011; 139(1):28-35.
  42. Rolinck-Werninghaus C, Hamelmann E, Keil T, et al. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Allergy. 2004; 59(9):973-979.
  43. Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol. 2010; 35(4):e127-129.
  44. Saini SS, Bindslev-Jensen C, Maurer M, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study. J Invest Dermatol. 2015; 135(1):67-75.
  45. Saini SS, MacGlashan DW Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FcRIα surface densities and mediator release by anti-IgE infusions is reversible in vitro and in vivo. J Immunol. 1999; 162(9):5624-5639.
  46. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol. 2011; 128(3):567-573.
  47. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid    requirement in allergic asthmatics. Eur Respir J. 2001; 18(2):254-261.
  48. Song CH, Stern S, Giruparajah M, et al. Long-term efficacy of fixed-dose omalizumab for patients with severe chronic spontaneous urticaria. Ann Allergy Asthma Immunol. 2013; 110(2):113-117.
  49. Strunk RC, Bloomberg GR. Omalizumab for asthma. N Engl J Med. 2006; 354(25):2689-2695.
  50. Tzortzaki EG, Georgiou A, Kampas D, et al. Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean "real-life" experience. Pulm Pharmacol Ther. 2012; 25(1):77-82.
  51. Vignola AM, Humbert M, Bousquet J, et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy. 2004; 59(7):709-717.
  52. Wagelie-Steffen AL, Kavanaugh AF, Wasserman SI. Biologic therapies for the treatment of asthma. Clin Chest Med. 2006; 27(1):133-147.
  53. Wahn U, Martin C, Freeman P, et al. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy. 2009; 64(12):1780-1787.
  54. Walker S, Burch J, McKenna C, et al. Omalizumab for the treatment of severe persistent allergic asthma in children aged 6-11 years. Health Technol Assess. 2011; 15 Suppl 1:13-21.
  55. Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-strauss syndrome in patients treated with omalizumab. Chest. 2009; 136(2):507-518.
  56. Zirbes JM, Milla CE. Steroid-sparing effect of omalizumab for allergic bronchopulmonary aspergillosis and cystic fibrosis. Pediatr Pulmonol. 2008; 43(6):607-610.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bernstein JA, Lang DM, Khan DA, et al.; Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. Practice parameter: the diagnosis and management of acute and chronic urticaria: 2014 update. J Allerg Clin Immunol. 2014; 133(5):1270-1277.
  2. Burch J, Griffin S, McKenna C, et al. Omalizumab for the treatment of severe persistent allergic asthma in children aged 6-11 years: a NICE single technology appraisal. Pharmacoeconomics. 2012; 30(11):991-1004.
  3. Canadian Agency for Drugs and Technologies in Health (CADTH), formerly the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Omalizumab as Add-on Therapy to Inhaled Steroids for Asthma. Issues in Emerging Health Technologies Bulletin, Issue 58. June 2004. Ottawa, ON.
  4. Genentech, Inc. A study of Xolair (omalizumab) in patients with chronic idiopathic urticaria (CIU) who remain symptomatic with antihistamine treatment (H1). NLM Identifier: NCT00866788. Last updated May 9, 2016. Available at: http://clinicaltrials.gov/ct2/show/NCT00866788?term=NCT00866788&rank=1. Accessed on July 6, 2017.
  5. Genentech, Inc. A Study of Xolair to Evaluate Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS). NLM Identifier: NCT00252135. Last updated May 11, 2017.  Available at: http://clinicaltrials.gov/ct2/show/NCT00252135. Accessed on July 6, 2017.
  6. Genentech, Inc. XOLAIR Injection. Medication Guide. Reference ID: 3475329. March 2014. Available at:  http://www.fda.gov/downloads/Drugs/DrugSafety/UCM089829.pdf. Accessed on July 6, 2017.
  7. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). Bethesda, MD. Update 2017. Available at: http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention/. Accessed on July 6, 2017.
  8. Leech S, Grattan C, Lloyd K, et al.; Science and Research Department, Royal College of Pediatrics and Child Health (RCPCH). The RCPCH care pathway for children with urticaria, angio-oedema or mastocytosis: an evidence and consensus based national approach. Arch Dis Child. 2011; 96(2):34-37.
  9. Li JT, Oppenheimer J, Bernstein IL, et al. Attaining optimal asthma control: a practice parameter. Developed by the Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2005; 116(5):S3-11. Available at: https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/attaining-optimal-asthma-control.pdf . Accessed on July 6, 2017.
  10. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication Number 08-5846. October 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf. Accessed on July 6, 2017.
  11. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
  12. Omalizumab (Xolair® ) In: DrugPoints® System [electronic].Truven Health Analytics, Greenwood Village, CO. Updated (2015). Available at: http://www.micromedexsolutions.com. Accessed on July 6, 2017.
  13. Pelligrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005; 26(5):948-968.
  14. U.S. Food and Drug Administration (FDA). Center for Drug Evaluation and Research. FDA Alert: Omalizumab (Xolair® ) Information. July, 2007. Now listed as archived but still available for reference. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126456.htm. Accessed on July 6, 2017.
  15. U.S. Food and Drug Administration (FDA). Omalizumab (Xolair® ) Original BLA 103976/5102. July 2007. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103976s5102lbl.pdf. Accessed on July 6, 2017.
  16. U.S. Food and Drug Administration (FDA). Post-marketing Safety Information. Updated 2015.  Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103291.htm. Accessed on July 6, 2017.
  17. U.S. Food and Drug Administration (FDA). Prescribing information. Omalizumab (Xolair® ). Genentech, Inc. South San Francisco, CA. July 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pdf. Accessed on July 6, 2017.
  18. U.S. Food and Drug Administration (FDA). Updated Drug Safety Communication. September 26, 2014. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm414911.htm. Accessed on July 6, 2017.
  19. Zuberbier T, Asero R, Bindslev-Jensen C, et al. European Academy of Allergology and Clinical Immunology (EAACI), the Eufunded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO). EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009a; 64(10):1427-1443.
  20. Zuberbier T, Asero R, Bindslev-Jensen C, et al. European Academy of Allergology and Clinical Immunology (EAACI), the Eufunded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO). EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy. 2009b; 64(10):1417-1426.
  21. Zuberbier T. European Academy of Allergology and Clinical Immunology (EAACI), the Eufunded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO). A summary of the new International EAACI/GA(2)LEN/EDF/WAO guidelines in urticaria. World Allergy Organ J. 2012; 5(Suppl 1):S1-5.
Websites for Additional Information
  1. National Institutes of Health, National Heart, Lung, and Blood Institute. Information for patients and the public about asthma. Available at: http://www.nhlbi.nih.gov/health/public/lung/index.htm#asthma. Accessed on July 6, 2017.
  2. National Institutes of Health (NIH). National Asthma Control Initiative (NACI). Available at: http://www.nhlbi.nih.gov/health/prof/lung/asthma/naci/. Accessed on July 6, 2017.
  3. National Institutes of Health (NIH). National Institute of Environmental Health Sciences. Updated information on asthma control and prevention. May 3, 2010. Available at:  http://www.niehs.nih.gov/news/newsroom/releases/2010/may03/index.cfm. Accessed on July 6, 2017.
  4. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Vital Statistics: May 2011. Asthma in the U.S. Updated May 2011. Available at: http://www.cdc.gov/vitalsigns/Asthma/. Accessed on July 6, 2017.
  5. U.S. Food and Drug Administration (FDA). Additional labeling history. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo. Accessed on July 6, 2017.
  6. U.S. Food and Drug Administration (FDA). Meeting of the Pulmonary-Allergy Drugs Advisory Committee.  Center for Drugs Evaluation and Research. Safety and efficacy of Omalizumab for treatment of asthma in patients 6-11 years of age with moderate to severe persistent asthma whose symptoms are inadequately controlled with inhaled corticosteroids. November 18, 2009. Available at:  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM194068.pdf. Accessed on July 6, 2017.
Index

Allergic Asthma
Omalizumab
Persistent Asthma
Xolair

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. The Rationale and References sections were updated.
Revised 08/04/2016 MPTAC review. The medically necessary criteria for use of Xolair in asthma were revised to lower the age to 6 years and older consistent with the new FDA labeling. The Rationale section and References were updated.
Reviewed 02/04/2016 MPTAC review. The Rationale and References were updated. Removed ICD-9 codes from Coding section.
Revised 02/05/2015 MPTAC review. The Note regarding fourth-line therapy in CIU has been removed.  References were updated.
Revised 11/13/2014 MPTAC review. The criteria for CIU were clarified regarding fourth-line therapy and the language about prior histamine treatment. The Rationale and References were updated.
Revised 08/14/2014 MPTAC review. A new position statement has been added which considers use in refractory chronic idiopathic urticaria as medically necessary fourth-line therapy when criteria are met. The Coding, Rationale and References sections were updated.
Revised 05/15/2014 MPTAC review. Added chronic idiopathic urticaria to the indications considered investigational and not medically necessary. The Rationale, Definitions, Coding and References sections were updated.
Revised 05/09/2013 MPTAC review. The medically necessary criterion for omalizumab regarding symptom control was revised to clarify that a minimum of 3 months of prior combination controller therapy is necessary to meet medical necessity.  Rationale and References were updated.
Revised 08/09/2012 MPTAC review. A position statement was added for continuation of therapy beyond 12 months when criteria are met. An investigational and not medically necessary statement was added to clarify that treatment is for moderate to severe persistent asthma only. The Rationale and References were updated.
Revised 08/18/2011 MPTAC review. No change to criteria except for clarification of the definitions of moderate and severe persistent asthma and how to determine asthma severity prior to treatment (all taken from the 2007 NHLBI asthma criteria). The Rationale, Definitions and References were updated.
Reviewed 08/19/2010 MPTAC review. The Rationale and References were updated.
Reviewed 08/27/2009 MPTAC review. The Background section has been updated with 2009 safety information from the FDA. References were also updated. The dosing attachment has been removed.
Revised 08/28/2008 MPTAC review. No change to criteria except for the changes made to the definitions of moderate persistent and severe persistent asthma, which were taken from the updated  2007 National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Background, Definitions and Reference Sections were also updated.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 08/23/2007 MPTAC review. The Background section was updated with recently issued FDA 'Alert' information about anaphylactic reactions to Xolair. References were also updated.
Reviewed 09/14/2006 MPTAC review. The information in the Rationale section was clarified regarding the severity criteria for moderate and severe persistent asthma. Coding updated; removed HCPCS S0107 deleted 03/31/05.
Reviewed 06/08/2006 MPTAC review. References were updated. 
Revised 07/14/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations Last Review Date Document Number Title
Anthem, Inc. 04/28/2005 DRUG.00024 Xolair®
WellPoint Health Networks, Inc. 04/28/2005 8.05.02 Omalizumab for the Treatment of Asthma