1. Aetna considers the use of Xolair (omalizumab) medically necessary as second line treatment for adolescents and adults (12 years of age and above) with moderate-to-severe persistent allergic asthma for at least three months who meet all of the criteria below:

   1. Member demonstrates atopy (has a positive skin test or in vitro reactivity (e.g., positive radioallergosorbent (RAST) test)) to a perennial aeroallergen; and
   2. Member's has baseline serum IgE level is between 30 and 700 IU/mL; and 
   3. Member's symptoms are inadequately controlled with a moderate dose of inhaled corticosteroids plus long-acting beta-agonists (LABAs)* or leukotriene inhibitors  for at least 3 months; and   
   4. Member has daily symptoms (e.g., coughing, wheezing, and dyspnea) and/or exacerbations affecting activity (e.g., exercise) and sleep; and

   5. Member exhibits any of the following signs of poor asthma control:

      1. Daily use of short-acting inhaled beta2-agonists; or
      2. Diurnal variation in peak expiratory flow (PEF) of greater than 30%; or
      3. PEF less than 80% of personal best; or
      4. Forced expiratory volume in 1 second (FEV1) less than 60% predicted; or

      5. A total of at least three of the following events within the preceding 12 months due to acute asthma exacerbations while on controller medications:

         1. Visits to the emergency room or urgent care center;
         2. Hospital admissions;

         3. Treatments with high dose injectable or oral corticosteroids.

   6. Exacerbation of asthma upon discontinuation of omalizumab.

2. Continued treatment with omalizumab beyond six months is considered medically necessary for members who met all of the following criteria:

   1. Member had met criteria for omalizumab in section I at initiation of omalizumab therapy; and

   2. Treatment with omalizumab has resulted in clinical improvement as documented by one or more of the following:

      1. Decreased utilization of rescue medications; or
      2. Decreased freqeuency of exacerbations (defined as worsening of asthma that requires increase in inhaled corticosteroid dose or treatment with systemic corticosteroids); or
      3. Increase in percent predicted FEV-1 from pretreatment baseline; or

      4. Reduction in reported symptoms (decrease in asthma symptom score), as evidenced by decreases in frequency or magnitude of one or more of the following symptoms:

         1. Sleep disturbance, night wakening, or symptoms upon awakening; or
         2. Shortness of breath; or
         3. Wheezing/heavy breathing/fighting for air; or
         4. Chest tightness or heaviness; or
         5. Asthma attacks; or
         6. Difficulty taking deep breath or difficulty breathing out; or
         7. Coughing or clearing throat; or

         8. Tiredness; and

   3. Member has not exhibited symptoms of anaphylaxis (bronchospasm, hypotension, syncope, urticara, and/or angioedema) after administration of omalizumab.

3. Serum IgE levels: Measurement of baseline total serum IgE level is considered medically necessary in persons who are being considered for treatment with omalizumab to determine eligibility for treatment and appropriate dose. Monitoring of total serum IgE levels during the course of therapy with omalizumab is not considered medically necessary, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes.

4. Aetna considers the use of omalizumab experimental and investigational for all other indications, including use as initial therapy for allergic asthma, non-allergic asthma, allergic broncho-pulmonary aspergillosis, and allergic conditions without asthma because omalizumab's safety and effectiveness for these other indications has not been established.

*See Appendix A for “Estimated Comparative Daily Dosages for Inhaled Corticosteroids”.

Allergic asthma is a chronic disorder in which exposure to allergens such as dust, mold and pollen triggers airway inflammation and obstruction. Bronchodilators (e.g., anti-cholinergic agents and inhaled beta2-agonists), alone or in combination, are used for patients with acute exacerbations. For patients with chronic symptoms, inhaled corticosteroids are used for those who have frequent exacerbations. A trial of 6 weeks to 3 months with inhaled corticosteroids to identify patients who may benefit from long-term inhaled corticosteroids therapy is recommended. On the other hand, chronic treatment with oral corticosteroids is not recommended.

In the stepwise approach to the management of asthma, progression to the next step is indicated when control is not achieved or is lost with the current treatment, and there is assurance that the patient is using medication correctly. The frequent presence of such symptoms as cough, wheezing, and dyspnea, and the increased use of rapid-acting bronchodilators (e.g., beta-2 agonists), may indicate inadequate control of asthma. Measurement of peak expiratory flow (PEF) and its variability is helpful in the initial assessment of asthma severity and in monitoring the initial treatment, assessing changes in severity, and preparing for a reduction in therapy.

According to the global strategy for asthma management and prevention of the National Heart, Lung and Blood Institute (NHLBI), patients with moderate persistent asthma exhibit some of the following characteristics:

• Symptoms daily
• Exacerbations may affect activity and sleep
• Daily use of inhaled short-acting beta2-agonist
• PEF 60 to 80% of personal best
• Diurnal PEF variation greater than 30%.

For patients with severe persistent asthma, they have some of the following characteristics:

• Symptoms daily
• Frequent exacerbations
• PEF less than or equal to 60% of personal best
• Diurnal PEF variation greater than 30%.

The preferred therapy for patients with moderate persistent asthma is regular treatment with a combination of inhaled corticosteroids and a long-acting inhaled beta2-agonist twice daily. For patients with severe persistent asthma, the primary therapy includes inhaled corticosteroid at higher doses plus a long-acting inhaled beta2-agonist twice daily. Furthermore, according to the NHLBI guidelines, control of asthma is defined as:

• Minimal (ideally no) chronic symptoms, including nocturnal symptoms
• Minimal (infrequent) exacerbations
• No visit to the emergency room
• Minimal (ideally no) use of p.r.n. (as needed) beta2-agonist
• No limitations on activities, including exercise
• PEF diurnal variation of less than 20%
• (Near) normal PEF
• Minimal (or no) adverse effects from medicine.

Xolair (omalizumab) is the first biotechnology treatment for allergy related asthma.  It is indicated for adults and adolescents (12 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, a recombinant humanized monoclonal anti-immunoglobulin E (IgE) antibody, is directed against the receptor-binding domain of IgE.  This binding is specific towards free IgE, thus preventing it from attaching to the mast cell and its subsequent activation.  Xolair is administered subcutaneously once or twice a month, and in some cases more than one injection at a time.  Clinical studies have shown that omalizumab improves the control of allergic asthma while lowering steroid consumption, and enhances long-term disease control in patients with recurrent symptoms.

FDA approved Xolair based on the findings of two clinical trials that included over 1,000 asthma patients, as well as data from several supportive safety and efficacy studies.  Although the FDA found Xolair to be generally safe, a few patients suffered severe allergic reactions that responded to medical treatment.  The most commonly observed side effects associated with Xolair include injection site reaction (45 %), viral infections (23 %), upper respiratory infections (20 %), sinusitis (16 %), headaches (15 %), and pharyngitis (11 %).  Moreover, the FDA is requiring the manufacturer to study an unexplained increase in the rate of cancer for patients taking the drug.  Cancers observed in Xolair-treated patients were a variety of types, including breast, non-melanoma skin, prostate, melanoma, and parotid.  Cancers developed in 0.5 % of those on Xolair, compared with 0.2 % on a placebo.

The FDA-approved indication for Omalizumab is moderate-to-severe persistent asthma of an allergic nature, not controlled with the use of inhaled corticosteroids. In addition, the patient should have an IgE level between 30 IU and 700 IU and not weigh more than 150 kg. An IgE level of 2.5 ng/mL corresponds to 1 IU/mL. The patient should also demonstrate allergies to common perennial allergens either via skin testing (in vivo) or radioallergosorbent testing (in vitro). The FDA-approved prescribing information states that omalizumab 150 to 375 mg is administered subcutaneously every 2 or 4 weeks. Doses and dosing frequency are determined by serum total IgE level, measured before the start of treatment, and body weight (see Appendix B).  A total serum IgE level should be measured in all patients who are being considered for treatment with omalizumab, because the dose of omalizumab is determined on the basis of the IgE level and body weight (Strunk & Bloomberg, 2006). The recommended dose is 0.016 mg per kilogram of body weight per international unit of IgE every four weeks, administered subcutaneously at either two-week or four-week intervals. This dose is based on the estimated amount of the drug that is required to reduce circulating free IgE levels to less than 10 IU per milliliter. The total dose should not exceed 375 mg and this will require multiple injections, as no single injection should exceed 150 mg. Monitoring of total serum IgE levels during the course of therapy with omalizumab is not indicated, because these levels will be elevated as a result of the presence of circulating IgE-anti-IgE complexes. No other laboratory tests seem to be necessary, since there have been no clinically significant laboratory abnormalities noted during treatment.

In a Cochrane review on the use of anti-IgE antibody for chronic asthma in adults and children, Walker et al (2006) concluded that omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids, but the clinical value of the reduction in steroid consumption has to be considered in the light of the high cost of omalizumab.  The impressive placebo effects observed in control groups bring into question the true effect of omalizumab.  Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids, and during steroid tapering phases of clinical trials.  Omalizumab was generally well-tolerated, although there were more injection site reactions with omalizumab.  Patient and physician assessments of the drug were positive. 

Current guidelines recommend use of omalizumab only in persons age 12 and older (NAEPP, 2007; NICE, 2007). The authors of the Cochrane review (Walker, et al., 2006)  stated that further assessment in pediatric populations is necessary, as is direct double-dummy comparison with inhaled steroid.  This is in agreement with the observation of Hadj (2004) who stated that further evaluation on omalizumab needs to be done in the pediatric (less than 12 years of age) population.

Milgrom, et al. (2001) evaluated omalizumab therapy in 6- to 12-year-old children with moderate to severe allergic asthma. The primary end point was the measurement of omalizumab's steroid-sparing effects. Eligibility criteria included: stable asthma that was well controlled with low-dose inhaled corticosteroids, a positive skin prick test to at least one common allergen, total serum IgE 30 - 1300 IU/mL, and a baseline FEV₁ greater than or equal to 60% of predicted. A total of 334 patients were enrolled; the mean FEV₁ was approximately 85% of predicted. After 28 weeks of therapy (12 in the steroid-stable and 16 in the steroid-reduction phases), the median inhaled beclamethasone diproprionate dose reduction in omalizumab recipients was 100% (versus 66.7% among placebo recipients, p = 0.001). A significantly greater proportion of omalizumab recipients reduced their inhaled corticosteroid dose, and more were able to withdraw inhaled corticosteroid therapy (55% versus 39%, p = 0.004). Regarding secondary end points, during the steroid-reduction phase, a smaller proportion of omalizumab recipients experienced an exacerbation (18.2% versus 38.5%, p < .001), and the exacerbation frequency was significantly lower. With omalizumab treatment, there were fewer urgent, unscheduled outpatient physician visits (12.9% versus 30.3%, p = 0.001), less variability in the morning peak expiratory flow rates, fewer 2- or 3-consecutive-night awakenings requiring rescue medications (11.6% versus 21.1%, p = .002), fewer requirements for rescue beta-agonist therapy, and fewer school days missed (0.65 days versus 1.21 days, p = .04). Inhaled beclamethasone diproprionate dose requirements and asthma control measurements were similar during the subsequent 24-week extension phase (Berger, et al., 2003).

In a review on omalizumab for asthma published in the New England Jounal of Medicine, Strunk and Bloomberg (2006) stated that "[s]ince asthma is a chronic disease, long-term studies, especially in children, are needed to evaluate the effect of serum IgE suppression throughout development; adverse effects may become apparent only with follow-up into adulthood.  We know of only one study to date that has been performed exclusively in the pediatric group (Milgrom et al, 2001).  Efficacy and safety studies are also needed for geriatric and nonwhite patients".

The effectiveness of omalizumab in the treatment of occupational rhinitis has not been evaluated. Occupational rhinitis is a heterogeneous group of inflammatory conditions in the nose, caused by exposure to airborne irritants as well as sensitizers in the occupational environment.  The mechanism can be allergic, neurogenic or toxic.  Animal dander, organic dusts, latex and chemicals can cause occupational rhinitis, but because of methodological problems as well as weaknesses in the definition of occupational rhinitis, occupational exposure is probably an underestimated cause of rhinitis. In a review on the management options of occupational rhinitis, Hellgren et al (2003) stated that avoidance of exposure, protective measures at the workplace and medical treatment, with agents such as second generation antihistamines and nasal corticosteroids, can make it possible to avoid progress of the disease from rhinitis to asthma.

Zirbes and Milla (2008) stated that allergic broncho-pulmonary aspergillosis (ABPA) is a complication commonly encountered in patients with cystic fibrosis (CF) that produces significant respiratory morbidity. Chronic airway colonization with Aspergillus induces strong inflammatory responses with high IgE levels. Current guidelines for therapy include prolonged courses of systemic corticosteroids as the main therapeutic strategy. However this has the potential to induce significant detrimental side effects in children. Omalizumab is a humanized monoclonal antibody directed against IgE that prevents its binding to high- and low-affinity receptors on effector cells. It has been shown to be effective in improving asthma control in patients with a strong allergic component. These investigators presented their long-term experience with the use of anti-IgE therapy in 3 children with CF and ABPA (mean age at start of therapy = 14.2 years) who were steroid-dependent. All 3 were already experiencing significant side effects from chronic steroid therapy. After the start of omalizumab, these children experienced significant and sustained clinical improvements at the same time that they were discontinued from chronic systemic steroids. The authors concluded that these findings suggested that IgE blockade has tremendous potential as a strategy to control this disease in steroid-dependent patients.

Recent reviews on the management of ABPA (Meza Brítez et al, 2008; Schubert, 2009) did not mention the use of omalizumab as a therapeutic option.

Appendix A

Estimated Comparative Daily Dosages for Inhaled Corticosteroids

Appendix B

Dosing Schedule for Subcutaneously Administered Omalizumab