Description:
Omalizumab (Xolair^®₎ is a monoclonal antibody that interferes with allergic response by binding to immuno-globulin E (IgE). The drug received FDA approval in 2003 and is indicated for individuals 6 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.

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. 

Asthma is a major chronic health problem, affecting a total of about 17 million Americans. Approximately 1.5 million emergency room visits and 500,000 hospitalizations occur annually in the United States as a result of asthma exacerbations, including 5,000 deaths. Treatment for acute exacerbations usually includes an inhaled beta-receptor agonist, such as albuterol and, when necessary, bursts of corticosteroid therapy. For chronic control, inhaled corticosteroids, leukotriene inhibitors, long-acting beta-agonists, theophylline and, in treatment-resistant cases, oral corticosteroids may be utilized.

Policy:
Medically Necessary
Xolair vials are considered MEDICALLY NECESSARY when one of the following criteria is met along with specific diagnosis criteria:  

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

• 6 years of age or older
• Symptoms are inadequately controlled after a minimum of three months of combination controller therapy (medium to high doses of inhaled corticosteroids plus long-acting beta₂-agonists or leukotriene modifiers) or cannot tolerate the medications
• Shows a positive skin test or in vitro reactivity to a perennial aeroallergen
• A forced expiratory volume in one second (FEV₁) less than 80 percent predicted
• A serum Immunoglobulin E (IgE) level equal to or greater than 30 IU/ml

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

• Criteria for omalizumab therapy, as set forth above, had been met at the time of initiation of therapy.
• Treatment with omalizumab has resulted in clinical improvement as documented by one or more of the following:
  • Decreased utilization of rescue medications
  • Decreased frequency of exacerbations (defined as worsening of asthma that requires increase in inhaled corticosteroid dose or treatment with systemic corticosteroids)
  • Increase in percent predicted FEV₁ from pretreatment baseline
  • Reduction in reported asthma-related symptoms, such as, but not limited to, wheezing, shortness of breath, coughing, fatigue, sleep disturbance or asthmatic symptoms upon awakening
• Patient is currently being treated with one of the following unless there is a contraindication or intolerance to these medications:
  • Inhaled corticosteroid (ICS) (e.g., fluticasone, budesonide)
  • Additional asthma controller medication (e.g., leukotriene receptor antagonist, long-acting beta-2 agonist [LABA], theophylline)
  • A combination ICS/LABA product (e.g., Advair [fluticasone propionate/salmeterol], Dulera [mometasone/formoterol], Symbicort [budesonide/formoterol])

Omalizumab (Xolair) is MEDICALLY NECESSARY for the treatment of chronic idiopathic urticaria in adults and adolescents (12 years and older) who meet the following criteria:

• Persistent symptoms (itching and hives) for at least 4 consecutive weeks despite titrating to an optimal dose with a second-generation H1 antihistamine, unless there is a contraindication or intolerance to H1 antihistamines
• Patient has tried and had an inadequate response or intolerance to at least TWO of the following additional therapies: [6]
  • Doxepin
  • H1 antihistamine
  • H2 antagonist (e.g., famotidine, cimetidine)
  • Hydroxyzine
  • Leukotriene receptor antagonist (e.g., montelukast)
• Used concurrently with an H1 antihistamine (e.g., cetirizine, fexofenadine), unless there is a contraindication or intolerance to H1 antihistamines

Continued treatment with omalizumab for the treatment of chronic idiopathic urticaria is considered MEDICALLY NECESSARY when the following criteria are met:

• Patient’s disease status has been re-evaluated since the last authorization to confirm the patient’s condition warrants continued treatment
• Patient has experienced at least one of the following:
  • Reduction in itching severity from baseline
  • Reduction in the number of hives from baseline 

Omalizumab (Xolair) is MEDICALLY NECESSARY for the treatment of nasal polyps in adults and adolescents (12 years and older) who meet ALL the following criteria: 

• Unless contraindicated, the patient has had an inadequate response to 2 months of treatment with an intranasal corticosteroid (e.g., fluticasone, mometasone)
• Used in combination with another agent for nasal polyps

Continued treatment with omalizumab for the treatment of nasal polyps is considered MEDICALLY NECESSARY when the following criteria are met: 

• Documentation of a positive clinical response to therapy (e.g., reduction in nasal polyps score [NPS; 0 – 8 scale], improvement in nasal congestion/obstruction score [NCS; 0 – 3 scale])
• Used in combination with another agent for nasal polyps

Omalizumab (Xolair) is considered NOT MEDICALLY NECESSARY for individuals who do not meet the criteria set forth above and for all other indications other than moderate to severe persistent asthma.

Dosage and Administration:
Dose for Allergic Asthma  
Administer Xolair 150 to 375 mg by subcutaneous (SC) injection every 2 or 4 weeks. Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg).

See the dose determination charts below (Table 1 and Table 2) for appropriate dose assignment.

Periodically reassess the need for continued therapy based upon the patient’s disease severity and level of asthma control.

Table 1 Administration Every 4 Weeks Xolair Doses (milligrams) Administered by Subcutaneous Injection Every 4 Weeks for Adults and Adolescents 12 Years of Age and Older for Allergic Asthma

Pre-treatment Serum IgE (IU/mL)				Body Weight (kg)
				30 – 60	> 60 – 70	> 70 – 90	> 90 – 150
> 30 – 100				150	150	150	300
> 100 – 200				300	300	300
> 200 – 300				300
> 300 − 400				SEE TABLE 2
> 400 − 500
> 500 − 600

 

Table 2 Administration Every 2 Weeks Xolair Doses (milligrams) Administered by Subcutaneous Injection Every 2 Weeks for Adults and Adolescents 12 Years of Age and Older for Allergic Asthma

Pre-treatment Serum IgE (IU/mL)				Body Weight (kg)
				30 – 60	> 60 – 70	> 70 – 90	> 90 – 150
> 30 – 100				SEE TABLE 1
> 100 – 200				SEE TABLE 1			225
> 200 − 300					225	225	300
> 300 − 400				225	225	300	DO NOT DOSE
> 400 − 500				300	300	375
> 500 − 600				300	375	DO NOT DOSE
> 600 – 700				375	DO NOT DOSE

Pediatric patients 6 to < 12 years of age: Initiate dosing according to Table 3. 

Table 3. Subcutaneous Xolair Doses Every 2 or 4 Weeks* for Pediatric Patients with Asthma Who Begin Xolair Between the Ages of 6 to < 12 Years 

Pre-treatment Serum IgE (IU/mL)				Dosing Freq.	Body Weight
					20 – 25 kg	> 25 – 30 kg	> 30 – 40 kg	> 40 – 50 kg	> 50 – 60 kg	> 60 – 70 kg	> 70 – 80 kg	> 80 – 90 kg	> 90 – 125 kg	> 125 – 150 kg
30 – 100				Every 4 weeks	Dose (mg)
> 100 – 200					75	75	75	150	150	150	150	150	300	300
> 200 − 300					150	150	150	300	300	300	300	300	225	300
> 300 − 400					150	150	225	300	300	225	225	225	300	375
> 400 − 500					225	225	300	225	225	225	300	300	**	**
> 500 − 600					225	300	225	225	300	300	375	375	**	**
> 600 − 700					300	300	225	300	300	375	**	**	**	**
> 700 − 800				Every 2 weeks	300	225	225	300	375	**	**	**	**	**
> 800 − 900					225	225	300	375	**	**	**	**	**	**
> 900 − 1,000					225	225	300	375	**	**	**	**	**	**
> 1,000 − 1,100					225	300	375	**	**	**	**	**	**	**
>1,100−1,200					300	300	375	**	**	**	**	**	**	**
>1,200−1,300					300	300	**	**	**	**	**	**	**	**

** DO NOT DOSE 

*Dosing Frequency:

4	Subcuutaneous doses to be administered every 4 weeks
2	Subcuutaneous doses to be administered every 2 weeks

Dosing Adjustments for Allergic Asthma
Adjust doses for significant changes in body weight (see Table 1 and Table 2). 

Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination.

• Interruptions lasting less than one year: Dose based on serum IgE levels obtained at the initial dose determination.
• Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination.

Dose for Chronic Idiopathic Urticaria
Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.

Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.

The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.

Rationale:
In June of 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. Xolair is approved by the FDA 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, 2011). 

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 percent 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). According to a recent open-label study performed in subjects with severe uncontrolled allergic asthma randomized to receive best standard anti-asthma therapy with or without omalizumab, a significant increase in percentage of predicted FEV₁ has been observed throughout a 1-year period of anti-IgE treatment, in comparison with control values (Holgate, 2009).

In 2007, the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma was issued with:

• A new focus on monitoring asthma control as the goal for asthma therapy and distinguishing between classifying asthma severity and monitoring asthma control.
• A new focus on impairment and risk as the two key domains of severity and control, and multiple measures for assessment.

According to this 2007 NAEPP document, which has not been updated since 2007 (sponsored by the National Heart, Lung and Blood Institute [NHLBI] of the National Institutes of Health [NIH]):

The level of asthma severity is determined by assessment of both impairment and risk. The degree of functional impairment domain is to be assessed by the affected individual or his/her caregiver by recalling symptoms (see lists below) within the previous 2 – 4 weeks and spirometry. Severity should be assigned to the most severe category in which any feature occurs. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization or ICU admission) indicate greater underlying disease severity. For treatment purposes, patients who had > 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma (NAEPP, 2007).

Asthma Severity Assessment

Moderate and severe persistent asthma are defined by the National Heart, Lung and Blood Institute (2007) criteria for determining asthma severity, as detailed below. These criteria are used to assess the individual's status prior to treatment or adequate control. 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:

• Symptoms throughout the day
• Extremely limited normal activity
• Nocturnal symptoms are frequent (often 7 times/week)
• FEV₁ or PEF less than 60 percent predicted
• Daily use of inhaled, short-acting, beta₂-agonist for symptom control (can be several times/day)
• FEV₁^/FVC (forced vital capacity) is reduced greater than 5 percent (see normal ranges below)
• Exacerbations requiring oral systemic corticosteroid use greater than or equal to 2 per year

Moderate persistent asthma:

• Daily symptoms
• Daily use of inhaled, short-acting, beta₂-agonist
• Somewhat limited activity
• Nocturnal symptoms occur greater than 1 time a week but not nightly
• FEV₁ or PEF is greater than 60 percent and less than 80 percent predicted
• FEV₁/FVC (forced vital capacity) is reduced 5 percent (see normal ranges below)
• Exacerbations requiring oral systemic corticosteroid use greater than or equal to 2 per year

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

• 8 – 19 years of age — 85 percent
• 20 – 39 years of age — 80 percent
• 40 – 59 years of age — 75 percent
• 60 – 80 years of age — 70 percent

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 NAEPP Asthma guidelines recommend 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 2009, the Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention Report was updated. This is a collaborative initiative of the NHLBI with the World Health Organization (WHO), which originally convened a workshop in 1993 and continues to present a comprehensive plan toward the management of asthma through the worldwide dissemination of information on asthma care. The 2009 update to the GINA Report revised its former classifications of asthma based on published evidence and consensus recommendations. The clinical characteristics of asthma (which is described as, "A working scheme based on current opinion and has not been formally validated") are now classified according to: "Controlled, partly controlled and uncontrolled asthma" on the basis of the intensity of treatment required to achieve good asthma control. It is noted by the GINA collaborators that this updated classification system correlates well with the NAEPP guidelines (GINA, 2010).

In 2010, the GINA document was updated with the following information, which was unchanged in the 2012 update:

Consensus Recommendation

For allergic patients with an elevated IgE not controlled on high-dose inhaled glucocortico-steroids 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).

Additional comments include a statement about use in children between 6 and 12 years of age, as follows:
"Anti-IgE (omalizumab) has proven efficacy in children aged 6 to 12 years with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma." This statement is based on the findings of available studies of omalizumab (Milgrim, 2001; Lemanske, 2002), as well as another study of omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. This randomized, double-blind, placebo-controlled trial enrolled children age 6 to less than 12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms, despite at least medium-dose ICSs. Subjects were randomized 2:1 to receive omalizumab or placebo over a period of 52 weeks (24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase). A total of 627 subjects (omalizumab, n = 421; placebo, n = 206) were randomized, with efficacy analyzed in 576 (omalizumab, n = 384; placebo, n = 192). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 31 percent versus placebo (0.45 vs. 0.64; rate ratio, 0.69; P = .007). Over a period of 52 weeks, the exacerbation rate was reduced by 43 percent versus placebo (P < .001). Over a period of 52 weeks, omalizumab had an acceptable safety profile with no difference in overall incidence of adverse events compared with placebo. The authors concluded that add-on omalizumab is effective and well tolerated as maintenance therapy in children (6 to less than 12 years) with moderate-to-severe persistent allergic (IgE-mediated) asthma whose symptoms are inadequately controlled despite medium to high doses of ICSs (Lanier, 2009).

The 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, 2012).

The manufacturer-recommended dose and dosing frequency 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 one 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 one 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 six 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 states, "Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control." Further studies are needed to clarify the optimal duration of treatment with omalizumab, which remains unclear at this time. However, the published evidence consistently demonstrates significant improvements in symptoms and asthma severity values, due to the addition of omalizumab to the combination therapy in moderate and severe persistent asthma, which supports a long-term treatment approach with omalizumab (Corren, 2008; Pelaia, 2011; Saini, 1999).

Xolair is administered through subcutaneous injection in a physician's office. The individual is then monitored for hypersensitivity reactions, including the possibility of anaphylaxis. Reported side effects of Xolair were similar to placebo in most instances, but the most common adverse events reported during clinical trials included injection site reactions, viral infections, upper respiratory tract infections, sinusitis, headache and pharyngitis. During a one-year follow-up of over 6,300 subjects, 0.5 percent of subjects receiving Xolair reported various malignancies, as compared to 0.2 percent of subjects in the control groups.

In February 2007, the FDA issued an "Alert" regarding Xolair following receipt of reports of serious, life-threatening allergic reactions (anap ylaxis) after treatment with omalizumab (Xolair). The FDA reported that usually these reactions occurred within two hours of receiving a Xolair subcutaneous injection. However, these reports also included individuals who had delayed anaphylaxis, with onset two to 24 hours or even longer, after receiving Xolair treatment. The FDA added that anaphylaxis may occur after any dose of Xolair (including the first dose), even if the individual had no allergic reaction to the first dose, and has also been reported in individuals beyond one year of regularly scheduled treatment (Xolair Package Labeling, July 2007). Based on reports from approximately 39,500 subjects, anaphylaxis following Xolair treatment occurred in at least 0.1 percent of treated people. Additional post-marketing results indicate the incidence to be 0.2 percent based on reports from use in 57,300 subjects (Xolair Package Labeling, July 2007). This "Alert" was updated in July 2007 to highlight important revisions to the full prescribing information for Xolair, which now contains a new Boxed Warning and updated "Warnings, Precautions and Adverse Reactions Reporting" sections of the 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 updated sections of the FDA labeling contain recommendations and considerations for health care professionals that state, due to the risk of anaphylaxis, Xolair should only be administered to individuals in a health care setting under direct medical supervision by providers who are knowledgeable about the signs and symptoms of anaphylaxis and are appropriately trained and equipped to treat life-threatening anaphylactic reactions that can occur with any dose and at any time following Xolair administration. Additional information is also provided regarding adverse event reporting and a recommendation for periodic reassessment of the need for continued Xolair therapy, based upon individual disease severity and level of asthma control. Xolair is contraindicated for use and should be discontinued in those individuals who have experienced a severe hypersensitivity reaction. The "Alert" noted that this information reflected the FDA's preliminary analysis of data concerning this drug. The FDA is considering, but has not reached, a final conclusion about this information and intends to update the public when additional information or analyses become available (FDA: July 2007).

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. The FDA has 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. For example, since EXCELS is an observational study, there could be differences in underlying risk factors for cardiovascular and cerebrovascular events between the two study groups. The agency will communicate any new findings when its analysis of the interim safety data is complete. The EXCELS study is ongoing, and final results are not expected until 2012 ... The FDA is not recommending any changes to the prescribing information for Xolair and is not advising patients to stop taking Xolair at this time. Until the evaluation of the EXCELS study is completed, health care 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). 

Updated information regarding this study has not been posted on the FDA website as of April 2013.

In 2009, the FDA convened a meeting of the Pulmonary-Allergy Drugs Advisory Committee of the Center for Drugs Evaluation and Research to review the safety and efficacy of omalizumab for the treatment of asthma in children 6 – 11 years of age with moderate to severe persistent asthma whose symptoms are inadequately controlled with ICS. The following summarizes the findings reviewed by this advisory committee:
Efficacy Findings:

1. Statistically-significant benefit in primary end-point rate of exacerbations (protocol-defined)
2. No consistent effect on supporting secondary end-points: Steroid-sparing effect, diminished use of rescue medications, rate of medical encounters, asthma symptoms; 
3. Clinical relevance unclear as rate of exacerbations low:
   No exacerbations: 64 percent Xolair vs. 58 percent placebo,
   Number needed to treat: 2.34 (1.30, 11.26) Patient-Years.

Safety Findings

1. Short-term data demonstrates Xolair is well tolerated in children 6 to 12 years old;
2. Two cases each of anaphylaxis and malignancy, not related to omalizumab;
3. Asthma Safety Database (n = 926; 624 exposed during placebo-controlled trials):
   1 year exposure (n = 292),
   6 month exposure (n = 583).

Note: The number treated may not be sufficient to detect anaphylaxis or malignancy if rates are in children.

The FDA Advisory Committee summarized its review determination as follows and added this information to the July 2010 updated Prescription Information for omalizumab:

Considering the risk of anaphylaxis and malignancy seen in Xolair-treated patients greater than or equal to 12 years old and the modest efficacy of Xolair in the pivotal pediatric study, the risk-benefit assessment does not support the use of Xolair in patients 6 to < 12 years of age. Although patients treated with Xolair in these two studies did not develop anaphylaxis or malignancy, the studies are not adequate to address these concerns because patients with a history of anaphylaxis or malignancy were excluded, and the duration of exposure and sample size were not large enough to exclude these risks in patients 6 to < 12 years of age. Furthermore, there is no reason to expect that younger pediatric patients would not be at risk of anaphylaxis and malignancy seen in adult and adolescent patients with Xolair (FDA, 2010).

Non-FDA labeled (off-label) indications for the use of omalizumab are:

• Allergic rhinitis, Prophylaxis — Recommendation for Adult & Pediatric Class llb, Strength of Evidence Category B.
• Allergy to peanuts — Recommendation for Adult Class llb, Strength of Evidence Category B.
• Latex allergy — Recommendation for Adult Class llb, Strength of Evidence Category B.
• Subcutaneous immunotherapy, Adjunct — Recommendation for Adult & Pediatric Class IIb, Strength of Evidence Category B. (DrugDEX, 2012)

Omalizumab has been proposed for the treatment of moderate to severe chronic idiopathic urticaria (CIU) that has not responded to adequate trials of standard or high-dose oral H₁ -antihistamine therapy with concomitant oral leukotriene receptor antagonist (montelukast) in individuals 12 years of age or older. 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 2009, recommendations regarding the management of CIU were released from the Third International Consensus Meeting on Urticaria, which was a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). Based on the available scientific evidence, omalizumab was recommended as one of several 4th-line, add-on treatment options for refractory CIU (Zuberbier, 2009a). 

In 2013, Maurer reported results of the ASTERIA II Trial, a Phase III, multi-center, randomized, double-blind study that 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. Trial participants were randomly assigned to receive three subcutaneous injections of omalizumab, spaced four 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 prespecified 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 percent) than in the placebo group (3 percent) or in either the 75 mg or 150 mg groups (1 percent 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).          

Similar results were noted in a prior Phase II, randomized, double-blind, placebo-controlled trial of single-dose omalizumab in 90 subjects (aged 12 to 75 years) with moderate to severe CIU that had been refractory to H₁- antihistamines. Trial participants were randomized to receive a single dose of placebo or omalizumab at 75 mg, 300 mg or 600 mg while continuing their stable doses of H₁-antihistamines. At week 4, for the primary efficacy outcome (mean [+ SD] change in urticaria activity scores [UASs]), both the 300 mg and 600 mg omalizumab treated groups showed greater improvement versus the placebo group. No meaningful differences in UAS were seen in the group treated with a single 75 mg dose of omalizumab. During the treatment period (from 0 to 4 weeks), 44.0 percent of subjects experienced at least one adverse event (placebo group: 47.6 percent; 75 mg omalizumab group: 34.8 percent; 300 mg group: 48 percent; 600 mg group: 47.6 percent). The authors acknowledged the need for further study with longer duration of treatment to fully evaluate the treatment potential for omalizumab in refractory CIU (Saini, 2011).   

According to the current FDA-approved prescribing information and the latest monograph, at the present time, omalizumab is not indicated for the treatment of other allergic conditions, for the relief of acute bronchospasm or status asthmaticus, chronic urticaria, nor for use in children less than 12 years of age. There is insufficient evidence to demonstrate the safety and effectiveness of Xolair for any off-label uses (Bez, 2004; Burch, 2012; Fonacier, 2010; Kanu, 2008; Leech, 2011; Maurer, 2011; Metz, 2011; Milgrom, 2011; Pinto, 2010; Pressler, 2013; Ricci, 2009; Sabroe, 2010; Walker, 2011; Zirbes, 2008).

Definition

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 percent 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).

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.

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 includes spirometry and other tests to determine lung functional parameters, such as lung capacity and forced expiratory volume in one second (FEV₁).

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, 2007):

• High-dose inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) is the preferred treatment (Evidence B).
• Omalizumab may be considered at this step for patients who have sensitivity to relevant perennial allergens (e.g., dust mites, cockroach, cat or dog) (Evidence B).
• Clinicians who administer omalizumab are advised to be prepared and equipped for the identification and treatment of anaphylaxis that may occur, to observe patients for an appropriate period of time following each omalizumab injection (the optimal length of the observation is not established) and to educate patients about the risks of anaphylaxis and how to recognize and treat it if it occurs (e.g., using prescription auto-injectors for emergency self-treatment, and seeking immediate medical care) (see "FDA Warning/Regulatory Alert" field).
• Consultation with an asthma specialist is recommended for patients who require this step of therapy (Evidence D).

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

• Add oral corticosteroids to step 5 therapy. Patients who are not controlled on step 5 therapy may require regular oral corticosteroids to achieve well-controlled asthma.

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.

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Coding Section

Codes	Number	Description
ICD-9 Diagnosis	493.00-493.92	Asthma
	708.0-708.9	Urticaria
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

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward     

05/08/2023	Annual review, removed duplicate paragraph in policy section.
04/27/2022	Annual review, adding policy verbiage related to Xolair vials and treatment for nasal polyps. No other changes made.
04/14/2021	Annual review, adding medical necessity coverage for adults and children over 12 years of age with nasal polyps. No other changes made.
04/20/2020	Annual review, updating policy for specificity and clarity of medical necessity criteria.
04/01/2019	Annual review, no change to policy intent.
04/02/2018	Annual review, no change to policy intent.
04/19/2017	Annual review, changing investigational statement to reflect not medically necessary, otherwise, no change to policy intent.
08/22/2016	Interim review. Added Table #3 to Dosage section.
04/24/2016	Annual review, no change to policy intent.
11/04/2015	Change category from Medicine to Prescription Drug.
04/23/2015	Annual review, no change to policy intent. Added coding.
4/1/2014	NEW POLICY