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* From the Practice Management Committee, American College of Chest Physicians, Chicago, IL.
Correspondence to: Philip Marcus, MD, MPH, FCCP, Nassau Chest Physicians, P.C., 233 East Shore Rd, Suite 112, Great Neck, NY 11023; e-mail: PMarcus192{at}aol.com
Abstract
Despite aggressive therapy, many asthma patients cannot achieve optimal control, and it is recognized that a small number of patients, generally those with severe persistent asthma, are the most difficult to control and are responsible for a large segment of the costs of asthma. These patients demonstrate a need for additional therapeutic options to achieve enhanced asthma control. Omalizumab should be considered a second-line therapy for patients with moderate-to-severe persistent allergic asthma not fully controlled on standard therapy. This article should not be considered a complete guide to incorporating this therapy into practice but serve as an introduction and a basic review of the practice management aspects of therapy for physicians practicing in the United States.
Key Words: asthma • management • omalizumab • therapeutic options
The treatment of asthma has changed considerably over the past 30 years. This has occurred as asthma prevalence has increased; until recently, asthma mortality has increased to alarming rates. Despite advances in therapy, asthma continues to cause significant morbidity (hospitalizations, emergency department visits) and results in lost productivity in terms of days lost from school and work, largely secondary to exacerbations that interfere with normal function.1
Asthma treatment guidelines in the United States were first introduced in 1991, revised in 1997, and updated in 2002.23 Another update is expected shortly. In addition to US guidelines for the management of asthma (National Asthma Education and Prevention Program [NAEPP]), many national and international guidelines (Global Initiative for Asthma [GINA])4 exist. Each of these guidelines makes asthma therapy recommendations based on asthma severity, and more recently on asthma control.
Despite aggressive therapy, many asthma patients cannot achieve optimal control, and it is recognized that a small number of patients, generally those with severe persistent asthma, are the most difficult to treat and are responsible for a large segment of the costs of asthma.5 These patients demonstrate a need for additional therapeutic options to achieve enhanced asthma control. One of these agents is the anti-IgE antibody omalizumab. Several studies6789 support the use of omalizumab in patients with difficult-to-control, moderate-to-severe persistent asthma, and this agent has been incorporated into the armamentarium of physicians treating patients with this level of asthma severity and into the updated Global Initiative for Asthma guidelines for patients with poorly controlled severe persistent asthma (step 4). In addition, studies are ongoing evaluating the use of anti-IgE therapy in other allergic conditions and in children < 12 years old.
Traditional pulmonary medicine practice has not typically utilized parenteral medications as asthma treatment except in managing an acute exacerbation. In many practices, IV or IM steroids are administered; in the past, some sites would administer IV aminophylline in order to avoid a hospitalization. Subcutaneous epinephrine has been used as well, but its use has declined dramatically, likely because of the availability of more effective nebulized bronchodilators. However, practices are now offering the ability to utilize biotechnology products in patients with persistent asthma. The single agent available at this time is omalizumab, and pulmonary medicine specialists have come to recognize that it may play a significant role in helping patients have an improved quality of life and a reduction in exacerbations. In contrast, allergy practices have integrated injection therapy, primarily in the form of allergen desensitization, in their practices, and omalizumab therapy seemed to be more readily accepted.
Omalizumab has been studied in the United States and Europe and has been found to be effective in reducing exacerbations in atopic patients 
12 years old with moderate-to-severe persistent asthma. The initial studies evaluated asthmatics still having exacerbations despite inhaled corticosteroids; both pivotal studies 67 found that omalizumab resulted in a reduction in exacerbations (33 to 75% vs placebo in the steroid-stable phase and 33 to 50% in the steroid-reduction phase) as well as the ability to reduce the dose of inhaled corticosteroid (41.3% of patients receiving omalizumab were able to eliminate beclomethasone vs 19.3% of patients receiving placebo) over the 28 weeks. Two additional studies89 demonstrated that use of omalizumab in atopic patients with moderate-to-severe persistent allergic asthma not well controlled despite inhaled corticosteroids and other controllers, including long-acting ß-agonists and leukotriene antagonists, resulted in a reduction in asthma exacerbations (1.12 exacerbations over 1 year in omalizumab-treated patients vs 2.86 exacerbations in patients receiving standard asthma care in Ayres et al8 and a 26% reduction in exacerbations over 28 weeks in patients treated with omalizumab vs standard care alone in Humbert et al9) and overall improvement in quality of life (absenteeism and unscheduled visits). These latter two studies represented a more real-world approach to asthma care because most patients with this degree of asthma are using multiple controllers and may still experience less-than-optimal control. Indeed, even in a study10 attempting to obtain total control of asthma, a large number of patients (> 30% of 3,421 patients) cannot be well controlled despite combination therapy with high doses of inhaled corticosteroids and long-acting ß agonists demonstrating a need for additional therapies. Of course, factors known to contribute to poor asthma control (gastroesophageal reflux, sinusitis, rhinitis) should be eliminated or controlled.
Several studies have tried to determine the ideal patient for omalizumab therapy. The US Food and Drug Administration (FDA)-approved indication for this agent 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 > 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).11 Accordingly, many physicians include such serum testing in the initial evaluation of patients with asthma. Bousquet et al12 gathered data from the pivotal trials and found that the greatest response would be expected in a patient with poor pulmonary function (FEV1 < 60%), utilizing emergency care, and receiving a relatively high dose of inhaled corticosteroid (> 800 µg of beclomethasone diproponiate per day).
Rosenwasser and Nash13 reported the results of a consensus panel to determine the place for omalizumab therapy. They proposed consideration for therapy for patients with severe persistent asthma who are controlled with high doses of inhaled corticosteroids as well as those requiring bursts of oral steroids, and also consideration for patients with moderate persistent asthma not well controlled on inhaled corticosteroids and long-acting ß-agonists or leukotriene modifiers. Lastly, they propose a role for omalizumab in patients poorly adherent to prescribed therapy and requiring frequent medical services.
The dosing of omalizumab has been standardized, and many aids have been developed to allow the clinician to determine the correct dose. The dosage is determined by matching the IgE level drawn at baseline and matching it to the patient’s weight12 (Appendix 1).
IgE levels, once drawn, should not be repeated since no dosage adjustments are necessary. The dosage of omalizumab chosen should result in neutralization of free IgE to levels < 5% at baseline and equates to 0.016 mg/kg of omalizumab per IU/mL per 4 weeks. However, total IgE may actually increase secondary to formation of omalizumab-IgE complexes.14
The decision to begin omalizumab therapy should be made with full understanding that this is a long-term therapy, administered subcutaneously every 2 or 4 weeks depending on body weight and baseline IgE level. The medication is not prescribed in a traditional manner, but rather a "statement of medical necessity" is completed and sent to a participating specialty pharmacy (Curascript Pharmacy Inc, Orlando, FL; Caremark Rx, Inc, Nashville, TN; Option Care, Inc, Buffalo Grove, IL; and Accredo Nova Factor, Inc, Memphis, TN). This statement of medical necessity (SMN) [Appendix 2] includes information about the patient, insurance coverage, clinical data, concomitant medications, IgE level, and dosage.
The preparation of omalizumab for administration has become standardized, and a set protocol exists. Each vial of omalizumab contains 150 mg of the drug and requires reconstitution prior to administration. Following reconstitution with 1.4 mL of sterile water for injection, the vial will contain 150 mg of omalizumab in 1.2 mL of liquid. The materials for reconstitution (syringes, needles, and even alcohol swabs) are provided by the specialty pharmacy along with the drug itself. After the diluent has been added to the vial, swirling is necessary to accomplish complete dissolution, and a "swirler" is provided to accomplish this task. The vial is then accessed with a sterile needle for subcutaneous injection. The total dose, as previously noted, should not exceed 375 mg and this will require multiple injections, with no single injection > 150 mg; at maximum dose, there will be wasting of some of the omalizumab that has already been reconstituted.11
Following injection, the patient should be observed to ensure that the dose is well tolerated and that no immediate adverse events have occurred. Severe hypersensitivity reactions are always a concern, but anaphylactoid reactions have been observed in only three patients in the pivotal clinical trials representing < 0.1% of patients. To date, > 50,000 patients have been prescribed omalizumab in the United States. Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, should be available. Most clinicians will observe the patient for up to 2 h following the first injection, and then for 
1 h thereafter. If a severe hypersensitivity reaction to omalizumab occurs, therapy should, of course, be discontinued. Injection site reactions have been observed in 45% of patients receiving omalizumab and 43% of patients receiving placebo. These reactions include bruising, redness, pain, stinging, itching, and burning. Most of these reactions occur within 1 h of injection and decrease in frequency with subsequent injections.11
Practice management issues appear to have played a major role in inhibiting physicians from incorporating this effective modality of therapy in their practices. However, since the introduction of omalizumab in June 2003, many of the problems initially encountered with reimbursement have been successfully resolved. Accordingly, there is now ample guidance to allow physicians to utilize this therapy for suitable patients. Issues of preauthorization, continuation of coverage and reimbursement have largely been standardized, but regional differences, particularly with individual insurance plans exist. Plans will either consider this to be a prescription benefit or a medical benefit. Different rules in terms of copayments and deductibles will apply accordingly.
Most insurance plans provide coverage for patients who are considered appropriate candidates for therapy with omalizumab. There exists considerable variation in the requirements for patients to be considered for this therapy. The FDA-approved indication is as follows:
Xolair® (omalizumab [Genentech, Inc; South San Francisco, CA]) is indicated for adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test result 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. Safety and efficacy have not been established in other allergic conditions.
However, many insurance plans have placed additional restrictions on the use of omalizumab in an attempt to control costs. These additional restrictions are insurance plan and locale specific, and in many cases are more stringent that the FDA-approved indication. Examples of some of these restrictions include levels of FEV1 abnormality, evidence of instability including emergency department visits, hospitalization, intubation, and use of systemic steroids.
In almost every situation, the decision to institute omalizumab therapy should be made on sound principles including the diagnosis of moderate or severe persistent IgE-mediated asthma with evidence for poor control despite the use of inhaled corticosteroids, and usually other controller medications as well, an IgE level between 30 and 700 IU/mL and evidence of reactivity to one or more aeroallergens. This should be documented in the progress note and on the SMN. The SMN is faxed to the specialty pharmacy chosen by the physician (and staff) along with a signed patient authorization. The specialty pharmacy will then determine if the patient has benefits for omalizumab coverage and what has to be done to obtain the necessary prior authorization. For patients with Medicare without any supplemental pharmacy benefit coverage, no preauthorization is needed and the physician practice would simply purchase the omalizumab and then submit to the appropriate carrier for reimbursement (buy and bill).
Most insurance carriers require that patients receiving omalizumab be recertified periodically for continued use. Common practices include reviews for continuation of omalizumab therapy at 6 months and 12 months. The carriers are probing as to the benefits of omalizumab and generally want to have documentation that there has been improved symptom control and/or exacerbation frequency and/or decreased use of rescue medication. Another benefit of omalizumab may a reduction in corticosteroid dosage while maintaining control. The benefits of omalizumab therapy may take up to several weeks to months to manifest and frequent assessments of symptoms and quality of life are necessary. In the pivotal trials, > 85% of patients showed response by 5 months.6789
Reimbursement for patients receiving omalizumab therapy incorporates payment for the drug itself, when applicable, as well as administration costs. It is assumed that all patients receiving omalizumab are suitable candidates, and the International Classification of Diseases, Ninth Revision code used should reflect allergic (extrinsic) asthma (code 493.00), assuming the patient is not experiencing an exacerbation at the time of the visit, in which 493.01 would be the appropriate code. Of course, omalizumab is not indicated for acute relief of asthma symptoms. The actual current procedural terminology (CPT) code used for the administration of the omalizumab is generally 90772 and can be billed for each injection administered. Discussion among coding specialists has also indicated that certain insurance carriers will reimburse for the more complex code, 96401, generally paid at a higher level, but usually reserved for chemotherapy administration via the subcutaneous route. Of course, if an office visit is also performed on the day of the injection, then that specific evaluation and management code should also be billed, commensurate with the level of complexity and with the appropriate modifier (– 25). Also, revisions to CPT necessitate updating information concerning appropriate billing codes.
In situations in which the patient does not have a pharmacy benefit plan but has Medicare, and in some areas Medicaid, the practice must purchase omalizumab from one of the specialty pharmacies and then bill for its cost as well as administration costs. In addition to the CPT code for administration, there exists a "J code" specific for omalizumab itself. This code is specific for the medication used and is required for reimbursement. This is J 2357 and applies when the omalizumab is administered in the office setting. The code is "per 5 mg" of medication; therefore, 150 mg of omalizumab is 30 U. In addition, some payers will request the actual NDC code (identifier for medication, dose form, and quantity) for completeness. The NDC code for omalizumab is 50242-0040-62. When the physician purchases omalizumab, the patient will generally be responsible for the 20% copayment unless the patient has secondary insurance coverage that would apply. This should be discussed with the patient in advance to avoid problems after the drug has been purchased and injected. If the claim is rejected, there will usually be a request for documentation of medical necessity, and this supports the need for excellent record keeping. If the claim is still rejected, often after an appeal, there exists a mechanism for a single point of contact program set up by the manufacturers of omalizumab to get involved to assist in securing reimbursement.
The manufacturers and distributors of omalizumab, including the specialty pharmacies listed above, have established several programs to assist physicians and patients obtain the medication and receive adequate reimbursement. A practice management manual is available and should be requested by physicians to aid in understanding the entire process. This should not be considered a "loss" for physicians, and mechanisms exist to optimize reimbursement so that this therapy can be provided to patients who would benefit and result in enhanced office management of persistent asthma.
There has been great acceptance of the use of omalizumab in allergy and pulmonary practices nationwide to assist patients achieve better control of asthma, particularly in reducing exacerbations that result in a decline in quality of life. There have been many studies that clearly show the benefits of this therapy for patients with allergic moderate-to-severe persistent asthma. However, despite the demonstration of the efficacy of the drug, there have also been skeptics, particularly in terms of the costs of therapy compared to the benefits obtained. Corren et al15 conducted a pooled analysis of three multicenter, randomized, double-blind, placebo-controlled, phase III trials investigating the effect of long-term treatment with omalizumab on the rate of serious asthma exacerbations. Patients in the omalizumab groups had fewer asthma exacerbations and asthma-related hospitalizations. Omalizumab was able to decrease hospitalizations by 92% and decrease the average hospital stay by up to 63%. This should substantially lower the cost of care for asthma patients. A retrospective study16 was conducted to determine the cost-effectiveness of therapy and found benefits primarily for patients with multiple hospitalizations despite maximal asthma therapy. More economic studies are needed to determine the cost-effectiveness of omalizumab in the treatment of asthma in the long term. At present, the cost of a single vial (150 mg) is approximately $470, and accordingly yearly costs for omalizumab administration range from $6,110 to $36,600.
Omalizumab should be considered a second-line therapy for patients with moderate-to-severe persistent allergic asthma not fully controlled with standard therapy. The use of this agent has resulted in improvements in quality of life for many patients, and in most settings should not result in a significant increase in cost because of a reduction in emergency care including hospitalization, as well as indirect cost reductions such as productivity and absenteeism. The adoption of this therapy by the pulmonary practice results from an appreciation of the benefits of this therapy as well as the practice management issues not previously encountered with other therapeutic modalities. It can be a "life changer" for many patients and should not be dismissed as too complicated or not cost effective in the practice setting. This article should not be considered a complete guide to incorporating this therapy into practice but serve as an introduction and a basic review of the practice management aspects of therapy for physicians practicing in the United States.
Appendix
Appendix 1: Dosing Table
Appendix 2: Statement of Medical Necessity
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Abbreviations: CPT = current procedural terminology; FDA = Food and Drug Administration
Dr. Marcus is on the speakers bureau for Genentech and Novartis, as well as Glaxo, Schering, Altana, Boehringer, and Pfizer.
Received for publication November 6, 2005. Accepted for publication December 14, 2005.
References
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