Continuing Education Activity

Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody used to treat allergic asthma and chronic urticaria. This activity will consider the indications, contraindications, mechanisms of action, adverse effects, and monitoring requirements of omalizumab; it will also provide an update on some of the key studies implemented with regards to asthma primarily and include urticarial reactions.

Objectives:

• Identify the mechanism of action of omalizumab.
• Describe the adverse effects of omalizumab.
• Outline the required monitoring and toxicity of omalizumab.
• Review interprofessional team strategies for improving care coordination and communication to advance the use of omalizumab and improve outcomes.

Indications

Omalizumab is a recombinant humanized IgG1 monoclonal antibody targeting human immunoglobulin E (IgE) and thereby preventing its interaction with the high-affinity receptor Fc-epsilon-RI typically found on eosinophils, mast cells, and basophils, and is critical in the allergic cascade.[1] Omalizumab has a vital role in managing moderate to severe Ig-E medicated asthma and, more recently, a role in chronic urticaria. 

It received initial approval for use in 2003 for the treatment of moderate to severe asthma. It later received approval for use in patients with chronic idiopathic or spontaneous urticaria in 2014 in both the United States and Europe. It is the first drug to be licensed for the treatment of chronic urticaria in a patient who remains symptomatic despite H1-antihistamine treatment.[2] 

Asthma

It is FDA-approved for moderate to severe persistent asthma for adults and pediatric patients six years of age and older who have a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms are not adequately controlled with inhaled corticosteroids. It is not approved for the relief of acute bronchospasm or status asthmatics. It is not approved for the treatment of other allergic conditions.

Nasal Polyps

It is FDA-approved as an add-on maintenance therapy of nasal polyps for adults 18 years of age and above with inadequate response to nasal corticosteroids.

Chronic Spontaneous Urticaria

It is FDA-approved for treating adolescents 12 years of age and older and adults with chronic spontaneous urticaria who has symptoms despite H1 antihistamine treatment. It is not approved for other types of urticaria.

Mechanism of Action

The mechanism of action of omalizumab is different for allergic asthma vs. chronic urticaria.

The direct action involves selectively binding to the C-epsilon-3 locus, the domain at which IgE binds to Fc-epsilon-RI, decreasing levels of the immunoglobulin, and preventing interactions with its high-affinity receptor, as stated earlier, primarily on eosinophils, basophils, and mast cells interrupting the allergic cascade. Also, due to the total reduction of free IgE, there is a reduction in the expression of the IgE high-affinity receptor on inflammatory cells and a reduction in peripheral eosinophilia.[3]

With regards to chronic urticaria, the mechanism is not as well understood; unlike in asthma, where a 95% reduction in serum IgE levels is required to modify allergen response, in chronic urticaria, it is not a classic allergen-driven response, and a fixed dose of omalizumab has approval for use.[2] The theory is that omalizumab could prevent activation of mast cells and basophils in 40 to 45% of patients with chronic urticaria who may have an autoimmune component by decreasing high-affinity IgE receptor density and preventing IgE antibody-mediated cross-linking of adjacent alpha-subunits or IgE itself.[4] There is some evidence to support that these patients with chronic urticaria have an abnormal basophil IgE high-affinity receptor and that basophils are generally present in chronic urticarial lesion sites. There is also some evidence that treatment with omalizumab reverses basopenia and increases IgE receptor expression, which is typical in the disease states of patients with chronic urticaria.[5]

Pharmacokinetics

Omalizumab administration is via subcutaneous injection. Absorption into the systemic circulation is rather slow, with peak serum concentrations achieved after an average of 7 to 8 days. Omalizumab demonstrates linear pharmacokinetics in the approved dosage regimens. IgG clearance process, as well as specific binding and complex formation with IgE, are involved in omalizumab clearance. The mean half-life is 26 days.[6]

Administration

Available Dosage Forms

• Omalizumab 75 mg / 0.5 mL injection solution in a single-dose prefilled syringe.
• Omalizumab 150 mg/mL injection solution in a single-dose prefilled syringe
• Omalizumab 150 mg lyophilized powder for reconstitution in a single-dose vial
• Generally, omalizumab dosing and frequency are determined by serum total IgE levels and the patient's body weight. In the United States, the total serum IgE should be in the range of 30 to 700 IU/ml, and in Europe for adults and children above the age of 12, the range is between 30 to 1500 IU/ml, while for children between 6 to 12, IgE levels should be under 1300 IU/ml.[7]

Asthma

• The recommended dose for treatment of asthma is 75 mg - 375 mg by subcutaneous injection every two or four weeks.
• The basis for dose and frequency is calculated considering patient weight and pretreatment total IgE serum levels.
• There is no dosing adjustment based on total IgE levels taken during treatment.
• No dose adjustment is necessary for any significant weight changes

Chronic Urticaria

• Administer omalizumab 150 mg or 300 mg every four weeks based on initial serum total IgE level or patient weight.
• A retrospective chart review of 43 chronic urticaria patients treated with omalizumab between 2006 to 2015 found that overall, 90.2% (37/41) responded within three months duration.[8]

Nasal Polyps

• Administer 75 mg to 600 mg omalizumab by subcutaneous injection every two or four weeks based on initial serum total IgE level and patient weight.

Adverse Effects

U.S. Boxed Warning for Anaphylaxis for Omalizumab

Typically omalizumab is characterized by a very good safety profile; the major side-effect concerns with omalizumab are in four categories: systemic reactions, the potential effect on malignancy, risk of parasite disease, and immunological effects including serum sickness and Churg-Strauss vasculitis.[9]

Subjects in clinical trials generally tolerate the drug well, with most adverse events being mild or moderate and reported with a similar frequency to those in control or placebo groups. The most commonly reported adverse events with omalizumab in clinical trials were injection-site reactions (45%), viral infection (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). There are reports of anaphylactic reactions occurring with omalizumab, usually within 2 hours of the first or subsequent doses, although the incidence is low (0.1 to 0.2%). t merits noting these reports have been in asthmatics and not chronic urticaria patients.[6]

Regarding anaphylaxis, the Omalizumab Joint Task Force, formed by two American institutions specializing in asthma, allergy, and immunology, reviewed the omalizumab clinical trials and the post-marketing surveillance data. ey concluded that out of the 39510 patients who received omalizumab from June 2003 and December 2005, 35 patients had 41 episodes, which corresponds to an anaphylaxis reporting rate of 0.09%; as a result of the data, recommendations were implemented, which included a 2-hour observation following the initial three injections and the provision of epinephrine pens to patients.[10] There has been some mention of a risk of malignancy associated with IgE in the literature. A pooled analysis of phase 1 through 4 clinical trials in 2012 demonstrated no clear association was observable between omalizumab treatment and risk of malignancy in randomized, double-blind, placebo-controlled trials.[11]

Immunoglobulin E is classically the primary antibody in combatting parasitic disease; there are concerns that omalizumab therapy puts patients at increased risk of helminth infections. Some data demonstrates that in areas with an increased risk of helminth infection, omalizumab treatment slightly raises the patient's risk compared to placebo.[12]

Cases of Churg-Strauss in omalizumab treatment do appear in the literature.[13] However, it is still uncertain if there is a causal link between omalizumab treatment and Churg-Strauss; it is unclear if its a consequence or perhaps a pre-existing condition that has previously been masked by the long-term corticosteroid treatments these patients are generally on.[14]

There are two case reports of transient hair loss in chronic urticaria patients treated with omalizumab.[15][16]

Contraindications

Contraindications include severe hypersensitivity reaction to omalizumab.

Monitoring

Due to the risk of anaphylaxis, patients require close observation for an appropriate period after omalizumab administration. Registered nurses or physicians administering omalizumab should be prepared and trained to manage episodes of omalizumab-induced anaphylaxis. Clinics administering omalizumab should have resuscitation equipment available.[17]

Total serum IgE levels are elevated while a patient is on treatment with omalizumab and it remains elevated for up to one year after discontinuation. Therefore, re-testing IgE levels during treatment can’t be used to guide dose determination. However, if the interruptions lasted less than one year, the dose is based on serum IgE levels obtained at the initial dose determination.

Toxicity

Assessing the toxicology profile of omalizumab has proven to be complicated. Based on the initial manufacturer information and literature searches, it is unclear what the actual toxicology profile is with regards to the initial animal studies; they identified no apparent single-dose toxicity or multiple dose toxicity. However, there was some discussion and delay in trials due to thrombocytopenia observed in monkey studies. Study data demonstrated no overt carcinogenic properties.[18]

Enhancing Healthcare Team Outcomes

The clinical efficacy of subcutaneous omalizumab as adjunctive therapy in patients with allergic asthma has evidence from several well-designed trials. After nearly two years of use, there is robust evidence that omalizumab is an effective and safe treatment of severe asthma. However, the optimum duration of therapy is not known, though trials have demonstrated that indefinite treatment is not always needed.[19] There is also a considerable amount of information supporting the health economic benefits of long-term omalizumab treatment in select populations, as the marked reduction in frequency and the severity of exacerbations and improved quality of life reduce the burden on acute healthcare services.[20]

Due to the risk of anaphylaxis, patients require close observation for an appropriate period after omalizumab administration. This risk necessitates an interprofessional team approach to therapy. Registered nurses or physicians administering omalizumab should be prepared and trained to manage episodes of omalizumab-induced anaphylaxis. Pharmacists should be consulted for dosing as well as performing complete medication reconciliation, and results reported back to the healthcare team. Clinics administering omalizumab should have resuscitation equipment available, including epinephrine at the bedside.[17] All nurses who administer omalizumab must be familiar with the drug and its adverse effects and report any signs of such reaction to the managing clinician or pharmacist. Further, patient education is vital to ensure that delayed reactions are not left untreated, which falls under the purview of all healthcare team members. This type of interprofessional collaboration increases the chance of successful therapy with omalizumab. [Level V]