Continuing Education Activity

Omalizumab received initial approval from the U.S. Food and Drug Administration (FDA) in 2003 for the treatment of moderate-to-severe asthma. Subsequently, in 2014, the drug was also approved for use in patients with chronic idiopathic or spontaneous urticaria in the United States and Europe. Omalizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal anti-IgE antibody utilized to treat allergic asthma and chronic urticaria. This medication works by interacting with the high-affinity receptor Fc-epsilon-RI, typically found on eosinophils, mast cells, and basophils, therefore playing a critical role in preventing the allergic cascade. As a result, omalizumab plays a vital role in managing moderate-to-severe IgE-mediated asthma and, more recently, in treating chronic urticaria. This activity will comprehensively cover the indications, contraindications, mechanisms of action, pharmacokinetics, adverse effects, warnings, precautions, and monitoring requirements of omalizumab. In addition, this activity will also provide updates on some of the critical studies implemented primarily for asthma and include information on urticarial reactions.

Objectives:

• Identify appropriate patients for omalizumab therapy based on indications, such as moderate-to-severe asthma or chronic urticaria.
• Screen patients thoroughly for eligibility, including total serum IgE levels, potential contraindications, and medical history, before initiating omalizumab treatment.
• Assess patients' responses to omalizumab treatment by monitoring their symptom improvement, exacerbation frequency, and quality of life measures and adjusting the therapy as needed.
• Communicate with patients effectively about omalizumab therapy, explaining its benefits, potential risks, and expected outcomes and addressing their concerns or questions.

Indications

Omalizumab is a recombinant humanized IgG1 monoclonal antibody that specifically targets human immunoglobulin E (IgE). This action prevents the drug's interaction with the high-affinity Fc-epsilon-RI receptor, typically found on eosinophils, mast cells, and basophils. This interaction plays a critical role in the allergic cascade.[1] Omalizumab is vital in managing moderate-to-severe asthma mediated by IgE and, more recently, treating chronic urticaria.

Omalizumab received initial approval from the U.S. Food and Drug Administration (FDA) in 2003 for treating moderate-to-severe asthma. Subsequently, in 2014, the drug was also approved for use in patients with chronic idiopathic or spontaneous urticaria in the United States and Europe. Omalizumab is the first drug licensed to treat chronic urticaria in patients who still experience symptoms despite receiving H1-antihistamine treatment.[2] 

Asthma

Omalizumab is an FDA-approved drug used for the treatment of moderate-to-severe persistent asthma in adults and pediatric patients 6 or older who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are not adequately controlled with inhaled corticosteroids. However, relieving acute bronchospasm or status asthmatics and treating other allergic conditions is not approved.

Nasal Polyps

Omalizumab is an FDA-approved medication for adults 18 or older who have not responded adequately to nasal corticosteroids and, therefore, require an add-on maintenance therapy for nasal polyps.

Chronic Spontaneous Urticaria

The FDA has approved omalizumab for treating chronic spontaneous urticaria in adolescents 12 or older, as well as adults, who still experience symptoms even after receiving the H1 antihistamine treatment. However, this drug is not approved for other types of urticaria.

Off-Label Uses

According to the American College of Rheumatology guidelines, omalizumab can be used to treat antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.[3] In addition, other off-label uses of omalizumab include bronchopulmonary aspergillosis, keratoconjunctivitis, drug and food allergies, eosinophilic otitis media, bullous pemphigoid, and atopic dermatitis.[4][5][6][7]

Mechanism of Action

The mechanism of action of omalizumab differs for allergic asthma and chronic urticaria.

The direct action of omalizumab involves selective binding to the C-epsilon-3 locus, the domain at which IgE binds to Fc-epsilon-RI. This action effectively lowers immunoglobulin levels and prevents them from interacting with their high-affinity receptor, mainly present on eosinophils, basophils, and mast cells. This interruption breaks the allergic cascade. Moreover, the total reduction of free IgE results in decreased expression of the IgE high-affinity receptor on inflammatory cells and a reduction in peripheral eosinophilia.[8]

Unlike in asthma, where a 95% reduction in serum IgE levels is required to modify allergen response, the mechanism for chronic urticaria is not as well understood. In the case of chronic urticaria, it does not involve a classic allergen-driven response.[2] The theory suggests that omalizumab may prevent the activation of mast cells and basophils in 40% to 45% of patients with chronic urticaria who might have an autoimmune component. This effect is achieved by decreasing the density of high-affinity IgE receptors and preventing the cross-linking of the adjacent alpha-subunits, or IgE molecules, mediated by IgE antibodies.[9] 

There is evidence supporting the notion that patients with chronic urticaria have an abnormal basophil IgE high-affinity receptor, and it is also observed that basophils are often found in chronic urticarial lesion sites. Another evidence suggests that omalizumab treatment can reverse basopenia and increase IgE receptor expression, typically observed in patients with chronic urticaria.[10]

Pharmacokinetics

Absorption: Omalizumab is administered via subcutaneous injection. The absorption of omalizumab into the systemic circulation is relatively slow, with peak serum concentrations typically achieved after an average of 7 to 8 days. Omalizumab demonstrates linear pharmacokinetics in the approved dosage regimens.

Distribution: After subcutaneous injection, omalizumab exhibits an apparent volume of distribution of 78±32 mL/kg.

Metabolism: Omalizumab undergoes degradation in the reticuloendothelial system and endothelial cells.[11]

Excretion: The clearance of omalizumab relies on the clearance of IgG and the clearance through complex formation. IgG, in its original form, is excreted through bile. The mean half-life of omalizumab is approximately 24 to 26 days.[12]

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.

The dosage and frequency of omalizumab are generally determined by the patient's body weight and serum total IgE levels. The recommended range for total serum IgE level in the United States should be 30 to 700 IU/mL. In Europe, the recommended range for the total serum IgE level for adults and children aged 12 or older should be between 30 and 1500 IU/mL, whereas, for children between the ages of 6 to 12, it should be under 1300 IU/mL.[13]

Asthma

• The recommended dosage of omalizumab for treating asthma is 75 to 375 mg, administered through a subcutaneous injection every 2 or 4 weeks.
• The appropriate dosage and frequency for omalizumab are established by considering the patient's weight and total IgE serum levels before treatment.
• No dosage adjustment is needed based on total IgE levels taken during omalizumab treatment or in response to significant weight changes.

Chronic Urticaria

• The recommended dosage for omalizumab for treating chronic urticaria is either 150 or 300 mg every 4 weeks, depending on the patient's initial serum total IgE level or weight.
• A retrospective chart review of 43 chronic urticaria patients who received omalizumab between 2006 and 2015 revealed that 37 out of 41 patients (90.2%) responded positively within 3 months duration.[14]
• Joint guidelines by the American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma, and Immunology (ACAAI) indicate that omalizumab can improve the quality of life, reduce the need for oral corticosteroids, and potentially decrease the need for surgery in chronic urticaria patients.[5]

Nasal Polyps

• The recommended dosage for omalizumab in the treatment of nasal polyps is 75 to 600 mg, administered through a subcutaneous injection every 2 or 4 weeks, depending on the patient's initial serum total IgE level and weight.

Specific Patient Populations

Patients with hepatic impairment: The manufacturer's labeling does not suggest any dose adjustment recommendations of omalizumab for patients with hepatic impairment. Furthermore, as the reticuloendothelial system metabolizes omalizumab, there is no need for dose adjustment in patients with hepatic impairment. 

Patients with renal impairment: Although the manufacturer's labeling does not include any dose adjustment recommendations of omalizumab for patients with renal impairment, it is essential to note that the pharmacokinetics and dosage of the medication are unlikely to be affected by renal impairment, as discussed above.[11]

Pregnancy considerations: Omalizumab, as an IgG antibody, can cross the placental barrier. Thus, low birth weight in infants exposed to omalizumab during maternal use is a potential risk. However, it is essential to consider that severe asthma can also contribute to low birth weight in infants. Therefore, a thorough risk-benefit analysis should be conducted individually to make informed decisions.[15]

Breastfeeding considerations: Primary evidence suggests that the concentration of omalizumab in maternal milk is low. As omalizumab is a large protein molecule, the amount present in milk is likely to be very low. Moreover, omalizumab is expected to be destroyed in the infant's gastrointestinal tract, leading to minimal absorption. Therefore, omalizumab is considered a permissible drug for use during breastfeeding.[16]

Pediatric patients: Omalizumab is an FDA-approved medication for managing chronic idiopathic urticaria in patients older than 12 and asthma in patients older than 6. As per the GINA (Global Initiative for Asthma) guidelines, omalizumab is indicated for patients with uncontrolled asthma who are currently on Step 4 or 5 of the treatment process. The administration of omalizumab is done through subcutaneous injection every 2 to 4 weeks, with the dose determined based on weight and serum IgE levels. Notably, patients with eosinophils ≥260/μL or fractional exhaled nitric oxide (FeNO) ≥20 ppb have shown favorable responses to omalizumab.[17]

Older patients: No dose adjustment is necessary for older patients.

Adverse Effects

U.S. Boxed Warning for Anaphylaxis for Omalizumab

Although omalizumab is generally considered to have an excellent safety profile, there are some significant concerns regarding the potential adverse effects of the drug. The significant adverse effects of omalizumab can be categorized into the following 4 groups: systemic reactions, potential effects on malignancy, risk of parasite disease, and immunological effects, including serum sickness and Churg-Strauss vasculitis.[18]

Subjects in clinical trials generally tolerate the drug well, as most adverse events are mild or moderate and reported with a similar frequency compared to those in control or placebo groups. The most commonly reported adverse events during omalizumab clinical trials were injection-site reactions (45%), viral infection (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Anaphylactic reactions have been reported with omalizumab, typically occurring within 2 hours of the first or subsequent doses, although the incidence is low (0.1% to 0.2%). These reports have been observed in patients with asthma and not in patients with chronic urticaria.[12]

Regarding anaphylaxis, the Omalizumab Joint Task Force, formed by 2 American institutions specializing in asthma, allergy, and immunology, reviewed the omalizumab clinical trials. The post-marketing surveillance data revealed that out of the 39,510 patients who received omalizumab between June 2003 and December 2005, 35 patients experienced 41 episodes of anaphylaxis, resulting in an anaphylaxis reporting rate of 0.09%. Specific recommendations were implemented in response to this data, including a 2-hour observation period after administering the first 3 injections and providing patients with epinephrine pens.[19]

There has been some mention of a risk of malignancy associated with IgE in the literature. However, a pooled analysis of phase 1 through 4 clinical trials conducted in 2012 demonstrated no clear association between omalizumab treatment and the risk of malignancy in randomized, double-blind, placebo-controlled trials.[20]

Immunoglobulin E is classically known as the primary antibody in combating parasitic diseases. Therefore, there are concerns that omalizumab therapy may increase patients' risk of helminth infections. As per some data, treatment with omalizumab may slightly elevate patients' risk in regions with an increased risk of helminth infection, compared to placebo.[21] In addition, cases of Churg-Strauss associated with omalizumab treatment have been documented in the literature.[22]

However, uncertainty remains regarding a causal link between omalizumab treatment and Churg-Strauss. It is uncertain whether Churg-Strauss is a consequence of omalizumab treatment or a preexisting condition previously masked by prolonged corticosteroid treatments, typically administered to these patients.[23] Two cases of transient hair loss in chronic urticaria patients treated with omalizumab have been reported.[24][25]

Drug-Drug Interactions

• The concomitant use of omalizumab with immunosuppressive agents has not yet been assessed; therefore, it is advised to avoid this combination.
• The concomitant use of omalizumab and immunotherapy has not been thoroughly evaluated; therefore, the manufacturer's labeling recommends avoiding this combination. However, a recent study indicated that it could be administered safely.[26]
• The concomitant use of ACE inhibitors in chronic spontaneous urticaria may reduce omalizumab's efficacy.[27]

Contraindications

Contraindications include a severe hypersensitivity reaction to omalizumab, and there have been reported cases of anaphylaxis.[28]

Monitoring

Due to the risk of anaphylaxis, patients must be closely observed for an appropriate period after omalizumab administration. Clinicians who administer omalizumab should be prepared and trained to manage episodes of omalizumab-induced anaphylaxis. Clinics administering omalizumab to patients should have resuscitation equipment readily available.[29]

Total serum IgE levels are elevated while a patient is on treatment with omalizumab, and they continue to remain elevated for up to 1 year even after the medication discontinuation. As a result, retesting IgE levels during treatment cannot be used to guide dose determination. However, if the interruptions in treatment last for less than 1 year, the dose will be determined based on serum IgE levels obtained during the initial dose determination. FeNO testing should be considered for patients with asthma.[17] Pulmonary function tests should be monitored to assess the response to therapy. Moreover, the sinonasal outcome test (SNOT-22) should be obtained for patients with rhinosinusitis.[5]

Toxicity

Assessing the toxicology profile of omalizumab has proven to be complex. Based on the available manufacturer information and literature searches, it remains unclear what the toxicology profile is regarding the initial animal studies. No signs of toxicity were found in either single-dose or multiple-dose testing. However, thrombocytopenia has been observed in preclinical studies. Nevertheless, study data demonstrated no overt carcinogenic properties.[30] In cases of anaphylaxis, omalizumab should be discontinued, and epinephrine should be promptly administered.[31]

Enhancing Healthcare Team Outcomes

The clinical efficacy of subcutaneous omalizumab as adjunctive therapy in patients with allergic asthma is supported by evidence from several well-designed trials. After nearly 2 years of use, robust evidence shows that omalizumab is effective and safe for treating severe asthma. However, the optimum duration of therapy remains unknown, although trials have demonstrated that indefinite treatment is not always necessary.[32]

There is also substantial evidence supporting the health-economic benefits of long-term omalizumab treatment in special populations. The marked reduction in the frequency and severity of exacerbations and improved quality of life significantly reduce the burden on acute healthcare services.[33]

Due to the risk of anaphylaxis, patients must be closely observed for an appropriate period after omalizumab administration. This risk underscores the importance of an interprofessional team approach to therapy. Registered nurses, physicians, or advanced practice practitioners who administer omalizumab should be prepared and trained to manage episodes of omalizumab-induced anaphylaxis. Immunologists should be consulted for the appropriate use of omalizumab in asthma. Pharmacists should provide input regarding the dosage of omalizumab and perform complete medication reconciliation, with results reported to the healthcare team. Clinics administering omalizumab should have resuscitation equipment, including epinephrine, readily available at the patient's bedside.[29]

All nurses administering omalizumab must be familiar with the drug and its potential adverse effects, and they should promptly report any signs of such reactions to the ordering clinician or pharmacist. Moreover, patient education is vital in ensuring that delayed reactions are not left untreated, a responsibility that falls under the purview of all healthcare team members. Effective interprofessional coordination and collaboration, with shared decision-making among physicians, advanced practice practitioners, specialists, pharmacists, and nurses, can significantly enhance patient outcomes when using omalizumab therapy.