Omalizumab

Class: Respiratory Tract Agents, Miscellaneous
VA Class: IM600
Chemical Name: Immunoglobulin G, anti-(human immunoglobulin E Fc region) (human-mouse monoclonal E25 clone pSVIE26 γ-chain), disulfide with human-mouse monoclonal E25 clone pSVIE26 κ-chain, dimer
CAS Number: 242138-07-4
Brands: Xolair

Introduction

Antiasthmatic agent; a chimeric human-murine (humanized) IgG1κ anti-IgE monoclonal antibody.^{1 2 3 4}

Uses for Omalizumab

Allergic Asthma

Management of moderate to severe persistent allergic (a positive skin test or in vitro reactivity to a perennial aeroallergen) asthma inadequately controlled with inhaled corticosteroids.^{1 5} However, some experts reserve use mainly for management of severe allergic asthma.^{5 10} Manufacturer states that the safety and efficacy of omalizumab in the management of other allergic conditions not established.¹ Some experts state that omalizumab is effective for the management of concurrent rhinitis†.⁵

In adults and adolescents with severe persistent allergic asthma inadequately controlled with high-dose inhaled corticosteroids and a long-acting β₂-adrenergic agonist bronchodilator, some experts recommend addition of omalizumab.¹⁰

Omalizumab Dosage and Administration

General

• If used for extended periods, periodically reassess the need for continued therapy based on the patient’s severity of asthma and degree of asthma control.^{1 8}

• After treatment interruptions of <1 year, base dosage on serum IgE concentrations obtained prior to treatment initiation.¹

• If omalizumab therapy has been interrupted for ≥1 year, may reevaluate total serum IgE concentrations for dosage determination.¹

• Adjust dosage if the patient’s body weight changes substantially; apparent clearance of the drug is proportional to body weight.^{1 4}

Reduction of Concurrent Inhaled Corticosteroid Therapy

• Should not discontinue abruptly concomitant inhaled or systemic corticosteroid therapy upon initiation of omalizumab therapy.¹ Reduce concomitant corticosteroid dosage gradually (after 16 weeks in clinical trials), and supervise such reduction carefully.^{1 4}

Administration

Sub-Q Administration

Administer once every 2 or 4 weeks by a clinician.^{1 8} (See Medical Personnel and Facilities under Cautions.)

In general, administer ≤150 mg per injection site; divide doses >150 mg and inject at various sites.^{1 10}

Reconstitution

Reconstitute vial containing 202.5 mg of omalizumab lyophilized powder with 1.4 mL of sterile water for injection to provide a solution containing 150 mg per 1.2 mL.¹

Swirl vial gently for approximately 1 minute to wet the lyophilized powder and then for 5–10 seconds approximately every 5 minutes in order to dissolve (could take >20 minutes) any remaining solids.¹ Do not shake vial.¹ Small bubbles or foam may remain in the vial.¹ Resulting solution will be slightly viscous.¹ Discard the solution if the drug does not dissolve completely within 40 minutes after attempting reconstitution.¹

Rate of Administration

May take 5–10 seconds to inject sub-Q.¹

Dosage

Pediatric Patients

Moderate to Severe Allergic Asthma

Sub-Q

Adolescents ≥12 years of age: 150–375 mg every 2 or 4 weeks.¹ Base dosage and dosing frequency on total serum IgE concentrations, measured prior to therapy, and body weight (see Table 1 and see Table 2).^{1 10}

Adults

Moderate to Severe Allergic Asthma

Sub-Q

150–375 mg every 2 or 4 weeks.¹ Base dosage and dosing frequency on total serum IgE concentrations, measured prior to therapy, and body weight (see Table 1 and see Table 2).¹

See Table 2.

See Table 1.

Do not administer.

Prescribing Limits

Pediatric Patients

Moderate to Severe Allergic Asthma

Sub-Q

Maximum 750 mg every 4 weeks.¹

Adults

Moderate to Severe Allergic Asthma

Sub-Q

Maximum 750 mg every 4 weeks.¹

Special Populations

No special population (i.e., age, race, ethnicity, gender) dosage recommendations at this time.¹

Cautions for Omalizumab

Contraindications

• Known history of severe hypersensitivity to omalizumab or any ingredient in the formulation.^{1 8 9}

Warnings/Precautions

Warnings

Cardiovascular and Cerebrovascular Effects

Disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic, and thrombophlebitic events observed in patients receiving omalizumab from an ongoing study, Evaluating the Clinical Effectiveness and Long-term Safety in Patients with Moderate to Severe Asthma (EXCELS).¹² FDA is continuing to review the strengths and limitations of these interim study results.¹²

Patients with asthma should not stop taking omalizumab before consulting their clinician.¹²

Be aware of the potential increased risk of cardiovascular and cerebrovascular events.¹² Report all such adverse events to FDA MedWatch Program.¹²

Malignancy

Breast, melanoma, non-melanoma skin, prostate, parotid gland neoplasms, and other types of neoplasms have been observed with <1 year of therapy.¹ Risk of malignancy with longer exposure to omalizumab or use in patients at higher risk for malignancy (e.g., geriatric individuals, current smokers) is not known.^{1 4}

Medical Personnel and Facilities

Should be administered by a clinician familiar with management of potentially life-threatening anaphylaxis in a setting where parenteral drugs, oxygen, and equipment are immediately available.^{1 8 10} Anaphylaxis can occur after any dose of omalizumab, even if prior doses were well tolerated;^{1 8 9} onset of anaphylaxis may be delayed (e.g., up to 4 days) after administration.^{1 8 9} Monitor patients following administration (e.g., 2 hours following administration of at least the first 3 doses); optimal observation period not established.^{1 4 8 10} If a severe hypersensitivity reaction occurs, discontinue drug.^{1 4 8 9} (See Sensitivity Reactions under Cautions.)

Sensitivity Reactions

Anaphylaxis (e.g., bronchospasm, hypotension, syncope, urticaria, angioedema of throat or tongue) has occurred in patients after administration of omalizumab.^{1 8} Other signs and symptoms of anaphylaxis included wheezing or dyspnea, dizziness, throat tightness, cough, cutaneous angioedema, generalized pruritus, rapid or weak heartbeat, anxiety (e.g., feeling of impending doom), hoarseness, dysphagia, and flushing or warm feeling.^{1 8 9} Most cases of anaphylaxis occurred within the first 60 minutes after the first or second dose of omalizumab, but may occur after >1 year of maintenance therapy.^{1 8 10}

Report all serious adverse effects to FDA MedWatch Program by phone (800-FDA-1088), fax (800-FDA-0178), through the Internet (), or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).⁸

General Precautions

Acute or Worsening Asthma

Not effective in alleviating acute asthma exacerbations; do not use for treatment of acute bronchospasm or status asthmaticus.¹

Eosinophilia and Churg-Strauss Syndrome

Systemic eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, reported rarely; in almost all cases, these events were associated with reduction of oral corticosteroid therapy.¹ Be alert to the development of such manifestations; causal relationship not established.¹

Parasitic (Geohelminthic) Infections

Increased incidence and risk of helminthic infection.¹ Monitor patients who are at high risk for geohelminthic infections during therapy.^{1 6} Insufficient data are available to determine the duration of monitoring for such infections after treatment discontinuance.¹

Specific Populations

Pregnancy

Category B. Pregnancy registry at 866-496-5247.¹

Lactation

Distributed into milk in cynomolgus monkeys.¹ Since IgG distributes into milk in humans, it is expected that omalizumab (IgG1κ monoclonal antibody) will be present in human milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy in children <12 years of age not established.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger adults.¹

Common Adverse Effects

Injection site reactions (bruising, redness, warmth, burning, stinging, pruritus, urticaria, pain, induration, injection site mass, inflammation), viral infections, upper respiratory tract infection, sinusitis, headache, pharyngitis.¹

Interactions for Omalizumab

No formal drug interaction studies to date.¹

Omalizumab Pharmacokinetics

Absorption

Bioavailability

Absorbed slowly; peak serum concentrations attained after an average of 7–8 days.¹ Absolute bioavailability averages 62%.¹

Onset

Serum free IgE concentrations reduced ≤1 hour following administration.¹

Duration

Total IgE does not return to pretreatment concentrations for ≤1 year after drug discontinuance.¹

Distribution

Extent

In animals, no specific uptake of radiolabeled drug by any organ or tissue.¹

Elimination

Metabolism

Degradation of omalizumab (IgG1κ monoclonal antibody) by the reticuloendothelial system and endothelial cells in the liver, and clearance of omalizumab-IgE complexes by the reticuloendothelial system.¹

Elimination Route

Eliminated in part into the bile as unchanged drug.¹

Half-life

26 days in asthmatic patients.¹

Stability

Storage

Parenteral

Powder for Sub-Q Injection

Ship at ≤30°C.¹ Store at 2–8°C.^{1 10} When reconstituted with sterile water for injection, solutions prepared in single-use vials are stable for ≤8 hours at 2–8°C or ≤4 hours at room temperature.¹

Actions

• Binds specifically to circulating IgE and blocks its binding with the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils.^{1 2} Inhibition of such binding interferes with the synthesis and release of mediators of the allergic response (e.g., leukotrienes, cytokines, chemokines).^{1 2 5 10}

• Reduces the number of FcεRI receptors on basophils and submucosal cells in atopic patients.^{1 10}

• Reduces mean serum concentrations of free (unbound) IgE in patients with allergic asthma at recommended dosages.^{1 2}

• Attenuates the early- and late-phase inflammatory response and the influx of eosinophils into the airways following allergen challenge.^{2 7 10}

Advice to Patients

• Importance of providing a copy of the manufacturer’s medication guide for omalizumab to the patient each time the drug is dispensed.^{1 8 9}

• Risk of potentially life-threatening anaphylaxis after any dose of omalizumab.^{1 8 9} Importance of informing patients of signs and symptoms of anaphylaxis.^{8 9} (See Sensitivity Reactions under Cautions.)

• Importance of receiving omalizumab in a health-care setting (e.g., doctor’s office) where monitoring for possible anaphylaxis can be performed.^{1 8 9 10} (See Medical Personnel and Facilities under Cautions.)

• Importance of informing patients of potential for delayed anaphylaxis (e.g., up to 4 days after administration).^{1 8}

• Importance of seeking emergency medical attention if signs or symptoms of anaphylaxis occur after leaving the doctor’s office.^{1 8 9}

• Importance of patient understanding how to obtain emergency medical treatment and further medical care for anaphylaxis.⁸

• Importance of adherence to dosing schedules of concomitant antiasthmatic therapy, including not altering the dose or frequency of such drugs unless otherwise instructed by a clinician.^{1 8 9}

• Importance of informing patients of possible delay in the effectiveness of omalizumab upon treatment initiation.^{1 8}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.