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Special Alerts
Omalizumab (Xolair®): Interim Findings From Ongoing Safety Review (EXCELS Study) - July 2009; Updated August 2009
The U.S. Food and Drug Administration (FDA) and Health Canada have issued independent communication to their respective healthcare professionals regarding interim safety findings from an ongoing observational trial titled Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) involving ~5000 patients treated with omalizumab and ~2500 patients not receiving omalizumab. Preliminary findings suggest an increased risk of cardiovascular (eg, arrhythmias, cardiomyopathy, ischemic heart disease, heart failure, pulmonary hypertension), cerebrovascular, and thromboembolic adverse events in patients treated with omalizumab compared to those not receiving omalizumab. The primary objective of the trial is to assess long-term safety (5 years) of omalizumab in patients ?12 years of age with moderate-to-severe persistent asthma and a positive skin/blood test for an aeroallergen.
At this time, the FDA and Health Canada are not recommending patients discontinue omalizumab therapy or recommending any changes to the current prescribing information for Xolair®. Analysis of this preliminary safety data is ongoing and neither regulatory agency has reached any conclusions at this time. The final results from the EXCELS trial are not expected until 2012.
For more information, healthcare professionals may refer to the following websites:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm172406.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_129-eng.php
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Omalizumab may be confused with ofatumumab
Pronunciation
(oh mah lye ZOO mab)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of moderate-to-severe, persistent allergic asthma not adequately controlled with inhaled corticosteroids
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. IgG molecules are known to cross the placenta; use during pregnancy only if clearly needed. A registry has been established to monitor outcomes of women exposed to omalizumab during pregnancy or within 8 weeks prior to pregnancy (866-496-5247).
Lactation
Excretion in breast milk unknown/use caution
Breast-Feeding Considerations
IgG is excreted in human milk and excretion of omalizumab is expected. Effects to nursing infant are not known; use with caution.
Contraindications
Hypersensitivity to omalizumab or any component of the formulation; acute bronchospasm, status asthmaticus
Warnings/Precautions
Boxed warnings:
• Anaphylaxis: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Anaphylaxis, including delayed-onset anaphylaxis, has been reported following administration; reactions usually occur within 2 hours of administration, but may occur up to 24 hours and in some cases >1 year after initiation of regular treatment. Patients should receive treatment only under direct medical supervision and be observed for a minimum of 2 hours following administration; appropriate medications for the treatment of anaphylactic reactions should be available. Hypersensitivity reactions may occur following any dose, even during chronic therapy; discontinue therapy following any severe reaction.
• Malignant neoplasms: Have been reported with use in short-term studies; impact of long-term use is not known.
Disease-related concerns:
• Patients at risk for parasitic infections: Use with caution and monitor patients at risk for parasitic (helminth) infections; risk of infection may be increased.
Concurrent drug therapy issues:
• Corticosteroid therapy: Gradually taper corticosteroid therapy, do not discontinue abruptly.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <12 years of age.
Other warnings/precautions:
• Appropriate use: For use in patients with a documented reactivity to a perennial aeroallergen and with symptoms uncontrolled using inhaled corticosteroids; not used to control acute asthma symptoms.
• Dosing/IgE levels: Dosing is based on pretreatment IgE serum levels and body weight. IgE levels remain elevated up to 1 year following treatment, therefore, levels taken during treatment cannot be used as a dosage guide.
Adverse Reactions
>10%:
Central nervous system: Headache (15%)
Local: Injection site reaction (45%; placebo 43%; severe 12%). Most reactions occurred within 1 hour, lasted <8 days, and decreased in frequency with additional dosing.
Respiratory: Upper respiratory tract infection (20%), sinusitis (16%), pharyngitis (11%)
Miscellaneous: Viral infection (23%)
1% to 10%:
Central nervous system: Pain (7%), fatigue (3%), dizziness (3%)
Dermatologic: Dermatitis (2%), pruritus (2%)
Neuromuscular & skeletal: Arthralgia (8%), leg pain (4%), arm pain (2%), fracture (2%)
Otic: Earache (2%)
<1%, postmarketing, and/or case reports: Alopecia; anaphylaxis (angioedema of the throat or tongue, bronchospasm, chest tightness, cough, cutaneous angioedema, dyspnea, hypotension, generalized pruritus, syncope, and urticaria); antibody formation to omalizumab, hot flushes, malignancy (0.5%; placebo 0.2%), throat edema, thrombocytopenia, tongue edema, urticaria, wheezing
Drug Interactions
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Storage
Prior to reconstitution, store under refrigeration at 2°C to 8°C (36°F to 46°F); product may be shipped at room temperature. Following reconstitution, protect from direct sunlight. May be stored for up to 8 hours if refrigerated or 4 hours if stored at room temperature.
Reconstitution
Prepare using SWFI, USP only; add SWFI 1.4 mL to upright vial and swirl gently for 5-10 seconds every 5 minutes until dissolved; may take >20 minutes to dissolve completely. Resulting solution is 150 mg/1.2 mL. Do not use if powder takes >40 minutes to dissolve.
Mechanism of Action
Omalizumab is an IgG monoclonal antibody (recombinant DNA derived) which inhibits IgE binding to the high-affinity IgE receptor on mast cells and basophils. By decreasing bound IgE, the activation and release of mediators in the allergic response (early and late phase) is limited. Serum-free IgE levels and the number of high-affinity IgE receptors are decreased. Long-term treatment in patients with allergic asthma showed a decrease in asthma exacerbations and corticosteroid usage.
Pharmacodynamics/Kinetics
Absorption: Slow following SubQ injection
Distribution: Vd: 78 ± 32 mL/kg
Metabolism: Hepatic; IgG degradation by reticuloendothelial system and endothelial cells
Bioavailability: 62%
Half-life elimination: 26 days
Time to peak: 7-8 days
Excretion: Primarily via hepatic degradation; intact IgG may be secreted in bile
Dosage
SubQ: Children ?12 years and Adults: Asthma: Dose is based on pretreatment IgE serum levels and body weight. Dosing should not be adjusted based on IgE levels taken during treatment or <1 year following discontinuation of therapy; doses should be adjusted during treatment for significant changes in body weight.
IgE ?30-100 int. units/mL:
30-90 kg: 150 mg every 4 weeks
>90-150 kg: 300 mg every 4 weeks
IgE >100-200 int. units/mL:
30-90 kg: 300 mg every 4 weeks
>90-150 kg: 225 mg every 2 weeks
IgE >200-300 int. units/mL:
30-60 kg: 300 mg every 4 weeks
>60-90 kg: 225 mg every 2 weeks
>90-150 kg: 300 mg every 2 weeks
IgE >300-400 int. units/mL:
30-70 kg: 225 mg every 2 weeks
>70-90 kg: 300 mg every 2 weeks
>90 kg: Do not administer dose
IgE >400-500 int. units/mL:
30-70 kg: 300 mg every 2 weeks
>70-90 kg: 375 mg every 2 weeks
>90 kg: Do not administer dose
IgE >500-600 int. units/mL:
30-60 kg: 300 mg every 2 weeks
>60-70 kg: 375 mg every 2 weeks
>70 kg: Do not administer dose
IgE >600-700 int. units/mL:
30-60 kg: 375 mg every 2 weeks
>60 kg: Do not administer dose
Administration: Other
For SubQ injection only; doses >150 mg should divided over more than one site. Injections may take 5-10 seconds to administer. Administer only under direct medical supervision and observe patient for a minimum of 2 hours following administration of any dose given.
Monitoring Parameters
Anaphylactic/hypersensitivity reactions, baseline IgE; FEV1, peak flow, and/or other pulmonary function tests; monitor for signs of infection
Test Interactions
Total IgE levels are elevated for up to 1 year following treatment. Total serum IgE may be retested after interruption of therapy for 1 year or more.
Patient Education
This medication is administered by injection and you will be closely monitored for some time following injection. Report immediately any sign of allergic response (redness, swelling, pain or itching at injection site; chest pain or tightness; difficulty breathing or swallowing; swelling of mouth or tongue; skin rash). If allergic response occurs after you leave, follow prescriber's directions for contacting emergency treatment immediately. May cause headache or dizziness (use caution when driving or engaging in hazardous tasks until response to drug is known); joint, bone, or ear pain (consult prescriber for analgesic). Report unusual or increased respiratory difficulty, signs of infection, skin rash, or other persistent reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if you are breast-feeding.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness and fatigue
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
For SubQ use only. Evaluate results of laboratory tests and pulmonary function tests at baseline and as necessary with treatment. Anaphylactic reactions have been reported within 2 -24 hours (or longer) of initial dose; patient should be monitored for a minimum of 2 hours following injection and appropriate medications for the treatment of hypersensitivity reactions should be available. Evaluate patient response (relief of asthmatic symptoms) and adverse reactions (eg, hypersensitivity reaction, upper respiratory tract infection, viral infection, dermatitis, arthralgia) at beginning and periodically during therapy. Caution patient to read the FDA-approved medication guide distributed when medication is dispensed. Teach patient possible side effects/interventions and adverse symptoms to report (eg, signs of hypersensitivity reaction).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Xolair®: 150 mg [contains sucrose 145.5 g]
Pricing: U.S. (www.drugstore.com)
Solution (reconstituted) (Xolair)
150 mg (1): $695.43
References
Casale TB, Condemi J, LaForce C, et al, “Effect of Omalizumab on Symptoms of Seasonal Allergic Rhinitis: A Randomized Controlled Trial,” JAMA, 2001, 286(23):2956-67.
Marcus P, “Incorporating Anti-IgE (Omalizumab) Therapy Into Pulmonary Medicine Practice,” Chest, 2006, 129(2):466-74.
Milgrom H, Berger W, Nayak A, et al, “Treatment of Childhood Asthma With Anti-immunoglobulin E Antibody (Omalizumab),” Pediatrics, 2001, 108(2):E36.
Milgrom H, Fick RB Jr, Su JQ, et al, “Treatment of Allergic Asthma With Monoclonal Anti-IgE Antibody. rhuMAb-E25 Study Group,” N Engl J Med, 1999, 341(26):1966-73.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
Content last modified October 2009
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