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Black Box Warning
WARNING: ANAPHYLAXIS
See full prescribing information for complete Boxed Warning.
Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of Xolair. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, observe patients closely for an appropriate period of time after Xolair administration. Health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur.
Administer Xolair 150 to 375 mg by subcutaneous (SC) injection every 2 or 4 weeks. Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg). See the dose determination charts below (Table 1 and Table 2) for appropriate dose assignment.
Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control.
Dosing adjustments for Allergic Asthma
Adjust doses for significant changes in body weight (see Table 1 and Table 2).
Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination.
Interruptions lasting less than one year: Dose based on serum IgE levels obtained at the initial dose determination.
Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination.
Chronic Idiopathic Urticaria
Dosage
Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.
Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.
The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.
Preparation and Administration
Prepare Xolair for subcutaneous injection using Sterile Water for Injection (SWFI), USP, ONLY. Each vial of Xolair is for single use only and contains no preservatives.
Reconstitution
The lyophilized product takes 15–20 minutes to dissolve. The fully reconstituted product will appear clear or slightly opalescent and it is acceptable if there are a few small bubbles or foam around the edge of the vial. The reconstituted product is somewhat viscous; in order to obtain the full 1.2 mL dose, ALL OF THE PRODUCT MUST BE WITHDRAWN from the vial before expelling any air or excess solution from the syringe.
Use the solution within 8 hours following reconstitution when stored in the vial at 2–8°C (36–46°F), or within 4 hours of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from sunlight.
Preparation
STEP 1: Draw 1.4 mL of SWFI, USP into a 3 mL syringe equipped with a 1 inch, 18-gauge needle.
STEP 2: Place the vial upright on a flat surface and using standard aseptic technique, insert the needle and inject the SWFI, USP directly onto the product.
STEP 3: Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake.
STEP 4: After completing STEP 3, gently swirl the vial for 5-10 seconds approximately every 5 minutes in order to dissolve any remaining solids. There should be no visible gel like particles in the solution. Do not use if foreign particles are present.
Note: If it takes longer than 20 minutes to dissolve completely, repeat STEP 4 until there are no visible gel-like particles in the solution. Do not use if the contents of the vial do not dissolve completely by 40 minutes.
STEP 5: Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into the inverted vial. Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
STEP 6: Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection.
STEP 7: Expel air, large bubbles, and any excess solution in order to obtain the required 1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe.
Administration
Administer Xolair by subcutaneous injection. The injection may take 5-10 seconds to administer because the solution is slightly viscous. Each vial delivers 1.2 mL (150 mg) of Xolair. Do not administer more than 150 mg per injection site. Divide doses of more than 150 mg among two or more injection sites (Table 3).
Dosage forms and strengths
150 mg of omalizumab as lyophilized, sterile powder in a single-use 5 mL vial.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omalizumab in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Omalizumab in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omalizumab in pediatric patients.
Contraindications
The use of Xolair is contraindicated in the following:
Severe hypersensitivity reaction to Xolair or any ingredient of Xolair.
Warnings
WARNING: ANAPHYLAXIS
See full prescribing information for complete Boxed Warning.
Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of Xolair. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, observe patients closely for an appropriate period of time after Xolair administration. Health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur.
Anaphylaxis
Anaphylaxis has been reported to occur after administration of Xolair in premarketing clinical trials and in postmarketing spontaneous reports. Signs and symptoms in these reported cases have included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Some of these events have been life-threatening. In premarketing clinical trials in allergic asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients in clinical trials. Anaphylaxis occurred with the first dose of Xolair in two patients and with the fourth dose in one patient. The time to onset of anaphylaxis was 90 minutes after administration in two patients and 2 hours after administration in one patient. In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond one year after beginning regularly scheduled treatment.
Administer Xolair only in a healthcare setting by healthcare providers prepared to manage anaphylaxis that can be life-threatening. Observe patients closely for an appropriate period of time after administration of Xolair, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing spontaneous reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur.
Discontinue Xolair in patients who experience a severe hypersensitivity reaction.
Malignancy
Malignant neoplasms were observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other allergic disorders. The observed malignancies in Xolair-treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each. The majority of patients were observed for less than 1 year. The impact of longer exposure to Xolair or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known.
Acute Asthma Symptoms
Xolair has not been shown to alleviate asthma exacerbations acutely. Do not use Xolair to treat acute bronchospasm or status asthmaticus.
Corticosteroid reduction
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Xolair therapy for allergic asthma. Decrease corticosteroids gradually under the direct supervision of a physician. In CIU patients, the use of Xolair in combination with corticosteroids has not been evaluated.
Eosiophilic Conditions
In rare cases, patients with asthma on therapy with Xolair may present with serious systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Xolair and these underlying conditions has not been established.
Fever, Arthralgia and Rash
In post-approval use, some patients have experienced a constellation of signs and symptoms including arthritis/arthralgia, rash, fever and lymphadenopathy with an onset 1 to 5 days after the first or subsequent injections of Xolair. These signs and symptoms have recurred after additional doses in some patients. Although circulating immune complexes or a skin biopsy consistent with a Type III reaction were not seen with these cases, these signs and symptoms are similar to those seen in patients with serum sickness. Physicians should stop Xolair if a patient develops this constellation of signs and symptoms.
Parasitic (helminth) infection
Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
In a one-year clinical trial conducted in Brazil in patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have received Xolair than a patient who did not have an infection. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups.
Laboratory Tests
Serum total IgE levels increase following administration of Xolair due to formation of Xolair:IgE complexes [see Clinical Pharmacology (12.2)]. Elevated serum total IgE levels may persist for up to 1 year following discontinuation of Xolair. Do not use serum total IgE levels obtained less than 1 year following discontinuation to reassess the dosing regimen for allergic asthma patients, because these levels may not reflect steady state free IgE levels.
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience in Allergic Asthma
Adult and Adolescent Patients 12 years of Age and Older
The data described below reflect Xolair exposure for 2076 adult and adolescent patients ages 12 and older, including 1687 patients exposed for six months and 555 exposed for one year or more, in either placebo-controlled or other controlled asthma studies. The mean age of patients receiving Xolair was 42 years, with 134 patients 65 years of age or older; 60% were women, and 85% Caucasian. Patients received Xolair 150 to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo.
The adverse events most frequently resulting in clinical intervention (e.g., discontinuation of Xolair, or the need for concomitant medication to treat an adverse event) were injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in Xolair-treated patients and control patients.
Table 4 shows adverse reactions from four placebo-controlled asthma studies that occurred ≥ 1% and more frequently in patients receiving Xolair than in those receiving placebo. Adverse events were classified using preferred terms from the International Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately from the reporting of other adverse events and are described following Table 4.
There were no differences in the incidence of adverse reactions based on age (among patients under 65), gender or race.
Injection Site Reactions
Injection site reactions of any severity occurred at a rate of 45% in Xolair-treated patients compared with 43% in placebo-treated patients. The types of injection site reactions included: bruising, redness, warmth, burning, stinging, itching, hive formation, pain, indurations, mass, and inflammation.
Severe injection site reactions occurred more frequently in Xolair-treated patients compared with patients in the placebo group (12% versus 9%).
The majority of injection site reactions occurred within 1 hour-post injection, lasted less than 8 days, and generally decreased in frequency at subsequent dosing visits.
Clinical Trials Experience in Chronic Idiopathic Urticaria
Adult and Adolescent Patients 12 years of Age and Older
The safety of Xolair for the treatment of CIU was assessed in three placebo-controlled, multiple-dose clinical studies of 12 weeks' (CIU Study 2) and 24 weeks' duration (CIU Studies 1 and 3). In CIU Studies 1 and 2, patients received Xolair 75, 150, or 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy throughout the treatment period. In CIU Study 3 patients were randomized to Xolair 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy. The data described below reflect Xolair exposure for 733 patients enrolled and receiving at least one dose of Xolair in the three clinical trials, including 684 patients exposed for 12 weeks and 427 exposed for 24 weeks. The mean age of patients receiving Xolair 300 mg was 43 years, 75% were women, and 89% were white. The demographic profiles for patients receiving Xolair 150 mg and 75 mg were similar.
Table 5 shows adverse events that occurred in ≥ 2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo. Adverse events are pooled from Study 2 and the first 12 weeks of Studies 1 and 3.
Additional events reported during the 24 week treatment period in Studies 1 and 3 [≥2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo] included: toothache, fungal infection, urinary tract infection, myalgia, pain in extremity, musculoskeletal pain, peripheral edema, pyrexia, migraine, sinus headache, anxiety, oropharyngeal pain, asthma, urticaria, and alopecia.
Injection Site Reactions
Injection site reactions of any severity occurred during the studies in more Xolair-treated patients [11 patients (2.7%) at 300 mg, 1 patient (0.6%) at 150 mg] compared with 2 placebo-treated patients (0.8%). The types of injection site reactions included: swelling, erythema, pain, bruising, itching, bleeding and urticaria. None of the events resulted in study discontinuation or treatment interruption.
Immunogenicity
Antibodies to Xolair were detected in approximately 1/1723 (< 0.1%) of patients treated with Xolair in the clinical studies for approval of asthma. There were no detectable antibodies in the patients treated in the phase 3 CIU clinical trials, but due to levels of Xolair at the time of anti-therapeutic antibody sampling and missing samples for some patients, antibodies to Xolair could only have been determined in 88% of the 733 patients treated in these clinical studies. The data reflect the percentage of patients whose test results were considered positive for antibodies to Xolair in ELISA assays and are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Xolair with the incidence of antibodies to other products may be misleading.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Xolair in adult and adolescent patients 12 years of age and older. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Anaphylaxis: Based on spontaneous reports and an estimated exposure of about 57,300 patients from June 2003 through December 2006, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients. Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to Xolair administration with no other identifiable cause. Signs and symptoms in these reported cases included bronchospasm, hypotension, syncope, urticaria, angioedema of the throat or tongue, dyspnea, cough, chest tightness, and/or cutaneous angioedema. Pulmonary involvement was reported in 89% of the cases. Hypotension or syncope was reported in 14% of cases. Fifteen percent of the reported cases resulted in hospitalization. A previous history of anaphylaxis unrelated to Xolair was reported in 24% of the cases.
Of the reported cases of anaphylaxis attributed to Xolair, 39% occurred with the first dose, 19% occurred with the second dose, 10% occurred with the third dose, and the rest after subsequent doses. One case occurred after 39 doses (after 19 months of continuous therapy, anaphylaxis occurred when treatment was restarted following a 3 month gap). The time to onset of anaphylaxis in these cases was up to 30 minutes in 35%, greater than 30 and up to 60 minutes in 16%, greater than 60 and up to 90 minutes in 2%, greater than 90 and up to 120 minutes in 6%, greater than 2 hours and up to 6 hours in 5%, greater than 6 hours and up to 12 hours in 14%, greater than 12 hours and up to 24 hours in 8%, and greater than 24 hours and up to 4 days in 5%. In 9% of cases the times to onset were unknown.
Twenty-three patients who experienced anaphylaxis were rechallenged with Xolair and 18 patients had a recurrence of similar symptoms of anaphylaxis. In addition, anaphylaxis occurred upon rechallenge with Xolair in 4 patients who previously experienced urticaria only.
Eosinophilic Conditions: Eosinophilic conditions have been reported [see Warnings and Precautions (5.5)].
Fever, Arthralgia, and Rash: A constellation of signs and symptoms including arthritis/arthralgia, rash (urticaria or other forms), fever and lymphadenopathy similar to serum sickness have been reported in post-approval use of Xolair [see Warnings and Precautions (5.6)].
Hematologic: Severe thrombocytopenia has been reported.
Skin: Hair loss has been reported.
