1 ML omalizumab 150 MG/ML Prefilled Syringe

INDICATIONS AND USAGE XOLAIR is an anti-IgE antibody indicated for: Moderate to severe persistent asthma in adults and pediatric patients 6 years of age and older with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids ( 1.1 ) Chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients 18 years of age and older with inadequate response to nasal corticosteroids, as add-on maintenance treatment ( 1.2 ) IgE-mediated food allergy in adult and pediatric patients aged 1 year and older for the reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods. To be used in conjunction with food allergen avoidance ( 1.3 ) Chronic spontaneous urticaria (CSU) in adults and adolescents 12 years of age and older who remain symptomatic despite H1 antihistamine treatment ( 1.4 ) Limitations of Use : Not indicated for acute bronchospasm or status asthmaticus. ( 1.1 , 5.3 ) Not indicated for the emergency treatment of allergic reactions, including anaphylaxis ( 1.3 ) Not indicated for other forms of urticaria. ( 1.4 ) 1.1 Asthma XOLAIR is indicated for adults and pediatric patients 6 years of age and older with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Limitations of Use: XOLAIR is not indicated for the relief of acute bronchospasm or status asthmaticus. 1.2 Chronic Rhinosinusitis with Nasal Polyps XOLAIR is indicated for add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients 18 years of age and older with inadequate response to nasal corticosteroids. 1.3 IgE-Mediated Food Allergy XOLAIR is indicated for the reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods in adult and pediatric patients aged 1 year and older with IgE-mediated food allergy. XOLAIR is to be used in conjunction with food allergen avoidance. Limitations of Use: XOLAIR is not indicated for the emergency treatment of allergic reactions, including anaphylaxis. 1.4 Chronic Spontaneous Urticaria XOLAIR is indicated for the treatment of adults and adolescents 12 years of age and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment. Limitations of Use: XOLAIR is not indicated for treatment of other forms of urticaria.

DOSAGE AND ADMINISTRATION For subcutaneous (SC) administration only. ( 2.2 , 2.3 , 2.4 , 2.5 ) See full prescribing information for administration instructions ( 2.6 , 2.7 , 2.8 ). Asthma : XOLAIR 75 to 375 mg SC every 2 or 4 weeks. Determine dose (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. ( 2.2 ) Chronic Rhinosinusitis with Nasal Polyps : XOLAIR 75 to 600 mg SC every 2 or 4 weeks. Determine dose (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. ( 2.3 ) IgE-Mediated Food Allergy : XOLAIR 75 mg to 600 mg SC every 2 or 4 weeks. Determine dose (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 chart. ( 2.4 ) Chronic Spontaneous Urticaria : XOLAIR 150 or 300 mg SC every 4 weeks. Dosing in CSU is not dependent on serum IgE level or body weight. ( 2.5 ) 2.1 Overview of Dosage Determination Asthma, and Chronic Rhinosinusitis with Nasal Polyps, and IgE-Mediated Food Allergy Determine dosage of XOLAIR by serum total IgE level (IU/mL) measured before the start of treatment, and by body weight (kg). For patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and IgE-mediated food allergy, dosage determination should be based on the primary diagnosis for which XOLAIR is being prescribed. Adjust doses for significant changes in body weight during treatment. Refer to Tables 1 and 2 for the recommended dosage for treatment of asthma, Table 3 for treatment of CRSwNP, and Table 4 for treatment of IgE-mediated food allergy. 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 ( Table 1 or 2 for treatment of asthma, based on the patient's age, Table 3 for treatment of CRSwNP, and Table 4 for treatment of IgE-mediated food allergy). Chronic Spontaneous Urticaria Dosage of XOLAIR in patients with chronic spontaneous urticaria (CSU) is not dependent on serum IgE (free or total) level or body weight [see Dosage and Administration (2.5) ] . 2.2 Recommended Dosage for Asthma The recommended dosage for asthma is XOLAIR 75 mg to 375 mg by subcutaneous injection every 2 or 4 weeks based on serum total IgE level (IU/mL) measured before the start of treatment and by body weight (kg) [see Dosage and Administration (2.1) ] . Adult and adolescent patients 12 years of age and older: Initiate dosing according to Table 1 . Pediatric patients 6 to <12 years of age: Initiate dosing according to Table 2 . Table 1. Subcutaneous XOLAIR Doses Every 2 or 4 Weeks* for Patients 12 Years of Age and Older with Asthma Table 2. Subcutaneous XOLAIR Doses Every 2 or 4 Weeks* for Pediatric Patients with Asthma Who Begin XOLAIR Between the Ages of 6 to <12 Years Duration of Therapy Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control. Table 1 Table 2 2.3 Recommended Dosage for Chronic Rhinosinusitis with Nasal Polyps The recommended dosage for chronic rhinosinusitis with nasal polyps (CRSwNP) is XOLAIR 75 mg to 600 mg by subcutaneous injection every 2 or 4 weeks based on serum total IgE level (IU/mL) measure before the start of treatment and by body weight (kg) [see Dosage and Administration (2.1) ] . Refer to Table 3 for recommended dosage based on serum total IgE level and body weight for patients with CRSwNP. Table 3. Subcutaneous XOLAIR Doses Every 2 or 4 Weeks* for Adult Patients with CRSwNP Table 3 Duration of Therapy Periodically reassess the need for continued therapy based upon the patient's disease severity and level of symptom control. 2.4 Recommended Dosage for IgE-Mediated Food Allergy The recommended dosage for IgE-mediated food allergy is XOLAIR 75 mg to 600 mg by subcutaneous injection every 2 or 4 weeks based on serum total IgE level (IU/mL), measured before the start of treatment, and by body weight [see Dosage and Administration (2.1) ] . Refer to Table 4 for recommended dosage based on serum IgE level and body weight for patients with IgE-mediated food allergy. Table 4. Subcutaneous XOLAIR Doses Every 2 or 4 Weeks* for Adult and Pediatric Patients 1 Year of Age and Older with IgE-Mediated Food Allergy Table 4 Duration of Therapy The appropriate duration of therapy for IgE-mediated food allergy has not been evaluated. Periodically reassess the need for continued therapy. 2.5 Recommended Dosage for Chronic Spontaneous Urticaria The recommended dosage for chronic spontaneous urticaria (CSU) is XOLAIR 150 mg or 300 mg by subcutaneous injection every 4 weeks. The 300 mg dose may be administered as one subcutaneous injection of 300 mg/2 mL or as two subcutaneous injections of 150 mg/mL. Dosing of XOLAIR in CSU patients is not dependent on serum IgE (free or total) level or body weight. Duration of Therapy The appropriate duration of therapy for CSU has not been evaluated. Periodically reassess the need for continued therapy. 2.6 Administration Overview Administer XOLAIR by subcutaneous injection. XOLAIR is intended for use under the guidance of a healthcare provider. Initiate therapy in a healthcare setting and once therapy has been safely established, the healthcare provider may determine whether self-administration of XOLAIR prefilled syringe or autoinjector by the patient or caregiver is appropriate, based on careful assessment of risk for anaphylaxis and mitigation strategies. Selection of Patients for Self-Administration of XOLAIR Prefilled Syringe or Autoinjector Healthcare providers should consider known risk factors for anaphylaxis to XOLAIR [see Warnings and Precautions (5.1) ] and mitigation strategies when selecting patients for self-administration. Patient-specific factors including the following criteria should be considered: 1a) Asthma, CRSwNP and CSU : Patient should have no prior history of anaphylaxis to XOLAIR or other agents, such as foods, drugs, biologics, etc. 1b) IgE-Mediated Food Allergy : Patient should have no prior history of anaphylaxis to XOLAIR or other agents (except foods), such as drugs, biologics, etc. 2) Patient should receive at least 3 doses of XOLAIR under the guidance of a healthcare provider with no hypersensitivity reactions 3) Patient or caregiver is able to recognize symptoms of anaphylaxis 4) Patient or caregiver is able to treat anaphylaxis appropriately 5) Patient or caregiver is able to perform subcutaneous injections with XOLAIR prefilled syringe or autoinjector with proper technique according to the prescribed dosing regimen and Instructions for Use 2.7 XOLAIR Prefilled Syringe and Autoinjector XOLAIR injection doses are available as a prefilled syringe or as an autoinjector. Instruct patients or caregivers to follow the directions provided in the " Instructions for Use " for preparation and administration of XOLAIR prefilled syringe or autoinjector [see Instructions for Use ] . XOLAIR Prefilled Syringe Adolescents 12 years of age and older: XOLAIR prefilled syringe may be self-administered under adult supervision. Pediatric Patients 1 to 11 years of age: XOLAIR prefilled syringe should be administered by a caregiver. XOLAIR Autoinjector Adolescents 12 years of age and older: XOLAIR autoinjector may be self-administered under adult supervision. The XOLAIR autoinjectors (all doses) are intended for use only in adults and adolescents aged 12 years and older. Pediatric Patients 1 to 11 years of age: The XOLAIR autoinjectors (all doses) are not intended for

WARNINGS AND PRECAUTIONS Anaphylaxis: Initiate XOLAIR therapy in a healthcare setting prepared to manage anaphylaxis which can be life-threatening and observe patients for an appropriate period of time after administration. ( 5.1 ) Malignancy: Malignancies have been observed in clinical studies. ( 5.2 ) Acute Asthma Symptoms: Do not use for the treatment of acute bronchospasm or status asthmaticus. ( 5.3 ) Corticosteroid Reduction: Do not abruptly discontinue corticosteroids upon initiation of XOLAIR therapy. ( 5.4 ) Eosinophilic Conditions: Be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, especially upon reduction of oral corticosteroids. ( 5.5 ) Fever, Arthralgia, and Rash: Stop XOLAIR if patients develop signs and symptoms similar to serum sickness. ( 5.6 ) Potential Medication Error Related to Emergency Treatment of Anaphylaxis: XOLAIR should not be used for emergency treatment of allergic reactions, including anaphylaxis. ( 5.9 ) 5.1 Anaphylaxis Anaphylaxis has been reported to occur after administration of XOLAIR in premarketing clinical trials and in postmarketing spontaneous reports [see Boxed Warning and Adverse Reactions (6.2) ] . 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 patients with asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients. 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. A case-control study in asthma patients showed that, among XOLAIR users, patients with a history of anaphylaxis to foods, medications, or other causes were at increased risk of anaphylaxis associated with XOLAIR, compared to those with no prior history of anaphylaxis [see Adverse Reactions (6.1) ] . 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. Approximately 60% to 70% of anaphylaxis cases have been reported to occur within the first three doses of XOLAIR, with additional cases occurring sporadically beyond the third dose. Initiate XOLAIR only in a healthcare setting equipped to manage anaphylaxis, which 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 [see Adverse Reactions (6.1 , 6.2) ] . Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur. Once XOLAIR therapy has been established, administration of XOLAIR prefilled syringe or autoinjector outside of a healthcare setting by a patient or a caregiver may be appropriate for selected patients. Patient selection, determined by the healthcare provider in consultation with the patient, should take into account the pattern of anaphylaxis events seen in premarketing clinical trials and postmarketing spontaneous reports, as well as individual patient risk factors (e.g., prior history of anaphylaxis), ability to recognize signs and symptoms of anaphylaxis, and ability to perform subcutaneous injections with XOLAIR prefilled syringe or autoinjector with proper technique according to the prescribed dosing regimen and Instructions for Use [see Dosage and Administration (2.6) , Adverse Reactions (6.1 , 6.2) ]. Discontinue XOLAIR in patients who experience a severe hypersensitivity reaction [see Contraindications (4) ] . 5.2 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. In a subsequent observational study of 5007 XOLAIR-treated and 2829 non-XOLAIR-treated adolescent and adult patients with moderate to severe persistent asthma and a positive skin test reaction or in vitro reactivity to a perennial aeroallergen, patients were followed for up to 5 years. In this study, the incidence rates of primary malignancies (per 1000 patient years) were similar among XOLAIR-treated (12.3) and non-XOLAIR-treated patients (13.0) [see Adverse Reactions (6.1) ] . However, study limitations preclude definitively ruling out a malignancy risk with XOLAIR. Study limitations include: the observational study design, the bias introduced by allowing enrollment of patients previously exposed to XOLAIR (88%), enrollment of patients (56%) while a history of cancer or a premalignant condition were study exclusion criteria, and the high study discontinuation rate (44%). 5.3 Acute Asthma Symptoms and Deteriorating Disease XOLAIR has not been shown to alleviate asthma exacerbations acutely. Do not use XOLAIR to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with XOLAIR. 5.4 Corticosteroid Reduction Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of XOLAIR therapy for asthma or CRSwNP. Decrease corticosteroids gradually under the direct supervision of a physician. In CSU patients, the use of XOLAIR in combination with corticosteroids has not been evaluated. 5.5 Eosinophilic 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. 5.6 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 [see Adverse Reactions (6.2) ] . 5.7 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 adult and adolescent patients at high risk for geohelminthic infections (roundwor

CONTRAINDICATIONS XOLAIR is contraindicated in patients with severe hypersensitivity reaction to XOLAIR or any ingredient of XOLAIR [see Warnings and Precautions (5.1) ] . Severe hypersensitivity reaction to XOLAIR or any ingredient of XOLAIR ( 4 , 5.1 )

Mechanism of Action Asthma, Chronic Rhinosinusitis with Nasal Polyps, and IgE-Mediated Food Allergy Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells, basophils, and dendritic cells, resulting in FcεRI down-regulation on these cells. In allergic asthmatics, treatment with omalizumab inhibits IgE-mediated inflammation, as evidenced by reduced blood and tissue eosinophils and reduced inflammatory mediators, including IL-4, IL-5, and IL-13. Chronic Spontaneous Urticaria Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-regulate. The mechanism by which these effects of omalizumab result in an improvement of chronic spontaneous urticaria (CSU) symptoms is unknown.