XOLAIR

1 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.

2 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 CR…

5 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 patien…

4 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 )

7 DRUG INTERACTIONS No formal drug interaction studies have been performed with XOLAIR. In patients with asthma, CRSwNP, and IgE-mediated food allergy the concomitant use of XOLAIR and allergen immunotherapy has not been evaluated . In patients with CSU, the use of XOLAIR in combination with immunosuppressive therapies has not been studied. No formal drug interaction studies have been performed. ( 7 )

8.1 Pregnancy Risk Summary A registry study of XOLAIR exposure during pregnancy showed no increase in the rate of major birth defects or miscarriage. There was an increased rate of low birth weight among registry infants compared to infants in the other cohorts, despite average gestational age at birth; however, women taking XOLAIR during pregnancy also had more severe asthma, which makes it difficult to determine whether the low birth weight is due to the drug or the disease severity [see Data ] . There are risks associated with poorly or moderately controlled asthma in pregnancy [see Clinical Considerations ] . Human IgG antibodies are known to cross the placental barrier; therefore, XOLAIR may be transmitted from the mother to the developing fetus. In animal reproduction studies, no evidence of fetal harm was observed in Cynomolgus monkeys with subcutaneous doses of omalizumab up to approximately 5 times the maximum recommended human dose (MRHD) [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. Data Human Data A prospective cohort pregnancy exposure registry study conducted in the US from 2006 to 2018, included 250 pregnant women with asthma treated with XOLAIR. Of these, 246 patients were exposed to XOLAIR in the first trimester of pregnancy, and the median exposure duration was 8.7 months. The registry findings for applicable mother and infant subgroups were compared to age-adjusted frequencies in a disease-matched external cohort of 1,153 pregnant women with asthma (without exposure to XOLAIR) identified from healthcare databases of residents in the Canadian province of Quebec, and referred to as the Quebec External Comparator Cohort ("comparator cohort"). Among applicable registry infants, the prevalence of major congenital anomalies (8.1%) was similar to that for infants in the comparator cohort (8.9%). Among applicable registry pregnancies, 99.1% led to live births, similar to 99.3% for the comparator cohort. There was an increased rate of low birth weight among registry infants (13.7%) as compared to the comparator cohort (9.8%); however, women taking XOLAIR during pregnancy also had more severe asthma, which makes it difficult to determine whether the low birth weight is due to the drug or the disease severity. The registry study cannot definitively establish the absence of any risk because of methodological limitations, including the observational nature of the registry, small sample size, and potential differences between the registry population and the comparator cohort. Animal Data Reproductive studies have been performed in Cynomolgus monkeys. There was no evidence of maternal toxicity, embryotoxicity, or teratogenicity when omalizumab was administered throughout the period of organogenesis at doses that produced exposures approximately 5 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 75 mg/kg/week). Omalizumab did not elicit adverse effects on fetal or neonatal growth when administered throughout late gestation, delivery, and nursing.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Anaphylaxis [see Boxed Warning and Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Asthma : The most common adverse reactions (≥ 1% of patients) in clinical studies with adult and adolescent patients ≥12 years of age were arthralgia, pain (general), leg pain, fatigue, dizziness, fracture, arm pain, pruritus, dermatitis, and earache. In clinical studies with pediatric patients 6 to <12 years of age, the most common adverse reactions (≥3% of patients) were nasopharyngitis, headache, pyrexia, upper abdominal pain, pharyngitis streptococcal, otitis media, viral gastroenteritis, arthropod bites, and epistaxis. ( 6.1 ) Chronic Rhinosinusitis with Nasal Polyps : The most common adverse reactions (≥ 3% of patients) in clinical studies with adult patients included the following: headache, injection site reaction, arthralgia, upper abdominal pain, and dizziness. ( 6.1 ) IgE-Mediated Food Allergy : The most common adverse reactions (≥3% of patients) were injection site reactions and pyrexia. ( 6.1 ) Chronic Spontaneous Urticaria : The most common adverse reactions (≥2% of patients) included the following: nausea, nasopharyngitis, sinusitis, upper respiratory tract infection, viral upper respiratory tract infection, arthralgia, headache, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions from Clinical Studies in Adult and Adolescent Patients 12 Years of Age and Older with Asthma 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 mg to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo. The adverse reactions most frequently resulting in clinical intervention (e.g., discontinuation of XOLAIR, or the need for concomitant medication to treat an adverse reaction) were injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These reactions were observed at similar rates in XOLAIR-treated patients and control patients. Table 7 shows adverse reactions from four placebo-controlled asthma trials that occurred ≥1% and more frequently in adult and adolescent patients 12 years of age and older receiving XOLAIR than in those receiving placebo. Adverse reactions were classified using preferred terms from the International Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately from the reporting of other adverse reactions. Table 7. Adverse Reactions ≥1% More Frequent in XOLAIR-Treated Adult or Adolescent Patients 12 years of Age and Older in Four Placebo-controlled Asthma Trials Adverse reaction XOLAIR n=738 Placebo n=717 Body as a whole Pain 7% 5% Fatigue 3% 2% Musculoskeletal system Arthralgia 8% 6% Fracture 2% 1% Leg pain 4% 2% Arm pain 2% 1% Nervous system Dizziness 3% 2% Skin and appendages Pruritus 2% 1% Dermatitis 2% 1% Special senses Earache 2% 1% There were no differences in the incidence of adverse reactions based on age (among patients under 65), gender or race. Anaphylaxis Case Control Study A retrospective case-control study investig…