Omalizumab

12.1 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.

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 mor

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 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

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 investigated risk factors for anaphylaxis to XOLAIR among patients treated with XOLAIR for asthma. Cases with an adjudicated history of anaphylaxis to XOLAIR were compared to controls with no such history. The study found that a self-reported history of anaphylaxis to foods, medications or other causes was more common among patients with XOLAIR anaphylaxis (57% of 30 cases) compared to controls (23% of 88 controls) [OR 8.1, 95% CI 2.7 to 24.3]. Because this is a case-control study, the study cannot provide the incidence of anaphylaxis among XOLAIR users. From other sources, anaphylaxis to XOLAIR was observed in 0.1% of patients in clinical trials and at least 0.2% of patients based upon postmarketing reports. Approximately 60% to 70% of cases were reported to occur within the first three doses of XOLAIR, with additional cases occurring sporadically beyond the third dose. The time to onset for anaphylaxis was reported to occur within 2 hours for the majority of cases (approximately 75%) [see Wa

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 )