Omalizumab

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 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 use in pediatric patients under 12 years of age. Administration Instructions for Prefilled Syringe and Autoinjector Persons with latex allergies should not handle XOLAIR prefilled syringe because the needle cap of the XOLAIR 75 mg/0.5 mL and 150 mg/mL prefilled syringes contains a derivative of natural rubber latex which may cause allergic reactions in latex sensitive individuals [see How Supplied/Storage and Handling (16) ] . Visually inspect the contents of the prefilled syringe or autoinjector for particulate matter and discoloration prior to administration. XOLAIR prefilled syringe or autoinjector solution should be clear and colorless to pale brownish yellow. Do not use the prefilled syringe or autoinjector if the medicine is cloudy, discolored, or contains particles. Determine the number of prefilled syringes or autoinjectors needed for patient's dosage (see Table 5 ). For pediatric patients 1 to 11 years of age, consideration should be given to the number of prefilled syringe injections needed and volume to be injected relative to the patient's bodyweight. For patients requiring more than 1 injection to complete a full dose, administer each injection at least 1 inch apart from other injection sites. Administer subcutaneous injection into the thigh or abdomen, avoiding the 2-inch (5 cm) area directly around the navel. The outer area of the upper arms may be used only if the injection is being given by a caregiver or healthcare provider [see Instructions for Use ] . The injection may take up to 15 seconds to administer. Table 5. Number of XOLAIR Prefilled Syringes or Autoinjectors The autoinjector (all doses) are not intended for use in patients under 12 years of age. , Injections and Total Injection Volumes This table represents the fewest number of injections for the patient, however, there are other syringe/autoinjector dosing combinations to achieve desired dose. XOLAIR Dose The 75 mg, 150 mg, 225 mg, 300 mg, and 375 mg XOLAIR doses are approved for use in asthma patients. All doses in the table are approved for use in CRSwNP and IgE-mediated food allergy patients. The 150 mg and 300 mg XOLAIR doses are also approved for use in CSU patients. 75 mg 150 mg 300mg Total Volume Injected 75 mg 1 0 0 0.5 mL 150 mg 0 1 0 1 mL 225 mg 1 1 0 1.5 mL 300 mg 0 0 1 2 mL 375 mg 1 0 1 2.5 mL 450 mg 0 1 1 3 mL 525 mg 1 1 1 3.5 mL 600 mg 0 0 2 4 mL 2.8 Preparation for Use and Injection of XOLAIR Lyophilized Powder XOLAIR lyophilized powder should only be prepared and injected by a healthcare provider. The supplied XOLAIR lyophilized powder must be reconstituted with Sterile Water for Injection (SWFI) USP, using the following instructions: 1) Before reconstitution, determine the number of vials that will need to be reconstituted (each vial delivers 150 mg of XOLAIR in 1.2 mL) (see Table 6 ) . Table 6. Number of Vials, Injections and Total Injection Volumes XOLAIR Dose The 75 mg, 150 mg, 225 mg, 300 mg, and 375 mg XOLAIR doses are approved for use in asthma patients. All doses in the table are approved for use in CRSwNP and IgE-mediated food allergy patients. The 150 mg and 300 mg XOLAIR doses are also approved for use in CSU patients. Number of Vials Number of Injections Total Volume Injected 75 mg 1 1 0.6 mL 150 mg 1 1 1.2 mL 225 mg 2 2 1.8 mL 300 mg 2 2 2.4 mL 375 mg 3 3 3.0 mL 450 mg 3 3 3.6 mL 525 mg 4 4 4.2 mL 600 mg 4 4 4.8 mL 2) Draw 1.4 mL of SWFI, USP, into a 3 mL syringe equipped with a 1-inch, 18-gauge needle. 3) 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. 4) Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake. 5) Gently swirl the vial for 5 to 10 seconds approximately every 5 minutes in order to dissolve any remaining solids. The lyophilized product takes 15 to 20 minutes to dissolve . If it takes longer than 20 minutes to dissolve completely, gently swirl the vial for 5 to 10 seconds approximately every 5 minutes 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. 6) After reconstitution, XOLAIR solution is somewhat viscous and will appear clear or slightly opalescent. It is acceptable if there are a few small bubbles or foam around the edge of the vial; there should be no visible gel-like particles in the reconstituted solution. Do not use if foreign particles are present. 7) Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. 8) Use the XOLAIR solution within 8 hours following reconstitution when stored in the vial at 2ºC to 8ºC (36ºF to 46ºF), or within 4 hours of reconstitution when stored at room temperature. Reconstituted XOLAIR vials should be protected from sunlight. 9) 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. The reconstituted product is somewhat viscous. Withdraw all of the product from the vial before expelling any air or excess solution from 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. 10) Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection. 11) Expel air, large bubbles, and any excess solution in order to obtain a volume of 1.2 mL corresponding to a dose of 150 mg of XOLAIR. To obtain a volume of 0.6 mL corresponding to a dose of 75 mg of XOLAIR, expel air, large bubbles and discard 0.6 mL from the syringe. A thin layer of small bubbles may remain at the top of the solution in the syringe. 12) Administer XOLAIR by subcutaneous injection. The injection may take 5-10 seconds to administer because the solution is slightly viscous. Do not administer more than 150 mg (contents of one vial) per injection site. Divide doses of more than 150 mg between two or more injection sites. Choose a different injection site for each new injection at least 1 inch from the area used for other injections.

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 Warnings and Precautions (5.1) , Adverse Reactions (6.2) ] . Injection Site Reactions In adults and adolescents, 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. Adverse Reactions from Clinical Studies in Pediatric Patients 6 to <12 Years of Age with Asthma The data described below reflect XOLAIR exposure for 926 patients 6 to <12 years of age, including 583 patients exposed for six months and 292 exposed for one year or more, in either placebo-controlled or other controlled asthma studies. The mean age of pediatric patients receiving XOLAIR was 8.8 years; 69% were male, and 64% were Caucasian. Pediatric patients received XOLAIR 75 mg to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo. No cases of malignancy were reported in patients treated with XOLAIR in these trials. The most common adverse reactions occurring at ≥3% in the pediatric patients receiving XOLAIR and more frequently than in patients treated with placebo were nasopharyngitis, headache, pyrexia, upper abdominal pain, pharyngitis streptococcal, otitis media, viral gastroenteritis, arthropod bite, and epistaxis. The adverse reactions most frequently resulting in clinical intervention (e.g., discontinuation of XOLAIR, or the need for concomitant medication to treat an adverse event) were bronchitis (0.2%), headache (0.2%) and urticaria (0.2%). These reactions were observed at similar rates in XOLAIR-treated patients and control patients. Adverse Reactions from Clinical Studies in Adult Patients with Chronic Rhinosinusitis with Nasal Polyps The data described below reflect XOLAIR exposure for 135 patients ≥ 18 years of age, exposed for six months in two placebo-controlled studies. The mean age of patients receiving XOLAIR was 49.7 years; 64% were male, and 94% were Caucasian. Patients received XOLAIR or placebo SC every 2 or 4 weeks, with dosage and frequency according to Table 3 . All patients received background nasal mometasone therapy throughout the study. Table 8 lists the adverse reactions occurring in ≥3% of XOLAIR-treated patients and more frequently than in patients treated with placebo in chronic rhinosinusitis with nasal polyps (CRSwNP) Trials 1 and 2; results were pooled. Table 8. Adverse Reactions Occurring in ≥3% of XOLAIR-Treated Patients and More Frequently than in Patients Treated with Placebo in CRSwNP Trials 1 and 2 Adverse reaction XOLAIR n=135 Placebo n=130 CRSwNP = Chronic Rhinosinusitis with Nasal Polyps. Gastrointestinal disorder Upper abdominal pain 4 (3.0%) 1 (0.8%) General disorders and administration site conditions Injection site reactions Injection site reactions terms: 'injection site reaction', 'injection related reaction' and 'injection site pain'. All injection site reactions were mild to moderate severity and none resulted in study discontinuation. 7 (5.2%) 2 (1.5%) Musculoskeletal system and connective tissue disorders Arthralgia 4 (3.0%) 2 (1.5%) Nervous system disorders Headache 11 (8.1%) 7 (5.4%) Dizziness 4 (3.0%) 1 (0.8%) Adverse Reactions from a Clinical Study in Patients with IgE-Mediated Food Allergy The safety of XOLAIR in patients with IgE-mediated allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods, was based on data from the Food Allergy (FA) Trial, a randomized, double-blind, placebo-controlled trial in 168 patients (165 pediatric patients and 3 adults) who were allergic to peanut and at least two other foods [see Clinical Studies (14.3) ] . Patients received a dosage of XOLAIR or placebo subcutaneously every 2 or 4 weeks for 16 to 20 weeks according to the recommended dosage based on IgE level (IU/mL), measured before the start of treatment, and by body weight (kg) provided in Table 4 [see Dosage and Administration (2.4) ] . Safety data provided in Table 9 are from the primary analysis population of pediatric patients aged 1 year to 17 years. Safety data obtained from adults (n=3) in this trial was limited. Table 9 lists the adverse reactions occurring in ≥3% of XOLAIR-treated pediatric patients and more frequently than in patients treated with placebo in the FA trial. There were no discontinuations due to adverse reactions. Table 9. Adverse Reactions Occurring in ≥3% of XOLAIR-Treated Pediatric Patients 1 Year of Age and Older and More Frequently than in Patients Treated with Placebo in FA Trial Adverse Reaction XOLAIR n=110 Placebo n=55 General disorders and administration site conditions Injection site reactions Injection site reactions terms: 'injection site reaction','injection site urticaria','injection site discomfort','injection site erythema','injection site pain' and 'injection site rash'. All injection site reactions were mild to moderate severity and none resulted in study discontinuation. 17 (15.5%) 6 (10.9%) Pyrexia 7 (6.4%) 2 (3.6%) Adverse Reactions from Clinical Studies in Patients with Chronic Spontaneous Urticaria The safety of XOLAIR for the treatment of chronic spontaneous urticaria (CSU) was assessed in three placebo-controlled, multiple-dose clinical trials of 12 weeks' (CSU Trial 2) and 24 weeks' duration (CSU Trials 1 and 3). In CSU Trials 1 and 2, patients received XOLAIR 75 mg, 150 mg, or 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy throughout the treatment period. In CSU Trial 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 10 shows adverse reactions that occurred in ≥2% of patients receiving XOLAIR (150 or 300 mg) and more frequently than those receiving placebo. Adverse reactions are pooled from CSU Trial 2 and the first 12 weeks of CSU Trials 1 and 3. Table 10. Adverse Reactions Occurring in ≥2% in XOLAIR-Treated Patients and More Frequently than in Patients Treated with Placebo (Day 1 to Week 12) in CSU Trials Adverse Reactions by MedDRA (15.1) System Organ Class and Preferred Term CSU Trials 1, 2 and 3 Pooled 150mg (n=175) 300mg (n=412) Placebo (n=242) Gastrointestinal disorders Nausea 2 (1.1%) 11 (2.7%) 6 (2.5%) Infections and infestations Nasopharyngitis 16 (9.1%) 27 (6.6%) 17 (7.0%) Sinusitis 2 (1.1%) 20 (4.9%) 5 (2.1%) Upper respiratory tract infection 2 (1.1%) 14 (3.4%) 5 (2.1%) Viral upper respiratory tract infection 4 (2.3%) 2 (0.5%) (0.0%) Musculoskeletal and connective tissue disorders Arthralgia 5 (2.9%) 12 (2.9%) 1 (0.4%) Nervous system disorders Headache 21 (12.0%) 25 (6.1%) 7 (2.9%) Respiratory, thoracic, and mediastinal disorders Cough 2 (1.1%) 9 (2.2%) 3 (1.2%) Additional reactions reported during the 24-week treatment period in CSU Trials 1 and 3 [≥2% of patients receiving XOLAIR (150 mg 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 in Patients with CSU 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. Cardiovascular and Cerebrovascular Events from Clinical Studies in Patients with Asthma A 5-year observational cohort study was conducted in patients ≥12 years of age with moderate to severe persistent asthma and a positive skin test reaction to a perennial aeroallergen to evaluate the long-term safety of XOLAIR, including the risk of malignancy [see Warnings and Precautions (5.2) ] . A total of 5007 XOLAIR-treated and 2829 non–XOLAIR-treated patients enrolled in the study. Similar percentages of patients in both cohorts were current (5%) or former smokers (29%). Patients had a mean age of 45 years and were followed for a mean of 3.7 years. More XOLAIR-treated patients were diagnosed with severe asthma (50%) compared to the non–XOLAIR-treated patients (23%) and 44% of patients prematurely discontinued the study. Additionally, 88% of patients in the XOLAIR-treated cohort had been previously exposed to XOLAIR for a mean of 8 months. A higher incidence rate (per 1000 patient-years) of overall cardiovascular and cerebrovascular serious adverse events (SAEs) was observed in XOLAIR-treated patients (13.4) compared to non–XOLAIR-treated patients (8.1). Increases in rates were observed for transient ischemic attack (0.7 versus 0.1), myocardial infarction (2.1 versus 0.8), pulmonary hypertension (0.5 versus 0), pulmonary embolism/venous thrombosis (3.2 versus 1.5), and unstable angina (2.2 versus 1.4), while the rates observed for ischemic stroke and cardiovascular death were similar among both study cohorts. The results suggest a potential increased risk of serious cardiovascular and cerebrovascular events in patients treated with XOLAIR. However, the observational study design, the inclusion of patients previously exposed to XOLAIR (88%), baseline imbalances in cardiovascular risk factors between the treatment groups, an inability to adjust for unmeasured risk factors, and the high study discontinuation rate limit the ability to quantify the magnitude of the risk. A pooled analysis of 25 randomized double-blind, placebo-controlled clinical trials of 8 to 52 weeks in duration was conducted to further evaluate the imbalance in cardiovascular and cerebrovascular SAEs noted in the above observational cohort study. A total of 3342 XOLAIR-treated patients and 2895 placebo-treated patients were included in the pooled analysis. The patients had a mean age of 38 years, and were followed for a mean duration of 6.8 months. No notable imbalances were observed in the rates of cardiovascular and cerebrovascular SAEs listed above. However, the results of the pooled analysis were based on a low number of events, slightly younger patients, and shorter duration of follow-up than the observational cohort study; therefore, the results are insufficient to confirm or reject the findings noted in the observational cohort study. Adverse Reactions from Clinical Study in Healthy Adults Injection Site Reactions in Healthy Adults In an open label trial in healthy adults, in which the 300 mg/2 mL autoinjector was compared to the 300 mg/2 mL prefilled syringe, injection site reactions (e.g., induration, pain, erythema, hemorrhage, swelling, discomfort, bruising, hypoesthesia, edema, pruritus) were observed in 24% (16/66) of subjects treated with the autoinjector compared with 14% (9/64) of subjects treated with the prefilled syringe. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of XOLAIR. 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.

12.3 Pharmacokinetics After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7–8 days. In patients with CSU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses greater than 0.5 mg/kg. In patients with asthma, following multiple doses of XOLAIR, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose. In patients with CSU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels. In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125 I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CSU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma. Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fcγ receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CSU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient). Specific Populations Asthma The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with asthma. Analyses of these data suggested that no dose adjustments are necessary for age (6 to 76 years), race, ethnicity, or gender. Chronic Rhinosinusitis with Nasal Polyps The population pharmacokinetics analyses of omalizumab suggested that the pharmacokinetics of omalizumab in chronic rhinosinusitis with nasal polyps (CRSwNP) were consistent with that in asthma. Graphical covariate analyses were performed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (18 to 75 years) or gender. Race and ethnicity data are too limited in CRSwNP studies to inform dose adjustment. IgE-Mediated Food Allergy Population pharmacokinetic (PK) analyses of omalizumab suggested that the PK of omalizumab in patients with IgE-mediated food allergy were generally consistent with that in patients with asthma. Covariate analyses were performed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (1 year and older), race, ethnicity, or gender. Chronic Spontaneous Urticaria The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with chronic spontaneous urticaria (CSU). Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index, or baseline IgE level.