OMLYCLO

WARNING: ANAPHYLAXIS Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of omalizumab products. Anaphylaxis has occurred as early as after the first dose of omalizumab products, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, initiate OMLYCLO therapy in a healthcare setting and closely observe patients for an appropriate period of time after OMLYCLO administration. Health care providers administering OMLYCLO should be prepared to manage anaphylaxis which can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur. Selection of patients for self-administration of OMLYCLO should be based on criteria to mitigate risk from anaphylaxis [see Dosage and Administration (2.6) , Warnings and Precautions (5.1) and Adverse Reactions (6.1 , 6.2) ] . WARNING: ANAPHYLAXIS See full prescribing information for complete boxed warning. Anaphylaxis, presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of omalizumab products. Anaphylaxis has occurred after the first dose of omalizumab products but also has occurred beyond 1 year after beginning treatment. Initiate OMLYCLO therapy in a healthcare setting, closely observe patients for an appropriate period of time after OMLYCLO administration and be prepared to manage anaphylaxis which can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Selection of patients for self-administration of OMLYCLO should be based on criteria to mitigate risk from anaphylaxis. ( 2.6 , 5.1 , 6.1 , 6.2 )

5 WARNINGS AND PRECAUTIONS Anaphylaxis: Initiate OMLYCLO 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 OMLYCLO 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 OMLYCLO if patients develop signs and symptoms similar to serum sickness. ( 5.6 ) Potential Medication Error Related to Emergency Treatment of Anaphylaxis: OMLYCLO 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 omalizumab products 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 3,507 (0.1%) patients. Anaphylaxis occurred with the first dose of omalizumab 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 omalizumab users, patients with a history of anaphylaxis to foods, medications, or other causes were at increased risk of anaphylaxis associated with omalizumab products, compared to those with no prior history of anaphylaxis [see Adverse Reactions (6.1) ] . In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients based on an estimated exposure of 57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as early as after the first dose of omalizumab, 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 omalizumab, with additional cases occurring sporadically beyond the third dose. Initiate OMLYCLO 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 OMLYCLO, 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 OMLYCLO therapy has been established, administration of OMLYCLO prefilled syringe 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 OMLYCLO prefilled syringe 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 OMLYCLO in patients who experience a severe hypersensitivity reaction [see Contraindications (4) ] . 5.2 Malignancy Malignant neoplasms were observed in 20 of 4,127 (0.5%) omalizumab-treated patients compared with 5 of 2,236 (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 omalizumab-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 omalizumab products or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known. In a subsequent observational study of 5,007 omalizumab-treated and 2,829 non-omalizumab- 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 1,000 patient years) were similar among omalizumab-treated (12.3) and non-omalizumab-treated patients (13.0) [see Adverse Reactions (6.1) ] . However, study limitations preclude definitively ruling out a malignancy risk with omalizumab products. Study limitations include: the observational study design, the bias introduced by allowing enrollment of patients previously exposed to omalizumab (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 Omalizumab products have not been shown to alleviate asthma exacerbations acutely. Do not use OMLYCLO to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with OMLYCLO. 5.4 Corticosteroid Reduction Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of OMLYCLO therapy for asthma or CRSwNP. Decrease corticosteroids gradually under the direct supervision of a physician. In CSU patients, the use of omalizumab products in combination with corticosteroids has not been evaluated. 5.5 Eosinophilic Conditions In rare cases, patients with asthma on therapy with omalizumab products 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 omalizumab products 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 omalizumab products. 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 OMLYCLO 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 OMLYCLO therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping omalizumab products treatment. In a one-year clinical trial conducted in Brazil in adult and adolescent patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of omalizumab-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have received omalizumab than a patient who did not have an infection. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups. 5.8 Laboratory Tests Serum total IgE levels increase following administration of omalizumab products due to formation of drug:IgE complexes [see Clinical Pharmacology (12.2) ] . Elevated serum total IgE levels may persist for up to 1 year following discontinuation of omalizumab products. Do not use serum total IgE levels obtained less than 1 year following discontinuation to reassess the dosing regimen for asthma, CRSwNP or IgE-mediated food allergy patients, because these levels may not reflect steady- state free IgE levels [see Dosage and Administration (2.2 , 2.3 , 2.4) ] . 5.9 Potential Medication Error Related to Emergency Treatment of Anaphylaxis OMLYCLO should not be used for the emergency treatment of allergic reactions, including anaphylaxis. In studies to simulate use, some patients and caregivers did not understand that omalizumab products are not intended for the emergency treatment of allergic reactions, including anaphylaxis. The safety and effectiveness of omalizumab products for emergency treatment of allergic reactions, including anaphylaxis, have not been established. Instruct patients that OMLYCLO is for maintenance use to reduce allergic reactions, including anaphylaxis, while avoiding food allergens.

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 CELLTRION USA, Inc. at 1-800-560-9414 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 omalizumab exposure for 2,076 adult and adolescent patients ages 12 and older, including 1,687 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 omalizumab was 42 years, with 134 patients 65 years of age or older; 60% were women, and 85% Caucasian. Patients received omalizumab 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 omalizumab, 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 omalizumab-treated patients and control patients. Table 6 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 omalizumab 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 6. Adverse Reactions ≥1% More Frequent in omalizumab-Treated Adult or Adolescent Patients 12 years of Age and Older in Four Placebo-controlled Asthma Trials Adverse reaction Omalizumab 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 omalizumab among patients treated with omalizumab for asthma. Cases with an adjudicated history of anaphylaxis to omalizumab 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 omalizumab 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 omalizumab users. From other sources, anaphylaxis to omalizumab 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 omalizumab, 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 omalizumab-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 omalizumab-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 omalizumab 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 omalizumab was 8.8 years; 69% were male, and 64% were Caucasian. Pediatric patients received omalizumab 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 omalizumab in these trials. The most common adverse reactions occurring at ≥3% in the pediatric patients receiving omalizumab 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 omalizumab, 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 omalizumab-treated patients and control patients. Adverse Reactions from Clinical Studies in Adult Patients with Chronic Rhinosinusitis with Nasal Polyps The data described below reflect omalizumab exposure for 135 patients ≥ 18 years of age, exposed for six months in two placebo-controlled studies. The mean age of patients receiving omalizumab was 49.7 years; 64% were male, and 94% were Caucasian. Patients received omalizumab 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 7 lists the adverse reactions occurring in ≥3% of omalizumab-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 7. Adverse Reactions Occurring in ≥3% of omalizumab-Treated Patients and More Frequently than in Patients Treated with Placebo in CRSwNP Trials 1 and 2 Adverse reaction Omalizumab 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'. Allinjection 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 omalizumab 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 omalizumab or placebo subcutaneously every 2 or 4 weeks for 16 to 20 weeks according to the recommended dosage based on total 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 8 are from the primary analysis population of pediatric patients aged 1 years to 17 years. Safety data obtained from adults (n=3) in this trial was limited. Table 8 lists the adverse reactions occurring in ≥3% of omalizumab-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 8. Adverse Reactions Occurring in ≥3% of omalizumab -Treated Pediatric Patients 1 Year of Age and Older and More Frequently than in Patients Treated with Placebo in FA Trial Adverse reaction Omalizumab 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 (CSU) The safety of omalizumab 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 omalizumab 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 omalizumab 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy. The data described below reflect omalizumab exposure for 733 patients enrolled and receiving at least one dose of omalizumab in the three clinical trials, including 684 patients exposed for 12 weeks and 427 exposed for 24 weeks. The mean age of patients receiving omalizumab 300 mg was 43 years, 75% were women, and 89% were white. The demographic profiles for patients receiving omalizumab 150 mg and 75 mg were similar. Table 9 shows adverse reactions that occurred in ≥2% of patients receiving omalizumab (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 9. Adverse Reactions Occurring in ≥2% in omalizumab-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 150 mg (n=175) 300 mg (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 omalizumab (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 omalizumab-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 omalizumab, including the risk of malignancy [see Warnings and Precautions (5.2) ] . A total of 5,007 omalizumab-treated and 2,829 non–omalizumab-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 omalizumab-treated patients were diagnosed with severe asthma (50%) compared to the non–omalizumab-treated patients (23%) and 44% of patients prematurely discontinued the study. Additionally, 88% of patients in the omalizumab- treated cohort had been previously exposed to omalizumab for a mean of 8 months. A higher incidence rate (per 1,000 patient-years) of overall cardiovascular and cerebrovascular serious adverse events (SAEs) was observed in omalizumab-treated patients (13.4) compared to non–omalizumab-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 omalizumab. However, the observational study design, the inclusion of patients previously exposed to omalizumab (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 3,342 omalizumab-treated patients and 2,895 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of omalizumab products. 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 omalizumab 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 omalizumab 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 omalizumab was reported in 24% of the cases. Of the reported cases of anaphylaxis attributed to omalizumab, 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 omalizumab and 18 patients had a recurrence of similar symptoms of anaphylaxis. In addition, anaphylaxis occurred upon rechallenge with omalizumab 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 omalizumab products [see Warnings and Precautions (5.6) ] . Hematologic : Severe thrombocytopenia has been reported. Skin : Hair loss has been reported.

<table width="75%" ID="Table6"><caption>Table 6. Adverse Reactions &#x2265;1% More Frequent in omalizumab-Treated Adult or Adolescent Patients 12 years of Age and Older in Four Placebo-controlled Asthma Trials</caption><col width="34%" align="left" valign="bottom"/><col width="33%" align="center" valign="bottom"/><col width="33%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule" valign="top">Adverse reaction</th><th>Omalizumab n=738</th><th styleCode="Rrule">Placebo n=717</th></tr></thead><tbody><tr><td styleCode="Lrule"><content styleCode="underline">Body as a whole</content></td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Pain</td><td>7%</td><td styleCode="Rrule">5%</td></tr><tr><td styleCode="Lrule"> Fatigue</td><td>3%</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Lrule"><content styleCode="underline">Musculoskeletal system</content></td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Arthralgia</td><td>8%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Lrule"> Fracture</td><td>2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule"> Leg pain</td><td>4%</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Lrule"> Arm pain</td><td>2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule"><content styleCode="underline">Nervous system</content></td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Dizziness</td><td>3%</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Lrule"><content styleCode="underline">Skin and appendages</content></td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Pruritus</td><td>2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule"> Dermatitis</td><td>2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule"><content styleCode="underline">Special senses</content></td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Earache</td><td>2%</td><td styleCode="Rrule">1%</td></tr></tbody></table>

<table width="75%" ID="Table7"><caption>Table 7. Adverse Reactions Occurring in &#x2265;3% of omalizumab-Treated Patients and More Frequently than in Patients Treated with Placebo in CRSwNP Trials 1 and 2</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule">Adverse reaction</th><th>Omalizumab N=135</th><th styleCode="Rrule">Placebo N=130</th></tr></thead><tfoot><tr><td colspan="3" align="left">CRSwNP = Chronic Rhinosinusitis with Nasal Polyps.</td></tr></tfoot><tbody><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="underline">Gastrointestinal disorder</content></td></tr><tr><td styleCode="Lrule"> Upper abdominal pain</td><td>4 (3.0%)</td><td styleCode="Rrule">1 (0.8%)</td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="underline">General disorders and administration site conditions</content></td></tr><tr><td styleCode="Lrule"> Injection site reactions<footnote>Injection site reactions terms: &apos;injection site reaction&apos;, &apos;injection related reaction&apos; and &apos;injection site pain&apos;. Allinjection site reactions were mild to moderate severity and none resulted in study discontinuation</footnote></td><td>7 (5.2%)</td><td styleCode="Rrule">2 (1.5%)</td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="underline">Musculoskeletal system and connective tissue disorders</content></td></tr><tr><td styleCode="Lrule"> Arthralgia</td><td>4 (3.0%)</td><td styleCode="Rrule">2 (1.5%)</td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="underline">Nervous system disorders</content></td></tr><tr><td styleCode="Lrule"> Headache</td><td>11 (8.1%)</td><td styleCode="Rrule">7 (5.4%)</td></tr><tr><td styleCode="Lrule"> Dizziness</td><td>4 (3.0%)</td><td styleCode="Rrule">1 (0.8%)</td></tr></tbody></table>

<table width="75%" ID="Table8"><caption>Table 8. Adverse Reactions Occurring in &#x2265;3% of omalizumab -Treated Pediatric Patients 1 Year of Age and Older and More Frequently than in Patients Treated with Placebo in FA Trial</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule">Adverse reaction</th><th>Omalizumab N=110</th><th styleCode="Rrule">Placebo N=55</th></tr></thead><tbody><tr><td colspan="3" styleCode="Lrule Rrule"><content styleCode="underline">General disorders and administration site conditions</content></td></tr><tr><td styleCode="Lrule"> Injection site reactions<footnote>Injection site reactions terms: &apos;injection site reaction&apos;,&apos;injection site urticaria&apos;,&apos;injection site discomfort&apos;,&apos;injection site erythema&apos;,&apos;injection site pain&apos; and &apos;injection site rash&apos;. All injection site reactions were mild to moderate severity and none resulted in study discontinuation.</footnote></td><td>17 (15.5%)</td><td styleCode="Rrule">6 (10.9%)</td></tr><tr><td styleCode="Lrule"> Pyrexia</td><td>7 (6.4%)</td><td styleCode="Rrule">2 (3.6%)</td></tr></tbody></table>