OMALIZUMAB: 63,846 Adverse Event Reports & Safety Profile

Omalizumab is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of approximately 149 kiloDaltons. XOLAIR is produced by a Chinese hamster ovary cell suspension culture. XOLAIR (omalizumab) is administered as a subcutaneous (SC) injection and is available in prefilled syringe, autoinjector and in vials.

Xolair

Injection (Prefilled Syringe or Autoinjector) XOLAIR (omalizumab) injection is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brownish-yellow solution for subcutaneous injection. XOLAIR (omalizumab) injection is available as a single-dose prefilled syringe or a single-dose autoinjector.

Each

75 mg prefilled syringe or autoinjector delivers 75 mg omalizumab in 0.5 mL and contains arginine hydrochloride (21.05 mg), histidine (0.68 mg), L-histidine hydrochloride monohydrate (1.17 mg), and polysorbate 20 (0.2 mg) in Sterile Water for Injection (SWFI), USP.

Each

150 mg prefilled syringe or autoinjector delivers 150 mg omalizumab in 1 mL and contains arginine hydrochloride (42.1 mg), histidine (1.37 mg), L-histidine hydrochloride monohydrate (2.34 mg), and polysorbate 20 (0.4 mg) in SWFI, USP.

Each

300 mg prefilled syringe or autoinjector delivers 300 mg omalizumab in 2 mL and contains arginine hydrochloride (84.2 mg), histidine (2.74 mg), L-histidine hydrochloride monohydrate (4.68 mg), and polysorbate 20 (0.8 mg) in SWFI, USP. The needle cap of the XOLAIR 75 mg/0.5 mL and 150 mg/mL prefilled syringe with 26-gauge staked needle contains a derivative of natural rubber latex which may cause allergic reactions in latex sensitive individuals [see How Supplied/Storage and Handling (16) ] . The XOLAIR autoinjector is not made with natural rubber latex. XOLAIR for Injection (Vial) XOLAIR (omalizumab) for injection is a sterile, white, preservative free, lyophilized powder in a single-dose vial. After reconstitution with 1.4 mL of Sterile Water for Injection, USP, the vial contains 150 mg of omalizumab per 1.2 mL of reconstituted solution for subcutaneous injection.

Each

1.2 mL of reconstituted solution also contains histidine (1.3 mg), L-histidine hydrochloride monohydrate (2.1 mg), polysorbate 20 (0.4 mg) and sucrose (108 mg).

AND USAGE Omalizumab-igec 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 Omalizumab-igec 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: Omalizumab-igec is not indicated for the relief of acute bronchospasm or status asthmaticus.

1.2 Chronic Rhinosinusitis with Nasal Polyps Omalizumab-igec 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 Omalizumab-igec 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. Omalizumab-igec is to be used in conjunction with food allergen avoidance. Limitations of Use: Omalizumab-igec is not indicated for the emergency treatment of allergic reactions, including anaphylaxis.

1.4 Chronic Spontaneous Urticaria Omalizumab-igec 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: Omalizumab-igec is not indicated for treatment of other forms of urticaria.

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) <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Adult and adolescent patients 12 years of age and older: Initiate dosing according to Table 1 . Pediatric patients 6 to &lt;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) <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> 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 &quot; Instructions for Use &quot; for preparation and administration of XOLAIR prefilled syringe or autoinjector <span class="opacity-50 text-xs">[see Instructions for Use ]</span> .

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.

Omalizumab-igec is contraindicated in patients with severe hypersensitivity reaction to omalizumab products or any ingredient of Omalizumab-igec [see Warnings and Precautions (5.1) ] . Severe hypersensitivity reaction to omalizumab productsor any ingredient of Omalizumab-igec ( 4 , 5.1 )

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'. 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 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.

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 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.

AND PRECAUTIONS Anaphylaxis: Initiate Omalizumab-igec 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 Omalizumab-igec 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 Omalizumab-igec if patients develop signs and symptoms similar to serum sickness. ( 5.6 )

Potential Medication Error

Related to Emergency Treatment of Anaphylaxis: Omalizumab-igec 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 <span class="opacity-50 text-xs">[see Boxed Warning and Adverse Reactions (6.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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

Omalizumab-igec 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 Omalizumab-igec, 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

Omalizumab-igec therapy has been established, administration of Omalizumab-igec 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 Omalizumab-igec 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

Omalizumab-igec 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) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 Omalizumab-igec to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Omalizumab-igec.

5.4 Corticosteroid Reduction Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Omalizumab-igec 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 Omalizumab-igec if a patient develops this constellation of signs and symptoms <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.7 Parasitic (Helminth)

Infection

Monitor patients at high risk of geohelminth infection while on Omalizumab-igec 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3 , 2.4) ]</span> .

5.9 Potential Medication Error Related to Emergency Treatment of Anaphylaxis Omalizumab-igec 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 Omalizumab-igec is for maintenance use to reduce allergic reactions, including anaphylaxis, while avoiding food allergens.

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