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mechanism of action is IgE-directed Antibody Interactions [MoA]

Xolair

(Omalizumab)

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Dosage & Administration

For subcutaneous (SC) administration only. (

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.

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 3for 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

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 4for 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

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.

)

See full prescribing information for administration instructions (

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 AutoinjectorsThe autoinjector (all doses) are not intended for use in patients under 12 years of age., Injections and Total Injection VolumesThis table represents the fewest number of injections for the patient, however, there are other syringe/autoinjector dosing combinations to achieve desired dose.
XOLAIR DoseThe 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 DoseThe 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.

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 Recommended Dosage for Asthma

[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.

)
*

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 Recommended Dosage for Chronic Rhinosinusitis with Nasal Polyps

[see Dosage and Administration (2.1)]

. Refer to Table 3for 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

Duration of Therapy

Periodically reassess the need for continued therapy based upon the patient's disease severity and level of symptom control.

)
*

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 Recommended Dosage for IgE-Mediated Food Allergy

[see Dosage and Administration (2.1)]

. Refer to Table 4for 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

Duration of Therapy

The appropriate duration of therapy for IgE-mediated food allergy has not been evaluated. Periodically reassess the need for continued therapy.

)
*

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 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.

)

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Xolair Prescribing Information

Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of XOLAIR. Anaphylaxis has occurred as early as after the first dose of XOLAIR, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, initiate XOLAIR therapy in a healthcare setting and closely observe patients for an appropriate period of time after XOLAIR administration. Health care providers administering XOLAIR 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 XOLAIR should be based on criteria to mitigate risk from anaphylaxis

[see

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

5.1 Anaphylaxis

Anaphylaxis has been reported to occur after administration of XOLAIR in premarketing clinical trials and in postmarketing spontaneous reports

[see Boxed Warningand Adverse Reactions (6.2)]

. Signs and symptoms in these reported cases have included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Some of these events have been life-threatening. In premarketing clinical trials in patients with asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients. Anaphylaxis occurred with the first dose of XOLAIR in two patients and with the fourth dose in one patient. The time to onset of anaphylaxis was 90 minutes after administration in two patients and 2 hours after administration in one patient.

A case-control study in asthma patients showed that, among XOLAIR users, patients with a history of anaphylaxis to foods, medications, or other causes were at increased risk of anaphylaxis associated with XOLAIR, compared to those with no prior history of anaphylaxis

[see Adverse Reactions (6.1)]

In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to XOLAIR use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as early as after the first dose of XOLAIR, but also has occurred beyond one year after beginning regularly scheduled treatment. Approximately 60% to 70% of anaphylaxis cases have been reported to occur within the first three doses of XOLAIR, with additional cases occurring sporadically beyond the third dose.

Initiate XOLAIR only in a healthcare setting equipped to manage anaphylaxis, which can be life-threatening. Observe patients closely for an appropriate period of time after administration of XOLAIR, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing spontaneous reports

[see Adverse Reactions (6.1, 6.2)]

. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur.

Once XOLAIR therapy has been established, administration of XOLAIR prefilled syringe or autoinjector outside of a healthcare setting by a patient or a caregiver may be appropriate for selected patients. Patient selection, determined by the healthcare provider in consultation with the patient, should take into account the pattern of anaphylaxis events seen in premarketing clinical trials and postmarketing spontaneous reports, as well as individual patient risk factors (e.g., prior history of anaphylaxis), ability to recognize signs and symptoms of anaphylaxis, and ability to perform subcutaneous injections with XOLAIR prefilled syringe or autoinjector with proper technique according to the prescribed dosing regimen and Instructions for Use

[see Dosage and Administration (2.6), Adverse Reactions (6.1, 6.2)].

Discontinue XOLAIR in patients who experience a severe hypersensitivity reaction

[see Contraindications (4)]

and

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 7shows 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 8lists 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 reactionsInjection 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 9are 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 9lists 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 reactionsInjection 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 10shows 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 Reactionsby 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.

]

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)

Indications and Usage, IgE-Mediated Food Allergy (

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.

)

2 /2024

Dosage and Administration (

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 1and 2for the recommended dosage for treatment of asthma, Table 3for treatment of CRSwNP, and Table 4for 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 . 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 AutoinjectorsThe autoinjector (all doses) are not intended for use in patients under 12 years of age., Injections and Total Injection VolumesThis table represents the fewest number of injections for the patient, however, there are other syringe/autoinjector dosing combinations to achieve desired dose.
XOLAIR DoseThe 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

Table 6. Number of Vials, Injections and Total Injection Volumes
XOLAIR DoseThe 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.

)2 /2024Warnings and Precautions (

5.1 Anaphylaxis

Anaphylaxis has been reported to occur after administration of XOLAIR in premarketing clinical trials and in postmarketing spontaneous reports

[see Boxed Warningand Adverse Reactions (6.2)]

[see Adverse Reactions (6.1)]

[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.

[see Dosage and Administration (2.6), Adverse Reactions (6.1, 6.2)].

Discontinue XOLAIR in patients who experience a severe hypersensitivity reaction

[see Contraindications (4)]

5.8 Laboratory Tests

Serum total IgE levels increase following administration of XOLAIR due to formation of XOLAIR:IgE complexes

[see Clinical Pharmacology (12.2)]

. Elevated serum total IgE levels may persist for up to 1 year following discontinuation of XOLAIR. 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

XOLAIR 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 XOLAIR is not intended for the emergency treatment of allergic reactions, including anaphylaxis. The safety and effectiveness of XOLAIR for emergency treatment of allergic reactions, including anaphylaxis, have not been established. Instruct patients that XOLAIR is for maintenance use to reduce allergic reactions, including anaphylaxis, while avoiding food allergens.

)2 /2024

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 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.
)
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 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.
)
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 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.
)
Chronic spontaneous urticaria (CSU) in adults and adolescents 12 years of age and older who remain symptomatic despite H1 antihistamine treatment (
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.
)

Limitations of Use

Not indicated for acute bronchospasm or status asthmaticus. (
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.
,
5.3 Acute Asthma Symptoms and Deteriorating Disease
XOLAIR has not been shown to alleviate asthma exacerbations acutely. Do not use XOLAIR to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with XOLAIR.
)
Not indicated for the emergency treatment of allergic reactions, including anaphylaxis (
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.
)
Not indicated for other forms of urticaria. (
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.
)

For subcutaneous (SC) administration only. (

2.2 Recommended Dosage for Asthma

[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.

2.3 Recommended Dosage for Chronic Rhinosinusitis with Nasal Polyps

[see Dosage and Administration (2.1)]

. Refer to Table 3for 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

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

[see Dosage and Administration (2.1)]

. Refer to Table 4for 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

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.

)

See full prescribing information for administration instructions (

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

[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 AutoinjectorsThe autoinjector (all doses) are not intended for use in patients under 12 years of age., Injections and Total Injection VolumesThis table represents the fewest number of injections for the patient, however, there are other syringe/autoinjector dosing combinations to achieve desired dose.
XOLAIR DoseThe 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

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 DoseThe 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.

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 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
)
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 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 3for 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.
)
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 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 4for 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.
)
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 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.
)

Injection:

75 mg/0.5 mL is a clear to slightly opalescent and colorless to pale brownish-yellow solution in a single-dose prefilled syringe with needle shield or single-dose prefilled autoinjector
150 mg/mL is a clear to slightly opalescent and colorless to pale brownish-yellow solution in a single-dose prefilled syringe with needle shield or single-dose prefilled autoinjector
300 mg/2 mL is a clear to slightly opalescent and colorless to pale brownish-yellow solution in a single-dose prefilled syringe with needle shield or single-dose prefilled autoinjector
For injection: 150 mg white lyophilized powder in a single-dose vial for reconstitution

Risk Summary

A registry study of XOLAIR exposure during pregnancy showed no increase in the rate of major birth defects or miscarriage. There was an increased rate of low birth weight among registry infants compared to infants in the other cohorts, despite average gestational age at birth; however, women taking XOLAIR during pregnancy also had more severe asthma, which makes it difficult to determine whether the low birth weight is due to the drug or the disease severity

[see

Data

Human Data

A prospective cohort pregnancy exposure registry study conducted in the US from 2006 to 2018, included 250 pregnant women with asthma treated with XOLAIR. Of these, 246 patients were exposed to XOLAIR in the first trimester of pregnancy, and the median exposure duration was 8.7 months.

The registry findings for applicable mother and infant subgroups were compared to age-adjusted frequencies in a disease-matched external cohort of 1,153 pregnant women with asthma (without exposure to XOLAIR) identified from healthcare databases of residents in the Canadian province of Quebec, and referred to as the Quebec External Comparator Cohort ("comparator cohort").

Among applicable registry infants, the prevalence of major congenital anomalies (8.1%) was similar to that for infants in the comparator cohort (8.9%). Among applicable registry pregnancies, 99.1% led to live births, similar to 99.3% for the comparator cohort. There was an increased rate of low birth weight among registry infants (13.7%) as compared to the comparator cohort (9.8%); however, women taking XOLAIR during pregnancy also had more severe asthma, which makes it difficult to determine whether the low birth weight is due to the drug or the disease severity.

The registry study cannot definitively establish the absence of any risk because of methodological limitations, including the observational nature of the registry, small sample size, and potential differences between the registry population and the comparator cohort.

Animal Data

Reproductive studies have been performed in Cynomolgus monkeys. There was no evidence of maternal toxicity, embryotoxicity, or teratogenicity when omalizumab was administered throughout the period of organogenesis at doses that produced exposures approximately 5 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 75 mg/kg/week). Omalizumab did not elicit adverse effects on fetal or neonatal growth when administered throughout late gestation, delivery, and nursing.

]

. There are risks associated with poorly or moderately controlled asthma in pregnancy

[see

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

]

Human IgG antibodies are known to cross the placental barrier; therefore, XOLAIR may be transmitted from the mother to the developing fetus.

In animal reproduction studies, no evidence of fetal harm was observed in Cynomolgus monkeys with subcutaneous doses of omalizumab up to approximately 5 times the maximum recommended human dose (MRHD)

[see

Data

Human Data

Animal Data

]

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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