XOLAIR

Omalizumab is a recombinant

DNA-derived humanized monoclonal antibody directed against human immunoglobulin E (IgE).

IgE promotes the release of inflammatory mediators from mast cells and basophils during allergic and inflammatory reactions.

By binding to

IgE and neutralizing it, omalizumab reduces free IgE levels and prevents IgE from binding to its receptors on immune cells.

Omalizumab was first approved in the

US in 2003 3 and in Europe in 2005.

It is used to treat a range of immune and inflammatory conditions, including allergies, urticaria, and asthma.

Omalizumab is indicated for: the treatment of patients six 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. 6, 7.

• add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adults with inadequate response to nasal corticosteroids. 6, 7.

• the reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods in patients aged one year and older with IgE-mediated food allergy.

Omalizumab is to be used in conjunction with food allergen avoidance. 6.

• the treatment of adults and adolescents 12 years of age and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment.

Omalizumab decreases free

IgE levels in serum in a dose-dependent manner.

Serum total

IgE levels, accounting for bound and unbound IgE, increased after the first dose of omalizumab due to the formation of drug:IgE complexes, which have a slower elimination rate compared with free IgE.

At 16 weeks after the first dose, average total IgE levels in serum were five-fold higher compared to pre-treatment levels in standard assays.

Drug effects on

IgE levels are reversible upon drug discontinuation, with no observed rebound in IgE levels after drug washout.

IgE levels did not return to pre-treatment levels for up to one year after discontinuation of omalizumab.

After subcutaneous administration, omalizumab has an average absolute bioavailability of 62%.

In adult and adolescent patients with asthma, omalizumab was absorbed slowly and the peak serum concentrations occurred after seven to eight days.

The pharmacokinetics of omalizumab were linear at doses which were higher than 0.5 mg/kg. In patients with asthma, after several doses of omalizumab, areas under the serum concentration-time curve from Day to Day at steady state were up to 6-fold of those after one dose.

After repeated dosing from 75 mg-300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose.

In patients with asthma, the apparent volume of distribution was 78 ± 32 mL/kg following subcutaneous administration.

Omalizumab is degraded in the reticuloendothelial system and endothelial cells.

Liver elimination of

IgG includes degradation in the liver reticuloendothelial system (RES) and endothelial cells.

IgG was also shown to be excreted in bile.

In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fc-gamma receptors within the RES at rates that were generally faster than IgG clearance.

In asthma patients, the serum elimination half-life averaged 26 days.

In CSU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days.

In pharmacokinetic studies, the clearance of omalizumab involved IgG clearance as well as clearance by specific binding and complex formation with its target ligand, IgE.

The apparent clearance averaged 2.4 ± 1.1 mL/kg/day in patients with asthma.

The apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).

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The intravenous

LD in monkeys is 200 mg/kg.

Maximum tolerated dose of omalizumab has not been determined.

Single intravenous doses up to 4000 mg have been administered to patients without evidence of dose-limiting toxicities.

The highest cumulative dose administered to patients was 44,000 mg over a 20-week period and this dose did not result in any untoward acute effects.

If an overdose is suspected, the patient should be monitored for any abnormal signs or symptoms.

Medical treatment should be sought and instituted appropriately.

is contraindicated in patients with severe hypersensitivity reaction to XOLAIR or any ingredient of XOLAIR.

Severe hypersensitivity reaction to XOLAIR or any ingredient of XOLAIR.

For subcutaneous (SC) administration only.

See full prescribing information for administration instructions.

XOLAIR 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.

XOLAIR to 600 mg SC every 2 or 4 weeks.

XOLAIR 75 mg to 600 mg SC every 2 or 4 weeks.

See the dose determination chart.

XOLAIR 150 or 300 mg SC every 4 weeks.

Dosing in CSU is not dependent on serum IgE level or body weight. 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 and 2 for the recommended dosage for treatment of asthma, Table for treatment of CRSwNP, and Table for treatment of IgE-mediated food allergy.

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 for treatment of asthma, based on the patient's age, Table for treatment of CRSwNP, and Table 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. 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) .

Adult and adolescent patients 12 years of age and older: Initiate dosing according to Table 1.

Pediatric patients to <12 years of age: Initiate dosing according to Table 2.

Table 1.

Every 2 or 4 Weeks* for Patients 12 Years of Age and Older with Asthma Table 2.

Every 2 or 4 Weeks* for Pediatric Patients with Asthma Who Begin XOLAIR Between the Ages of 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) .

Refer to Table for recommended dosage based on serum total IgE level and body weight for patients with CRSwNP.

Table 3.

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.

Refer to Table for recommended dosage based on serum IgE level and body weight for patients with IgE-mediated food allergy.

Table 4.

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 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.

Adolescents 12 years of age and older: XOLAIR prefilled syringe may be self-administered under adult supervision.

Patients to 11 years of age: XOLAIR prefilled syringe should be administered by a caregiver.

Adolescents 12 years of age and older: XOLAIR autoinjector may be self-administered under adult supervision.

XOLAIR autoinjectors (all doses) are intended for use only in adults and adolescents aged 12 years and older.

Patients 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.

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.

For pediatric patients 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.

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.

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) .

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.

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 to 10 seconds approximately every 5 minutes in order to dissolve any remaining solids.

The lyophilized product takes to 20 minutes to dissolve.

If it takes longer than 20 minutes to dissolve completely, gently.

Injection (Prefilled Syringe or Autoinjector) XOLAIR (omalizumab) injection is a clear to slightly opalescent and colorless to pale brownish-yellow solution for subcutaneous use.

XOLAIR injection is provided as either a single-dose prefilled syringe with staked needle, rigid needle cap, and needle shield or a single-dose prefilled autoinjector with staked needle, needle cap and needle guard.

XOLAIR is available as prefilled syringe and autoinjector as described in Tables and 19.

Table 18.

XOLAIR Prefilled Syringe Strengths and Package Configurations Package Configuration Strength NDC 1 prefilled syringe with a 26-gauge staked needle The needle cap of the XOLAIR prefilled syringe contains a derivative of natural rubber latex which may cause allergic reactions in latex sensitive individuals. 75 mg/0.5 mL NDC 50242-214-01 1 prefilled syringe with a 26-gauge staked needle 150 mg/mL NDC 50242-215-01 1 prefilled syringe with a 27-gauge staked needle 75 mg/0.5 mL NDC 50242-214-03 1 prefilled syringe with a 27-gauge staked needle 150 mg/mL NDC 50242-215-03 1 prefilled syringe with a 27-gauge staked needle 300 mg/2 mL NDC 50242-227-01 Table 19.

XOLAIR Autoinjector Strengths and Package Configurations Package Configuration Strength NDC 1 autoinjector with a 27-gauge staked needle 75 mg/0.5 mL NDC 50242-214-55 1 autoinjector with a 27-gauge staked needle 150 mg/mL NDC 50242-215-55 1 autoinjector with a 27-gauge staked needle 300 mg/2 mL NDC-50242-227-55 The XOLAIR autoinjector is not made with natural rubber latex.

XOLAIR prefilled syringe and autoinjector should be shipped and stored under refrigerated conditions 2°C to 8°C (36°F to 46°F) in the original carton.

Protect from direct sunlight.

XOLAIR prefilled syringe and autoinjector can be removed from and placed back in the refrigerator if needed.

The total combined time out of the refrigerator may not be more than 2 days.

Do not use if prefilled syringe or autoinjector is left at temperatures above 25°C (77°F).

Do not freeze.

Do not use if the prefilled syringe or autoinjector has been frozen.

Injection (Vial) XOLAIR is supplied as a lyophilized, white, sterile powder in a single-dose vial without preservatives.

Each carton contains: one single-dose vial of XOLAIR ® (omalizumab) 150 mg for injection NDC 50242-040-62.

XOLAIR should be shipped at controlled ambient temperature (≤30°C [≤86°F]).

XOLAIR under refrigerated conditions 2°C to 8°C (36°F to 46°F) in the original carton.

Do not use beyond the expiration date stamped on carton.

XOLAIR prefilled syringe and autoinjector should be shipped and stored under refrigerated conditions 2°C to 8°C (36°F to 46°F) in the original carton.

Protect from direct sunlight.

XOLAIR prefilled syringe and autoinjector can be removed from and placed back in the refrigerator if needed.

The total combined time out of the refrigerator may not be more than 2 days.

Do not use if prefilled syringe or autoinjector is left at temperatures above 25°C (77°F).

Do not freeze.

Do not use if the prefilled syringe or autoinjector has been frozen.

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.

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

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) .

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.

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.

A prospective cohort pregnancy exposure registry study conducted in the US from 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.

Asthma Safety and effectiveness of

XOLAIR for moderate to severe persistent asthma who had a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids, have been established in pediatric patients aged 6 years and older.

Use of

XOLAIR for this indication is supported by evidence from adequate and well-controlled studies.

XOLAIR was evaluated in 2 trials in 926 (XOLAIR 624; placebo 302) pediatric patients to <12 years of age with moderate to severe persistent asthma who had a positive skin test or in vitro reactivity to a perennial aeroallergen.

One trial was a pivotal trial of similar design and conduct to that of adult and adolescent Asthma Trials and 2.

The other trial was primarily a safety study and included evaluation of efficacy as a secondary outcome.

In the pivotal trial, XOLAIR-treated patients had a statistically significant reduction in the rate of exacerbations (exacerbation was defined as worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose) .

Safety and efficacy in pediatric patients with asthma below 6 years of age have not been established.

Safety and effectiveness in pediatric patients with chronic rhinosinusitis with nasal polyps (CRSwNP) below 18 years of age have not been established.

IgE-Mediated Food Allergy The safety and effectiveness of XOLAIR for the reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods have been established in pediatric patients aged 1 year and older with IgE-mediated food allergy.

XOLAIR for this indication is supported by evidence from an adequate and well-controlled study that included a total of 165 pediatric patients; 61 patients aged 1 year to less than 6 years of age and 104 patients aged to less than 18 years of age.

A significantly greater percentage of

XOLAIR-treated patients compared to placebo-treated patients was able to consume a single dose of food (peanut, cashew, milk, egg) without dose.

• limiting symptoms.

Safety and effectiveness in pediatric patients with IgE-mediated food allergy below 1 year of age have not been established.

Chronic Spontaneous Urticaria The safety and effectiveness of XOLAIR for chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment have been established in pediatric patients aged 12 years and older.

XOLAIR in this population is supported by evidence from adequate and well-controlled studies.

Adolescent patients with

CSU were evaluated in 39 patients to 17 years of age (XOLAIR 29, placebo 10) included in three randomized, placebo-controlled CSU trials.

A numerical decrease in weekly itch score was observed, and adverse reactions were similar to those reported in patients 18 years and older.

Safety and effectiveness in pediatric patients with CSU below 12 years of age have not been established.

In clinical studies, 134 asthma patients, 20 CRSwNP patients, 37 CSU patients and no IgE-mediated food allergy patients 65 years of age or older were treated with XOLAIR.

Although there were no apparent age-related differences observed in these studies, the number of patients aged and over is not sufficient to determine whether they respond differently from younger patients.