|Dosage Form||Package Information||Links|
|INJECTION, SOLUTION||1 VIAL, SINGLE-USE in 1 CARTON (50242-040-62) > 1.4 mL in 1 VIAL, SINGLE-USE||Label 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, observe patients closely for an appropriate period of time after Xolair administration. Health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.3)].
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 after the first dose of Xolair but also has occurred beyond 1 year after beginning treatment. Closely observe patients for an appropriate period of time after Xolair administration and be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. (5.1)
Xolair is an anti-IgE antibody indicated for:
Limitations of use:
Divide doses of more than 150 mg among more than one injection site to limit injections to not more than 150 mg per site. (2.4)
For injection: Lyophilized, sterile powder in a single-use vial, 150 mg. (3)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
No formal drug interaction studies have been performed. (7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Xolair is indicated for 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.
Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.
Xolair is indicated for the treatment of adults and adolescents 12 years of age and older with chronic idiopathic urticaria who remain symptomatic despite H1 antihistamine treatment.
Administer Xolair 75 to 375 mg by subcutaneous injection 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 by body weight (kg).
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.
Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control.
|Pre-treatment Serum IgE||Body Weight|
|30â€“60 kg||> 60â€“70 kg||> 70â€“90 kg||> 90â€“150 kg|
|â‰¥ 30â€“100 IU/mL||150 mg||150 mg||150 mg||300 mg|
|> 100â€“200 IU/mL||300 mg||300 mg||300 mg|
|> 200â€“300 IU/mL||300 mg|
|> 300â€“400 IU/mL||SEE TABLE 2|
|> 400â€“500 IU/mL|
|> 500â€“600 IU/mL|
|Pre-treatment Serum IgE||Body Weight|
|30â€“60 kg||> 60â€“70 kg||> 70â€“90 kg||> 90â€“150 kg|
|â‰¥ 30â€“100 IU/mL||SEE TABLE 1|
|> 100â€“200 IU/mL||225 mg|
|> 200â€“300 IU/mL||225 mg||225 mg||300 mg|
|> 300â€“400 IU/mL||225 mg||225 mg||300 mg|
|> 400â€“500 IU/mL||300 mg||300 mg||375mg|
|> 500â€“600 IU/mL||300 mg||375 mg||DO NOT DOSE|
|> 600â€“700 IU/mL||375 mg|
Pediatric patients 6 to <12 years of age: Initiate dosing according to Table 3.
|Table 3. Subcutaneous Xolair Doses Every 2 or 4 Weeks* for Pediatric Patients with Asthma Who Begin Xolair Between the Ages of 6 to <12 Years|
Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.
Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.
The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.
The supplied Xolair lyophilized powder must be reconstituted with Sterile Water for Injection (SWFI) USP, using the following instructions:1)
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 among two or more injection sites (Table 4).
|Xolair Dose*||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|
The use of Xolair is contraindicated in the following:
Severe hypersensitivity reaction to Xolair or any ingredient of Xolair [see Warnings and Precautions (5.1)].
Anaphylaxis has been reported to occur after administration of Xolair in premarketing clinical trials and in postmarketing spontaneous reports [see Boxed Warning and Adverse Reactions (6.3)]. 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 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.
Administer Xolair only in a healthcare setting by healthcare providers prepared to manage anaphylaxis that 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)]. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur.
Discontinue Xolair in patients who experience a severe hypersensitivity reaction [see Contraindications (4)].
Malignant neoplasms were observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents â‰¥ 12 years of age with asthma and other allergic disorders. The observed malignancies in Xolair-treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each. The majority of patients were observed for less than 1 year. The impact of longer exposure to Xolair or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known.
In a subsequent observational study of 5007 Xolair-treated and 2829 non-Xolair-treated adolescent and adult patients with moderate to severe persistent asthma and a positive skin test reaction or in vitro reactivity to a perennial aeroallergen, patients were followed for up to 5 years. In this study, the incidence rates of primary malignancies (per 1000 patient years) were similar among Xolair-treated (12.3) and non-Xolair-treated patients (13.0) [see Adverse Reactions (6)]. However, study limitations preclude definitively ruling out a malignancy risk with Xolair. Study limitations include: the observational study design, the bias introduced by allowing enrollment of patients previously exposed to Xolair (88%), enrollment of patients (56%) while a history of cancer or a premalignant condition were study exclusion criteria, and the high study discontinuation rate (44%).
Xolair has not been shown to alleviate asthma exacerbations acutely. Do not use Xolair to treat acute bronchospasm or status asthmaticus.
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Xolair therapy for asthma. Decrease corticosteroids gradually under the direct supervision of a physician. In CIU patients, the use of Xolair in combination with corticosteroids has not been evaluated.
In rare cases, patients with asthma on therapy with Xolair may present with serious systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Xolair and these underlying conditions has not been established.
In post-approval use, some patients have experienced a constellation of signs and symptoms including arthritis/arthralgia, rash, fever and lymphadenopathy with an onset 1 to 5 days after the first or subsequent injections of Xolair. These signs and symptoms have recurred after additional doses in some patients. Although circulating immune complexes or a skin biopsy consistent with a Type III reaction were not seen with these cases, these signs and symptoms are similar to those seen in patients with serum sickness. Physicians should stop Xolair if a patient develops this constellation of signs and symptoms [see Adverse Reactions (6.3)].
Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
In a one-year clinical trial conducted in Brazil in adult and adolescent patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have received Xolair than a patient who did not have an infection. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups.
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 patients, because these levels may not reflect steady state free IgE levels [see Dosage and Administration (2.1)].
Use of Xolair has been associated with:
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 to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo.
The adverse events most frequently resulting in clinical intervention (e.g., discontinuation of Xolair, or the need for concomitant medication to treat an adverse event) were injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in Xolair-treated patients and control patients.
Table 5 shows adverse reactions from four placebo-controlled asthma trials that occurred â‰¥ 1% and more frequently in adult and adolescent patients 12 years of age and older receiving Xolair than in those receiving placebo. Adverse events were classified using preferred terms from the International Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately from the reporting of other adverse events.
n = 738
n = 717
|Body as a whole|
|Skin and appendages|
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 [see Warnings and Precautions (5.1), Adverse Reactions (6.3)].
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 â‰¥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 events 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 events were observed at similar rates in Xolair-treated patients and control patients.
Adverse Reactions from Clinical Studies in Patients with Chronic Idiopathic Urticaria (CIU)
The safety of Xolair for the treatment of CIU was assessed in three placebo-controlled, multiple-dose clinical trials of 12 weeks' (CIU Trial 2) and 24 weeks' duration (CIU Trials 1 and 3). In CIU Trials 1 and 2, patients received Xolair 75, 150, or 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy throughout the treatment period. In CIU 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 6 shows adverse reactions that occurred in â‰¥ 2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo. Adverse reactions are pooled from Trial 2 and the first 12 weeks of Trials 1 and 3.
|CIU Trials 1, 2 and 3 Pooled|
|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 Trials 1 and 3 [â‰¥2% of patients receiving Xolair (150 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
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 â‰¥ 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.
Antibodies to Xolair were detected in approximately 1/1723 (< 0.1%) of patients treated with Xolair in the clinical studies evaluated for approval of asthma in patients 12 years of age and older. In three pediatric studies, antibodies to Xolair were detected in one patient out of 581 patients 6 to <12 years of age treated with Xolair and evaluated for antibodies. There were no detectable antibodies in the patients treated in the phase 3 CIU clinical trials, but due to levels of Xolair at the time of anti-therapeutic antibody sampling and missing samples for some patients, antibodies to Xolair could only have been determined in 88% of the 733 patients treated in these clinical studies. The data reflect the percentage of patients whose test results were considered positive for antibodies to Xolair in ELISA assays and are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Xolair with the incidence of antibodies to other products may be misleading.
The following adverse reactions have been identified during post-approval use of Xolair in adult and adolescent patients 12 years of age and older. 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.
The data with XOLAIR use in pregnant women are insufficient to inform on drug associated risk. Monoclonal antibodies, such as omalizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimesters of pregnancy.
In animal reproduction studies, no evidence of fetal harm was observed in Cynomolgus monkeys with subcutaneous doses of omalizumab up to approximately 10 times the maximum recommended human dose (MRHD) [see Animal Data].
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.
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 10 times the MHRD (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 is no information regarding the presence of omalizumab in human milk, the effects on the breastfed infant, or the effects on milk production. However, omalizumab is a human monoclonal antibody (IgG1 kappa), and immunoglobulin (IgG) is present in human milk in small amounts. In Cynomolgus monkeys, neonatal serum levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal serum level. Levels of omalizumab in milk were 0.15% of maternal serum concentration.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Xolair and any potential adverse effects on the breastfed child from omalizumab or from the underlying maternal condition.
Safety and efficacy of Xolair for asthma were evaluated in 2 trials in 926 (Xolair 624; placebo 302) pediatric patients 6 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 1 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) [see Clinical Studies (14.1)].
Safety and efficacy in pediatric patients with asthma below 6 years of age have not been established.
Chronic Idiopathic Urticaria
The safety and effectiveness of Xolair for adolescent patients with CIU were evaluated in 39 patients 12 to 17 years of age (Xolair 29, placebo 10) included in three randomized, placebo-controlled CIU 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 efficacy in pediatric patients with CIU below 12 years of age have not been established.
In clinical studies 134 asthma patients and 37 CIU phase 3 study 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 65 and over is not sufficient to determine whether they respond differently from younger patients.
The maximum tolerated dose of Xolair has not been determined. Single intravenous doses of up to 4,000 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, which was not associated with toxicities.
Xolair is a recombinant DNA-derived humanized IgG1Îº monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of approximately 149 kiloDaltons. Xolair is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.
Xolair is a sterile, white, preservative free, lyophilized powder contained in a single use vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a subcutaneous (SC) injection. Each 202.5 mg vial of omalizumab also contains L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 20 (0.5 mg) and sucrose (145.5 mg) and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.
Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcÎµRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcÎµRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcÎµRI receptors on basophils in atopic patients.
In clinical studies, serum free IgE levels were reduced in a dose dependent manner within 1 hour following the first dose and maintained between doses. Mean serum free IgE decrease was greater than 96% using recommended doses. Serum total IgE levels (i.e., bound and unbound) increased after the first dose due to the formation of omalizumab:IgE complexes, which have a slower elimination rate compared with free IgE. At 16 weeks after the first dose, average serum total IgE levels were five-fold higher compared with pre-treatment when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to one year after discontinuation of Xolair.
Chronic Idiopathic Urticaria
In clinical studies in CIU patients, Xolair treatment led to a dose-dependent reduction of serum free IgE and an increase of serum total IgE levels, similar to the observations in asthma patients. Maximum suppression of free IgE was observed 3 days following the first subcutaneous dose. After repeat dosing once every 4 weeks, predose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the first dose due to the formation of omalizumab-IgE complexes which have a slower elimination rate compared with free IgE. After repeat dosing once every 4 weeks at 75 mg up to 300 mg, average predose serum total IgE levels at Week 12 were two-to three-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair dosing, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week follow-up period.
After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses greater than 0.5 mg/kg. In patients with asthma, following multiple doses of Xolair, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose. In patients with CIU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels.
In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CIU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma.
Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with FcÎ³ receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CIU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with asthma. Analyses of these data suggested that no dose adjustments are necessary for age (6-76 years), race, ethnicity, or gender.
Chronic Idiopathic Urticaria
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with CIU. Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index or baseline IgE level.
No long-term studies have been performed in animals to evaluate the carcinogenic potential of Xolair.
There were no effects on fertility and reproductive performance in male and female Cynomolgus monkeys that received Xolair at subcutaneous doses up to 75 mg/kg/week (approximately 10 times the maximum recommended human dose on a mg/kg basis).
Adult and Adolescent Patients 12 Years of Age and Older
The safety and efficacy of Xolair were evaluated in three randomized, double-blind, placebo-controlled, multicenter trials.
The trials enrolled patients 12 to 76 years old, with moderate to severe persistent (NHLBI criteria) asthma for at least one year, and a positive skin test reaction to a perennial aeroallergen. In all trials, Xolair dosing was based on body weight and baseline serum total IgE concentration. All patients were required to have a baseline IgE between 30 and 700 IU/mL and body weight not more than 150 kg. Patients were treated according to a dosing table to administer at least 0.016 mg/kg/IU (IgE/mL) of Xolair or a matching volume of placebo over each 4-week period. The maximum Xolair dose per 4 weeks was 750 mg.
In all three trials an exacerbation was defined as a worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose. Most exacerbations were managed in the out-patient setting and the majority were treated with systemic steroids. Hospitalization rates were not significantly different between Xolair and placebo-treated patients; however, the overall hospitalization rate was small. Among those patients who experienced an exacerbation, the distribution of exacerbation severity was similar between treatment groups.
Asthma Trials 1 and 2
At screening, patients in Asthma Trials 1 and 2 had a forced expiratory volume in one second (FEV1) between 40% and 80% predicted. All patients had a FEV1 improvement of at least 12% following beta2-agonist administration. All patients were symptomatic and were being treated with inhaled corticosteroids (ICS) and short acting beta2-agonists. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
Each trial was comprised of a run-in period to achieve a stable conversion to a common ICS (beclomethasone dipropionate), followed by randomization to Xolair or placebo. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 12 weeks during which ICS dose reduction was attempted in a step-wise manner.
The distribution of the number of asthma exacerbations per patient in each group during a study was analyzed separately for the stable steroid and steroid-reduction periods.
In both Asthma Trials 1 and 2 the number of exacerbations per patient was reduced in patients treated with Xolair compared with placebo (Table 7).
Measures of airflow (FEV1) and asthma symptoms were also evaluated in these trials. The clinical relevance of the treatment-associated differences is unknown. Results from the stable steroid phase Asthma Trial 1 are shown in Table 8. Results from the stable steroid phase of Asthma Trial 2 and the steroid reduction phases of both Asthma Trials 1 and 2 were similar to those presented in Table 8.
|Stable Steroid Phase (16 wks)|
|Asthma Trial 1||Asthma Trial 2|
|Exacerbations per patient||Xolair
N = 268
N = 257
N = 274
N = 272
|Mean number exacerbations/patient||0.2||0.3||0.1||0.4|
|Steroid Reduction Phase (12 wks)|
|Exacerbations per patient|| Xolair
N = 268
N = 257
N = 274
N = 272
|Mean number exacerbations/patient||0.2||0.4||0.2||0.3|
|Asthma symptom scale: total score from 0 (least) to 9 (most); nocturnal and daytime scores from 0 (least) to 4 (most symptoms).|
N = 268*
N = 257*
|Endpoint||Mean Baseline||Median Change
(Baseline to Wk 16)
|Mean Baseline||Median Change
(Baseline to Wk 16)
|Total asthma symptom score||4.3||â€“1.5â€||4.2||â€“1.1â€|
|Nocturnal asthma score||1.2||â€“0.4â€||1.1||â€“0.2â€|
|Daytime asthma score||2.3||â€“0.9â€||2.3||â€“0.6â€|
|FEV1 % predicted||68||3â€||68||0â€|
Asthma Trial 3
In Asthma Trial 3, there was no restriction on screening FEV1, and unlike Asthma Trials 1 and 2, long-acting beta2-agonists were allowed. Patients were receiving at least 1000 µg/day fluticasone propionate and a subset was also receiving oral corticosteroids. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
The trial was comprised of a run-in period to achieve a stable conversion to a common ICS (fluticasone propionate), followed by randomization to Xolair or placebo. Patients were stratified by use of ICS-only or ICS with concomitant use of oral steroids. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 16 weeks during which ICS or oral steroid dose reduction was attempted in a step-wise manner.
The number of exacerbations in patients treated with Xolair was similar to that in placebo-treated patients (Table 9). The absence of an observed treatment effect may be related to differences in the patient population compared with Asthma Trials 1 and 2, study sample size, or other factors.
|Stable Steroid Phase (16 wks)|
|Inhaled Only||Oral + Inhaled|
N = 126
N = 120
N = 50
N = 45
|% Patients with â‰¥ 1 exacerbations||15.9%||15.0%||32.0%||22.2%|
|Steroid Reduction Phase (16 wks)|
N = 126
N = 120
N = 50
N = 45
|% Patients with â‰¥ 1 exacerbations||22.2%||26.7%||42.0%||42.2%|
In all three of the trials, a reduction of asthma exacerbations was not observed in the Xolair-treated patients who had FEV1 > 80% at the time of randomization. Reductions in exacerbations were not seen in patients who required oral steroids as maintenance therapy.
Pediatric Patients 6 to < 12 Years of Age
The safety and efficacy of Xolair in pediatric patients 6 to <12 years of age with moderate to severe asthma is based on one randomized, double-blind, placebo controlled, multi-center trial (Trial 4) and an additional supportive study (Trial 5).
Trial 4 was a 52-week study that evaluated the safety and efficacy of Xolair as add-on therapy in 628 pediatric patients ages 6 to <12 years with moderate to severe asthma inadequately controlled despite the use of inhaled corticosteroids (fluticasone propionate DPI â‰¥200 mcg/day or equivalent) with or without other controller asthma medications. Eligible patients were those with a diagnosis of asthma >1 year, a positive skin prick test to at least one perennial aeroallergen, and a history of clinical features such as daytime and/or night-time symptoms and exacerbations within the year prior to study entry. During the first 24 weeks of treatment, steroid doses remained constant from baseline. This was followed by a 28-week period during which inhaled corticosteroid adjustment was allowed.
The primary efficacy variable was the rate of asthma exacerbations during the 24-week, fixed steroid treatment phase. An asthma exacerbation was defined as a worsening of asthma symptoms as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose for at least 3 days and/or treatment with rescue systemic (oral or IV) corticosteroids for at least 3 days. At 24 weeks, the Xolair group had a statistically significantly lower rate of asthma exacerbations (0.45 vs. 0.64) with an estimated rate ratio of 0.69 (95% CI: 0.53, 0.90).
The Xolair group also had a lower rate of asthma exacerbations compared to placebo over the full 52-week double-blind treatment period (0.78 vs. 1.36; rate ratio: 0.57; 95% CI: 0.45, 0.72). Other efficacy variables such as nocturnal symptom scores, beta-agonist use, and measures of airflow (FEV1) were not significantly different in Xolair-treated patients compared to placebo.
Trial 5 was a 28-week randomized, double blind, placebo-controlled study that primarily evaluated safety in 334 pediatric patients, 298 of whom were 6 to <12 years of age, with moderate to severe asthma who were well-controlled with inhaled corticosteroids (beclomethasone dipropionate 168-420 mcg/day). A 16-week steroid treatment period was followed by a 12-week steroid dose reduction period. Patients treated with Xolair had fewer asthma exacerbations compared to placebo during both the 16-week fixed steroid treatment period (0.18 vs. 0.32; rate ratio: 0.58; 95% CI: 0.35, 0.96) and the 28-week treatment period (0.38 vs. 0.76; rate ratio: 0.50; 95% CI: 0.36, 0.71).
Adult and Adolescent Patients 12 Years of Age and Older
The safety and efficacy of Xolair for the treatment of CIU was assessed in two placebo-controlled, multiple-dose clinical trials of 24 weeks' duration (CIU Trial 1; n= 319) and 12 weeks' duration (CIU Trial 2; n=322). Patients received Xolair 75, 150, or 300 mg or placebo by SC injection every 4 weeks in addition to their baseline level of H1 antihistamine therapy for 24 or 12 weeks, followed by a 16-week washout observation period. A total of 640 patients (165 males, 475 females) were included for the efficacy analyses. Most patients were white (84%) and the median age was 42 years (range 12â€“72).
Disease severity was measured by a weekly urticaria activity score (UAS7, range 0â€“42), which is a composite of the weekly itch severity score (range 0â€“21) and the weekly hive count score (range 0â€“21). All patients were required to have a UAS7 of â‰¥ 16, and a weekly itch severity score of â‰¥ 8 for the 7 days prior to randomization, despite having used an H1 antihistamine for at least 2 weeks.
The mean weekly itch severity scores at baseline were fairly balanced across treatment groups and ranged between 13.7 and 14.5 despite use of an H1 antihistamine at an approved dose. The reported median durations of CIU at enrollment across treatment groups were between 2.5 and 3.9 years (with an overall subject-level range of 0.5 to 66.4 years).
In both CIU Trials 1 and 2, patients who received Xolair 150 mg or 300 mg had greater decreases from baseline in weekly itch severity scores and weekly hive count scores than placebo at Week 12. Representative results from CIU Trial 1 are shown (Table 10); similar results were observed in CIU Trial 2. The 75-mg dose did not demonstrate consistent evidence of efficacy and is not approved for use.
|Weekly Itch Severity Score|
|Mean Baseline Score (SD)||14.5 (3.6)||14.1 (3.8)||14.2 (3.3)||14.4 (3.5)|
|Mean Change Week 12(SD)||-6.46 (6.14)||-6.66 (6.28)||-9.40 (5.73)||-3.63 (5.22)|
|Difference in LS means vs. placebo||-2.96||-2.95||-5.80|
|95% CI for difference||â€“4.71, â€“1.21||â€“4.72, â€“1.18||â€“7.49, â€“4.10||-|
|Weekly Hive Count Score â€|
|Mean Baseline Score (SD)||17.2 (4.2)||16.2 (4.6)||17.1 (3.8)||16.7 (4.4)|
|Mean Change Week 12(SD)||-7.36 (7.52)||-7.78 (7.08)||-11.35 (7.25)||-4.37 (6.60)|
|Difference in LS means vs. placebo||-2.75||-3.44||-6.93|
|95% CI for difference||â€“4.95, â€“0.54||â€“5.57, â€“1.32||â€“9.10, â€“4.76||-|
The mean weekly itch severity score at each study week by treatment groups is shown in Figure 1. Representative results from CIU Trial 1 are shown; similar results were observed in CIU Trial 2. The appropriate duration of therapy for CIU with Xolair has not been determined.
In CIU Trial 1, a larger proportion of patients treated with Xolair 300 mg (36%) reported no itch and no hives (UAS7=0) at Week 12 compared to patients treated with Xolair 150 mg (15%), Xolair 75 mg (12%), and placebo group (9%). Similar results were observed in CIU Trial 2.
Xolair is supplied as a lyophilized, sterile powder in a single-use vial without preservatives. Each vial delivers 150 mg of Xolair upon reconstitution with 1.4 mL SWFI, USP. Each carton contains one single-use vial of Xolair® (omalizumab) NDC 50242-040-62.
Xolair should be shipped at controlled ambient temperature (â‰¤ 30°C [ â‰¤ 86°F]). Store Xolair under refrigerated conditions 2 to 8°C (36 to 46°F). Do not use beyond the expiration date stamped on carton.
Use the solution for subcutaneous administration within 8 hours following reconstitution when stored in the vial at 2 to 8°C (36 to 46°F), or within 4 hours of reconstitution when stored at room temperature.
Reconstituted Xolair vials should be protected from direct sunlight.
Information for Patients
Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment. The complete text of the Medication Guide is reprinted at the end of this document.
Instruct patients receiving Xolair not to decrease the dose of, or stop taking any other asthma or CIU medications unless otherwise instructed by their physician. Inform patients that they may not see immediate improvement in their asthma or CIU symptoms after beginning Xolair therapy.
|This Medication Guide has been approved by the U.S. Food and Drug Administration||Revised:6/2017|
injection, for subcutaneous use
XOLAIR may cause serious side effects, including:
Severe allergic reaction. A severe allergic reaction called anaphylaxis can happen when you receive XOLAIR. The reaction can occur after the first dose, or after many doses. It may also occur right after a XOLAIR injection or days later. Anaphylaxis is a life-threatening condition and can lead to death. Go to the nearest emergency room right away if you have any of these symptoms of an allergic reaction:
Your healthcare provider will monitor you closely for symptoms of an allergic reaction while you are receiving XOLAIR and for a period of time after your injection. Your healthcare provider should talk to you about getting medical treatment if you have symptoms of an allergic reaction after leaving the healthcare provider's office or treatment center.
What is XOLAIR?
XOLAIR is an injectable prescription medicine used to treat:
XOLAIR is not used to treat other allergic conditions, other forms of urticaria, acute bronchospasm or status asthmaticus.
Who should not receive XOLAIR?
Do not receive XOLAIR if you:
What should I tell my healthcare provider before receiving XOLAIR?
Before receiving XOLAIR, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.
How should I receive XOLAIR?
What are the possible side effects of XOLAIR?
XOLAIR may cause serious side effects, including:
The most common side effects of XOLAIR:
These are not all the possible side effects of XOLAIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of XOLAIR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information, talk to your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about XOLAIR that is written for health professionals. Do not use XOLAIR for a condition for which it was not prescribed.
For more information, go to www.xolair.com or call 1-866-4XOLAIR (1-866-496-5247).
What are the ingredients in XOLAIR?
Active ingredient: omalizumab
Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20 and sucrose
Manufactured by: Genentech, Inc. A Member of the Roche Group. 1 DNA Way, South San Francisco, CA 94080-4990.
Jointly marketed by:
Genentech USA, Inc. A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080
Xolair® is a registered trademark of Novartis AG. ©2017 Genentech USA, Inc.
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):
omalizumab injection, solution
|Labeler - Genentech, Inc. (080129000)|
|Genentech, Inc. (SSF)||080129000||ANALYSIS(50242-040) , MANUFACTURE(50242-040)|
|Genentech, Inc. (Vacaville)||004074162||API MANUFACTURE(50242-040) , ANALYSIS(50242-040)|
|Novartis Pharma S.A.S. - Centre de Biotechnologie||263159719||API MANUFACTURE(50242-040) , ANALYSIS(50242-040)|
|Novartis Pharma Stein AG||488152505||ANALYSIS(50242-040) , MANUFACTURE(50242-040)|
|Genentech, Inc. (Hillsboro)||833220176||PACK(50242-040) , LABEL(50242-040)|