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 7 shows adverse reactions from four placebo-controlled asthma trials that occurred ≥1% and more frequently in adult and adolescent patients 12 years of age and older receiving 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.

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 8 lists 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.

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 9 are 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 9 lists 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.

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 10 shows 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.

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.