Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock, may occur when taking omalizumab, even after a long duration of treatment. However, most of these reactions occurred within 2 hours after the first and subsequent injections of omalizumab but some started beyond 2 hours and even beyond 24 hours after the injection. The majority of anaphylactic reactions occurred within the first 3 doses of omalizumab. Therefore, the first 3 doses must be administered either by or under the supervision of a healthcare professional. A history of anaphylaxis unrelated to omalizumab may be a risk factor for anaphylaxis following omalizumab administration. Therefore for patients with a known history of anaphylaxis, omalizumab must be administered by a health care professional, who should always have medicinal products for the treatment of anaphylactic reactions available for immediate use following administration of omalizumab. If an anaphylactic or other serious allergic reaction occurs, administration of omalizumab must be discontinued immediately and appropriate therapy initiated. Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur.

Antibodies to omalizumab have been detected in a low number of patients in clinical trials. The clinical relevance of anti-omalizumab antibodies is not well understood.

IgE may be involved in the immunological response to some helminth infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial in allergic patients showed a slight increase in infection rate with omalizumab, although the course, severity, and response to treatment of infection were unaltered. The helminth infection rate in the overall clinical programme, which was not designed to detect such infections, was less than 1 in 1,000 patients. However, caution may be warranted in patients at high risk of helminth infection, in particular when travelling to areas where helminthic infections are endemic. If patients do not respond to recommended anti-helminth treatment, discontinuation of omalizumab should be considered.

Serum sickness and serum sickness-like reactions, which are delayed allergic type III reactions, have been seen in patients treated with humanised monoclonal antibodies including omalizumab. The suggested pathophysiologic mechanism includes immune-complex formation and deposition due to development of antibodies against omalizumab. The onset has typically been 1-5 days after administration of the first or subsequent injections, also after long duration of treatment. Symptoms suggestive of serum sickness include arthritis/arthralgias, rash (urticaria or other forms), fever and lymphadenopathy. Antihistamines and corticosteroids may be useful for preventing or treating this disorder, and patients should be advised to report any suspected symptoms.

Patients with severe asthma may rarely present systemic hypereosinophilic syndrome or allergic eosinophilic granulomatous vasculitis (Churg-Strauss syndrome), both of which are usually treated with systemic corticosteroids.

In rare cases, patients on therapy with anti-asthma medicinal products, including omalizumab, may present or develop systemic eosinophilia and vasculitis. These events are commonly associated with the reduction of oral corticosteroid therapy.

In these patients, physicians should be alert to the development of marked eosinophilia, vasculitic rash, worsening pulmonary symptoms, paranasal sinus abnormalities, cardiac complications, and/or neuropathy.

Discontinuation of omalizumab should be considered in all severe cases with the above mentioned immune system disorders.

A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) based on pregnancy registry and post-marketing spontaneous reports, indicates no malformative or foeto/neonatal toxicity. A prospective pregnancy registry study (EXPECT) in 250 pregnant women with asthma exposed to omalizumab showed the prevalence of major congenital anomalies was similar (8.1% vs. 8.9%) between EXPECT and disease-matched (moderate and severe asthma) patients. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomised design.

Omalizumab crosses the placental barrier. However, animal studies do not indicate either direct or indirect harmful effects with respect to reproductive toxicity.

Omalizumab has been associated with age-dependent decreases in blood platelets in non-human primates, with a greater relative sensitivity in juvenile animals.

If clinically needed, the use of omalizumab may be considered during pregnancy.

Immunoglobulins G (IgGs) are present in human milk and therefore it is expected that omalizumab will be present in human milk. Available data in non-human primates have shown excretion of omalizumab into milk.

The EXPECT study, with 154 infants who had been exposed to omalizumab during pregnancy and through breast-feeding did not indicate adverse effects on the breast-fed infant. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomised design.

Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No effects on the breast-fed newborns/infants are anticipated. Consequently, if clinically needed, the use of omalizumab may be considered during breast-feeding.

Fertility

There are no human fertility data for omalizumab. In specifically-designed non-clinical fertility studies, in non-human primates including mating studies, no impairment of male or female fertility was observed following repeated dosing with omalizumab at dose levels up to 75 mg/kg. Furthermore, no genotoxic effects were observed in a separate non-clinical genotoxicity study.

Omalizumab has no or negligible influence on the ability to drive and use machines.

Allergic asthma

Summary of the safety profile

During clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were headaches and injection site reactions, including injection site pain, swelling, erythema and pruritus. In clinical trials in children 6 to <12 years of age, the most commonly reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.

List of adverse reactions

The adverse reactions recorded in clinical studies in the total safety population treated with omalizumab are listed below by MedDRA system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Reactions reported in the post-marketing setting are listed with frequency not known (cannot be estimated from the available data).

Infections and infestations

Uncommon: Pharyngitis

Rare: Parasitic infection

Blood and lymphatic system disorders

Not known: Idiopathic thrombocytopenia, including severe cases

Immune system disorders

Rare: Anaphylactic reaction, other serious allergic conditions, anti-omalizumab antibody development

Not known: Serum sickness, may include fever and lymphadenopathy

Nervous system disorders

Common: Headache*

Uncommon: Syncope, paraesthesia, somnolence, dizziness

Vascular disorders

Uncommon: Postural hypotension, flushing

Respiratory, thoracic and mediastinal disorders

Uncommon: Allergic bronchospasm, coughing

Rare: Laryngoedema

Not known: Allergic granulomatous vasculitis (i.e. Churg-Strauss syndrome)

Gastrointestinal disorders

Common: Abdominal pain upper**

Uncommon: Dyspeptic signs and symptoms, diarrhoea, nausea

Skin and subcutaneous tissue disorders

Uncommon: Photosensitivity, urticaria, rash, pruritus

Rare: Angioedema

Not known: Alopecia

Musculoskeletal and connective tissue disorders

Rare: Systemic lupus erythematosus (SLE)

Not known: Arthralgia, myalgia, joint swelling

General disorders and administration site conditions

Very common: Pyrexia**

Common: Injection site reactions such as swelling, erythema, pain, pruritus

Uncommon: Influenza-like illness, swelling arms, weight increase, fatigue

* Very common in children 6 to <12 years of age
** In children 6 to <12 years of age

Chronic spontaneous urticaria (CSU)

Summary of the safety profile

The safety and tolerability of omalizumab were investigated with doses of 75 mg, 150 mg and 300 mg every four weeks in 975 CSU patients, 242 of whom received placebo. Overall, 733 patients were treated with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. Of those, 412 patients were treated for up to 12 weeks and 333 patients were treated for up to 24 weeks at the 300 mg dose.

Tabulated list of adverse reactions

A separate table shows the adverse reactions for the CSU indication resulting from differences in dosages and treatment populations (with significantly different risk factors, comorbidities, co-medications and ages [e.g. asthma trials included children from 6-12 years of age]).

The table below lists the adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any omalizumab treatment group than with placebo (after medical review)) reported with 300 mg in the three pooled phase III studies. The adverse reactions presented are divided into two groups: those identified in the 12-week and the 24-week treatment periods.

The adverse reactions are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions listed first. The corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Adverse reactions from the pooled CSU safety database (day 1 to week 24) at 300 mg omalizumab:

* Despite not showing a 2% difference to placebo, injection site reactions were included as all cases were assessed causally related to study treatment.

Description of selected adverse reactions pertinent to allergic asthma and CSU indications

No relevant data was obtained in clinical studies in CSU that would require a modification of the sections below.

Anaphylaxis

Anaphylactic reactions were rare in clinical trials. However, post-marketing data following a cumulative search in the safety database retrieved a total of 898 anaphylaxis cases. Based on an estimated exposure of 566,923 patient treatment years, this results in a reporting rate of approximately 0.20%.

Arterial thromboembolic events (ATE)

In controlled clinical trials and during interim analyses of an observational study, a numerical imbalance of ATE was observed. The definition of the composite endpoint ATE included stroke, transient ischaemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the rate of ATE per 1,000 patient years was 7.52 (115/15,286 patient years) for omalizumab-treated patients and 5.12 (51/9,963 patient years) for control patients. In a multivariate analysis controlling for available baseline cardiovascular risk factors, the hazard ratio was 1.32 (95% confidence interval 0.91-1.91). In a separate analysis of pooled clinical trials, which included all randomised double-blind, placebo-controlled clinical trials lasting 8 or more weeks, the rate of ATE per 1,000 patient years was 2.69 (5/1,856 patient years) for omalizumab-treated patients and 2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24-5.71).

Platelets

In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates, has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia, including severe cases, have been reported in the post-marketing setting.

Parasitic infections

In allergic patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight numerical increase in infection rate with omalizumab that was not statistically significant. The course, severity, and response to treatment of infections were unaltered.

Systemic lupus erythematosus

Clinical trial and post-marketing cases of systemic lupus erythematosus (SLE) have been reported in patients with moderate to severe asthma and CSU. The pathogenesis of SLE is not well understood.