XOLAIR 75 mg Solution for injection Ref.[7999] Active ingredients: Omalizumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General

Omalizumab is not indicated for the treatment of acute asthma exacerbations, acute bronchospasm or status asthmaticus.

Omalizumab has not been studied in patients with hyperimmunoglobulin E syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions, including those provoked by food allergy, atopic dermatitis, or allergic rhinitis. Omalizumab is not indicated for the treatment of these conditions.

Omalizumab therapy has not been studied in patients with autoimmune diseases, immune complex-mediated conditions, or pre-existing renal or hepatic impairment (see section 4.2). Caution should be exercised when administering omalizumab in these patient populations.

Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of omalizumab therapy in allergic asthma or CRSwNP is not recommended. Decreases in corticosteroids should be performed under the direct supervision of a physician and may need to be performed gradually.

Immune system disorders

Allergic reactions type I

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 (see section 4.8). The clinical relevance of anti-omalizumab antibodies is not well understood.

Serum sickness

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.

Churg-Strauss syndrome and hypereosinophilic syndrome

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.

Parasitic (helminth) infections

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 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.

Latex-sensitive individuals (pre-filled syringe)

The removable needle cap of the pre-filled syringe contains a derivative of natural rubber latex. No natural rubber latex has to date been detected in the removable needle cap. Nevertheless, the use of Xolair solution for injection in pre-filled syringe in latex-sensitive individuals has not been studied and thus there is a potential risk for hypersensitivity reactions which cannot be completely ruled out.

Since IgE may be involved in the immunological response to some helminth infections, omalizumab may indirectly reduce the efficacy of medicinal products for the treatment of helminthic or other parasitic infections (see section 4.4).

Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of omalizumab; thus, there is little potential for interactions. Medicinal product or vaccine interaction studies have not been performed with omalizumab. There is no pharmacological reason to expect that commonly prescribed medicinal products used in the treatment of asthma or CRSwNP will interact with omalizumab.

Allergic asthma

In clinical studies omalizumab was commonly used in conjunction with inhaled and oral corticosteroids, inhaled short-acting and long-acting beta agonists, leukotriene modifiers, theophyllines and oral antihistamines. There was no indication that the safety of omalizumab was altered with these other commonly used anti-asthma medicinal products. Limited data are available on the use of omalizumab in combination with specific immunotherapy (hypo-sensitisation therapy). In a clinical trial where omalizumab was co-administered with immunotherapy, the safety and efficacy of omalizumab in combination with specific immunotherapy were found to be no different to that of omalizumab alone.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

In clinical studies omalizumab was used in conjunction with intranasal mometasone spray as per protocol. Other commonly used concomitant medicinal products included other intranasal corticosteroids, bronchodilators, antihistamines, leukotriene receptor antagonists, adrenergics/sympathomimetics and local nasal anaesthetics. There was no indication that the safety of omalizumab was altered by the concomitant use of these other commonly used medicinal products.

Pregnancy

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 (see section 5.3).

Omalizumab has been associated with age-dependent decreases in blood platelets in non-human primates, with a greater relative sensitivity in juvenile animals (see section 5.3).

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

Breast-feeding

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 (see section 5.3).

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 and chronic rhinosinusitis with nasal polyps (CRSwNP)

Summary of the safety profile

During allergic asthma 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. In clinical trials in patients ≥18 years of age in CRSwNP, the most commonly reported adverse reactions were headache, dizziness, arthralgia, abdominal pain upper and injection site reactions.

Tabulated list of adverse reactions

Table 4 lists the adverse reactions recorded in clinical studies in the total allergic asthma and CRSwNP safety population treated with Xolair 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).

Table 4. Adverse reactions in allergic asthma and CRSwNP:

^* Very common in children 6 to <12 years of age
^** In children 6 to <12 years of age
^# Common in nasal polyp trials
^† Unknown in allergic asthma trials

Description of selected adverse reactions

Immune system disorders

For further information, see section 4.4.

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 Xolair-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 Xolair-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. Isolated cases of idiopathic thrombocytopenia, including severe cases, have been reported in the post-marketing setting.

Parasitic infections

In 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 (see section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products.