4.1. Therapeutic indications

Allergic asthma

Omlyclo is indicated in adults, adolescents and children (6 to < 12 years of age).

Omlyclo treatment should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma (see section 4.2).

Adults and adolescents (12 years of age and older)

Omlyclo is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (FEV1 < 80 %) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

Children (6 to < 12 years of age)

Omlyclo is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

Omlyclo is indicated as an add-on therapy with intranasal corticosteroids (INC) for the treatment of adults (18 years and above) with severe CRSwNP for whom therapy with INC does not provide adequate disease control.

Chronic spontaneous urticaria (CSU)

Omlyclo is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment.

4.2. Posology and method of administration

Treatment should be initiated by physicians experienced in the diagnosis and treatment of severe persistent asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) or chronic spontaneous urticaria.

Posology

Allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP)

Dosing for allergic asthma and CRSwNP follows the same dosing principles. The appropriate dose and frequency of omalizumab for these conditions is determined by baseline IgE (IU/ml), measured before the start of treatment, and body weight (kg). Prior to administration of the initial dose, patients should have their IgE level determined by any commercial serum total IgE assay for their dose assignment. Based on these measurements, 75 to 600 mg of omalizumab in 1 to 4 injections may be needed for each administration.

Allergic asthma patients with baseline IgE lower than 76 IU/ml were less likely to experience benefit (see section 5.1). Prescribing physicians should ensure that adult and adolescent patients with IgE below 76 IU/ml and children (6 to < 12 years of age) with IgE below 200 IU/ml have unequivocal in vitro reactivity (RAST) to a perennial allergen before starting therapy.

See Table 1 for a conversion chart and Tables 2 and 3 for the dose determination charts.

Patients whose baseline IgE levels or body weight in kilograms are outside the limits of the dose table should not be given omalizumab.

The maximum recommended dose is 600 mg omalizumab every two weeks.

Table 1 Conversion from dose to number of pre-filled pens*, number of injections** and total injection volume for each administration

Dose (mg)

Number of pens*

Number of injections

Total injection volume (ml)

75 mg

150 mg

75

1

0

1

0.5

150

0

1

1

1.0

225

1

1

2

1.5

300

0

2

2

2.0

375

1

2

3

2.5

450

0

3

3

3.0

525

1

3

4

3.5

600

0

4

4

4.0

*All dose strengths of Omlyclo pre-filled pen are not intended for use in patients <12 years of age.

**This table represents the least number of injections for the patients, however there are other pen dosing combinations possible to achieve the desired dose.

Table 2 ADMINISTRATION EVERY 4 WEEKS. Omalizumab doses (milligrams per dose) administered by subcutaneous injection every 4 weeks

Table 3 ADMINSTRATION EVERY 2 WEEKS. Omalizumab doses (milligrams per dose) administered by subcutaneous injection every 2 weeks

Treatment duration, monitoring and dose adjustments

Allergic asthma

Omlyclo is intended for long-term treatment. Clinical trials have demonstrated that it takes at least 12 – 16 weeks for the treatment to show effectiveness. At 16 weeks after commencing Omlyclo therapy patients should be assessed by their physician for treatment effectiveness before further injections are administered. The decision to continue treatment following the 16‑week timepoint, or on subsequent occasions, should be based on whether a marked improvement in overall asthma control is seen (see section 5.1, Physician's overall assessment of treatment effectiveness).

Chronic rhinosinusitis with nasal polyps (CRSwNP)

In clinical trials for CRSwNP, changes in nasal polyps score (NPS) and nasal congestion score (NCS) were observed at 4 weeks. The need for continued therapy should be periodically reassessed based upon the patient's disease severity and level of symptom control.

Allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP)

Discontinuation of treatment generally results in a return to elevated free IgE levels and associated symptoms. 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 treatment cannot be used as a guide for dose determination. Dose determination after treatment interruptions lasting less than one year should be based on serum IgE levels obtained at the initial dose determination. Total serum IgE levels may be re-tested for dose determination if treatment has been interrupted for one year or more.

Doses should be adjusted for significant changes in body weight (see Tables 2 and 3).

Chronic spontaneous urticaria (CSU)

The recommended dose is 300 mg by subcutaneous injection every four weeks. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

Prescribers are advised to periodically reassess the need for continued therapy.

Clinical trial experience of long-term treatment in this indication is described in section 5.1.

Special populations

Elderly (65 years of age and older)

There are limited data available on the use of omalizumab in patients older than 65 years but there is no evidence that elderly patients require a different dose from younger adult patients.

Renal or hepatic impairment

There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. Because omalizumab clearance at clinical doses is dominated by the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended for these patients, omalizumab should be administered with caution (see section 4.4).

Paediatric population

In allergic asthma, the safety and efficacy of omalizumab in patients below the age of 6 years have not been established. No data are available.

In CRSwNP, the safety and efficacy of omalizumab in patients below the age of 18 years have not been established. No data are available.

In CSU, the safety and efficacy of omalizumab in patients below the age of 12 years have not been established. No data are available.

Method of administration

For subcutaneous administration only. Omalizumab must not be administered by the intravenous or intramuscular route.

All dose strengths of Omlyclo pre-filled pen are not intended for use in children <12 years of age. Omlyclo 75 mg pre-filled syringe and Omlyclo 150 mg pre-filled syringe may be used in children 6 to 11 years of age with allergic asthma.

If more than one injection is needed to achieve the required dose, injections should be divided across two or more injection sites (Table 1).

Patients with no known history of anaphylaxis may self-inject Omlyclo or be injected by a caregiver from the 4th dose onwards if a physician determines that this is appropriate (see section 4.4). The patient or the caregiver must have been trained in the correct injection technique and the recognition of the early signs and symptoms of serious allergic reactions.

Patients or caregivers should be instructed to inject the full amount of Omlyclo according to the instructions provided in the package leaflet.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 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.

Excipient with known effect

This medicine contains 0.40 mg of polysorbate 20 (E 432) in each pre-filled pen, which is equivalent to 0.40 mg/ml. Polysorbates may cause allergic reactions. Patients with polysorbate allergy should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

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 drug-drug 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, CRSwNP or CSU 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 anesthetics. There was no indication that the safety of omalizumab was altered by the concomitant use of these other commonly used medicinal products.

Chronic spontaneous urticaria (CSU)

In clinical studies in CSU, omalizumab was used in conjunction with antihistamines (anti-H1, anti-H2) and leukotriene receptor antagonists (LTRAs). There was no evidence that the safety of omalizumab was altered when used with these medicinal products relative to its known safety profile in allergic asthma. In addition, a population pharmacokinetic analysis showed no relevant effect of H2 antihistamines and LTRAs on omalizumab pharmacokinetics (see section 5.2).

Paediatric population

Clinical studies in CSU included some patients aged 12 to 17 years taking omalizumab in conjunction with antihistamines (anti-H1, anti-H2) and LTRAs. No studies have been performed in children under 12 years.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 omalizumab 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

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

Common

Arthralgia†

Rare

Systemic lupus erythematosus (SLE)

Not known

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

#: Common in nasal polyp trials

†: Unknown in allergic asthma trials

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 (Table 5) 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]).

Table 5 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).

Table 5 Adverse reactions from the pooled CSU safety database (day 1 to week 24) at 300 mg omalizumab

12‑Week

Omalizumab studies 1, 2 and 3 Pooled

Frequency category

Placebo N = 242

300 mg N = 412

Infections and infestations

Sinusitis

5 (2.1 %)

20 (4.9 %)

Common

Nervous system disorders

Headache

7 (2.9 %)

25 (6.1 %)

Common

Musculoskeletal and connective tissue disorders

Arthralgia

1 (0.4 %)

12 (2.9 %)

Common

General disorder and administration site conditions

Injection site reaction*

2 (0.8 %)

11 (2.7 %)

Common

24‑Week

Omalizumab studies 1 and 3 Pooled

Frequency category

Placebo N = 163

300 mg N = 333

Infections and infestations

Upper respiratory tract infection

5 (3.1 %)

19 (5.7 %)

Common

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

In a 48‑week study, 81 CSU patients received omalizumab 300 mg every 4 weeks (see section 5.1). The safety profile of long-term use was similar to the safety profile observed in 24‑week studies in CSU.

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 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. 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 (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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Maximum tolerated dose of Omlyclo has not been determined. Single intravenous doses 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 and this dose did not result in any untoward acute effects.

If an overdose is suspected, the patient should be monitored for any abnormal signs or symptoms. Medical treatment should be sought and instituted appropriately.