XOLAIR 75mg powder + solvent for injection medication leaflet

Xolair 75 mg powder and solvent for solution for injection

One vial contains 75 mg of omalizumab*.

After reconstitution one vial contains 125 mg/ml of omalizumab (75 mg in 0.6 ml).

*Omalizumab is a humanised monoclonal antibody produced in a Chinese hamster ovary (CHO)mammalian cell line by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection

Powder: white to off-white lyophilisate

Solvent: clear and colourless solution

Allergic asthma

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

Xolair 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)

Xolair is indicated as add-on therapy to improve asthma control in patients with severe persistentallergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whohave reduced lung function (FEV1 <80%) as well as frequent daytime symptoms or night-timeawakenings 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)

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

Chronic rhinosinusitis with nasal polyps (CRSwNP)

Xolair is indicated as an add-on therapy with intranasal corticosteroids (INC) for the treatment ofadults (18 years and above) with severe CRSwNP for whom therapy with INC does not provideadequate disease control.

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

Dosing for allergic asthma and CRSwNP follows the same dosing principles. The appropriate doseand frequency of omalizumab for these conditions is determined by baseline IgE (IU/ml), measuredbefore the start of treatment, and body weight (kg). Prior to administration of the initial dose, patientsshould have their IgE level determined by any commercial serum total IgE assay for their doseassignment. Based on these measurements, 75 to 600 mg of omalizumab in 1 to 4 injections may beneeded 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 IgEbelow 76 IU/ml and children (6 to < 12 years of age) with IgE below 200 IU/ml have unequivocal invitro 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 tableshould not be given omalizumab.

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

Table 1 Conversion from dose to number of vials, number of injections and total injectionvolume for each administration

Dose (mg) Number of vials Number of injections Total injection volume (ml)75 mg a 150 mg b75 1c 0 1 0.6150 0 1 1 1.2225 1c 1 2 1.8300 0 2 2 2.4375 1c 2 3 3.0450 0 3 3 3.6525 1c 3 4 4.2600 0 4 4 4.8a 0.6 ml = maximum delivered volume per vial (Xolair 75 mg).b 1.2 ml = maximum delivered volume per vial (Xolair 150 mg).

c or use 0.6 ml from a 150 mg vial.

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

Body weight (kg)

Baseline

IgE 20- >25- >30- >40- >50- >60- >70- >80- >90- >125-(IU/ml) 25* 30* 40 50 60 70 80 90 125 15030-100 75 75 75 150 150 150 150 150 300 300>100-200 150 150 150 300 300 300 300 300 450 600>200-300 150 150 225 300 300 450 450 450 600>300-400 225 225 300 450 450 450 600 600>400-500 225 300 450 450 600 600>500-600 300 300 450 600 600>600-700 300 450 600>700-800>800-900 ADMINISTRATION EVERY 2 WEEKS

SEE TABLE 3>900-1 000>1 000-1 100

*Body weights below 30 kg were not studied in the pivotal trials for CRSwNP.

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

Body weight (kg)

Baseline

IgE 20- >25- >30- >40- >50- >60- >70- >80- >90- >125-(IU/ml) 25* 30* 40 50 60 70 80 90 125 15030-100 ADMINISTRATION EVERY4 WEEKS>100-200 SEE TABLE 2>200-300 375>300-400 450 525>400-500 375 375 525 600>500-600 375 450 450 600>600-700 225 375 450 450 525>700-800 225 225 300 375 450 450 525 600>800-900 225 225 300 375 450 525 600>900- 225 300 375 450 525 6001 000>1 000- 225 300 375 450 6001 100>1 100- 300 300 450 525 600 Insufficient data to recommend a dose1 200>1 200- 300 375 450 5251 300>1 300- 300 375 525 6001 500

*Body weights below 30 kg were not studied in the pivotal trials for CRSwNP.

Treatment duration, monitoring and dose adjustments

Allergic asthma

Xolair is intended for long-term treatment. Clinical trials have demonstrated that it takes at least12-16 weeks for the treatment to show effectiveness. At 16 weeks after commencing Xolair therapypatients should be assessed by their physician for treatment effectiveness before further injections areadministered. The decision to continue treatment following the 16-week timepoint, or on subsequentoccasions, should be based on whether a marked improvement in overall asthma control is seen (seesection 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 basedupon 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 associatedsymptoms. Total IgE levels are elevated during treatment and remain elevated for up to one year afterthe discontinuation of treatment. Therefore, re-testing of IgE levels during treatment cannot be used asa guide for dose determination. Dose determination after treatment interruptions lasting less than oneyear should be based on serum IgE levels obtained at the initial dose determination. Total serum IgElevels 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).

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 isno evidence that elderly patients require a different dose from younger adult patients.

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

In allergic asthma, the safety and efficacy of omalizumab in patients below the age of 6 years have notbeen established. No data are available.

In CRSwNP, the safety and efficacy of omalizumab in patients below the age of 18 years have notbeen established. No data are available.

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

Doses of more than 150 mg (Table 1) should be divided across two or more injection sites.

Xolair powder and solvent for solution for injection is intended to be administered by a healthcareprovider only.

For instructions on reconstitution of the medicinal product before administration, see section 6.6 andalso information for the healthcare professional section of the package leaflet.

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

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

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

Omalizumab has not been studied in patients with hyperimmunoglobulin E syndrome or allergicbronchopulmonary aspergillosis or for the prevention of anaphylactic reactions, including thoseprovoked by food allergy, atopic dermatitis, or allergic rhinitis. Omalizumab is not indicated for thetreatment 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 beexercised when administering omalizumab in these patient populations.

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

Allergic reactions type I

Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock, may occurwhen taking omalizumab, even after a long duration of treatment. However, most of these reactionsoccurred within 2 hours after the first and subsequent injections of omalizumab but some startedbeyond 2 hours and even beyond 24 hours after the injection. The majority of anaphylactic reactionsoccurred within the first 3 doses of omalizumab. A history of anaphylaxis unrelated to omalizumabmay be a risk factor for anaphylaxis following omalizumab administration. Therefore medicinalproducts for the treatment of anaphylactic reactions should always be available for immediate usefollowing 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 besought if allergic reactions occur.

Antibodies to omalizumab have been detected in a low number of patients in clinical trials (seesection 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, havebeen seen in patients treated with humanised monoclonal antibodies including omalizumab. Thesuggested pathophysiologic mechanism includes immune-complex formation and deposition due todevelopment of antibodies against omalizumab. The onset has typically been 1-5 days afteradministration of the first or subsequent injections, also after long duration of treatment. Symptomssuggestive of serum sickness include arthritis/arthralgias, rash (urticaria or other forms), fever andlymphadenopathy. Antihistamines and corticosteroids may be useful for preventing or treating thisdisorder, 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 allergiceosinophilic granulomatous vasculitis (Churg-Strauss syndrome), both of which are usually treatedwith systemic corticosteroids.

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

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

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

Parasitic (helminth) infections

IgE may be involved in the immunological response to some helminth infections. In patients at chronichigh risk of helminth infection, a placebo-controlled trial showed a slight increase in infection ratewith 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 suchinfections, was less than 1 in 1 000 patients. However, caution may be warranted in patients at highrisk of helminth infection, in particular when travelling to areas where helminthic infections areendemic. If patients do not respond to recommended anti-helminth treatment, discontinuation ofomalizumab should be considered.

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

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

Allergic asthma

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

Chronic rhinosinusitis with nasal polyps (CRSwNP)

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

A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) based onpregnancy registry and post-marketing spontaneous reports, indicates no malformative orfoeto/neonatal toxicity. A prospective pregnancy registry study (EXPECT) in 250 pregnant womenwith 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. Theinterpretation of data may be impacted due to methodological limitations of the study, including smallsample size and non-randomised design.

Omalizumab crosses the placental barrier. However, animal studies do not indicate either direct orindirect harmful effects with respect to reproductive toxicity (see section 5.3).

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

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 omalizumabwill be present in human milk. Available data in non-human primates have shown excretion ofomalizumab into milk (see section 5.3).

The EXPECT study, with 154 infants who had been exposed to omalizumab during pregnancy andthrough breast-feeding did not indicate adverse effects on the breast-fed infant. The interpretation ofdata may be impacted due to methodological limitations of the study, including small sample size andnon-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, theuse of omalizumab may be considered during breast-feeding.

There are no human fertility data for omalizumab. In specifically-designed non-clinical fertility studiesin non-human primates, including mating studies, no impairment of male or female fertility wasobserved following repeated dosing with omalizumab at dose levels up to 75 mg/kg. Furthermore, nogenotoxic 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)

During allergic asthma clinical trials in adult and adolescent patients 12 years of age and older, themost commonly reported adverse reactions were headaches and injection site reactions, includinginjection 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 agein CRSwNP, the most commonly reported adverse reactions were headache, dizziness, arthralgia,abdominal pain upper and injection site reactions.

Table 4 lists the adverse reactions recorded in clinical studies in the total allergic asthma and CRSwNPsafety population treated with Xolair by MedDRA system organ class and frequency. Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencycategories 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

Uncommon Pharyngitis

Rare Parasitic infection

Not known Idiopathic thrombocytopenia, including severe cases

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

Not known Serum sickness, may include fever and lymphadenopathy

Common Headache*

Uncommon Syncope, paraesthesia, somnolence, dizziness#

Uncommon Postural hypotension, flushing

Uncommon Allergic bronchospasm, coughing

Rare Laryngoedema

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

Common Abdominal pain upper**,#

Uncommon Dyspeptic signs and symptoms, diarrhoea, nausea

Uncommon Photosensitivity, urticaria, rash, pruritus

Rare Angioedema

Not known Alopecia

Common Athralgia†

Rare Systemic lupus erythematosus (SLE)

Not known Myalgia, joint swelling

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

For further information, see section 4.4.

Anaphylaxis

Anaphylactic reactions were rare in clinical trials. However, post-marketing data following acumulative search in the safety database retrieved a total of 898 anaphylaxis cases. Based on anestimated exposure of 566 923 patient treatment years, this results in a reporting rate of approximately0.20%.

Arterial thromboembolic events (ATE)

In controlled clinical trials and during interim analyses of an observational study, a numericalimbalance of ATE was observed. The definition of the composite endpoint ATE included stroke,transient ischaemic attack, myocardial infarction, unstable angina, and cardiovascular death (includingdeath from unknown cause). In the final analysis of the observational study, the rate of ATE per 1 000patient years was 7.52 (115/15 286 patient years) for Xolair-treated patients and 5.12 (51/9 963 patientyears) for control patients. In a multivariate analysis controlling for available baseline cardiovascularrisk factors, the hazard ratio was 1.32 (95% confidence interval 0.91-1.91). In a separate analysis ofpooled clinical trials, which included all randomised double-blind, placebo-controlled clinical trialslasting 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 slightnumerical 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).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Maximum tolerated dose of Xolair has not been determined. Single intravenous doses up to 4 000 mghave been administered to patients without evidence of dose-limiting toxicities. The highestcumulative dose administered to patients was 44 000 mg over a 20-week period and this dose did notresult 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.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs forobstructive airway diseases, ATC code: R03DX05

Omalizumab is a recombinant DNA-derived humanised monoclonal antibody that selectively binds tohuman immunoglobulin E (IgE) and prevents binding of IgE to FcRI (high-affinity IgE receptor) onbasophils and mast cells, thereby reducing the amount of free IgE that is available to trigger theallergic cascade. The antibody is an IgG1 kappa that contains human framework regions with thecomplementary-determining regions of a murine parent antibody that binds to IgE.

Treatment of atopic subjects with omalizumab resulted in a marked down-regulation of FcRIreceptors on basophils. Omalizumab inhibits IgE-mediated inflammation, as evidenced by reducedblood and tissue eosinophils and reduced inflammatory mediators, including IL-4, IL-5, and IL-13 byinnate, adaptive and non-immune cells.

Allergic asthma

The in vitro histamine release from basophils isolated from omalizumab-treated subjects was reducedby approximately 90% following stimulation with an allergen compared to pre-treatment values.

In clinical studies in allergic asthma patients, serum free IgE levels were reduced in a dose-dependentmanner within one hour following the first dose and maintained between doses. One year afterdiscontinuation of omalizumab dosing, the IgE levels had returned to pre-treatment levels with noobserved rebound in IgE levels after washout of the medicinal product.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

In clinical studies in patients with CRSwNP, omalizumab treatment led to a reduction in serum free

IgE (approx. 95%) and an increase in serum total IgE levels, to a similar extent as observed in patientswith allergic asthma. Total IgE levels in serum increased due to the formation of omalizumab-IgEcomplexes that have a slower elimination rate compared with free IgE.

Allergic asthma

Adults and adolescents ≥12 years of age

The efficacy and safety of omalizumab were demonstrated in a 28-week double-blind placebo-controlled study (study 1) involving 419 severe allergic asthmatics, ages 12-79 years, who had reducedlung function (FEV1 40-80% predicted) and poor asthma symptom control despite receiving high doseinhaled corticosteroids and a long-acting beta2-agonist. Eligible patients had experienced multipleasthma exacerbations requiring systemic corticosteroid treatment or had been hospitalised or attendedan emergency room due to a severe asthma exacerbation in the past year despite continuous treatmentwith high-dose inhaled corticosteroids and a long-acting beta2-agonist. Subcutaneous omalizumab orplacebo were administered as add-on therapy to >1 000 micrograms beclomethasone dipropionate (orequivalent) plus a long-acting beta2-agonist. Oral corticosteroid, theophylline and leukotriene-modifier maintenance therapies were allowed (22%, 27%, and 35% of patients, respectively).

The rate of asthma exacerbations requiring treatment with bursts of systemic corticosteroids was theprimary endpoint. Omalizumab reduced the rate of asthma exacerbations by 19% (p = 0.153). Furtherevaluations which did show statistical significance (p<0.05) in favour of omalizumab includedreductions in severe exacerbations (where patient’s lung function was reduced to below 60% ofpersonal best and requiring systemic corticosteroids) and asthma-related emergency visits (comprisedof hospitalisations, emergency room, and unscheduled doctor visits), and improvements in Physician’soverall assessment of treatment effectiveness, Asthma-related Quality of Life (AQL), asthmasymptoms and lung function.

In a subgroup analysis, patients with pre-treatment total IgE ≥76 IU/ml were more likely to experienceclinically meaningful benefit to omalizumab. In these patients in study 1 omalizumab reduced the rateof asthma exacerbations by 40% (p = 0.002). In addition more patients had clinically meaningfulresponses in the total IgE ≥76 IU/ml population across the omalizumab severe asthma programme.

Table 5 includes results in the study 1 population.

Table 5 Results of study 1

Whole study 1 population

Omalizumab Placebo

N=209 N=210

Asthma exacerbations

Rate per 28-week period 0.74 0.92% reduction, p-value for rate ratio 19.4%, p = 0.153

Severe asthma exacerbations

Rate per 28-week period 0.24 0.48% reduction, p-value for rate ratio 50.1%, p = 0.002

Emergency visits

Rate per 28-week period 0.24 0.43% reduction, p-value for rate ratio 43.9%, p = 0.038

Physician’s overall assessment% responders* 60.5% 42.8%p-value** <0.001

AQL improvement% of patients ≥0.5 improvement 60.8% 47.8%p-value 0.008

* marked improvement or complete control

** p-value for overall distribution of assessment

Study 2 assessed the efficacy and safety of omalizumab in a population of 312 severe allergicasthmatics which matched the population in study 1. Treatment with omalizumab in this open labelstudy led to a 61% reduction in clinically significant asthma exacerbation rate compared to currentasthma therapy alone.

Four additional large placebo-controlled supportive studies of 28 to 52 weeks duration in 1,722 adultsand adolescents (studies 3, 4, 5, 6) assessed the efficacy and safety of omalizumab in patients withsevere persistent asthma. Most patients were inadequately controlled but were receiving lessconcomitant asthma therapy than patients in studies 1 or 2. Studies 3-5 used exacerbation as primaryendpoint, whereas study 6 primarily evaluated inhaled corticosteroid sparing.

In studies 3, 4 and 5 patients treated with omalizumab had respective reductions in asthmaexacerbation rates of 37.5% (p = 0.027), 40.3% (p<0.001) and 57.6% (p<0.001) compared to placebo.

In study 6, significantly more severe allergic asthma patients on omalizumab were able to reduce theirfluticasone dose to 500 micrograms/day without deterioration of asthma control (60.3%) compared tothe placebo group (45.8%, p<0.05).

Quality of life scores were measured using the Juniper Asthma-related Quality of Life Questionnaire.

For all six studies there was a statistically significant improvement from baseline in quality of lifescores for omalizumab patients versus the placebo or control group.

Physician’s overall assessment of treatment effectiveness:

Physician’s overall assessment was performed in five of the above studies as a broad measure ofasthma control performed by the treating physician. The physician was able to take into account PEF(peak expiratory flow), day and night time symptoms, rescue medicinal product use, spirometry andexacerbations. In all five studies a significantly greater proportion of omalizumab-treated patientswere judged to have achieved either a marked improvement or complete control of their asthmacompared to placebo patients.

Children 6 to <12 years of age

The primary support for safety and efficacy of omalizumab in the group aged 6 to <12 years comesfrom one randomised, double-blind, placebo-controlled, multi-centre trial (study 7).

Study 7 was a placebo-controlled trial which included a specific subgroup (n=235) of patients asdefined in the present indication, who were treated with high-dose inhaled corticosteroids(≥500 µg/day fluticasone equivalent) plus long-acting beta agonist.

A clinically significant exacerbation was defined as a worsening of asthma symptoms as judgedclinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose for at least3 days and/or treatment with rescue systemic (oral or intravenous) corticosteroids for at least 3 days.

In the specific subgroup of patients on high dose inhaled corticosteroids, the omalizumab group had astatistically significantly lower rate of clinically significant asthma exacerbations than the placebogroup. At 24 weeks, the difference in rates between treatment groups represented a 34% (rate ratio0.662, p = 0.047) decrease relative to placebo for omalizumab patients. In the second double-blind 28-week treatment period the difference in rates between treatment groups represented a 63% (rate ratio0.37, p<0.001) decrease relative to placebo for omalizumab patients.

During the 52-week double-blind treatment period (including the 24-week fixed-dose steroid phaseand the 28-week steroid adjustment phase) the difference in rates between treatment groupsrepresented a 50% (rate ratio 0.504, p<0.001) relative decrease in exacerbations for omalizumabpatients.

The omalizumab group showed greater decreases in beta-agonist rescue medicinal product use thanthe placebo group at the end of the 52-week treatment period, although the difference betweentreatment groups was not statistically significant. For the global evaluation of treatment effectivenessat the end of the 52-week double-blind treatment period in the subgroup of severe patients on high-dose inhaled corticosteroids plus long-acting beta agonists, the proportion of patients rated as having‘excellent’ treatment effectiveness was higher, and the proportions having ‘moderate’ or ‘poor’treatment effectiveness lower in the omalizumab group compared to the placebo group; the differencebetween groups was statistically significant (p<0.001), while there were no differences between theomalizumab and placebo groups for patients’ subjective Quality of Life ratings.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

The safety and efficacy of omalizumab were evaluated in two randomised, double-blind, placebo-controlled trials in patients with CRSwNP (Table 7). Patients received omalizumab or placebosubcutaneously every 2 or 4 weeks (see section 4.2). All patients received background intranasalmometasone therapy throughout the study. Prior sino-nasal surgery or prior systemic corticosteroidusage were not required for inclusion in the studies. Patients received omalizumab or placebo for24 weeks followed by a 4-week follow-up period. Demographics and baseline characteristics,including allergic comorbidities, are described in Table 6.

Table 6 Demographics and baseline characteristics of nasal polyp studies

Parameter Nasal polyp study 1 Nasal polyp study 2

N=138 N=127

Mean age (years) (SD) 51.0 (13.2) 50.1 (11.9)% Male 63.8 65.4

Patients with systemic 18.8 26.0corticosteroid use in theprevious year (%)

Bilateral endoscopic nasal 6.2 (1.0) 6.3 (0.9)polyp score (NPS): mean (SD),range 0-8

Nasal congestion score (NCS): 2.4 (0.6) 2.3 (0.7)mean (SD), range 0-3

Sense of smell score: mean 2.7 (0.7) 2.7 (0.7)(SD), range 0-3

SNOT-22 total score: mean 60.1 (17.7) 59.5 (19.3)(SD) range 0-110

Blood eosinophils (cells/µl): 346.1 (284.1) 334.6 (187.6)mean (SD)

Total IgE IU/ml: mean (SD) 160.9 (139.6) 190.2 (200.5)

Asthma (%) 53.6 60.6

Mild (%) 37.8 32.5

Moderate (%) 58.1 58.4

Severe (%) 4.1 9.1

Aspirin exacerbated respiratory 19.6 35.4disease (%)

Allergic rhinitis 43.5 42.5

SD = standard deviation; SNOT-22 = Sino-Nasal Outcome Test 22 Questionnaire; IgE =

Immunoglobulin E; IU = international units. For NPS, NCS, and SNOT-22 higher scores indicategreater disease severity.

The co-primary endpoints were bilateral nasal polyps score (NPS) and average daily nasal congestionscore (NCS) at Week 24. In both nasal polyp studies 1 and 2, patients who received omalizumab hadstatistically significant greater improvements from baseline at Week 24 in NPS and weekly average

NCS than patients who received placebo. Results from nasal polyp studies 1 and 2 are shown in

Table 7.

Table 7 Change from baseline at Week 24 in clinical scores from nasal polyp study 1, nasalpolyp study 2, and pooled data

Nasal polyp Nasal polyp Nasal polypstudy 1 study 2 pooled results

Placebo Omalizumab Placebo Omalizumab Placebo Omalizumab

N 66 72 65 62 131 134

Nasal polyp score

Baseline mean 6.32 6.19 6.09 6.44 6.21 6.31

LS mean change at 0.06 -1.08 -0.31 -0.90 -0.13 -0.99

Week 24

Difference (95% CI) -1.14 (-1.59, -0.69) -0.59 (-1.05, -0.12) -0.86 (-1.18, -0.54)p-value <0.0001 0.0140 <0.00017-day average ofdaily nasalcongestion score

Baseline mean 2.46 2.40 2.29 2.26 2.38 2.34

LS mean change at -0.35 -0.89 -0.20 -0.70 -0.28 -0.80

Week 24

Difference (95% CI) -0.55 (-0.84, -0.25) -0.50 (-0.80, -0.19) -0.52 (-0.73, -0.31)p-value 0.0004 0.0017 <0.0001

TNSS

Baseline mean 9.33 8.56 8.73 8.37 9.03 8.47

LS mean change at -1.06 -2.97 -0.44 -2.53 -0.77 -2.75

Week 24

Difference (95% CI) -1.91 (-2.85, -0.96) -2.09 (-3.00, -1.18) -1.98 (-2.63, -1.33)p-value 0.0001 <0.0001 <0.0001

SNOT-22

Baseline mean 60.26 59.82 59.80 59.21 60.03 59.54

LS mean change at -8.58 -24.70 -6.55 -21.59 -7.73 -23.10

Week 24

Difference (95% CI) -16.12 (-21.86, -10.38) -15.04 (-21.26, -8.82) -15.36 (-19.57, -11.16)p-value <0.0001 <0.0001 <0.0001(MID = 8.9)

UPSIT

Baseline mean 13.56 12.78 13.27 12.87 13.41 12.82

LS mean change at 0.63 4.44 0.44 4.31 0.54 4.38

Week 24

Difference (95% CI) 3.81 (1.38, 6.24) 3.86 (1.57, 6.15) 3.84 (2.17, 5.51)p-value 0.0024 0.0011 <0.0001

LS=least-square; CI = confidence interval; TNSS = Total nasal symptom score; SNOT-22 = Sino-Nasal

Outcome Test 22 Questionnaire; UPSIT = University of Pennsylvania Smell Identification Test; MID =minimal important difference.

Figure 1 Mean change from baseline in nasal congestion score and mean change from baselinein nasal polyp score by treatment group in nasal polyp study 1 and study 20.25 Study 1/Placebo (N=66) Study 2/Placebo (N=65) 0.25 Study 1/Placebo (N=66) Study 2/Placebo (N=65)

Study 1/Omalizumab (N=72) Study 2/Omalizumab (N=62) Study 1/Omalizumab (N=72) Study 2/Omalizumab (N=62)0.00 0.00

- 0.25 -0.25

- 0.50 -0.50

- 0.75 -0.75

- 1.00 -1.00

- 1.25 Secondary Primary efficacy -1.25 Secondary Primary efficacyefficacy analysis analysis efficacy analysis analysis

Baseline 4 8 12 16 20 24 Baseline 4 8 12 16 20 24

Week Week

In a pre-specified pooled analysis of rescue treatment (systemic corticosteroids for 3 consecutivedays or nasal polypectomy) during the 24-week treatment period, the proportion of patients requiringrescue treatment was lower in omalizumab compared to placebo (2.3% versus 6.2%, respectively).

The odds-ratio of having taken rescue treatment in omalizumab compared to placebo was 0.38 (95%

CI: 0.10, 1.49). There were no sino-nasal surgeries reported in either study.

The long-term efficacy and safety of omalizumab in patients with CRSwNP who had participated innasal polyp studies 1 and 2 was assessed in an open-label extension study. Efficacy data from thisstudy suggest that clinical benefit provided at Week 24 was sustained through to Week 52. Safety datawere overall consistent with the known safety profile of omalizumab.

The pharmacokinetics of omalizumab have been studied in adult and adolescent patients with allergicasthma as well as in adult patients with CRSwNP. The general pharmacokinetic characteristics ofomalizumab are similar in these patient populations.

After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailabilityof 62%. Following a single subcutaneous dose in adult and adolescent patients with asthma,omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days.

The pharmacokinetics of omalizumab are linear at doses greater than 0.5 mg/kg. Following multipledoses of omalizumab, areas under the serum concentration-time curve from Day 0 to Day 14 at steadystate were up to 6-fold of those after the first dose.

Administration of Xolair manufactured as a lyophilised or liquid formulation resulted in similar serumconcentration-time profiles of omalizumab.

In vitro, omalizumab forms complexes of limited size with IgE. Precipitating complexes andcomplexes larger than one million Daltons in molecular weight are not observed in vitro or in vivo.

The apparent volume of distribution in patients following subcutaneous administration was78 ± 32 ml/kg.

Mean change from baseline in Nasal Polyp Score

Mean change from baseline in Nasal Congestion Score

Clearance of omalizumab involves IgG clearance processes as well as clearance via specific bindingand complex formation with its target ligand, IgE. Liver elimination of IgG includes degradation in thereticuloendothelial system and endothelial cells. Intact IgG is also excreted in bile. In asthma patientsthe omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging2.4  1.1 ml/kg/day. In addition, doubling of body weight approximately doubled apparent clearance.

Characteristics in patient populations

Age, Race/Ethnicity, Gender, Body Mass Index

The population pharmacokinetics of omalizumab were analysed to evaluate the effects of demographiccharacteristics. Analyses of these limited data suggest that no dose adjustments are necessary for age(6-76 years for patients with allergic asthma; 18 to 75 years for patients with CRSwNP),race/ethnicity, gender or Body Mass Index (see section 4.2).

There are no pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment(see sections 4.2 and 4.4).

The safety of omalizumab has been studied in the cynomolgus monkey, since omalizumab binds tocynomolgus and human IgE with similar affinity. Antibodies to omalizumab were detected in somemonkeys following repeated subcutaneous or intravenous administration. However, no apparenttoxicity, such as immune complex-mediated disease or complement-dependent cytotoxicity, was seen.

There was no evidence of an anaphylactic response due to mast-cell degranulation in cynomolgusmonkeys.

Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14 times the highestrecommended clinical dose in mg/kg according to the recommended dosing table) was well toleratedin non-human primates (both adult and juvenile animals), with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals. The serumconcentration required to attain a 50% drop in platelets from baseline in adult cynomolgus monkeyswas roughly 4- to 20-fold higher than anticipated maximum clinical serum concentrations. In addition,acute haemorrhage and inflammation were observed at injection sites in cynomolgus monkeys.

Formal carcinogenicity studies have not been conducted with omalizumab.

In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg/kg per week (at least8 times the highest recommended clinical dose in mg/kg over a 4-week period) did not elicit maternaltoxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did notelicit adverse effects on foetal or neonatal growth when administered throughout late gestation,delivery and nursing.

Omalizumab is excreted in breast milk in cynomolgus monkeys. Milk levels of omalizumab were0.15% of the maternal serum concentration.

Sucrose

Histidine

Histidine hydrochloride monohydrate

Polysorbate 20

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

4 years.

The chemical and physical stability of the reconstituted medicinal product have been demonstrated for8 hours at 2°C to 8°C and for 4 hours at 30°C.

From a microbiological point of view, the medicinal product should be used immediately afterreconstitution. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 8 hours at 2°C to 8°C or 2 hours at25°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder vial: Clear, colourless type I glass vial with a butyl rubber stopper and grey flip-off seal.

Solvent ampoule: Clear, colourless type I glass ampoule containing 2 ml water for injections.

Pack containing one vial of powder for solution for injection and one ampoule of water for injections.

Xolair 75 mg powder for solution for injection is supplied in a single-use vial.

From a microbiological point of view, the medicinal product should be used immediately afterreconstitution (see section 6.3).

The lyophilised medicinal product takes 15-20 minutes to dissolve, although in some cases it may takelonger. The fully reconstituted medicinal product will appear clear to slightly opalescent, colourless topale brownish-yellow and may have a few small bubbles or foam around the edge of the vial. Becauseof the viscosity of the reconstituted medicinal product care must be taken to withdraw all of themedicinal product from the vial before expelling any air or excess solution from the syringe in order toobtain the 0.6 ml.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/05/319/001

Date of first authorisation: 25 October 2005

Date of latest renewal: 22 June 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu