FASENRA 30mg injection for pre-filled pen medication leaflet

Fasenra 30 mg solution for injection in pre-filled syringe

Fasenra 30 mg solution for injection in pre-filled pen

Each pre-filled syringe contains 30 mg benralizumab* in 1 mL.

Pre-filled pen

Each pre-filled pen contains 30 mg benralizumab* in 1 mL.

*Benralizumab is a humanised monoclonal antibody produced in Chinese hamster ovary (CHO) cellsby recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection) in pre-filled syringe

Solution for injection (injection) in pre-filled pen (Fasenra Pen)

Clear to opalescent, colourless to yellow solution and may contain translucent or white to off-whiteparticles.

Asthma

Fasenra is indicated as an add-on maintenance treatment in adult patients with severe eosinophilicasthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting β-agonists(see section 5.1).

Eosinophilic granulomatosis with polyangiitis (EGPA)

Fasenra is indicated as an add-on treatment for adult patients with relapsing or refractory eosinophilicgranulomatosis with polyangiitis (see section 5.1).

Fasenra treatment should be initiated by a physician experienced in the diagnosis and treatment ofconditions for which benralizumab is indicated (see section 4.1).

After proper training in the subcutaneous injection technique and education about signs and symptomsof hypersensitivity reactions (see section 4.4), patients with no known history of anaphylaxis or theircaregivers may administer Fasenra if their physician determines that it is appropriate, with medicalfollow-up as necessary. Self-administration should only be considered in patients already experiencedwith Fasenra treatment.

Fasenra is intended for long-term treatment. A decision to continue the therapy should be made at leastannually based on disease severity, level of disease control and blood eosinophil counts.

Asthma

The recommended dose of benralizumab is 30 mg by subcutaneous injection every 4 weeks for thefirst 3 doses, and then every 8 weeks thereafter.

EGPA

The recommended dose of benralizumab is 30 mg by subcutaneous injection every 4 weeks.

Patients who develop life-threatening manifestations of EGPA should be evaluated for the need forcontinued therapy, as Fasenra has not been studied in this population.

If an injection is missed on the planned date, dosing should resume as soon as possible on theindicated regimen; a double dose must not be administered.

No dose adjustment is required for elderly patients (see section 5.2).

No dose adjustment is required for patients with renal or hepatic impairment (see section 5.2).

The safety and efficacy of Fasenra in children and adolescents aged 6 to 17 years with asthma has notbeen established. Currently limited data in children 6 to 11 years old and data in adolescents aged 12to 17 are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

The safety and efficacy of Fasenra in children less than 6 years with asthma have not been established.

No data are available.

The safety and efficacy of Fasenra in children and adolescents less than 18 years with EGPA have notbeen established.

This medicinal product is administered as a subcutaneous injection.

It should be injected into the thigh or abdomen. If the healthcare professional or caregiver administersthe injection, the upper arm can also be used. It should not be injected into areas where the skin istender, bruised, erythematous, or hardened.

Comprehensive instructions for administration using the pre-filled syringe/pre-filled pen are providedin the ‘Instructions for Use’.

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.

Asthma exacerbations

Fasenra should not be used to treat acute asthma exacerbations.

Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsensafter initiation of treatment.

Abrupt discontinuation of corticosteroids after initiation of Fasenra therapy is not recommended.

Reduction in corticosteroid doses, if appropriate, should be gradual and performed under thesupervision of a physician.

Acute systemic reactions including anaphylactic reactions and hypersensitivity reactions(e.g. urticaria, papular urticaria, rash) have occurred following administration of benralizumab (seesection 4.8). These reactions may occur within hours of administration, but in some instances have adelayed onset (i.e. days).

A history of anaphylaxis unrelated to benralizumab may be a risk factor for anaphylaxis following

Fasenra administration (see section 4.3). In line with clinical practice, patients should be monitored foran appropriate time after administration of Fasenra.

In the event of a hypersensitivity reaction, Fasenra should be discontinued permanently andappropriate therapy should be initiated.

Parasitic (Helminth) infection

Eosinophils may be involved in the immunological response to some helminth infections. Patientswith known helminth infections were excluded from participation in clinical trials. It is unknown ifbenralizumab may influence a patient’s response against helminth infections.

Patients with pre-existing helminth infections should be treated before initiating therapy withbenralizumab. If patients become infected, while receiving treatment and do not respond toanti-helminth treatment, therapy with benralizumab should be discontinued until infection resolves.

Organ threatening or life-threatening EGPA

Fasenra has not been studied in patients with active organ threatening or life-threateningmanifestations of EGPA (see section 4.2).

No interaction studies have been performed. In a randomised, double-blind parallel-group study of 103patients aged between 12 and 21 years with severe asthma, the humoral antibody responses induced byseasonal influenza virus vaccination do not appear to be affected by benralizumab treatment. An effectof benralizumab on the pharmacokinetics of co-administered medicinal products is not expected (seesection 5.2).

Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in theclearance of benralizumab. There is no evidence of IL-5Rα expression on hepatocytes. Eosinophildepletion does not produce chronic systemic alterations of proinflammatory cytokines.

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of benralizumab inpregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

Monoclonal antibodies, such as benralizumab, are transported across the placenta linearly aspregnancy progresses; therefore, potential exposure to the fetus is likely to be greater during thesecond and third trimester of pregnancy.

As a precautionary measure, it is preferable to avoid the use of Fasenra during pregnancy. Itsadministration to pregnant women should only be considered if the expected benefit to the mother isgreater than any possible risk to the fetus.

It is unknown whether benralizumab or its metabolites are excreted in human or animal milk. A risk tothe breast-fed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from using

Fasenra taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

There are no fertility data in humans. Animal studies showed no adverse effects of benralizumabtreatment on fertility (see section 5.3).

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

The safety profile of benralizumab in asthma and EGPA are similar.

The most commonly reported adverse reactions during treatment in asthma are headache (8%) andpharyngitis (3%). The most commonly reported adverse reaction in EGPA is headache (17%). Casesof anaphylactic reaction of varied severity have been reported for benralizumab.

The following adverse reactions have been reported with benralizumab during clinical studies inasthma and EGPA and from post-marketing experience. The frequency of adverse reactions is definedusing 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 <1/1 000); very rare (<1/10 000); and not known (cannot beestimated from available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 1. Tabulated list of adverse reactions

MedDRA System organ class Adverse reaction Frequency

Infections and infestations Pharyngitisa Common

Immune system disorders Hypersensitivity reactionsb Common

Anaphylactic reaction Not known

Nervous system disorders Headachec Common

General disorders and Pyrexia Commonadministration site conditions Injection site reactiond

a. Pharyngitis was defined by the following grouped preferred terms: ‘Pharyngitis’, ‘Pharyngitis bacterial’,‘Viral pharyngitis’, ‘Pharyngitis streptococcal’.

b. Hypersensitivity reactions were defined by the following grouped preferred terms: ‘Urticaria’, ‘Papularurticaria’, and ‘Rash’. For examples of the associated manifestations reported and a description of the timeto onset, see section 4.4.

c. Very common in EGPA study.

d. See ‘Description of selected adverse reaction’.

Description of selected adverse reaction

In placebo-controlled asthma studies, injection site reactions (e.g. pain, erythema, pruritus, papule)occurred at a rate of 2.2% in patients treated with the recommended benralizumab dose compared with1.9% in patients treated with placebo. The events were transient in nature.

In a 56-week extension trial (Trial 4) in patients with asthma from Trials 1, 2 and 3, 842 patients weretreated with Fasenra at the recommended dose and remained in the trial. The overall safety profile wassimilar to the asthma trials described above. Additionally, in an open-label safety extension trial(Trial 5) in patients with asthma from previous trials, 226 patients were treated with Fasenra at therecommended dose for up to 43 months. Combined with the treatment period in previous studies, thiscorresponds to a median follow-up of 3.4 years (range 8.5 months - 5.3 years). The safety profileduring this follow-up period was consistent with the known safety profile of Fasenra.

There are limited data in paediatric patients. There were 108 adolescents aged 12 to 17 with asthmaenrolled in the phase 3 trials (Trial 1: n=53, Trial 2: n=55). Of these, 46 received placebo, 40 receivedbenralizumab every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 receivedbenralizumab every 4 weeks. Adolescent patients aged 12 to 17 (n=86) from Trials 1 and 2 continuedthe treatment with benralizumab in Trial 4 for up to 108 weeks. The frequency, type and severity ofadverse reactions in the adolescent population were observed to be similar to those seen in adults.

In an open-label, uncontrolled pharmacokinetic and pharmacodynamic study of 48 weeks duration in alimited number of paediatric patients (n=28) with uncontrolled severe asthma, the safety profile forpatients aged 6 to 11 years old was similar to the adult and adolescent population (see section 4.2).

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.

Doses of up to 200 mg were administered subcutaneously in clinical trials to patients with eosinophilicasthma without evidence of dose-related toxicities.

There is no specific treatment for an overdose with benralizumab. If overdose occurs, the patientshould be treated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs forobstructive airway diseases, ATC code: R03DX10

Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). Itspecifically binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα). The IL-5 receptoris specifically expressed on the surface of eosinophils and basophils. The absence of fucose in the Fcdomain of benralizumab results in high affinity for FcɣRIII receptors on immune effector cells such asnatural killer (NK) cells. This leads to apoptosis of eosinophils and basophils through enhancedantibody-dependent cell-mediated cytotoxicity (ADCC), which reduces eosinophilic inflammation.

Effect on blood eosinophils

In patients with asthma, treatment with benralizumab results in near complete depletion of bloodeosinophils within 24 hours following the first dose which is maintained throughout treatment. Thedepletion of blood eosinophils is accompanied by a reduction in serum eosinophil granule proteins(eosinophil derived neurotoxin [EDN] and eosinophil cationic protein [ECP]) and a reduction in bloodbasophils.

In patients with EGPA, depletion of blood eosinophils was consistent with the effect observed inasthma trials. Blood eosinophil depletion was seen at the first observed time point, 1 week oftreatment, and was maintained throughout the 52-week treatment period.

Effect on eosinophils in the airway mucosa

The effect of benralizumab on eosinophils in the airway mucosa in asthmatic patients with elevatedsputum eosinophil counts (at least 2.5%) was evaluated in a 12-week, phase 1, randomised,double-blind, placebo-controlled clinical study with benralizumab 100 or 200 mg administeredsubcutaneously. In this study, there was a median reduction from baseline in airway mucosaeosinophils of 96% in the benralizumab-treated group compared to a 47% reduction in the placebogroup (p=0.039).

Asthma

The efficacy of benralizumab was evaluated in 3 randomised, double-blind, parallel-group,placebo-controlled clinical trials between 28 to 56 weeks duration, in patients aged 12 to 75 years.

In these studies, benralizumab was administered at a dose of 30 mg once every 4 weeks for the first3 doses, and then every 4 or 8 weeks thereafter as add-on to background treatment and was evaluatedin comparison with placebo.

The two exacerbation trials, SIROCCO (Trial 1) and CALIMA (Trial 2), enrolled a total of2 510 patients with severe uncontrolled asthma, 64% females, with a mean age of 49 years. Patientshad a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment(mean of 3) in the past 12 months, Asthma Control Questionnaire-6 (ACQ-6) score of 1.5 or more atscreening, and reduced lung function at baseline (mean predicted pre-bronchodilator forced expiratoryvolume in 1 second [FEV1] of 57.5%), despite regular treatment with high-dose inhaled corticosteroid(ICS) (Trial 1) or with medium or high-dose ICS (Trial 2) and a long-acting β-agonist (LABA); atleast one additional controller was administered to 51% and 41% of these patients, respectively.

For the oral corticosteroid (OCS) reduction trial ZONDA (Trial 3), a total of 220 asthma patients (61%female; mean age of 51 years) were enrolled; they were treated with daily OCS (8 to 40 mg per day;median of 10 mg) in addition to regular use of high-dose ICS and LABA with at least one additionalcontroller to maintain asthma control in 53% of the cases. The trial included an 8-week run-in periodduring which the OCS was titrated to the minimum effective dose without losing asthma control.

Patients had blood eosinophil counts ≥150 cells/μL and a history of at least one exacerbation in thepast 12 months.

While 2 dose regimens were studied in Trials 1, 2, and 3, the recommended dose regimen isbenralizumab administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (seesection 4.2) as no additional benefit was observed by more frequent dosing. The results summarisedbelow are those for the recommended dose regimen.

Exacerbation trials

The primary endpoint was the annual rate of clinically significant asthma exacerbations in patientswith baseline blood eosinophil counts ≥300 cells/μL who were taking high-dose ICS and LABA.

Clinically significant asthma exacerbation was defined as worsening of asthma requiring use oforal/systemic corticosteroids for at least 3 days, and/or emergency department visits requiring use oforal/systemic corticosteroids and/or hospitalisation. For patients on maintenance OCS, this wasdefined as a temporary increase in stable oral/systemic corticosteroids for at least 3 days or a singledepo-injectable dose of corticosteroids.

In both trials, patients receiving benralizumab experienced significant reductions in annualexacerbation rates compared to placebo in patients with blood eosinophils ≥300 cells/μL. In addition,change from baseline in mean FEV1 showed benefit as early as 4 weeks, which was maintainedthrough to end of treatment (Table 2).

Reductions in exacerbation rates were observed irrespective of baseline eosinophil count; however,increasing baseline eosinophil counts was identified as a potential predictor of improved treatmentresponse particularly for FEV1.

Table 2. Results of annual exacerbation rate and lung function at end of treatment of Trial 1 and2 by eosinophil count

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo

Blood eosinophil count n=267 n=267 n=239 n=248≥300 cells/μLa

Clinically significant exacerbations

Rate 0.74 1.52 0.73 1.01

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo

Difference -0.78 -0.29

Rate ratio (95% CI) 0.49 (0.37, 0.64) 0.72 (0.54, 0.95)p-value <0.001 0.019

Pre-bronchodilator FEV1 (L)

Mean baseline 1.660 1.654 1.758 1.815

Improvement from baseline 0.398 0.239 0.330 0.215

Difference (95% CI) 0.159 (0.068, 0.249) 0.116 (0.028, 0.204)p-value 0.001 0.010

Blood eosinophil count n=131 n=140 n=125 n=122<300 cells/μLb

Clinically significant exacerbations

Rate 1.11 1.34 0.83 1.38

Difference -0.23 -0.55

Rate ratio (95% CI) 0.83 (0.59, 1.16) 0.60 (0.42, 0.86)

Pre-bronchodilator FEV1 (L)

Mean change 0.248 0.145 0.140 0.156

Difference (95% CI) 0.102 (-0.003, 0.208) -0.015 (-0.127, 0.096)

a. Intent-to-treat population (patients on high-dose ICS and blood eosinophils ≥300 cells/μL).

b. Not powered to detect a treatment difference in patients with blood eosinophils <300 cells/μL.

Across Trials 1 and 2 combined, there was a numerically greater exacerbation rate reduction andgreater improvements in FEV1 with increasing baseline blood eosinophils.

The rate of exacerbations requiring hospitalisation and/or emergency room visits for patients receivingbenralizumab compared to placebo for Trial 1 were 0.09 versus 0.25 (rate ratio 0.37, 95% CI: 0.20,0.67, p≤0.001) and for Trial 2 were 0.12 versus 0.10 (rate ratio 1.23, 95% CI: 0.64, 2.35, p=0.538). In

Trial 2, there were too few events in the placebo treatment arm to draw conclusions for exacerbationsrequiring hospitalisation or emergency room visits.

In both Trials 1 and 2, patients receiving benralizumab experienced statistically significant reductionsin asthma symptoms (Total Asthma Score) compared to patients receiving placebo. Similarimprovement in favour of benralizumab was observed for the ACQ-6 and Standardised Asthma

Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) (Table 3).

Table 3. Treatment difference in mean change from baseline in total asthma symptom score,

ACQ-6 and AQLQ(s)+12 at end of treatment - Patients on high-dose ICS and blood eosinophils≥300 cells/μL

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo(na=267) (na=267) (na=239) (na=248)

Total asthma symptom scoreb

Mean baseline 2.68 2.74 2.76 2.71

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo(na=267) (na=267) (na=239) (na=248)

Improvement from -1.30 -1.04 -1.40 -1.16baseline

Difference (95% CI) -0.25 (-0.45, -0.06) -0.23 (-0.43, -0.04)p-value 0.012 0.019

ACQ-6

Mean baseline 2.81 2.90 2.80 2.75

Improvement from -1.46 -1.17 -1.44 -1.19baseline

Difference (95% CI) -0.29 (-0.48, -0.10) -0.25 (-0.44, -0.07)

AQLQ(S)+12

Mean baseline 3.93 3.87 3.87 3.93

Improvement from 1.56 1.26 1.56 1.31baseline

Difference (95% CI) 0.30 (0.10, 0.50) 0.24 (0.04, 0.45)

a. Number of patients (n) varies slightly due to the number of patients for whom data were available for eachvariable. Results shown based on last available data for each variable.

b. Asthma symptom scale: total score from 0 (least) to 6 (most); day and night time asthma symptom scoresfrom 0 (least) to 3 (most) symptoms. Individual day and night time scores were similar.

Subgroup analyses by prior exacerbation history

Subgroup analyses from Trials 1 and 2 identified patients with higher prior exacerbation history as apotential predictor of improved treatment response. When considered alone or in combination withbaseline blood eosinophils count, these factors may further identify patients who may achieve greaterresponse from benralizumab treatment (Table 4).

Table 4. Exacerbation rate and pulmonary function (FEV1) at end of treatment by number ofexacerbations in the previous year - Patients on high-dose ICS and blood eosinophils≥300 cells/μL

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo(N=267) (N=267) (N=239) (N=248)

Baseline of 2 exacerbationsn 164 149 144 151

Exacerbation rate 0.57 1.04 0.63 0.62

Difference -0.47 0.01

Rate ratio (95% CI) 0.55 (0.37, 0.80) 1.01 (0.70, 1.46)

Pre-bronchodilator 0.343 0.230 0.266 0.236

FEV1 mean change

Difference (95% CI) 0.113 (-0.002, 0.228) 0.029 (-0.079, 0.137)

Baseline of 3 or more exacerbationsn 103 118 95 97

Exacerbation rate 0.95 2.23 0.82 1.65

Difference -1.28 -0.84

Rate ratio (95% CI) 0.43 (0.29, 0.63) 0.49 (0.33, 0.74)

Trial 1 Trial 2

Benralizumab Placebo Benralizumab Placebo(N=267) (N=267) (N=239) (N=248)

Pre-bronchodilator 0.486 0.251 0.440 0.174

FEV1 mean change

Difference (95% CI) 0.235 (0.088, 0.382) 0.265 (0.115, 0.415)

Oral corticosteroid dose reduction trials

ZONDA (Trial 3), a placebo-controlled study, and PONENTE (Trial 6), a single arm, open-labelstudy, evaluated the effect of benralizumab on reducing the use of maintenance OCS.

In Trial 3, the primary endpoint was percent reduction from baseline of the final OCS dose during

Weeks 24 to 28, while maintaining asthma control. Table 5 summarises the study results for Trial 3.

Table 5. Effect of benralizumab on OCS dose reduction, Trial 3

Benralizumab Placebo(N=73) (N=75)

Wilcoxon rank sum test (primary analysis method)

Median % reduction in daily OCS dose from baseline (95% CI) 75 (60, 88) 25 (0, 33)

Wilcoxon rank sum test p-value <0.001

Proportional odds model (sensitivity analysis)

Percent reduction in OCS from baseline at Week 28≥90% reduction 27 (37%) 9 (12%)≥75% reduction 37 (51%) 15 (20%)≥50% reduction 48 (66%) 28 (37%)>0% reduction 58 (79%) 40 (53%)

No change or no decrease in OCS 15 (21%) 35 (47%)

Odds ratio (95% CI) 4.12 (2.22, 7.63)

Reduction in the daily OCS dose to 0 mg/day* 22 (52%) 8 (19%)

Odds ratio (95% CI) 4.19 (1.58, 11.12)

Reduction in the daily OCS dose to ≤5 mg/day 43 (59%) 25 (33%)

Odds ratio (95% CI) 2.74 (1.41, 5.31)

Exacerbation rate 0.54 1.83

Rate ratio (95% CI) 0.30 (0.17, 0.53)

Exacerbation rate requiring hospitalisation/emergency room0.02 0.32visit

Rate ratio (95% CI) 0.07 (0.01, 0.63)

* Only patients with an optimised baseline OCS dose of 12.5 mg or less were eligible to achieve a 100%reduction in OCS dose during the study.

Lung function, asthma symptom score, ACQ-6 and AQLQ(S)+12 were also assessed in Trial 3 andshowed results similar to those in Trials 1 and 2.

Trial 6 enrolled 598 adult patients with severe asthma (blood eosinophil count ≥150 cells/μL at entryor ≥300 cells/μL in the past 12 months if study entry count was <150 cells/μL) who were oralcorticosteroid-dependent. The primary endpoints were proportion of patients who eliminated OCSwhile maintaining asthma control and proportion of patients who achieved a final OCS dose less thanor equal to 5 mg while maintaining asthma control and taking into account adrenal function. Theproportion of patients who eliminated maintenance OCS was 62.9%. The proportion of patients whoachieved an OCS dose less than or equal to 5 mg (while maintaining asthma control and not limited byadrenal function) was 81.9%. Effects on OCS reduction were similar irrespective of blood eosinophilcount at study entry (including patients with blood eosinophils <150 cells/μL) and maintained over anadditional period of 24 to 32 weeks. The annualised exacerbation rate in Trial 6 was comparable tothat reported in previous trials.

Long-term extension trials

The long-term efficacy and safety of benralizumab was evaluated in a phase 3, 56-week extension trial

BORA (Trial 4). The trial enrolled 2 123 patients, 2 037 adults and 86 adolescent patients (aged12 years and older) from Trials 1, 2 and 3. Trial 4 assessed the long-term effect of benralizumab onannual exacerbation rate, lung function, ACQ-6, AQLQ(S)+12 and maintenance of OCS reduction atthe 2 dose regimens studied in the predecessor studies.

At the recommended dose regimen, the reduction in annual rate of exacerbations observed in theplacebo-controlled predecessor Trials 1 and 2 (in patients with baseline blood eosinophil counts≥300 cells/μL who were taking high-dose ICS) was maintained over the second year of treatment(Table 6). In patients who received benralizumab in predecessor Trials 1 and 2, 73% wereexacerbation-free in the extension Trial 4.

Table 6. Exacerbations over an extended treatment perioda

Placebob Benralizumab(N=338) (N=318)

Trial 1 & 2 Trial 1 & 2 Trial 4 Trial 1, 2 & 4c

Rate 1.23 0.65 0.48 0.56

a. Patients that entered Trial 4 from predecessor Trials 1 and 2 with baseline blood eosinophil counts≥300 cells/μL who were taking high-dose ICS.

b. Placebo patients in Trials 1 and 2 are included up to the end of the predecessor trial (Week 48 in Trial 1,

Week 56 in Trial 2).

c. Total duration of treatment: 104 - 112 weeks.

Similar maintenance of effect was observed throughout Trial 4 in lung function, ACQ-6 and

AQLQ(S)+12 (Table 7).

Table 7. Change from baseline for lung function, ACQ-6, and AQLQ(S)+12a

Trial 1 & 2 Trial 1 & 2 EOTc Trial 4 EOTd

Baselineb

Pre-bronchodilator FEV1 (L)n 318 305 290

Mean baseline (SD) 1.741 (0.621) -- --

Change from baseline (SD) e -- 0.343 (0.507) 0.404 (0.555)

ACQ-6n 318 315 296

Mean baseline (SD) 2.74 (0.90) -- --

Change from baseline (SD) e -- -1.44 (1.13) -1.47 (1.05)

AQLQ(S)+12n 307 306 287

Mean baseline (SD) 3.90 (0.99) -- --

Change from baseline (SD) e -- 1.58 (1.23) 1.61 (1.21)n=number of patients with data at timepoint. SD=standard deviation.

a. Baseline blood eosinophil counts ≥300 cells/μL and taking high-dose ICS: benralizumab administered at therecommended dose regimen.

b. Integrated analysis of Trial 1 and 2 baseline includes adults and adolescents.

c. Integrated analysis at End of Treatment (EOT) of Trial 1 (Week 48) and Trial 2 (Week 56).

d. EOT for Trial 4 was Week 48 (the last timepoint for adults and adolescent data).

e. Baseline is prior to benralizumab treatment in Trial 1 and 2.

Efficacy in Trial 4 was also evaluated in patients with baseline blood eosinophil counts <300 cells/µLand was consistent with Trials 1 and 2.

Maintenance of the reduction in daily OCS dose was also observed over the extension trial in patientsenrolled from Trial 3 (Figure 1).

Figure 1. Median percent reductions in daily OCS over time (Trial 3 and 4)a

Benra 30 mg q. 8 weeks

Trial 3 Trial 4n =

Week(s)

Median percent reduction

a. Predecessor Trial 3 patients who continued benralizumab treatment into Trial 4. Patients were permitted toenter a second extension trial after a minimum of 8 weeks in Trial 4 without completing the 56-weekextension period.

In Trial 5, a second long-term safety extension study (see section 4.8), the annualised exacerbation rate(0.47) in patients receiving the approved dose regimen was comparable to that reported in thepredecessor Trials 1, 2 (0.65) and 4 (0.48).

Eosinophilic granulomatosis with polyangiitis (EGPA)

The efficacy of benralizumab was evaluated in a randomised, double-blind, active-controlled,non-inferiority clinical trial of 52-weeks treatment duration, in patients aged 18 years and older with

EGPA. A total of 140 patients were randomised to receive either 30 mg of benralizumab or 300 mg ofmepolizumab administered subcutaneously every 4 weeks. Patients enrolled had a history of relapsingor refractory disease and were on stable OCS therapy (OCS; ≥7.5 to ≤50 mg/dayprednisolone/prednisone), with or without stable immunosuppressant therapy (excludingcyclophosphamide). The median baseline OCS daily dose was 10 mg and 36% were receivingimmunosuppressive therapy. The OCS dose was tapered at the discretion of the investigator. Patientswith active organ threatening or life-threatening EGPA were excluded from the trial.

Remission

The primary endpoint was the proportion of subjects in remission, defined as Birmingham Vasculitis

Activity Score (BVAS)=0 (no active vasculitis) plus prednisolone/prednisone dose ≤4 mg/day, at both

Week 36 and Week 48. As shown in Table 8, benralizumab demonstrated non-inferiority tomepolizumab for the primary endpoint. Results for accrued duration of remission and the componentsof remission are also shown in Table 8.

Table 8. Remission and components of remission in EGPA

Remission OCS≤4 mg/day BVAS=0(OCS≤4 mg/day +

BVAS=0)

Benraa Mepob Benraa Mepob Benraa Mepob

N=70 N=70 N=70 N=70 N=70 N=70

Patients in remission at both Weeks 36 and 48

Patients, n (%)c 40 (58) 40 (57) 42 (61) 41 (58) 58 (83) 59 (84)

Differences in 1.21 2.64 -1.17remission rate (%)c(95% CI) (-14.12, 16.53) (-12.67, 17.95) (-13.27, 10.94)(p-value) (0.88)d (0.74)d e (0.85)d e

Accrued duration over 52 weeks, n (%)0 weeksf 9 (13) 15 (21) 9 (13) 12 (17) 0 0>0 to <12 weeks 13 (19) 10 (14) 11 (16) 12 (17) 0 2 (3)12 to <24 weeks 8 (11) 8 (11) 9 (13) 8 (11) 2 (3) 2 (3)24 to <36 weeks 20 (29) 19 (27) 19 (27) 18 (26) 6 (9) 7 (10)≥36 weeks 20 (29) 18 (26) 22 (31) 20 (29) 62 (89) 59 (84)

N=number of patients in analysis.

a. Benralizumab (Benra) 30 mg administered every 4 weeks.

b. Mepolizumab (Mepo) 300 mg administered every 4 weeks.

c. Model adjusted percentages.

d. Used for superiority testing.

e. Not formally tested in a pre-specified multiplicity testing procedure.

f. Did not achieve remission at any point.

The proportion of patients achieving remission within the first 24 weeks of treatment and remaining inremission through Week 52 was 42% for benralizumab and 37% for mepolizumab (difference inresponder rate 5.54%, 95% CI: -9.30, 20.37, nominal p-value 0.46).

Using an alternative remission definition of BVAS=0 plus prednisolone/prednisone ≤7.5 mg/day, aconsistent efficacy between groups for these endpoints was observed.

Patients achieved the primary remission endpoint across the prespecified demographic and baselinecharacteristic subgroups.

Relapse

The hazard ratio for time to first relapse (vasculitis, asthma, or sino-nasal) was 0.98 (95% CI: 0.53,1.82, nominal p-value 0.95). Relapse was observed in 30% of patients on benralizumab and 30% ofpatients on mepolizumab. The annualised relapse rate was 0.50 for patients receiving benralizumabversus 0.49 for patients receiving mepolizumab (rate ratio 1.03, 95% CI: 0.56, 1.90, nominal p-value0.93). The types of relapse were consistent for patients receiving benralizumab or mepolizumab.

Oral corticosteroids

The average daily OCS dose during Weeks 48 to 52 is presented in Table 9. A 100% reduction in the

OCS dose was observed in 41% of patients receiving benralizumab compared to 26% of thosereceiving mepolizumab (difference 15.69%, 95% CI: 0.67, 30.71, nominal p-value 0.04).

Table 9. Average daily oral corticosteroid dose during weeks 48 to 52 in EGPA

Number (%) of Patients

Benralizumaba (N=70) Mepolizumabb (N=70)0 mg 29 (41) 19 (27)>0 to ≤4.0 mg 19 (27) 30 (43)>4.0 to ≤7.5 mg 15 (21) 13 (19)>7.5 mg 7 (10) 8 (11)

N=number of patients in analysis.

a. Benralizumab 30 mg administered every 4 weeks.

b. Mepolizumab 300 mg administered every 4 weeks.

Asthma Control Questionnaire-6 (ACQ-6)

The ACQ-6 mean change from baseline was -0.57 for benralizumab versus -0.61 for mepolizumab(difference 0.05, 95% CI: -0.18, 0.27, nominal p-value 0.67).

Overall, treatment-emergent anti-drug antibody (ADA) response developed in 107 out of 809 (13%)patients with asthma treated with benralizumab at the recommended dose regimen during the 48 to56 week treatment period of the phase 3 placebo-controlled exacerbation trials. Most antibodies wereneutralising and persistent. Anti-benralizumab antibodies were associated with increased clearance ofbenralizumab and increased blood eosinophil levels in patients with high ADA titres compared toantibody negative patients; in rare cases, blood eosinophil levels returned to pre-treatment levels.

Based on current patient follow-up, no evidence of an association of ADA with efficacy or safety wasobserved.

Following a second year of treatment of these patients with asthma from the phase 3placebo-controlled trials, an additional 18 out of 510 (4%) had newly developed treatment-emergentantibodies. Overall, in patients who were ADA positive in the predecessor trials, titres remained stableor declined in the second year of treatment. No evidence of an association of ADA with efficacy orsafety was observed.

In patients with EGPA, treatment-emergent ADA response developed in 6 out of 67 (9%) patientstreated with benralizumab during the Phase 3 active-controlled 52-week treatment period. Neutralisingantibody activity was detected in one of the ADA positive patients.

Asthma

There were 108 adolescents aged 12 to 17 with asthma enrolled in the phase 3 trials (Trial 1: n=53,

Trial 2: n=55). Of these, 46 received placebo, 40 received benralizumab every 4 weeks for 3 doses,followed by every 8 weeks thereafter, and 22 received benralizumab every 4 weeks. In these trials, theasthma exacerbation rate in adolescent patients treated with benralizumab administered at therecommended dose regimen was 0.70 (n=40, 95% CI: 0.42, 1.18) compared to 0.41 for placebo (n=46,95% CI: 0.23, 0.73) [rate ratio 1.70, 95% CI: 0.78, 3.69].

Adolescent patients aged 12 to 17 (n=86) from Trials 1 and 2 continued treatment with benralizumabin Trial 4 for up to 108 weeks. Efficacy and safety were consistent with the predecessor trials.

In an open-label, uncontrolled pharmacokinetic and pharmacodynamic study of 48 weeks duration in alimited number of patients 6 to 11 years (n=28) with uncontrolled severe asthma, the magnitude ofblood eosinophil depletion was similar to adults and adolescents.

No conclusion can be drawn regarding asthma efficacy in the paediatric population (see section 4.2).

The European Medicines Agency has deferred the obligation to submit the results of studies withbenralizumab in one or more subsets of the paediatric population in asthma (see section 4.2 forinformation on paediatric use).

Eosinophilic granulomatosis with polyangiitis (EGPA)

The European Medicines Agency has deferred the obligation to submit the results of studies withbenralizumab in one or more subsets of the paediatric population in EGPA (see section 4.2 forinformation on paediatric use).

The pharmacokinetic properties of benralizumab below are based on the population pharmacokineticsanalyses from the asthma trials. The pharmacokinetics of benralizumab were dose-proportional inpatients with asthma following subcutaneous administration over a dose range of 2 to 200 mg.

Following subcutaneous administration to patients with asthma, the absorption half-life was 3.5 days.

Based on population pharmacokinetic analysis, the estimated absolute bioavailability wasapproximately 59% and there was no clinically relevant difference in relative bioavailability in theadministration to the abdomen, thigh, or upper arm.

Based on population pharmacokinetic analysis, central and peripheral volume of distribution ofbenralizumab was 3.1 L and 2.5 L, respectively, for a 70 kg individual.

Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymeswidely distributed in the body and not restricted to hepatic tissue.

From population pharmacokinetic analysis, benralizumab exhibited linear pharmacokinetics and noevidence of target receptor-mediated clearance pathway. The estimated systemic clearance (CL) forbenralizumab was at 0.29 L/d. In patients with EGPA, the model estimated systemic clearance was0.22 L/d. Following subcutaneous administration, the elimination half-life was approximately15.5 days.

Based on population pharmacokinetic analysis, age did not affect benralizumab clearance. However,no data are available in patients over 75 years of age.

Based on population pharmacokinetic analysis and clinical study data, the pharmacokinetics ofbenralizumab in children and adolescents aged 6 to 17 years with asthma were consistent with adultsafter accounting for bodyweight as applicable (see section 4.2).

Gender, race

A population pharmacokinetics analysis, indicated that there was no significant effect of gender andrace on benralizumab clearance.

No formal clinical studies have been conducted to investigate the effect of renal impairment onbenralizumab. Based on population pharmacokinetic analysis, benralizumab clearance was comparablein subjects with creatinine clearance values between 30 and 80 mL/min and patients with normal renalfunction. There are limited data available in subjects with creatinine clearance values less than30 mL/min; however, benralizumab is not cleared renally.

No formal clinical studies have been conducted to investigate the effect of hepatic impairment onbenralizumab. IgG monoclonal antibodies are not primarily cleared via hepatic pathway; change inhepatic function is not expected to influence benralizumab clearance. Based on populationpharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had noclinically relevant effect on benralizumab clearance.

Interaction

Based on the population pharmacokinetic analysis, commonly co-administered medicinal products(montelukast, paracetamol, proton pump inhibitors, macrolides and theophylline/aminophylline) hadno effect on benralizumab clearance in patients with asthma.

As benralizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have beenconducted.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology or repeated dose toxicity studies in monkeys. Intravenous and subcutaneousadministration to cynomolgus monkeys was associated with reductions in peripheral blood and bonemarrow eosinophil counts, with no toxicological findings.

In a prenatal and postnatal development study in pregnant cynomolgus monkeys, there were nobenralizumab-related maternal, embryo-foetal, or postnatal effects observed.

No dedicated animal studies have been conducted. No benralizumab-related impairment was observedin reproductive parameters of male and female cynomolgus monkeys. Examination of surrogatefertility parameters (including organ weights and histopathology of reproductive tissues) in animalstreated with benralizumab suggested no impairment of fertility. However, in the offspring of monkeysdosed while pregnant, there was a reduction in eosinophils.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Polysorbate 20 (E 432)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2°C to 8°C).

Fasenra may be kept at room temperature up to 25°C for a maximum of 14 days. After removal fromthe refrigerator, Fasenra must be used within 14 days or discarded.

Store in the original package in order to protect from light.

Do not freeze. Do not shake. Do not expose to heat.

One mL solution in a single-use pre-filled syringe made from type I glass with a staked 29-gauge½-inch (12.7 mm) stainless steel needle, rigid needle shield, and Fluorotec-coated plunger stopper in apassive safety device.

Pack containing 1 pre-filled syringe.

Pre-filled pen

One mL solution in a sterile, single use pre-filled pen made from type I glass with staked 29-gauge½-inch (12.7 mm) stainless steel needle, rigid needle shield, and Fluorotec-coated stopper in apre-filled pen.

Pack containing 1 pre-filled pen.

Not all presentations may be marketed.

Prior to administration, allow the pre-filled syringe or pre-filled pen to reach room temperature 20°C

to 25°C by leaving the carton out of the refrigerator for around 30 minutes.

Visually inspect Fasenra for particulate matter and discolouration prior to administration. Fasenra isclear to opalescent, colourless to yellow, and may contain translucent or white to off-white particles.

Do not use Fasenra if liquid is cloudy, discoloured, or if it contains large particles or foreignparticulate matter.

Additional information and instructions for the preparation and administration of Fasenra using thepre-filled syringe or pre-filled pen are given in the package leaflet and ‘Instructions for Use’.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/17/1252/001 1 pre-filled syringe

EU/1/17/1252/002 1 pre-filled pen

Date of first authorisation: 08 January 2018

Date of latest renewal: 15 September 2022

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

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