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Fasenra

Fasenra

Manufacturer:

AstraZeneca

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Benralizumab.
Description
Each prefilled syringe contains 30 mg benralizumab in 1 mL.
Benralizumab is a humanised, afucosylated, monoclonal antibody selective for interleukin-5Rα. Benralizumab is of the IgG1/κ-class produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Benralizumab has a molecular weight of approximately 150 kDa.
Excipients/Inactive Ingredients: L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, Polysorbate 20, Water for Injection.
Action
Pharmacology: Mechanism of action: Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). Benralizumab binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with high affinity (16 pM) and specificity. The IL-5 receptor is specifically expressed on the surface of eosinophils and basophils. The absence of fucose in the Fc domain of benralizumab results in high affinity (45.5 nM) for FcγRIII receptors on immune effectors cells such as natural killer (NK) cells leading to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).
Eosinophilic inflammation is an important component in the pathogenesis of asthma. Eosinophils are a rich source of proinflammatory mediators (e.g., eicosanoids, leukotrienes, cytokines) and granule proteins (e.g. eosinophil cationic protein, eosinophil peroxidase, eosinophil neurotoxin and major basic protein). Benralizumab, by enhanced ADCC, reduces eosinophilic inflammation.
Pharmacodynamics: The pharmacodynamic response (blood eosinophil depletion) following repeat SC dosing was evaluated in asthma patients in a 12-week Phase 2 trial. Patients received 1 of 3 doses of benralizumab [25 mg (n=7), 100 mg (n=6) or 200 mg (n=6) SC] or placebo (n=6) every 4 weeks for a total of 3 doses. Median blood eosinophil levels at baseline were 400, 200, 120 and 200 cells/μL in the 25, 100, and 200 mg benralizumab and placebo groups, respectively. Blood eosinophil depletion was observed following SC administration of benralizumab at all dose levels and no depletion was observed in the placebo group. Twenty-four hours post dosing, all benralizumab dosage groups demonstrated complete or near complete depletion of median blood eosinophil levels (0, 0, and 5 cells/μL, respectively). There were no changes in median blood eosinophils in the placebo group. The effect on blood eosinophil depletion was maintained throughout the dosing period.
In a Phase 1 trial, the effect of benralizumab on eosinophils in airway mucosa was evaluated in asthmatic patients with 2.5% or more eosinophils in sputum. Patients received 100 or 200 mg SC benralizumab once every 4 weeks for 8 weeks (total benralizumab SC group n=9) or matching placebo (n=5). At the end of the 12 week treatment period, there was a median reduction from baseline in eosinophils in the airway mucosa of 96% in the total benralizumab SC group compared to a 47% reduction from baseline in the placebo group which was statistically significant (p=0.039).
In the Phase 1 trial, treatment with benralizumab was also associated with reductions in blood basophils, and in both Phase 1 and 2 trials eosinophil granule products such as serum eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP).
In Trials 1 and 2, following SC administration of benralizumab at the recommended dose blood eosinophils were reduced to a median absolute blood eosinophil count of 0 cells/μL, which corresponds to a median reduction of 100% (see Clinical efficacy as follows). This magnitude of reduction was seen at the first observed time point, 4 weeks of treatment, and was maintained throughout the treatment period. Maintenance of eosinophil depletion was observed throughout the 56 week extension phase (Trial 4) consistent with previous trials.
Immunogenicity: Overall, treatment-emergent anti-drug antibody response developed in 107 out of 809 (13%) patients treated with FASENRA at the recommended dosing regimen during the 48 to 56 week treatment period of the phase 3 placebo controlled exacerbation trials. Most antibodies were neutralising and persistent. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titres compared to antibody 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 anti-drug antibodies with efficacy or safety was observed.
Following a second year of treatment of these patients from the phase 3 placebo-controlled trials, an additional 18 out of 510 (4%) had newly developed treatment emergent antibodies. Overall, in patients who were anti-drug antibody positive in the predecessor trials, titers remained stable or declined in the second year of treatment. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.
Clinical efficacy: The efficacy of FASENRA 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.
The two exacerbation trials SIROCCO (Trial 1) and CALIMA (Trial 2) were 48 and 56 weeks duration, respectively, and randomised a total of 2,510 patients with uncontrolled asthma. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months, ACQ-6 score of 1.5 or more at screening, and reduced lung function at baseline [pre-bronchodilator forced expiratory volume in 1 second (FEV1) below 80% in adults, and below 90% in adolescents] despite regular treatment with high dose ICS (Trial 1) or with medium or high dose ICS (Trial 2) and their current standard of care. Patients were stratified by geography, age, and blood eosinophils count (≥300 cells/μL or <300 cells/μL). FASENRA administered once every 4 weeks for the first 3 doses, and then every 4 or 8 weeks thereafter as add-on to background treatment was evaluated compared to placebo.
For the oral corticosteroid-reduction trial ZONDA (Trial 3), a total of 220 asthma patients were enrolled who were being treated with daily OCS (7.5 to 40 mg per day) in addition to regular use of high-dose ICS and LABA with or without additional controller(s) to maintain asthma control. The trial included an 8-week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. Baseline median OCS dose was similar across all treatment groups. Patients were required to have blood eosinophil counts greater than or equal to 150 cells/μL and a history of at least one exacerbation in the past 12 months. The baseline median OCS dose was 10 mg (range: 8 to 40 mg) for all 3 treatment groups (placebo, FASENRA every 4 weeks, and FASENRA every 4 weeks for the first 3 doses, and then once every 8 weeks).
While 2 dosing regimens were studied in Trials 1, 2, and 3, the recommended dosing regimen is FASENRA administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (see Dosage & Administration). (See Table 1.)

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Exacerbations: The primary endpoint for Trials 1 and 2 was the rate of clinically significant asthma exacerbations in patients with baseline blood eosinophil counts of greater than or equal to 300 cells/μL who were taking high-dose ICS and LABA. Clinically significant asthma exacerbation was defined as worsening of asthma requiring use of oral/systemic corticosteroids for at least 3 days, and/or emergency department visits requiring use of oral/systemic corticosteroids and/or hospitalization. For patients on maintenance oral corticosteroids, a clinically significant asthma exacerbation requiring oral corticosteroids was defined as a temporary increase in stable oral/systemic corticosteroids for at least 3 days or a single depo-injectable dose of corticosteroids. In Trial 1, 35% of patients receiving FASENRA experienced a clinically significant exacerbation compared to 51% on placebo. In Trial 2, 40% of patients receiving FASENRA experienced a clinically significant exacerbation compared to 51% on placebo. Compared with placebo, patients receiving FASENRA experienced significant reductions in annual exacerbation rate (Table 2). In Trial 2, there were too few events in the placebo treatment arm to draw conclusions for exacerbations requiring hospitalization or emergency room visits. (See Table 2.)

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Exacerbation results in patients with baseline blood eosinophil counts less than 300 cells/μL who were taking high-dose ICS are presented in Table 5.
The time to first exacerbation was longer for the patients receiving FASENRA compared with placebo in Trials 1 and 2 (Figure 1). (See Figure 1.)

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Lung Function: Change from baseline in mean FEV1 was measured in both trials and is presented in Figure 2. Compared with placebo, FASENRA provided consistent improvements over time in the mean change from baseline in FEV1. (See Figure 2.)

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Additionally, an improvement in mean change of morning and evening peak expiratory flow (PEF) from baseline was observed in patients receiving FASENRA compared to placebo at end of treatment.
Additional results from Trials 1 and 2 in patients with baseline blood eosinophil counts of greater than or equal to 300 cells/μL who were taking high-dose ICS and LABA are shown in Table 3.
Results in patients with baseline blood eosinophil counts less than 300 cells/μL who were taking high-dose ICS are presented in Table 5. (See Table 3.)

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During Trials 1 and 2, patients had an average of 68 and 88 symptom free days with FASENRA compared to 58 and 74 symptom free days with placebo, respectively.
The Asthma Control Questionnaire-6 (ACQ-6) and Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) were assessed in Trials 1 and 2. The responder rate for both measures was defined as improvement in score of 0.5 or more as threshold at the end of Trials 1 and 2 (48 and 56 weeks, respectively). In Trial 1, the ACQ-6 responder rate for FASENRA was 60% vs 50% placebo (odds ratio 1.55; 95% CI: 1.09, 2.19). In Trial 2, the ACQ-6 responder rate for the FASENRA was 63% vs 59% placebo (odds ratio 1.16; 95% CI: 0.80, 1.68). In Trial 1, the responder rate for AQLQ(S)+12 for FASENRA was 57% vs 49% placebo (odds ratio 1.42; 95% CI: 0.99, 2.02), and in Trial 2, 60% FASENRA vs 59% placebo (odds ratio of 1.03; 95% CI: 0.70,1.51).
Subgroup analyses: Subgroup analyses from Trials 1 and 2 identified patients with higher prior exacerbation history and baseline blood eosinophil count as potential predictors of improved treatment response. When considered alone or in combination, these factors may further identify patients who may achieve greater response from benralizumab treatment.
Prior Exacerbation History: In both trials, patients with a history of 3 or more exacerbations within 12 months prior to FASENRA randomization showed a numerically greater exacerbation response than those with fewer prior exacerbations. (See Table 4.)

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Patients with a prior exacerbation history of 3 or more had mean differences in FEV1 of 0.235 L (95% CI: 0.088, 0.382) and 0.265 L (95% CI: 0.115, 0.415) at end of treatment with FASENRA, in Trials 1 and 2 respectively. Those with a prior exacerbation history of 2 had mean differences in FEV1 of 0.113 L (95% CI: -0.002, 0.228) and 0.029 L (95% CI: -0.079, 0.137), in Trials 1 and 2 respectively.
Patients with a prior exacerbation history of 3 or more had differences from baseline in mean asthma symptom score of -0.32 (95% CI: -0.62, -0.01) and -0.41 (95% CI: -0.73, -0.09) at the end of treatment with FASENRA, in Trials 1 and 2 respectively. Those with a prior exacerbation history of 2 had differences from baseline in mean asthma symptom score of -0.22 (95% CI: -0.49, 0.04) and -0.12 (95% CI: -0.37, 0.13) at the end of treatment with FASENRA, in Trials 1 and 2 respectively.
Blood Eosinophil Count: Reductions in exacerbation rates were observed irrespective of baseline eosinophil count; however increasing baseline eosinophil counts was identified as a potential predictor of improved treatment response particularly for FEV1 with FASENRA (see Tables 2 and 3). Table 5 presents results in patients with baseline blood eosinophil counts less than 300 cells/uL who were taking high-dose ICS. (See Table 5.)

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Across Trials 1 and 2 combined, there was a numerically greater exacerbation rate reduction with increasing baseline blood eosinophils. Analyses also showed greater improvements in FEV1 in patients with increasing baseline blood eosinophil counts.
OCS Dose Reduction Trial: Trial 3 evaluated the effect of FASENRA on reducing the use of maintenance oral corticosteroids. The primary endpoint was percent reduction from baseline of the final OCS dose during Weeks 24 to 28, while maintaining asthma control. Compared to placebo, patients receiving FASENRA achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. Reductions of 50% or higher in the OCS dose were observed in 48 (66%) patients receiving FASENRA compared to those receiving placebo 28 (37%). The proportion of patients with a mean final dose less than or equal to 5 mg at Weeks 24 to 28 were 59% for FASENRA and 33% for placebo (odds ratio 2.74, 95% CI: 1.41, 5.31). At the same time, patients treated with FASENRA maintained asthma control as reflected by improved lung function, reduced symptoms, and a need for rescue medication. Only patients with an optimized baseline OCS dose of 12.5 mg or less were eligible to achieve a 100% reduction in OCS dose during the study. Of those patients, 52.4% (22 of 42) receiving FASENRA and 19% (8 of 42) on placebo achieved a 100% reduction in OCS dose. Table 6 summarizes the study results for Trial 3. Additionally, the percent reduction in exacerbations and exacerbations requiring hospitalization and/or emergency room visits for patients receiving FASENRA compared to placebo were 70% (rate 0.54 versus 1.83, rate ratio 0.30, 95% CI: 0.17, 0.53) and 93% (rates 0.02 versus 0.32, rate ratio 0.07, 95% CI: 0.01, 0.63), respectively. (See Table 6.)

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Lung function, asthma symptom score, ACQ-6 and AQLQ(S)+12 were also assessed in Trial 3 and showed results similar to those in Trials 1 and 2.
Long term Extension Trial: The long-term efficacy and safety of FASENRA was evaluated in a double-blind, randomized, parallel group, Phase 3, 56 week extension trial BORA (Trial 4). The trial enrolled 2,123 adults and adolescent patients (aged 12 years and older) from Trials 1, 2 and 3. Trial 4 assessed the long-term effect of FASENRA on annual exacerbation rate, lung function, ACQ-6, AQLQ(S)+12 and maintenance of OCS reduction at the 2 dosing regimens studied in the predecessor studies.
At the recommended dosing regimen, the reduction in annual rate of exacerbations observed in the placebo-controlled predecessor Trials 1 and 2 (in patients with baseline blood eosinophil counts of greater than or equal to 300 cells/μL who were taking high-dose ICS) was maintained over the second year of treatment (Table 7). In patients who received FASENRA in predecessor Trials 1 and 2, 73% were exacerbation free in the extension Trial 4. (See Table 7.)

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Similar maintenance of effect was observed throughout Trial 4 in lung function, ACQ-6 and AQLQ(S)+12 (Table 8). (See Table 8.)

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Efficacy in Trial 4 was also evaluated in patients with baseline blood eosinophil counts less than 300 cells/μl and was consistent with Trials 1 and 2.
Maintenance of the reduction in daily OCS dose was also observed over the extension trial in patients enrolled from Trial 3 (Figure 3). (See Figure 3.)

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Paediatric population: 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 FASENRA every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received FASENRA every 4 weeks. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV1<90%) despite regular treatment with medium or high dose ICS and LABA with or without OCS or other controller therapy. In these trials, the asthma exacerbation rate in adolescent patients treated with FASENRA administered at the recommended dosing 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]. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies (see Adverse Reactions).
Adolescent patients aged 12 to 17 (n=86) from Trials 1 and 2 continued treatment with FASENRA in Trial 4 for up to 108 weeks. Efficacy and safety were consistent with the predecessor trials.
Pharmacokinetics: The pharmacokinetics of benralizumab were dose-proportional in patients with asthma following subcutaneous administration over a dose range of 2 to 200 mg.
Absorption: Following subcutaneous administration to patients with asthma, the absorption half-life was 3.5 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 59% and there was no clinically relevant difference in relative bioavailability in the administration to the abdomen, thigh, or upper arm.
Distribution: Based on population pharmacokinetic analysis, central and peripheral volume of distribution of benralizumab was 3.1 L and 2.5 L, respectively, for a 70 kg individual.
Biotransformation: Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.
Elimination: From population pharmacokinetic analysis, benralizumab exhibited linear pharmacokinetics and no evidence of target receptor-mediated clearance pathway. The estimated systemic clearance (CL) for benralizumab was at 0.29 L/d. Following subcutaneous administration, the elimination half-life was approximately 15.5 days.
Special populations: Elderly patients (≥65 years old): Based on population pharmacokinetic analysis, age did not affect benralizumab clearance.
Gender, race: A population pharmacokinetics analysis indicated that there was no significant effect of gender and race on benralizumab clearance.
Renal impairment: No formal clinical studies have been conducted to investigate the effect of renal impairment on benralizumab. Based on population pharmacokinetic analysis, benralizumab clearance was comparable in subjects with creatinine clearance values between 30 and 80 mL/min and patients with normal renal function. There are limited data available in subjects with creatinine clearance values less than 30 mL/min; however benralizumab is not cleared renally.
Hepatic impairment: No formal clinical studies have been conducted to investigate the effect of hepatic impairment on benralizumab. IgG monoclonal antibodies are not primarily cleared via hepatic pathway; change in hepatic function is not expected to influence benralizumab clearance. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had no clinically relevant effect on benralizumab clearance.
Paediatric: Based on the population pharmacokinetic analysis, the pharmacokinetics of benralizumab in adolescents aged 12 to 17 years were consistent with adults. Benralizumab has not been studied in children (6-11 years old) (see Dosage & Administration).
Drug-drug interaction: An effect of benralizumab on the pharmacokinetics of co-administered medications is not expected. Based on the population pharmacokinetic analysis, commonly co-administered medications had no effect on benralizumab clearance in patients with asthma.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeated dose toxicity studies in monkeys. Intravenous and subcutaneous administration to cynomolgus monkeys was associated with reductions in peripheral blood and bone marrow eosinophil counts, with no toxicological findings.
Carcinogenesis and mutagenesis: As benralizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Reproductive toxicology: In a prenatal and postnatal development study, pregnant cynomolgus monkeys there were no benralizumab-related maternal, embryo-fetal, or postnatal effects observed.
In cynomolgus monkeys, male and female fertility were unaffected.
Indications/Uses
FASENRA is indicated as an add-on maintenance treatment in adult patients from 18 years with severe eosinophilic asthma characterised by the following criteria: At least two exacerbations in the past 12 months on the current standard therapy (high-dose inhaled corticosteroids plus long-acting bronchodilators) and/or need for treatment with systemic corticosteroids.
Eosinophil count in the blood of ≥0.3 G/L (corresponding to ≥300 cells/μL).
For detailed information about the patient populations investigated in trials, please see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions.
Dosage/Direction for Use
Fasenra treatment should be initiated by a physician experienced in the diagnosis and treatment of severe asthma.
Posology: The recommended dose is 30 mg of FASENRA by subcutaneous injection every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.
Fasenra is intended for long-term treatment. A decision to continue the therapy should be made at least annually based on disease severity, level of exacerbation control and blood eosinophil counts.
Paediatric population: The safety and efficacy of FASENRA in children aged 6 to 18 years have not been established.
No data are available for children aged 6 to 11 years old. Currently available data in children 12 to less than 18 years old are described in Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions but no recommendation on a posology can be made.
Elderly patients: No dose adjustment is required for elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Renal and hepatic impairment: No dose adjustment is required for patients with renal or hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: FASENRA is administered as a subcutaneous injection by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended (see Hypersensitivity reactions under Precautions).
Administer FASENRA into the upper arm, thigh, or abdomen. Do not administer into areas where the skin is tender, bruised, erythematous, or hardened (see Instructions for use, handling and disposal under Cautions for Usage).
Overdosage
Doses of up to 200 mg were administered subcutaneously in clinical trials to patients with eosinophilic disease without evidence of dose-related toxicities.
There is no specific treatment for an overdose with benralizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Contraindications
FASENRA is contraindicated in patients who have known hypersensitivity to benralizumab or any of its excipients (see Description).
Special Precautions
FASENRA should not be used to treat acute asthma exacerbations.
Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsens after 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 the supervision of a physician.
Hypersensitivity reactions: Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, urticaria papular, rash) have occurred following administration of FASENRA. These reactions may occur within hours of administration, but in some instances have a delayed onset (i.e., days).
In the event of a hypersensitivity reaction, FASENRA should be discontinued.
Parasitic (helminth) infection: Eosinophils may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if FASENRA may influence a patient's response against helminth infections.
Treat patients with pre-existing helminth infections before initiating therapy with FASENRA. If patients become infected while receiving treatment with FASENRA and do not respond to anti-helminth treatment, discontinue treatment with FASENRA until infection resolves.
Effects on ability to drive and use machines: FASENRA has no or negligible influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk.
Monoclonal antibodies such as benralizumab are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential exposure to a fetus is likely to be greater during the second and third trimester of pregnancy.
In a pre- and postnatal development study conducted in cynomolgus monkeys there were no maternal, embryo-fetal, or postnatal developmental effects observed for benralizumab doses 10 or 30 mg/kg IV (bolus) beginning on gestation day (GD) 20 to GD22, on GD35, and once every 14 days thereafter through gestation and 1-month postpartum (see Pharmacology: Toxicology: Preclinical safety data under Actions).
It is preferable to avoid the use of FASENRA during pregnancy. Administration of FASENRA to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
Lactation: It is unknown whether benralizumab or its metabolites are excreted in human or animal milk, therefore risk to the breastfed child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from benralizumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
Fertility: No fertility studies have been conducted in humans.
Fertility parameters were assessed in a 9 month repeat dose study in cynomolgus monkeys at IV doses up to 25 mg/kg or at SC doses of up to 30 mg/kg once every 2 weeks (approximately 409 and 275 times the MRHD on an AUC basis, and 396 and 193 times the MRHD on a Cmax basis). No benralizumab-related adverse changes in reproductive parameters of female or male cynomolgus monkeys were observed.
Adverse Reactions
Overall Summary of Adverse Drug Reactions: In clinical studies, in patients with severe asthma with eosinophilic phenotype the most commonly reported adverse reaction during treatment was headache and pharyngitis.
Adverse Drug Reactions: A total of 1,663 patients with uncontrolled severe asthma received benralizumab during the two placebo-controlled Phase 3 clinical studies of 48 to 56 weeks duration. Table 9 presents the adverse reactions from the two placebo-controlled studies in patients receiving benralizumab 30 mg every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.
The frequency of adverse reactions is defined using 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 be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 9.)

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Description of selected adverse reaction: Injection site reactions: In placebo-controlled studies, injection site reactions (e.g., pain, erythema, pruritus, papule) occurred at a rate of 2.2% in patients treated with the indicated benralizumab dose compared with 1.9% in patients treated with placebo.
Summary of post-marketing data: The following adverse reactions have been identified during post approval use of FASENRA. It is generally not possible to reliably determine the frequency because such reactions have been reported spontaneously from a population of uncertain size and therefore represent reporting rates. The frequency of these adverse reactions is therefore 'not known' (cannot be estimated from available data).
Immune system disorders: Anaphylaxis (defined by the grouped preferred terms: 'Anaphylactic reaction', 'Angioedema').
Long-term safety: In a 56-week double blind, randomized, parallel-group extension trial in patients with asthma from Trials 1, 2 and 3, 842 patients were treated with FASENRA at the recommended dose and remained in the trial. The overall adverse event profile was similar to the asthma trials described previously.
Drug Interactions
In a randomized, double-blind parallel-group study of 103 patients aged between 12 and 21 years with severe asthma, the humoral antibody responses induced by seasonal influenza virus vaccination were similar between benralizumab 30 mg and placebo.
Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of benralizumab. There is no evidence of IL-5Rα expression on hepatocytes. Eosinophil depletion does not produce chronic systemic alterations of proinflammatory cytokines.
Caution For Usage
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Instructions for use, handling and disposal: Do not shake. Do not use if frozen.
Instructions for administration: Prior to administration, warm FASENRA by leaving carton at room temperature. This generally takes 30 minutes. Administer within 14 days or discard into sharps container.
Instructions for Prefilled Syringe with Needle Safety Guard: Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.
1. Grasp the syringe body, not the plunger, to remove prefilled syringe from the tray. Check the expiration date on the syringe. Visually inspect FASENRA for particulate matter and discoloration prior to administration. FASENRA is clear, 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 foreign particulate matter. The syringe may contain a small air bubble; this is normal. Do not expel the air bubble prior to administration.
2. Do not remove needle cover until ready to inject. Hold the syringe body and remove the needle cover by pulling straight off. Do not hold the plunger or plunger head while removing the needle cover or the plunger may move. If prefilled syringe is damaged or contaminated (for example, dropped without needle cover in place), discard and use a new prefilled syringe.
3. Gently pinch the skin and insert the needle at the recommended injection site (i.e., upper arm, thighs, or abdomen).
4. Inject all of the medication by pushing in the plunger all the way until the plunger head is completely between the needle guard activation clips. This is necessary to activate the needle guard.
5. After injection, maintain pressure on the plunger head and remove the needle from the skin. Release pressure on the plunger head to allow the needle guard to cover the needle. Do not re-cap the prefilled syringe.
6. Discard the used syringe into a sharps container.
Storage
Store in a refrigerator (2°C - 8°C). FASENRA may be kept at room temperature up to 25°C for a maximum of 14 days. After removal from the refrigerator, FASENRA must be used within 14 days or discarded. Store the prefilled syringe in the original package in order to protect from light. Do not freeze. Do not expose to heat.
ATC Classification
R03DX10 - benralizumab ; Belongs to the class of other systemic drugs used in the treatment of obstructive airway diseases.
Presentation/Packing
Soln for inj 30 mg/mL (clear to opalescent, colourless to yellow solution in pre-filled syringe) x 1's.
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