英文药名：Fasenra(Benralizumab for Subcutaneous Injection)
Hypersensitivity reactions were defined by the following grouped preferred terms: 'Urticaria', 'Papular urticaria', and 'Rash'. For examples of the associated manifestations reported and a description of the time to onset, see section 4.4
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 recommended benralizumab dose compared with 1.9% in patients treated with placebo.
There are limited data in paediatric patients (see section 5.1). The frequency, type and severity of adverse reactions in the adolescent population were observed to be similar to those seen in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Doses of up to 200 mg were administered subcutaneously in clinical trials to patients with eosinophilic asthma 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.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX10
Mechanism of action
Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). It binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with high affinity 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 for FcɣRIII receptors on immune effectors cells such as natural killer (NK) cells. This leads to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), which reduces eosinophilic inflammation.
Effect on blood eosinophils
Treatment with benralizumab results in near complete depletion of blood eosinophils within 24 hours following the first dose which is maintained throughout the treatment period. The depletion 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 blood basophils.
Effect on eosinophils in the airway mucosa
The effect of benralizumab on eosinophils in the airway mucosa in asthmatic patients with elevated sputum 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 SC. In this study there was a median reduction from baseline in airway mucosa eosinophils of 96% in the benralizumab treated group compared to a 47% reduction in the placebo group (p=0.039).
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.
In these studies, Fasenra was administered at a dose of 30 mg once every 4 weeks for the first 3 doses, and then every 4 or 8 weeks thereafter as add-on to background treatment and was evaluated in comparison with placebo.
The two exacerbation trials, SIROCCO (Trial 1) and CALIMA (Trial 2), enrolled a total of 2,510 patients with severe uncontrolled asthma, 64% females, with a mean age of 49 years. Patients had a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment (mean of 3) in the past 12 months, ACQ-6 score of 1.5 or more at screening, and reduced lung function at baseline (mean predicted pre-bronchodilator forced expiratory volume 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); at least 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 additional controller to maintain asthma control in 53% of the cases. The trial included an 8-week run-in period during 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 the past 12 months.
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 section 4.2) as no additional benefit was observed by more frequent dosing. The results summarised below are those for the recommended dosing regimen.
The primary endpoint was the annual rate of clinically significant asthma exacerbations in patients with 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 of oral/systemic corticosteroids for at least 3 days, and/or emergency department visits requiring use of oral/systemic corticosteroids and/or hospitalisation. For patients on maintenance oral corticosteroids, this 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 both trials, patients receiving Fasenra experienced significant reductions in annual exacerbation 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 maintained through 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 treatment response particularly for FEV1.
Table 2. Results of annual exacerbation rate and lung function at end of treatment of Trial 1 and 2 by eosinophil count.
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 and greater improvements in FEV1 with increasing baseline blood eosinophils.
The rate of exacerbations requiring hospitalisation and/or emergency room visits for patients receiving Fasenra 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 exacerbations requiring hospitalisation or emergency room visits.
In both Trials 1 and 2, patients receiving Fasenra experienced statistically significant reductions in asthma symptoms (Total Asthma Score) compared to patients receiving placebo. Similar improvement in favour of Fasenra was observed for the Asthma Control Questionnaire-6 (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
b. Asthma symptom scale: total score from 0 (least) to 6 (most); day and night time asthma symptom scores from 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 a potential predictor of improved treatment response. When considered alone or in combination with baseline blood eosinophils count, these factors may further identify patients who may achieve greater response from benralizumab treatment (Table 4).
Table 4. Exacerbation rate and pulmonary function (FEV1) at end of treatment by number of exacerbations in the previous year - Patients on high-dose ICS and blood eosinophils ≥300 cells/μL
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. Table 5 summarizes the study results for Trial 3.
Table 5. Effect of Fasenra on OCS dose reduction, Trial 3
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.
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 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.
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. 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]. No conclusion can be drawn regarding asthma efficacy in the paediatric population.
The European Medicines Agency has waived the obligation to submit the results of studies with Fasenra in paediatric population aged from birth to less than 5 years in asthma (see section 4.2 for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with Fasenra in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of benralizumab were dose-proportional in patients 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 was approximately 59% and there was no clinically relevant difference in relative bioavailability in the administration to the abdomen, thigh, or upper arm.
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.
Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.
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.
Elderly patients (≥65 years old)
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 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 (5 to 11 years old) (see section 4.2).
A population pharmacokinetics analysis, indicated that there was no significant effect of gender and race on benralizumab clearance.
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.
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.
No formal drug-drug interaction studies have been conducted. An effect of benralizumab on the pharmacokinetics of co-administered medicinal products is not expected. Based on the population pharmacokinetic analysis, commonly co-administered medicinal products (montelukast, paracetamol, proton pump inhibitors, macrolides and theophylline/aminophylline) had no effect on benralizumab clearance in patients with asthma.
5.3 Preclinical safety data
As benralizumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
Animal toxicology and/or pharmacology
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.
In a prenatal and postnatal development study in pregnant cynomolgus monkeys, there were no benralizumab-related maternal, embryo-foetal, or postnatal effects observed.
No dedicated animal studies have been conducted. No benralizumab-related impairment was observed in reproductive parameters of male and female cynomolgus monkeys. Examination of surrogate fertility parameters (including organ weights and histopathology of reproductive tissues) in animals treated with benralizumab suggested no impairment of fertility. However, in the offspring of monkeys dosed while pregnant, there was a reduction in eosinophils.
6. Pharmaceutical particulars
6.1 List of excipients
Histidine hydrochloride monohydrate
Water for injections
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
6.4 Special precautions for storage
Store in a refrigerator (2°C to 8°C). Store the pre-filled syringe in the original package in order to protect from light. Do not freeze. Do not shake.
6.5 Nature and contents of container
One mL solution in a single-use pre-filled syringe made from type I glass with a staked 29-gauge ½-inch stainless steel needle, rigid needle shield, and Fluorotec-coated plunger stopper in a passive safety device.
Pack containing 1 single-use pre-filled syringe.
6.6 Special precautions for disposal and other handling
Fasenra solution for injection is supplied in a sterile single-use pre-filled syringe for individual use. 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 24 hours or discard into sharps container.
Instructions for Pre-filled Syringe with Needle Safety Guard
Refer to Figure 1 below to identify the pre-filled syringe components for use in the administration steps.
Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.
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 pre-filled syringe is damaged or contaminated (for example, dropped without needle cover in place), discard and use a new pre-filled syringe.
3.Gently pinch the skin and insert the needle at the recommended injection site (i.e. upper arm, thighs, or abdomen).
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 pre-filled syringe.
6.Discard the used syringe into a sharps container.
Fasenra 30mg solution injection pre（贝那利珠单抗预充式注射器）
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