2.1 Recommended Dosage

Adult and Adolescent Patients 12 Years of Age and Older

The recommended dosage of FASENRA is 30 mg (one injection) administered subcutaneously every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.

Pediatric Patients 6 to 11 Years of Age

The recommended dosage of FASENRA for pediatric patients 6 to 11 years of age is based on body weight as provided in Table 1.

2.2 General Administration Instructions

FASENRA is for subcutaneous use only.

FASENRA is intended for use under the guidance of a healthcare provider. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions (5.1)].

Administer FASENRA into the thigh or abdomen. The upper arm can also be used if a healthcare provider or caregiver administers the injection. Prior to administration, warm FASENRA by leaving carton at room temperature for about 30 minutes. Visually inspect FASENRA for particulate matter and discoloration prior to administration. FASENRA is clear to opalescent, colorless to slightly yellow, and may contain a few translucent or white to off-white particles. Do not use FASENRA if the liquid is cloudy, discolored, or if it contains large particles or foreign particulate matter.

Prefilled Syringe

The prefilled syringe is for administration by a healthcare provider.

Autoinjector (FASENRA PEN™)

FASENRA PEN is intended for administration by patients/caregivers. Patients/caregivers may inject after proper training in subcutaneous injection technique, and after the healthcare provider determines it is appropriate.

In patients aged 6 to 11 years weighing 35 kg or more, FASENRA PEN should only be administered by a caregiver or healthcare provider.

2.3 Instructions for Administration of FASENRA Prefilled Syringe (Healthcare Providers)

To prepare FASENRA prefilled syringe for subcutaneous administration, please carefully read and adhere to these instructions for use. FASENRA is available in a 10 mg and a 30 mg prefilled syringe. Check the labels on the FASENRA carton and prefilled syringe to ensure the correct 10 mg or 30 mg product is being used (Figure 1). Refer to Figure 1 to identify the prefilled syringe components for use in the administration steps.

 

Figure 1 FASENRA Prefilled Syringes

Prefilled Syringe Components

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. The syringe may contain small air bubbles; this is normal. Do not expel the air bubbles 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 the 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, thigh, 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.

2.4 Instructions for Administration of FASENRA PEN

Refer to the FASENRA PEN ‘Instructions for Use’ for more detailed instructions on the preparation and administration of FASENRA PEN [see Instructions for Use]. A patient may self-inject or the patient’s caregiver may administer FASENRA PEN subcutaneously after the healthcare provider determines it is appropriate. In patients aged 6 to 11 years weighing 35 kg or more, FASENRA PEN should only be administered by a caregiver or healthcare provider.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred following administration of FASENRA. These reactions generally 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 [see Contraindications (4)].

5.2 Acute Asthma Symptoms or Deteriorating Disease

FASENRA should not be used to treat acute asthma symptoms or acute exacerbations. Do not use FASENRA to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with FASENRA.

5.3 Reduction of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with FASENRA. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

5.4 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 will 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult and Adolescent Patients 12 Years of Age and Older

Across three clinical trials (SIROCCO, CALIMA, and ZONDA), 1,808 patients received at least 1 dose of FASENRA [see Clinical Studies (14)]. The data described below reflect exposure to FASENRA in 1,663 patients, including 1,556 exposed for at least 24 weeks and 1,387 exposed for at least 48 weeks. The safety exposure for FASENRA is derived from two Phase 3 placebo-controlled trials (SIROCCO and CALIMA) from 48 weeks duration [FASENRA every 4 weeks (n=841), FASENRA every 4 weeks for 3 doses, then every 8 weeks (n=822), and placebo (n=847)]. While a dosing regimen of FASENRA every 4 weeks was included in clinical trials, FASENRA administered every 4 weeks for 3 doses, then every 8 weeks thereafter is the recommended dose [see Dosage and Administration (2.1)]. The population studied was 12 to 75 years of age, of which 64% were female and 79% were White.

Adverse reactions that occurred at greater than or equal to 3% incidence are shown in Table 2.

28-Week Trial

Adverse reactions from ZONDA with 28 weeks of treatment with FASENRA (n=73) or placebo (n=75) in which the incidence was more common in FASENRA than placebo include headache (8.2% compared to 5.3%, respectively) and pyrexia (2.7% compared to 1.3%, respectively) [see Clinical Studies (14)]. The frequencies for the remaining adverse reactions with FASENRA were similar to placebo.

Injection Site Reactions

In SIROCCO and CALIMA, injection site reactions (e.g., pain, erythema, pruritus, papule) occurred at a rate of 2.2% in patients treated with FASENRA compared with 1.9% in patients treated with placebo.

Pediatric Patients 6 to 11 Years of Age

The safety data for FASENRA is based on a 48-week, open-label, parallel group, pharmacokinetic and pharmacodynamic trial (TATE) of 28 pediatric patients aged 6 to 11 years with severe asthma, and with an eosinophilic phenotype [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2,12.3)]. Patients received subcutaneous dose of 10 mg (for those weighing less than 35 kg) or 30 mg (for those weighing 35 kg or more) of FASENRA administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter [see Dosage and Administration (2.1)]. No new safety signals were observed in these patients.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of FASENRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to FASENRA or a combination of these factors.

Immune System Disorders: Hypersensitivity reactions, including anaphylaxis.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FASENRA during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.

Risk Summary

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 during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of benralizumab throughout pregnancy at doses that produced exposures up to approximately 310 times the exposure at the maximum recommended human dose (MRHD) of 30 mg SC [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data

Animal Data

In a prenatal and postnatal development study, pregnant cynomolgus monkeys received benralizumab from beginning on GD20 to GD22 (dependent on pregnancy determination), on GD35, once every 14 days thereafter throughout the gestation period and 1-month postpartum (maximum 14 doses) at doses that produced exposures up to approximately 310 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 30 mg/kg once every 2 weeks). Benralizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 6.5 months after birth. There was no evidence of treatment-related external, visceral, or skeletal malformations. Benralizumab was not teratogenic in cynomolgus monkeys. Benralizumab crossed the placenta in cynomolgus monkeys. Benralizumab concentrations were approximately equal in mothers and infants on postpartum day 7 but were lower in infants at later time points. Eosinophil counts were suppressed in infant monkeys with gradual recovery by 6 months postpartum; however, recovery of eosinophil counts was not observed for one infant monkey during this period.

8.2 Lactation

Risk Summary

There is no information regarding the presence of benralizumab in human or animal milk, and the effects of benralizumab on the breast‑fed infant and on milk production are not known. However, benralizumab is a humanized monoclonal antibody (IgG1/κ-class), and immunoglobulin G (IgG) is present in human milk in small amounts. If benralizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to benralizumab are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for benralizumab and any potential adverse effects on the breast-fed child from benralizumab or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of FASENRA for add-on maintenance treatment of patients with severe asthma and with an eosinophilic phenotype have been established in pediatric patients 6 years and older. Use of FASENRA for this indication is supported by evidence from the following:

Pediatric Patients 12 to 17 Years of Age

Use of FASENRA in adolescents with severe asthma and with an eosinophilic phenotype is supported by evidence from SIROCCO (n=53) and CALIMA (n=55) that enrolled 108 adolescents aged 12 to 17 years (mean age 14 years, 42% female, White 82%, Asian 2%, Black or African American 4%) with asthma. Of these patients, 46 received placebo, 40 received 30 mg of FASENRA every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received 30 mg of FASENRA every 4 weeks. Patients were required to weigh 40 kg or more and 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 [see Clinical Studies (14)]. The pharmacokinetics of benralizumab in adolescents 12 to 17 years of age were consistent with adults based on population pharmacokinetic analysis and the reduction in blood eosinophil counts was similar to that observed in adults following the same FASENRA treatment. The adverse reaction profile in adolescents was generally similar to the overall population in the clinical trials [see Adverse Reactions (6.1)].

Pediatric Patients 6 to 11 Years of Age

Use of FASENRA in pediatric patients aged 6 to 11 years with severe asthma, and with an eosinophilic phenotype is supported by evidence from adequate and well-controlled trials in adults and adolescents with additional pharmacokinetic, pharmacodynamic, and safety data in pediatric patients aged 6 to 11 years. The effectiveness of FASENRA in pediatric patients 6 to 11 years of age is extrapolated from efficacy in three clinical trials (SIROCCO, CALIMA, and ZONDA) [see Clinical Studies (14)] with support from pharmacokinetic analysis and pharmacodynamic response in pediatric patients aged 6 to 11 years compared to adults and adolescents. TATE is a 48-week, open-label, pharmacokinetic and pharmacodynamic trial that was conducted in 28 patients aged 6 to 11 years (mean age 9 years; 6-8 years, n=11; 9-11 years n=17; 32% female, White 29%, Asian 32%, Black or African American 29%) with severe asthma, and with an eosinophilic phenotype.

Based upon the pharmacokinetic data from TATE, a subcutaneous dose of 10 mg (patients <35 kg) and subcutaneous dose of 30 mg (patients ≥35 kg) of benralizumab administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter in patients aged 6 to 11 years was determined to have similar or higher exposure, respectively, to adults and adolescents administered a subcutaneous dose of 30 mg with the same dosing regimen [see Clinical Pharmacology (12.3)]. The pharmacodynamic response observed in TATE for pediatric patients aged 6 to 11 years was similar to that observed in adults and adolescents [see Clinical Pharmacology (12.2)]. No new safety signals were observed from TATE and safety for the higher drug exposure is supported by safety data from SIROCCO and CALIMA in adults and adolescents, and ZONDA in adults, who received 30 mg of FASENRA every 4 weeks for 1 year.

The safety and effectiveness in patients younger than 6 years of age have not been established.

8.5 Geriatric Use

Of the total number of patients in clinical trials of benralizumab, 13% (n=320) were 65 and over, while 0.4% (n=9) were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

Benralizumab is a humanized afucosylated, monoclonal antibody (IgG1, kappa) that directly binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a dissociation constant of 11 pM. The IL-5 receptor is expressed on the surface of eosinophils and basophils. In an in vitro setting, the absence of fucose in the Fc domain of benralizumab facilitates binding (45.5 nM) to FcɣRIII receptors on immune effector cells, such as natural killer (NK) cells, leading to apoptosis of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC).

Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Benralizumab, by binding to the IL-5Rα chain, reduces eosinophils through ADCC; however, the mechanism of benralizumab action in asthma has not been definitively established.

12.2 Pharmacodynamics

In the 52-week Phase 2 dose-ranging trial, asthma patients received 1 of 3 doses of benralizumab [2 mg (n=81), 20 mg (n=81), or 100 mg (n=222)] or placebo (n=222). All doses were administered every 4 weeks for the first 3 doses, followed by every 8 weeks thereafter. Median blood eosinophil levels at baseline were 310, 280, 190 and 190 cells/μL in the 2, 20, and 100 mg benralizumab and placebo groups, respectively. Dose-dependent reductions in blood eosinophils were observed. At the time of the last dose (Week 40), median blood eosinophil counts were 100, 50, 40, 170 cells/μL in the 2, 20, and 100 mg benralizumab and placebo groups, respectively.

A reduction in blood eosinophil counts was observed 24 hours post dosing in a Phase 2 trial.

In SIROCCO and CALIMA, following SC administration of benralizumab at the recommended dose blood eosinophils were reduced to a median absolute blood eosinophil count of 0 cells/μL [see Clinical Studies (14)]. This magnitude of reduction was observed at the first time point, 4 weeks of treatment, and was maintained throughout the treatment period.

Treatment with benralizumab was also associated with reductions in blood basophils, which was consistently observed across all clinical studies. In the Phase 2 dose-ranging trial, blood basophil counts were measured by flow cytometry. Median blood basophil counts were 45, 52, 46, and 40 cells/µL in the 2 mg, 20 mg and 100 mg benralizumab and placebo groups, respectively. At 52 weeks (12 weeks after the last dose), median blood basophil counts were 42, 18, 17, and 46 cells/µL in the 2 mg, 20 mg and 100 mg benralizumab and placebo groups, respectively.

In TATE, a 48-week trial with patients aged 6 to 11 years who had severe asthma, and with an eosinophilic phenotype [see Use in Specific Populations (8.4)], the magnitude of blood eosinophil reduction was similar to that observed in adults and adolescents. Median blood eosinophil levels at baseline were 400 and 340 cells/µL in patients weighing <35 kg and ≥35 kg, respectively. Across all post-dose time points, median eosinophil counts reduced to 10 to 20 cells/µL in patients weighing <35 kg, and to 20 to 30 cells/µL in patients weighing ≥35 kg. Blood eosinophil reduction was observed at the first time point, 4 weeks of treatment, and was maintained throughout the treatment period.

12.3 Pharmacokinetics

The pharmacokinetics of benralizumab was approximately dose-proportional in adult and adolescent patients with asthma following subcutaneous administration over a dose range of 20 to 200 mg.

Absorption

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

Elimination

From population pharmacokinetic analysis, benralizumab exhibited linear pharmacokinetics and no evidence of target receptor-mediated clearance pathway. The estimated typical systemic clearance (CL) for benralizumab was 0.29 L/d for a subject weighing 70 kg. Following subcutaneous administration, the elimination half-life was approximately 15.5 days.

Metabolism

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

Specific populations:

Age

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.

Patients with 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.

Patients with 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.

Pediatric Patients

Benralizumab pharmacokinetics following subcutaneous administration of 10 mg or 30 mg in patients aged 6 to 11 years with severe asthma and with an eosinophilic phenotype asthma was investigated in the initial 16-week treatment phase of TATE, a 48-week open-label trial. Among patients aged 6 to 11 years weighing <35 kg who received 10 mg, the median trough concentration at Week 16 was similar to that of adults and adolescents who received 30 mg. Among patients aged 6 to 11 years weighing ≥35 kg who received 30 mg, the median trough concentration at Week 16 was 62% higher relative to adults and adolescents receiving the same dose, due to lower body weight in pediatric patients.

Drug Interaction Studies

No formal drug-drug interaction studies have been conducted.

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 and eosinophil depletion does not produce chronic systemic alterations of proinflammatory cytokines.

An effect of benralizumab on the pharmacokinetics of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on benralizumab clearance in patients with asthma.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of benralizumab and other products.

In adult and adolescent patients with asthma, treatment-emergent ADA response developed in 13% of patients treated with FASENRA at the recommended dosing regimen during the 48 to 56-week treatment period. A total of 12% of patients treated with FASENRA developed neutralizing antibodies. In patients 6 to 11 years with severe asthma and with an eosinophilic phenotype, the incidence of ADA to benralizumab during an open-label 48-week treatment period was comparable to adult and adolescent patients.

Anti-Drug Antibody Effects on Pharmacokinetics and Pharmacodynamics

Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titers compared to antibody negative patients.

In the asthma trials in adults and adolescents, no evidence of an association of anti-drug antibodies with efficacy or safety was observed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of benralizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody that binds to IL-5Rα such as benralizumab is unknown.

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with benralizumab for 9 months at IV doses up to 25 mg/kg or at SC doses of up to 30 mg/kg once every 2 weeks (approximately 400 and 270 times the MRHD on an AUC basis).