Fasenra

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)].

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.

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.

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.

No formal drug interaction studies have been conducted.

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 effectors 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.

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 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 [see Clinical Studies (14)]. This magnitude of reduction was seen at the first observed 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.

Pharmacokinetics

The pharmacokinetics of benralizumab was approximately dose-proportional in 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 3.6 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 58% 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 3.2 L and 2.5 L, respectively, for a 70kg individual.

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.

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 70kg. Following subcutaneous administration, the elimination half-life was approximately 15 days.

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.

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.

Drug-Drug Interaction:

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.

Fasenra (benralizumab) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for subcutaneous injection supplied as a single-dose prefilled syringe.

Carton contains one 30 mg/mL single-dose prefilled syringe: NDC 0310-1730-30

Store the prefilled syringe refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.

NDC 0310-1730-30                          Rx only

Fasenra is a prescription medicine used with other asthma medicines for the maintenance treatment of asthma in people 12 years and older whose asthma is not controlled with their current asthma medicines. It helps prevent severe asthma attacks (exacerbations) and may improve your breathing. Medicines such as Fasenra reduce blood eosinophils. Eosinophils are a type of white blood cell that may contribute to your asthma.

Fasenra is not used to treat:

• other problems caused by eosinophils.
• sudden breathing problems. Tell your healthcare provider if your asthma does not get better or if it gets worse after you start treatment.

It is not known if Fasenra is safe and effective in children under 12 years of age.

You should not receive Fasenra if you are allergic to benralizumab or any of the ingredients in Fasenra. See the end of this page for a complete list of ingredients.

Before receiving Fasenra, tell your healthcare provider about all of your medical conditions, including if you:

• are taking oral or inhaled corticosteroid medicines. Do not stop taking your corticosteroid medicines unless instructed by your healthcare provider. This may cause other symptoms that were controlled by the corticosteroid medicine to come back.
• have a parasitic (helminth) infection.
• are pregnant or plan to become pregnant. It is not known if Fasenra will harm your unborn baby. Tell your healthcare provider if you become pregnant during your treatment.
• are breastfeeding or plan to breastfeed. It is not known if Fasenra passes into your breast milk. You and your healthcare provider should decide if you will receive Fasenra and breastfeed. Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Do not stop taking your other asthma medicines unless your healthcare provider tells you to.

A healthcare provider will inject Fasenra under your skin (subcutaneously) one time every four weeks for the first three doses, and then every eight weeks.

The following adverse reactions are described in greater detail in other sections:

• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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.

Across Trials 1, 2, and 3, 1,808 patients received at least 1 dose of FASENRA [see Clinical Studies]. 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 studies (Trials 1 and 2) 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]. 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 1.

Table 1: Adverse Reactions with FASENRA with Greater than or Equal to 3% Incidence in Patients with Asthma (Trials 1 and 2)

Adverse reactions from Trial 3 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]. The frequencies for the remaining adverse reactions with FASENRA were similar to placebo.

In Trials 1 and 2, 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.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to benralizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Overall, treatment-emergent anti-drug antibody 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. 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. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.

The data reflect the percentage of patients whose test results were positive for antibodies to benralizumab in specific assays.

Read the entire FDA prescribing information for Fasenra (Benralizumab for Subcutaneous Injection)