Benralizumab is a subcutaneous humanized interleukin-5 receptor alpha-directed cytolytic monoclonal antibody (IgG1, kappa) used for add-on maintenance treatment of adult and pediatric patients 6 years and older who have severe asthma with an eosinophilic phenotype. This biologic therapy is directed against interleukin (IL)-5, which is known to play an important role in regulating the function of eosinophils, an inflammatory cell responsible for airway inflammation in some types of asthma. Benralizumab is not approved for the treatment of other eosinophilic conditions. During clinical trials, all subjects with severe asthma (eosinophilic phenotype) continued their background asthma therapy, including systemic corticosteroids. In clinical trials, the use of benralizumab resulted in the ability to reduce the annual rate of severe exacerbations of asthma requiring emergency department care and/or hospitalization. Some trial data indicated that with maintenance treatment, benralizumab almost completely reduced blood eosinophils and allowed for oral corticosteroid dose reductions while maintaining asthma control in selected patients.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.-Benralizumab is clear to opalescent, colorless to slightly yellow, and may contain a few translucent or white to off-white particles. Do not use if the liquid is cloudy, discolored, or if it contains large particles or foreign particulate matter. The liquid may contain a small air bubble; this is normal. Do not expel the air bubble(s) prior to administration.
-Benralizumab is for subcutaneous use only.
-Benralizumab is intended for use under the guidance of a healthcare provider. In line with clinical practice, monitoring of patients after the administration of biologic agents is recommended.
-The prefilled syringe should be administered by a healthcare professional.
-The autoinjector (pen) can be administered by patients/caregivers after proper training and after the healthcare provider determines it is appropriate. In patients age 6 to 11 years weighing 35 kg or more, the autoinjector (pen) should only be administered by a caregiver or a healthcare provider.
Subcutaneous Administration
Prefilled Syringe (Fasenra)
-For administration by a healthcare provider only.
-Prefilled Syringe is available in 10 mg (gray plunger rod) and 30 mg (blue plunger rod). Verify the correct 10 mg or 30 mg product is being used.
Preparation of prefilled syringe
-Prior to administration, warm the prefilled syringe by leaving carton at room temperature for about 30 minutes.
-Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard. Grasp the syringe body, not the plunger, to remove prefilled syringe from the tray.
-Do not remove the needle cover until ready to inject. Hold the syringe body and remove the needle cover by pulling straight off. Be careful 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.
Subcutaneous Administration using prefilled syringe
-Gently pinch the skin and insert the needle at the recommended injection site (i.e., upper arm, thigh, or abdomen).
-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.
-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.
-The prefilled syringe is for single-use only.
Autoinjector (Fasenra Pen)
-The autoinjector is appropriate for patient/caregiver use. Patients/caregivers may inject after proper training in subcutaneous injection technique, and after the healthcare provider determines it is appropriate. In patients age 6 to 11 years weighing 35 kg or more, the autoinjector should be administered by a caregiver or healthcare provider.
-Provide proper training in subcutaneous injection technique and on the preparation and administration of benralizumab injection prior to use according to the "Instructions for Use".
Subcutaneous Administration using autoinjector pen:
-Choose the injection site. For patient-administered injection, administer into the thigh or abdomen, avoiding the 5 cm (2 inches) around the navel. The upper arm can also be used if a caregiver administers the injection. Never give injections into areas where the skin is tender, bruised, red, or hard.
-Clean the injection site.
-Remove the cap to expose the green needle guard.
-Place the needle guard flat against the skin at a 90-degree angle to ensure that the viewing window is still visible.
-To inject, gently pinch the skin at the recommended injection site or give the injection without pinching the skin. A "click" will be heard when the injection has started, and the green plunger will move down in the viewing window during the injection. A second "click" will be audible to indicate that the injection has finished, and the green plunger will fill the viewing window. If the green plunger does not fill the viewing window, the patient may not have received the full dose; contact the healthcare provider.
-Lift the pen straight up and the needle guard will slide down and lock into place over the needle.
-Check the injection site to see if there is bleeding, gently hold pressure over the skin with a cotton ball or gauze until the bleeding stops; do not rub injection site. A bandage may be used if needed.
-The autoinjector contains only 1 dose. Do not use the pen more than 1 time.
Storage and disposal of prefilled syringes and injectors after removal from the refrigerator:
-If needed, an unopened carton that has been brought to room temperature can be stored outside the refrigerator at up to 25 degrees C (77 degrees F) for up to 14 days. Keep in the original carton to protect from light. Do not expose to heat. Dispose of the injection properly if it is left out of the refrigerator in the unopened carton for more than 14 days.
-Discard an expired or used syringe or pen autoinjector into a proper sharps disposal container.
Headache was one of the most common adverse events reported during benralizumab clinical trials, occurring in 8% to 8.2% of patients receiving subcutaneous benralizumab and 5.3% to 6% of those receiving placebo. Pharyngitis was reported in 5% of patients receiving benralizumab compared to 3% of patients receiving placebo. Fever (reported as pyrexia) was reported in 2.7% to 3% of patients receiving benralizumab compared to 1.3% to 2% receiving placebo.
Hypersensitivity reactions, including anaphylactoid reactions, angioedema, urticaria, and rash (unspecified) have occurred after benralizumab administration. Such reactions generally occur within hours of administration, but may have a delayed onset (i.e., days). If a hypersensitivity reaction occurs, discontinue the drug and institute appropriate treatment. Overall, systemic allergic/hypersensitivity reactions were reported by 3% of benralizumab-treated patients, compared to 3% of those receiving placebo.
During clinical trials, an injection site reaction (e.g., pain, erythema, pruritus, papule) occurred in 2.2% of patients receiving subcutaneous benralizumab compared to 1.9% of those receiving placebo.
Anti-benralizumab antibody formation occurred in 13% of patients treated with benralizumab during clinical trials; however, the reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 12% of patients. The clinical relevance of the presence of anti-benralizumab antibodies is unknown. Antibodies increased the clearance of benralizumab by about 20%. 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.
Benralizumab is contraindicated in patients with a history of hypersensitivity to benralizumab or excipients in the formulation. Use with caution in patients with hamster protein hypersensitivity, as the drug is produced in Chinese hamster ovary cells. Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after benralizumab administration. Such reactions generally occur within hours of administration, but may have a delayed onset (i.e., days). If a hypersensitivity reaction occurs, discontinue the drug and institute appropriate treatment.
Benralizumab should not be used to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after benralizumab initiation. Short-acting beta-agonists, such as albuterol, should be available for rescue therapy.
Do not discontinue systemic or inhaled corticosteroid therapy abruptly upon benralizumab initiation. Corticosteroid withdrawal and dosage reduction, if appropriate, should be done gradually 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.
Treat patients with a pre-existing helminth infection prior to initiating therapy with benralizumab. If a patient becomes infected while receiving benralizumab therapy and does not respond to anti-helminth treatment, discontinue benralizumab therapy until the infection resolves. Benralizumab reduces the production and survival of eosinophils, which may be involved in the immunological response to some helminth infections. Although it is not known whether if benralizumab will influence the body's response against parasitic infections, caution is warranted. Patients with known parasitic infections were excluded from clinical trials.
Pregnancy exposure data for benralizumab is insufficient to inform on drug-associated risk. Monoclonal antibodies, such as benralizumab, are transported across the placenta as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the third trimester. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to benralizumab during pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with intravenous benralizumab administration throughout pregnancy at drug exposures approximately 310 times the exposure at the maximum recommended human dose (MRHD, 30 mg subcutaneously). Uncontrolled asthma also presents risks during pregnancy. In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Asthma control should be closely monitored during pregnancy and treatment adjusted to maintain optimal control. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to benralizumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/fasenra or by calling 1-877-311-8972.
There is no information regarding the presence of benralizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Benralizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. Consider the developmental and health benefits of breast-feeding, the mother's need for benralizumab therapy, and potential adverse effects of the drug or inadequately treated asthma on the breastfed infant.
Benralizumab safety and efficacy have not been established for infants and children less than 6 years of age.
For asthma maintenance treatment as add-on therapy in severe asthma (eosinophilic phenotype):
Subcutaneous dosage:
Adults: 30 mg subcutaneously every 4 weeks for 3 doses, then 30 mg subcutaneously every 8 weeks.
Children and Adolescents 12 to 17 years: 30 mg subcutaneously every 4 weeks for 3 doses, then 30 mg subcutaneously every 8 weeks.
Children 6 to 11 years weighing 35 kg or more: 30 mg subcutaneously every 4 weeks for 3 doses, then 30 mg subcutaneously every 8 weeks.
Children 6 to 11 years weighing less than 35 kg: 10 mg subcutaneously every 4 weeks for 3 doses, then 10 mg subcutaneously every 8 weeks.
Maximum Dosage Limits:
-Adults
30 mg/dose subcutaneously.
-Geriatric
30 mg/dose subcutaneously.
-Adolescents
30 mg/dose subcutaneously.
-Children
12 years: 30 mg/dose subcutaneously.
6 to 11 years weighing 35 kg or more: 30 mg/dose subcutaneously.
6 to 11 years weighing less than 35 kg: 10 mg/dose subcutaneously.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are needed. While there are limited data in patient with CrCl less than 30 mL/minute, the drug is not cleared renally.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Benralizumab is a fully humanized monoclonal antibody (IgG1 kappa) that targets human interleukin (IL)-5. IL-5 is the major cytokine responsible for eosinophilic airway inflammation in patients with asthma. IL-5 is responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Benralizumab selectively binds to IL-5, blocking it from binding to the alpha chain of the IL-5 receptor complex located on the eosinophil cell surface. This, in turn, inhibits IL-5 signaling and reduces the production and survival of eosinophils. Other undefined mechanisms of action may also play a role.
Benralizumab is administered by subcutaneous injection. The central and peripheral volume of distribution (Vd) of benralizumab was 3.1 L and 2.5 L, respectively, for a 70-kg individual. Benralizumab is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue. Benralizumab exhibited linear pharmacokinetics and no evidence of target receptor-mediated clearance pathway in a population pharmacokinetic analysis. The estimated typical systemic clearance (CL) for benralizumab was 0.29 L/day for a subject weighing 70-kg. Following subcutaneous administration, the elimination half-life was approximately 15.5 days.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
CYP450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of benralizumab. There is no evidence of IL-5R alpha 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.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Following subcutaneous administration of benralizumab to patients with asthma, the absorption half-life was approximately 3.5 days. In a 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.
-Special Populations
Hepatic Impairment
Benralizumab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue. Changes in hepatic function are not expected to affect elimination; however, no clinical trials have been conducted to investigate the effect of hepatic impairment on benralizumab pharmacokinetics. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had no clinically relevant effect on benralizumab clearance.
Renal Impairment
Benralizumab is not cleared renally. Based on population pharmacokinetic analyses, benralizumab clearance was comparable between patients with a creatinine clearance (CrCl) 30 to 80 mL/minute and those with normal renal function. There are limited data in patients with a CrCl less than 30 mL/minute.
Pediatrics
Pharmacokinetic data was collected in pediatric patients age 6 to 11 years using a subcutaneous dose of 10 mg (patients less than 35 kg) and 30 mg (patients 35 kg or more) administered every 4 weeks for the first 3 doses and then every 8 weeks. After 16 weeks, pediatric patients who received 10 mg (weighing less than 35 kg) had a trough concentration similar to that of adults and adolescents who received benralizumab 30 mg. Pediatric patients who received 30 mg (weighing 35 kg or more) had a median trough concentration 62% higher than those adults and adolescents receiving the same dose, due to lower body weight in pediatric patients.
Geriatric
There is no significant effect of age on benralizumab clearance.
Gender Differences
A population pharmacokinetics analysis indicated that there is no significant effect of gender on benralizumab clearance.
Ethnic Differences
A population pharmacokinetics analysis indicated that there is no significant effect of race on benralizumab clearance.