Depemokimab

1 INDICATIONS AND USAGE EXDENSUR is indicated for the add‑on maintenance treatment of severe asthma characterized by an eosinophilic phenotype in adult and pediatric patients aged 12 years and older. Limitations of Use EXDENSUR is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions ( 5.2 )] . EXDENSUR is an interleukin‑5 (IL‑5) antagonist, a monoclonal antibody (humanized immunoglobulin G1 [IgG1] kappa) indicated for add‑on maintenance treatment of severe asthma characterized by an eosinophilic phenotype in adult and pediatric patients aged 12 years and older. ( 1 ) Limitations of Use : Not for relief of acute bronchospasm or status asthmaticus. ( 1 )

12.1 Mechanism of Action Depemokimab‑ulaa is an IL‑5 antagonist (humanized IgG1 kappa monoclonal antibody), which binds to IL‑5 with a dissociation constant of 10.5 pM, inhibiting the bioactivity of IL‑5 with in vitro IC50 value of 4 pM by blocking its binding to the alpha chain of the IL‑5 receptor complex expressed on the cell surface. Depemokimab‑ulaa contains a triple amino acid substitution (YTE) in the fragment crystallizable (Fc) region which increases binding to the neonatal Fc receptor and thereby extends the elimination half‑life. These properties support the dosing interval of every 6 months. IL‑5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. 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. Depemokimab‑ulaa, by inhibiting IL‑5 signaling, reduced the production and survival of eosinophils; however, the mechanism of depemokimab‑ulaa action in asthma has not been definitively established.

2 DOSAGE AND ADMINISTRATION The recommended dosage is 100 mg administered once every 6 months by subcutaneous injection into the upper arm, thigh, or abdomen. ( 2.1 ) • EXDENSUR should be administered by a healthcare provider. ( 2.2 ) • See full prescribing information for preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage is 100 mg once every 6 months administered by subcutaneous injection into the upper arm, thigh, or abdomen avoiding 2 inches (5 cm) around the navel [see Dosage and Administration ( 2.2 )] . Missed Dose(s) If a dose is missed, administer the missed dose as soon as possible and resume the once every 6‑month injection schedule from the date of when the missed dose was given. 2.2 Preparation and Administration Instructions for EXDENSUR • EXDENSUR is for subcutaneous use only. • EXDENSUR should be administered by a healthcare provider. • Do not use EXDENSUR prefilled syringe if the security seal on the carton has been broken or if it has been dropped or damaged. Preparation Instructions 1. Remove the prefilled syringe from the refrigerator. Holding the middle of the prefilled syringe, take it out from the tray and allow it to sit at room temperature for 30 minutes prior to injection. Do not warm EXDENSUR injection in any other way. Do not remove the needle cap until you are ready to inject. Do not use the syringe if it has been left out of the carton for more than 8 hours. 2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. EXDENSUR should be colorless to yellow to brown, clear to opalescent in color. Do not use EXDENSUR if the product exhibits discoloration, cloudiness, or particulate matter. It is normal to see an air bubble. Do not expel the air bubble prior to administration. Do not shake the device. 3. Choose the injection site; administer EXDENSUR into upper arm, thigh, or abdomen, avoiding the 2 inches (5 cm) around the navel. Do not give injections into areas where the skin is tender, bruised, red, or hard. Administration Instructions Figure 1. EXDENSUR Prefilled Syringe Components 1. Pull Off the Gray Needle Cap Remove the gray needle cap from the syringe by pulling it straight off, away from the needle. Do not handle the syringe by the white plunger while removing the gray needle cap. Do not put the gray needle cap back onto the syringe. Inject within 5 minutes after removing the gray needle cap. 2. Position the Syringe at the Injection Site Use your free hand to gently pinch the skin around the cleaned injection site. Do not handle the syringe by the white plunger while inserting the needle into the pinched skin. Hold the middle of the syringe and insert the entire needle into the pinched skin at a 45 degree angle, as shown. 3. Start the Injection and Fully Press the White Plunger Slowly push down on the white plunger with your thumb to inject the full dose. Make sure the white plunger is pushed all the way down until the stopper reaches the bottom of the syringe and all of the medication is injected. 4. Slowly Lift Thumb After Injection Completes Slowly lift your thumb up. This will allow the white plunger to come up and the needle to automatically pull up (retract) into the needle guard. After removing the syringe from the injection site, release the pinched skin. 5. Throw Away Dispose of used syringe according to local health and safety laws. Figure 1 1. Pull Off the Gray Needle Cap 2. Position the Syringe at the Injection Site 3. Start the Injection and Fully Press the White Plunger 4. Slowly Lift Thumb After Injection Completes

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] . The most common adverse reactions (incidence ≥4%) are upper respiratory tract infection, allergic rhinitis, influenza, arthralgia, and pharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of EXDENSUR was based on a pooled safety population from 2 replicate, randomized, double‑blind, parallel‑group, placebo‑controlled, multicenter clinical trials (SWIFT‑1 and SWIFT‑2) of 52 weeks duration. The 2 trials included 762 adult and pediatric patients 12 years of age and older with asthma, who received either EXDENSUR 100 mg or placebo administered subcutaneously once every 6 months in addition to their existing background medications for asthma [see Clinical Studies ( 14 )] . A total of 475 patients received 2 doses of EXDENSUR 100 mg in these trials. Adverse reactions with EXDENSUR with incidence of ≥4% are shown in Table 1 . Table 1. Adverse Reactions With EXDENSUR With an Incidence ≥4% and More Common Than Placebo in Patients With Asthma Adverse Reaction EXDENSUR (N = 501) n (%) Placebo (N = 261) n (%) Upper respiratory tract infection 46 (9) 20 (8) Allergic rhinitis 29 (6) 7 (3) Influenza 24 (5) 11 (4) Arthralgia 19 (4) 8 (3) Pharyngitis 18 (4) 3 (1) Specific Adverse Reactions Injection Site Reactions: In the pooled safety population (SWIFT‑1 and SWIFT‑2), in which EXDENSUR was administered by a healthcare provider, injection site reactions (e.g., erythema, swelling, and itching) occurred in 7 (1%) and 2 (<1%) patients receiving EXDENSUR and placebo, respectively.

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions, including anaphylaxis, can occur after administration of EXDENSUR. If a hypersensitivity reaction occurs, discontinue EXDENSUR and initiate appropriate therapy. ( 5.1 ) • Do not abruptly discontinue systemic or inhaled corticosteroids upon initiation of therapy with EXDENSUR. Reduce corticosteroid dose gradually, if appropriate. ( 5.3 ) • Treat pre-existing helminth infections before initiating therapy with EXDENSUR. If patients become infected while receiving treatment with EXDENSUR and do not respond to anti‑helminth treatment, discontinue EXDENSUR until the parasitic infection resolves. ( 5.4 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur following administration of EXDENSUR. If a hypersensitivity reaction occurs, discontinue EXDENSUR and initiate appropriate therapy. 5.2 Acute Asthma Symptoms or Deteriorating Disease EXDENSUR should not be used to treat acute asthma symptoms or acute exacerbations. Do not use EXDENSUR to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with EXDENSUR. 5.3 Risk Associated With Abrupt Reduction of Corticosteroid Dosage Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Do not abruptly discontinue systemic or inhaled corticosteroids upon initiation of EXDENSUR therapy. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the supervision of a healthcare provider. 5.4 Parasitic (Helminth) Infection Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre‑existing helminth infections were excluded from participation in the clinical trials. It is unknown if EXDENSUR will influence a patient’s response against parasitic infections. Patients with pre‑existing helminth infections should be treated for their infection prior to initiation of EXDENSUR therapy. If patients become infected while receiving treatment with EXDENSUR and do not respond to anti‑helminth treatment, discontinue treatment with EXDENSUR until the infection resolves.

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE If an overdosage occurs, the patient should be treated supportively with appropriate monitoring as necessary. Consider contacting the Poison Help line (1‑800‑222‑1222) or a medical toxicologist for additional overdose management recommendations.