Get your patient on Exdensur (Depemokimab)

The recommended dosage is 100 mg once every 6 months administered by subcutaneous (SC) 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.

• EXDENSUR is for subcutaneous (SC) use only.
• EXDENSUR should be administered by a healthcare provider.
  Do not use EXDENSUR prefilled pen or syringe if the security seal on the carton has been broken.
  Do not use EXDENSUR prefilled pen or syringe if it has been dropped or damaged.

Preparation Instructions

1. Remove the prefilled pen or prefilled syringe from the refrigerator. Holding the middle of the prefilled pen or 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 pen or 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 the injection 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 for Single ‑ Dose Prefilled Pen

Figure 1. EXDENSUR Prefilled Pen Components

1. Pull Off the Clear Cap

Remove the clear cap by pulling it straight off, away from the yellow needle guard. Do not press the yellow needle guard. Do not put the cap back on the pen. This could accidentally start the injection. Inject within 5 minutes after removing the clear cap.

1. Position the Pen at the Injection Site and Press Firmly to Start the Injection

Place the yellow needle guard flat against the skin (at a 90 degree angle to the skin). Make sure you can see the inspection window. The yellow needle guard will slide up into the pen. You may hear a “click” that tells you the injection has started. Do not use the pen if the yellow needle guard does not slide up into the pen.

1. Continue to Hold Down

Keep the pen held down against the skin. Do not lift or move the pen during the injection. The yellow indicator will move down through the inspection window during the injection. The injection is done when you hear the second click. Injection may take up to 20 seconds. If you do not hear the second click, check that: The inspection window is filled with the yellow indicator. The black stopper has stopped moving.

1. Lift Pen After Injection Completes
2. Throw Away

Dispose of used pen and clear cap according to local health and safety laws.

Administration Instructions for Single ‑ Dose Prefilled Syringe

Figure 2. 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.

1. 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.

1. 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.

1. 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.

1. Throw Away

Dispose of used syringe according to local health and safety laws.

Risk Summary

Available data from clinical trials with EXDENSUR use in pregnant women are insufficient to identify a drug‑associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with asthma in pregnancy (see Clinical Considerations).

Transport of endogenous IgG antibodies and monoclonal antibodies, such as depemokimab-ulaa, across the placenta increases as pregnancy progresses and peaks during the third trimester. The impact of the YTE modification on placental transfer is uncertain [see Clinical Pharmacology (12.1 )] ; however, the presence of the YTE modification may lead to prolonged and increased exposure of the infant exposed in utero , and the potential of clinical impact is unknown and should be considered. No treatment-related effects on embryofetal or postnatal development have been shown in animal studies targeting IL‑5 signaling pathways (see Data) .

The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Pregnant women exposed to EXDENSUR, or their healthcare providers, should report EXDENSUR exposure by calling 1‑888‑825‑5249.

Clinical Considerations

Disease ‑ Associated Maternal and/or Embryofetal 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: Reproductive toxicology studies have not been conducted with depemokimab‑ulaa. In animal studies targeting the IL‑5 signaling pathway with a related biologic product without the YTE modification, there were no developmental effects observed [see Nonclinical Toxicology (13 )] . Embryofetal development of IL‑5 deficient mice has been reported to be generally unaffected relative to wild‑type mice.

Risk Summary

There are no data on the presence of depemokimab‑ulaa in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, depemokimab‑ulaa is a humanized monoclonal antibody (immunoglobulin G1 [IgG1] kappa), and maternal IgG is present in human milk in small amounts. The effects of local gastrointestinal exposure and the extent of systemic exposure in the breastfed infant to EXDENSUR are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXDENSUR, and any potential adverse effects on the breastfed child from EXDENSUR or from the underlying maternal condition.

Asthma

The safety and effectiveness of EXDENSUR for add‑on maintenance treatment of severe asthma characterized by an eosinophilic phenotype have been established in pediatric patients aged 12 years and older.

Use of EXDENSUR for this indication is supported by evidence from adequate and well‑controlled trials (SWIFT‑1 and SWIFT‑2) in adults and pediatric patients aged 12 years and older, and pharmacokinetic data in pediatric patients aged 12 years and older. A total of 30 pediatric patients aged 12 to 17 years with asthma were enrolled in the SWIFT‑1 and SWIFT‑2 trials, of whom 15 received EXDENSUR 100 mg. Pharmacokinetic and pharmacodynamic data have demonstrated no clinically significant differences in systemic exposure of depemokimab‑ulaa and reduction in blood eosinophil counts in pediatric patients aged 12 years and older compared to that observed in adults following administration of the recommended dosage of EXDENSUR. The safety of EXDENSUR in pediatric patients aged 12 years and older was generally similar to that of the adult population in SWIFT‑1 and SWIFT‑2 [see Adverse Reactions (6.1 ), Clinical Pharmacology (12.3 ), Clinical Studies (14 )] .

The safety and effectiveness of EXDENSUR have not been established in pediatric patients younger than 12 years of age.

Of the 501 patients with asthma treated with EXDENSUR, 133 (27%) were 65 years of age and older and 22 (4%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Hypersensitivity reactions, including anaphylaxis, can occur following administration of EXDENSUR. If a hypersensitivity reaction occurs, discontinue EXDENSUR and initiate appropriate therapy.

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.

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.

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.

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 .

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.

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.

In placebo‑controlled studies involving adult and pediatric patients aged 12 years and older with asthma, a 100 mg dose of EXDENSUR administered SC every 6 months for 52 weeks reduced blood eosinophils to a geometric mean count of 57 cells/mcL (95% CI: 51, 63) at Week 52. This corresponded to a geometric mean reduction of 79% (95% CI: 75.8, 81.8) compared to placebo. This magnitude of blood eosinophil reduction was observed within 2 weeks of treatment (at the first assessment) and was maintained throughout the treatment period.

The pharmacokinetics of depemokimab‑ulaa were approximately dose‑proportional in patients with asthma following SC administration over a dose range of 0.1‑times the recommended dose to 3‑times the recommended dose. After SC administration of 100 mg of EXDENSUR every 6 months in patients with severe asthma, the mean (SD) model-based estimated trough concentration of depemokimab‑ulaa at Week 26 was approximately 1.30 (0.44) mcg/mL. The mean (SD) model-based estimated average steady‑state plasma concentration over a single dosing interval was 6.16 (1.62) mcg/mL.

Absorption

Depemokimab‑ulaa median T _max was approximately 14 days. There was no accumulation following repeat SC administration once every 6 months.

Distribution

The estimated typical apparent volume of distribution is 6.3 L.

Elimination

The estimated mean (SD) elimination half‑life was 48 (4.7) days following SC administration of EXDENSUR. The estimated typical apparent clearance was 0.092 L/day.

Metabolism: Depemokimab‑ulaa is a monoclonal antibody which is expected to be metabolized into small peptides and amino acids by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of depemokimab‑ulaa were observed based on age (12 to 93 years), sex, race (73% White, 7% Black, 19% Asian), body weight (34.6 to 161 kg), renal impairment (eGFR ≥90 mL/min/1.73 m ² [normal, N = 548]; eGFR 60 to <90 mL/min/1.73 m ² [mild, N = 380]; eGFR 30 to <60 mL/min/1.73 m ² [moderate, N = 31], and eGFR ≤30 mL/min/1.73 m ² [severe, N = 2]), or baseline hepatic function biomarkers (alanine aminotransferase [ALT; 5 to 153 IU/L], aspartate aminotransferase [AST; 9 to 115 IU/L], and bilirubin [1.7 to 42 micromol/L]).

Pediatric Patients: There are limited pharmacokinetic data available in the pediatric population. The pharmacokinetics of depemokimab‑ulaa in pediatric patients aged 12 to 17 years were consistent with adults. The pharmacokinetics of depemokimab‑ulaa have not been studied in pediatric patients aged less than 12 years.

Drug Interaction Studies

No drug interaction studies have been conducted.

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

In adults and pediatric patients aged 12 years and older with asthma, the incidence of ADA to depemokimab in patients treated with EXDENSUR 100 mg once every 6 months in SWIFT‑1, SWIFT‑2, and an open‑label extension was 10% (66/691). Among ADA‑positive patients, 6% (4/66) developed neutralizing antibodies.

There was no identified clinically significant effect of ADA on the pharmacokinetics, pharmacodynamics, safety, or efficacy of EXDENSUR.

No genotoxicity or carcinogenicity studies have been conducted.

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys receiving SC dosages up to 100 mg/kg depemokimab‑ulaa for 6 months. Mating and reproductive performance were unaffected in male and female CD‑1 mice receiving an analogous antibody, which inhibits the activity of murine IL‑5.