Tagraxofusp

1 INDICATIONS AND USAGE ELZONRIS is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older. ELZONRIS is a CD123-directed cytotoxin indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older ( 1 )

2 DOSAGE AND ADMINISTRATION Premedicate with an H1-histamine antagonist, acetaminophen, corticosteroid and H2-histamine antagonist prior to each ELZONRIS infusion. ( 2.1 ) Administer ELZONRIS intravenously at 12 mcg/kg over 15 minutes once daily on days 1 to 5 of a 21-day cycle. ( 2.1 ) Administer the first cycle of ELZONRIS in the inpatient setting. Subsequent cycles may be administered in the inpatient or appropriate outpatient setting. ( 2.1 ) Additional important preparation and administration information is in full prescribing information. See full prescribing information for instructions on preparation and administration. ( 2.3 , 2.4 ) 2.1 Recommended Dosage Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days 1 to 5 of a 21-day cycle. The dosing period may be extended for dose delays up to day 10 of the cycle. Continue treatment with ELZONRIS until disease progression or unacceptable toxicity. The dose is calculated based on the patient’s actual weight. Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL before administering ELZONRIS. Premedicate patients with an H1-histamine antagonist (e.g., diphenhydramine hydrochloride), H2-histamine antagonist (e.g., famotidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion. Administer Cycle 1 of ELZONRIS in the inpatient setting with patient observation through at least 24 hours after the last infusion. Administer subsequent cycles of ELZONRIS in the inpatient setting or in a suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for a minimum of 4 hours following each infusion. 2.2 Dosage Modifications Monitor vital signs and check albumin, transaminases, and creatinine prior to preparing each dose of ELZONRIS. See Table 1 for recommended dose modifications and Table 2 for CLS management guidelines. Table 1. Recommended ELZONRIS Dosage Modifications Parameter Severity Criteria Dosage Modification Serum albumin Serum albumin < 3.5 g/dL or reduced ≥ 0.5 g/dL from value measured prior to initiation of the current cycle See CLS Management Guidelines ( Table 2 ) Body weight Body weight increase ≥ 1.5 kg over pretreatment weight on prior treatment day See CLS Management Guidelines ( Table 2 ) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ALT or AST increase > 5 times the upper limit of normal Withhold ELZONRIS until transaminase elevations are ≤ 2.5 times the upper limit of normal. Serum creatinine Serum creatinine > 1.8 mg/dL (159 micromol/L) or creatinine clearance < 60 mL/minute Withhold ELZONRIS until serum creatinine resolves to ≤ 1.8 mg/dL (159 micromol/L) or creatinine clearance ≥ 60 mL/minute. Systolic blood pressure Systolic blood pressure ≥ 160 mmHg or ≤ 80 mmHg Withhold ELZONRIS until systolic blood pressure is < 160 mmHg or > 80 mmHg. Heart rate Heart rate ≥ 130 bpm or ≤ 40 bpm Withhold ELZONRIS until heart rate is < 130 bpm or > 40 bpm. Body temperature Body temperature ≥ 38°C Withhold ELZONRIS until body temperature is < 38°C. Hypersensitivity reactions Mild or moderate Withhold ELZONRIS until resolution of any mild or moderate hypersensitivity reaction. Resume ELZONRIS at the same infusion rate. Severe or life-threatening Discontinue ELZONRIS permanently. Table 2. CLS Management Guidelines 1 If ELZONRIS dose is held: ELZONRIS administration may resume in the same cycle if all CLS signs/symptoms have resolved and the patient did not require measures to treat hemodynamic instability ELZONRIS administration should be held for the remainder of the cycle if CLS signs/symptoms have not resolved or the patient required measures to treat hemodynamic instability (e.g., required administration of intravenous fluids and/or vasopressors to treat hypotension) (even if resolved), and ELZONRIS administration may only resume in the next cycle if all CLS signs/symptoms have resolved, and the patient is hemodynamically stable. Time of Presentation CLS Sign/Symptom Recommended Action ELZONRIS Dosing Management Prior to first dose of ELZONRIS in cycle 1 Serum albumin < 3.2 g/dL Administer ELZONRIS when serum albumin ≥ 3.2 g/dL. During ELZONRIS dosing Serum albumin < 3.5 g/dL Administer 25g intravenous albumin (q12h or more frequently as practical) until serum albumin is ≥ 3.5 g/dL AND not more than 0.5 g/dL lower than the value measured prior to dosing initiation of the current cycle. Interrupt ELZONRIS dosing until the relevant CLS sign/symptom has resolved 1 . Serum albumin reduced by ≥ 0.5 g/dL from the albumin value measured prior to ELZONRIS dosing initiation of the current cycle A predose body weight that is increased by ≥ 1.5 kg over the previous day’s predose weight Administer 25g intravenous albumin (q12h or more frequently as practical), and manage fluid status as indicated clinically (e.g., generally with intravenous fluids and vasopressors if hypotensive and with diuretics if normotensive or hypertensive), until body weight increase has resolved (i.e. the increase is no longer ≥ 1.5 kg greater than the previous day’s predose weight). Edema, fluid overload and/or hypotension Administer 25g intravenous albumin (q12h, or more frequently as practical) until serum albumin is ≥ 3.5 g/dL. Administer 1 mg/kg of methylprednisolone (or an equivalent) per day, until resolution of CLS sign/symptom or as indicated clinically. Aggressive management of fluid status and hypotension if present, which could include intravenous fluids and/or diuretics or other blood pressure management, until resolution of CLS sign/symptom or as clinically indicated. 2.3 Preparation for Administration Assure the following components required for dose preparation and administration are available prior to thawing ELZONRIS: One infusion syringe pump One empty 10 mL sterile vial 0.9% Sodium Chloride Injection, USP Three 10 mL sterile syringes One 1 mL sterile syringe One mini-bifuse Y-connector Microbore tubing One 0.2 micron polyethersulfone in-line filter Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Thawed ELZONRIS appearance should be a clear, colorless liquid that may contain a few white to translucent particles. Prior to dose preparation thaw at room temperature, between 15°C and 25°C (59°F and 77°F), for 15 to 30 minutes in original carton, and verify thaw visually. Thawed vials may be held at room temperature for approximately 1 hour prior to dosage preparation. Do not force thaw. Do not refreeze vial once thawed. Use aseptic technique for preparation of the ELZONRIS dose. A 2-step process is required for preparation of the final ELZONRIS dose: - Step 1 - Prepare 10 mL of 100 mcg/mL ELZONRIS - Using a sterile 10 mL syringe, transfer 9 mL of 0.9% Sodium Chloride Injection, USP to an empty sterile 10 mL vial. - Gently swirl the ELZONRIS vial to mix the contents, remove the cap, and using a sterile 1 mL syringe, withdraw 1 mL of thawed ELZONRIS from the product vial. - Transfer the 1 mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection, USP. Gently invert the vial at least 3 times to mix the contents. Do not shake vigorously. - Following dilution the final concentration of ELZONRIS is 100 mcg/mL. - Step 2 – Prepare the ELZONRIS infusion set. - Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patient’s weight. - Draw up the required volume into a new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step 1 with a second vial of ELZONRIS). Label the ELZONRIS syringe. - Prepare a separate syringe with at least 3 mL of 0.9% Sodium Chloride Injection, USP to be used to flush the administration set once the ELZONRIS dose is delivered. - Label the 0.9% Sodium Chloride Injection, USP flush syringe. - Connect the 0.9% Sodium Chloride Injection, USP flush syringe to one arm of the Y-connector and ensure the clamp is closed. - Connect the product syringe to the other arm of the Y-connector and ensure the clamp is closed. - Connect the terminal end of the Y-connector to the microbore tubing. - Remove the cap from the supply side of the 0.2 micron filter and attach it to the terminal end of the microbore tubing. - Unclamp the arm of the Y-connector connected to the 0.9% Sodium Chloride Injection, USP flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with 0.9% Sodium Chloride Injection, USP). Re-clamp the Y-connector line on the 0.9% Sodium Chloride Injection, USP flush arm. - Remove the cap on the terminal end of the 0.2 micron filter and set it aside. Unclamp the arm of the Y-connector connected to the product syringe, and prime the entire infusion set, including the filter. Recap the filter, and re-clamp the Y-connector line on the product side. The infusion set is now ready for delivery for dose administration. Administer ELZONRIS within 4 hours. During this 4-hour window, the prepared dose should remain at room temperature. Do not reuse excess ELZONRIS. Any excess material should be thrown away immediately following infusion. 2.4 Administration Establish venous access and maintain with sterile 0.9% Sodium Chloride Injection, USP. Administer the prepared ELZONRIS dose via infusion syringe pump over 15 minutes. The total infusion time will be controlled using a syringe pump to deliver the entire dose and the 0.9% Sodium Chloride Injection, USP flush over 15 minutes. Insert the ELZONRIS syringe into the syringe pump, open the clamp on the ELZONRIS side of the Y-connector and deliver the prepared ELZONRIS dose. Once the ELZONRIS syringe has been emptied, remove it from the pump and place the 0.9% Sodium Chloride Injection, USP flush syringe in the syringe pump. Open the clamp on the 0.9% Sodium Chloride Injection, USP flush side of the Y-connector and resume infusion via the syringe pump at the pre-specified flow to push remaining ELZONRIS dose out of the infusion line to complete delivery.

6 ADVERSE REACTIONS The following serious adverse drug reactions are described elsewhere in the labeling: Capillary Leak Syndrome [see Warnings and Precautions ( 5.1 ) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [see Warnings and Precautions ( 5.3 ) ] Most common adverse reactions (incidence ≥ 30%) are capillary leak syndrome, nausea, fatigue, pyrexia, peripheral edema, and weight increase. Most common laboratory abnormalities (incidence ≥ 50%) are decreases in albumin, platelets, hemoglobin, calcium, and sodium, and increases in glucose, ALT and AST. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety of ELZONRIS was assessed in a single-arm clinical trial that included 122 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 86 with BPDCN, treated with ELZONRIS 12 mcg/kg daily for 5 days of a 21-day cycle. The overall median number of cycles started was 2.5 (range, 1-76), and 4 in patients with BPDCN (range, 1-76). Four (3%) patients (4/122) had fatal adverse reactions, all of which were related to capillary leak syndrome. Overall, 8% (10/122) of patients discontinued treatment with ELZONRIS due to an adverse reaction; the most common adverse reactions resulting in treatment discontinuation were hepatic toxicities, hypoalbuminemia and CLS (2% each). Table 3 summarizes the common (≥ 10%) adverse reactions with ELZONRIS in patients with myeloid malignancies. The rate of any given adverse reaction or lab abnormality was derived from all the reported events of that type. Table 3. Adverse Reactions in ≥ 10% of Patients Receiving 12 mcg/kg of ELZONRIS 1 Capillary leak syndrome defined as any event reported as CLS during treatment with ELZONRIS or the occurrence of at least 2 of the following CLS manifestations within 7 days of each other: hypoalbuminemia (including albumin value less than 3.0 g/dL), edema (including weight increase of 5 kg or more), hypotension (including systolic blood pressure less than 90 mmHg). N=122 All Grades % Grade ≥ 3 % Vascular disorders Capillary leak syndrome 1 53 11 Hypotension 25 7 Hypertension 14 6 General disorders and administration site conditions Fatigue 45 7 Pyrexia 43 0 Peripheral edema 39 1 Chills 26 1 Gastrointestinal disorders Nausea 45 0 Constipation 24 0 Diarrhea 21 0 Vomiting 19 0 Investigations Weight increase 31 0 Nervous system disorders Headache 28 0 Dizziness 21 0 Metabolism and nutrition disorders Decreased appetite 22 0 Respiratory, thoracic and mediastinal disorders Dyspnea 20 3 Epistaxis 12 1 Cough 12 0 Blood and lymphatic system disorders Febrile neutropenia 19 16 Musculoskeletal and connective tissue disorders Back pain 19 2 Pain in extremity 10 2 Cardiac disorders Tachycardia 17 0 Psychiatric disorders Insomnia 16 0 Anxiety 15 0 Skin and subcutaneous tissue disorders Pruritus 10 0 Clinically relevant adverse reactions occurring in less than 10% of patients treated with ELZONRIS included tumor lysis syndrome. Table 4 summarizes the clinically important laboratory abnormalities that occurred in ≥ 10% patients with myeloid malignancies treated with ELZONRIS. Table 4. Selected Laboratory Abnormalities in Patients Receiving 12 mcg/kg of ELZONRIS Treatment-Emergent Laboratory Abnormalities All Grades % Grade ≥ 3 % Hematology Platelets decrease 68 49 Hemoglobin decrease 61 30 Neutrophils decrease 38 29 Chemistry Glucose increase 89 21 ALT increase 79 26 AST increase 76 33 Albumin decrease 72 1 Calcium decrease 57 2 Sodium decrease 52 9 Potassium decrease 36 6 Phosphate decrease 32 10 Creatinine increase 26 0 Magnesium decrease 25 0 Alkaline phosphatase increase 22 1 Potassium increase 20 3 Magnesium increase 13 4 Bilirubin increase 11 0 Glucose decrease 10 0