LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of ELZONRIS in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from ELZONRIS, breast feeding is not recommended during treatment and for week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tagraxofusp-erzs is CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123-expressing cells.

ADVERSE REACTIONS SECTION.

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)]. 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, peripheral edema, pyrexia 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 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 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 single-arm clinical trial that included 94 adults with newly-diagnosed or relapsed/refractory myeloid malignancies, including 58 with BPDCN, treated with ELZONRIS 12 mcg/kg daily for days of 21-day cycle. The overall median number of cycles administered was (range, 1-43), and in patients with BPDCN (range, 1-43).Two (2%) patients had fatal adverse reaction, both capillary leak syndrome. Overall, 10 (11%) patients discontinued treatment with ELZONRIS due to an adverse reaction; the most common adverse reactions resulting in treatment discontinuation were hepatic toxicities and CLS.Table 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 ELZONRIS1 Capillary leak syndrome defined as any event reported as CLS during treatment with ELZONRIS or the occurrence of at least of the following CLS manifestations within days of each other: hypoalbuminemia (including albumin value less than 3.0 g/dL), edema (including weight increase of kg or more), hypotension (including systolic blood pressure less than 90 mmHg).N=94All Grades%Grade >= 3%Vascular disorders Capillary leak syndrome1 559 Hypotension299 Hypertension156Gastrointestinal disorders Nausea490 Constipation230 Vomiting210 Diarrhea200General disorders and administration site conditions Fatigue457 Peripheral edema 431 Pyrexia430 Chills291Investigations Weight increase310Nervous system disorders Headache290 Dizziness200Metabolism and nutrition disorders Decreased appetite240Blood and lymphatic system disorders Febrile neutropenia2018Musculoskeletal and connective tissue disorders Back pain202 Pain in extremity102Respiratory, thoracic and mediastinal disorders Dyspnea192 Cough140 Epistaxis141 Oropharyngeal pain120Psychiatric disorders Insomnia170 Anxiety150 Confusional state110Cardiac disorders Tachycardia170Skin and subcutaneous tissue disorders Petechiae100 Pruritus100Renal and urinary disorders Hematuria100Table 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 AbnormalitiesAll Grades%Grade >= 3%Hematology Platelets decrease6753 Hemoglobin decrease6035 Neutrophils decrease3731Chemistry Glucose increase8720 ALT increase8230 AST increase7937 Albumin decrease770 Calcium decrease572 Sodium decrease5010 Potassium decrease394 Phosphate decrease3011 Creatinine increase270 Alkaline phosphatase increase261 Potassium increase212 Magnesium decrease200 Magnesium increase143 Bilirubin increase140 Glucose decrease110 Sodium increase100. 6.2 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 ELZONRIS with the incidences of antibodies to other products may be misleading.Immune response to ELZONRIS was evaluated by assessment of serum binding reactivity against ELZONRIS (anti-drug antibodies; ADA) and neutralizing antibodies by inhibition of functional activity. Immune response to ELZONRIS was assessed using two immunoassays. The first assay detected reactivity directed against ELZONRIS (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of ELZONRIS. Two cell-based assays were used to investigate the presence of neutralizing antibodies by inhibition of cell-based functional activity.The presence of ADA had clinically significant effect on the pharmacokinetics of tagraxofusp-erzs [see Clinical Pharmacology (12.2)]. In 130 patients treated with ELZONRIS in clinical trials: 96% (115/120) of patients evaluable for the presence of pre-existing ADA at baseline before treatment were confirmed positive with 21% being positive for the presence of neutralizing antibodies. The high prevalence of ADA at baseline was anticipated due to diphtheria immunization.99% (107/108) of patients evaluable for treatment-emergent ADA tested positive with most patients showing an increase in ADA titer by the end of Cycle of ELZONRIS.85% (86/101) of ADA-positive patients evaluable for the presence of neutralizing antibodies were neutralizing antibody-positive.68% (73/108) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive with most patients testing positive by Cycle of ELZONRIS.. 96% (115/120) of patients evaluable for the presence of pre-existing ADA at baseline before treatment were confirmed positive with 21% being positive for the presence of neutralizing antibodies. The high prevalence of ADA at baseline was anticipated due to diphtheria immunization.. 99% (107/108) of patients evaluable for treatment-emergent ADA tested positive with most patients showing an increase in ADA titer by the end of Cycle of ELZONRIS.. 85% (86/101) of ADA-positive patients evaluable for the presence of neutralizing antibodies were neutralizing antibody-positive.. 68% (73/108) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive with most patients testing positive by Cycle of ELZONRIS.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. At human equivalent doses greater than or equal to 1.6 times the recommended dose based on body surface area, severe kidney tubular degeneration/necrosis was observed in cynomolgus monkeys. At human equivalent doses equal to the recommended dose, degeneration/necrosis of the choroid plexus in the brain was observed in cynomolgus monkeys. The reversibility of this finding was not assessed at lower doses, but the finding was irreversible and became progressively more severe at human equivalent dose 1.6 times the recommended dose, weeks after dosing stopped.

BOXED WARNING SECTION.

WARNING: CAPILLARY LEAK SYNDROME. Capillary Leak Syndrome (CLS) which may be life-threatening or fatal if not properly managed, can occur in patients receiving ELZONRIS. Monitor for signs and symptoms of CLS and take actions as recommended [see Warnings and Precautions (5.1)].. WARNING: CAPILLARY LEAK SYNDROMESee full prescribing information for complete boxed warning.Capillary Leak Syndrome (CLS), which may be life-threatening or fatal if not properly managed, can occur in patients receiving ELZONRIS. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been conducted to assess the carcinogenic or genotoxic potential of tagraxofusp. Animal fertility studies have not been conducted with tagraxofusp-erzs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tagraxofusp-erzs is CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123-expressing cells.. 12.2 Pharmacokinetics. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr.mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.DistributionMean (SD) volume of distribution of tagraxofusp-erzs is 5.1 (1.9) in patients with BPDCN.EliminationMean (SD) clearance is 7.1 (7.2) L/hr in patients with BPDCN. Mean (SD) terminal half-life of tagraxofusp-erzs is 0.7 (0.3) hours.Anti-Product Antibody Formation Affecting PharmacokineticsPharmacokinetic data obtained following doses given in Cycle showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp-erzs is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr.mcg/L and Cmax is 80.0 (82.2) mcg/L.Specific PopulationsNo clinically significant differences in the pharmacokinetics of tagraxofusp-erzs were observed based on age (22 to 84 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD), mild (total bilirubin <= ULN and AST >ULN, or total bilirubin to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to times ULN and any AST) hepatic impairment or body weight after adjusting dose by body weight. The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), or severe hepatic impairment (total bilirubin >3 times ULN and any AST) on tagraxofusp-erzs pharmacokinetics is unknown.Drug Interaction StudiesNo drug-drug interaction studies have been conducted with ELZONRIS.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 First-Line Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). STML-401-0114 (NCT 02113982; Study 0114) was multicenter, open-label, single-arm, clinical trial that included prospective cohort of 13 patients with treatment-naive BPDCN. Treatment consisted of ELZONRIS 12 mcg/kg intravenously over 15 minutes once daily on days to of 21-day cycle. Patient baseline characteristics are presented in Table 5.Table 5. Baseline Demographics of Patients with Treatment-Naive BPDCNParameterN=13Gender, (%) Male11 (84.6) Female2 (15.4)Age (years), (%) Median65.0 Minimum, Maximum22, 84ECOG, (%) 08 (61.5) 15 (38.5)BPDCN at Baseline, (%) Skin13 (100.0) Bone Marrow7 (53.8) Peripheral Blood3 (23.1) Lymph Nodes6 (46.2) Viscera2 (15.4)The efficacy of ELZONRIS in patients with treatment-naive BPDCN was based on the rate of complete response or clinical complete response (CR/CRc). Key efficacy measures are presented in Table 6. The median time to CR/CRc was 57 days (range: 14 to 107).Table 6. Efficacy Measures in Patients with Treatment-Naive BPDCN CRc is defined as complete response with residual skin abnormality not indicative of active disease.ParameterN=13CR/CRc Rate, (%)7 (53.8)(95% CI)(25.1, 80.8)Duration of CR/CRc (months) MedianNot Reached Minimum, Maximum3.9, 12.2Duration of follow up (months) Median11.5 Minimum, Maximum0.2, 12.7. 14.2 Relapsed or Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). STML-401-0114 (NCT02113982; Study 0114) was multicenter, open-label, single-arm, clinical trial that included 15 patients with relapsed or refractory BPDCN. Treatment consisted of ELZONRIS 12 mcg/kg on days to of each 21-day cycle. Patient baseline characteristics are presented in Table 7. Table 7. Baseline Demographics of Patients with Relapsed or Refractory BPDCNParameter(N=15)Gender, (%) Male13 (86.7) Female2 (13.3)Age (years) Median72 Minimum, Maximum44, 80 ECOG, (%) 05 (33.3) 110 (66.7)BPDCN at Baseline, (%) Skin13 (86.7) Bone marrow9 (60.0) Lymph node8 (53.3) Visceral4 (26.7) Peripheral blood1 (6.7)In the 15 patients with relapsed/refractory BPDCN, one patient achieved CR (duration: 111 days) and one patient achieved CRc (duration: 424 days).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4). None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Tagraxofusp-erzs, CD123-directed cytotoxin, is fusion protein comprised of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT). Tagraxofusp-erzs has an approximate molecular weight of 57,695 Daltons. Tagraxofusp-erzs is constructed by recombinant DNA technology and produced in Escherichia coli cells.ELZONRIS (tagraxofusp-erzs) injection is preservative-free, sterile, clear, colorless solution that may contain few white to translucent particles and requires dilution prior to intravenous infusion. ELZONRIS is supplied at concentration of 1,000 mcg/mL in single-dose vial. Each mL of ELZONRIS contains 1,000 mcg tagraxofusp-erzs, sodium chloride (4.38 mg), sorbitol (50 mg), tromethamine (2.42 mg) and Water for Injection, USP and pH is 7.5.

DOSAGE & ADMINISTRATION SECTION.

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 to of 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). 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 to of 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). 2.1Recommended Dose. Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days to of 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.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., ranitidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.Administer Cycle 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 suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for minimum of hours following each infusion.. Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days to of 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.. 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., ranitidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.. Administer Cycle 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 suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for minimum of hours following each infusion.. 2.2Dose Modifications. Monitor vital signs and check albumin, transaminases, and creatinine prior to preparing each dose of ELZONRIS. See Table for recommended dose modifications and Table for CLS management guidelines.Table 1. Recommended ELZONRIS Dose ModificationsParameterSeverity CriteriaDose ModificationSerum albuminSerum albumin 3.5 g/dL or reduced >= 0.5 g/dL from value measured prior to initiation of the current cycleSee CLS Management Guidelines (Table 2)Body weight Body weight increase >= 1.5 kg over pretreatment weight on prior treatment daySee CLS Management Guidelines (Table 2)Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ALT or AST increase 5 times the upper limit of normalWithhold 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/minuteWithhold ELZONRIS until serum creatinine resolves to <= 1.8 mg/dL (159 micromol/L) or creatinine clearance >= 60 mL/minute.Systolic blood pressureSystolic blood pressure >= 160 mmHg or <= 80 mmHgWithhold ELZONRIS until systolic blood pressure is 160 mmHg or 80 mmHg.Heart rateHeart rate >= 130 bpm or <= 40 bpmWithhold ELZONRIS until heart rate is 130 bpm or 40 bpm.Body temperature Body temperature >= 38CWithhold ELZONRIS until body temperature is 38C.Hypersensitivity reactionsMild or moderateWithhold ELZONRIS until resolution of any mild or moderate hypersensitivity reaction. Resume ELZONRIS at the same infusion rate.Severe or life-threateningDiscontinue ELZONRIS permanently.Table 2. CLS Management Guidelines1ELZONRIS 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 PresentationCLS Sign/SymptomRecommended ActionELZONRIS Dosing ManagementPrior to first dose of ELZONRIS in cycle Serum albumin 3.2 g/dL Administer ELZONRIS when serum albumin >= 3.2 g/dL.During ELZONRIS dosingSerum 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 resolved1.Serum albumin reduced by >= 0.5 g/dL from the albumin value measured prior to ELZONRIS dosing initiation of the current cycleA predose body weight that is increased by >= 1.5 kg over the previous days predose weightAdminister 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 days predose weight).Edema, fluid overload and/or hypotensionAdminister 25g intravenous albumin (q12h, or more frequently as practical) until serum albumin is >= 3.5 g/dL.Administer 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.. 2.3Preparation for Administration. Assure the following components required for dose preparation and administration are available prior to thawing ELZONRIS: One empty 10 mL sterile vial 0.9% Sodium Chloride Injection, USP (sterile saline)Three 10 mL sterile syringesOne mL sterile syringe One mini-bifuse Y-connector Microbore tubing One 0.2 micron polyethersulfone in-line filterParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Thawed ELZONRIS appearance should be clear, colorless liquid that may contain few white to translucent particles.Prior to dose preparation thaw at room temperature, between 15C and 25C (59F and 77F), for 15 to 30 minutes in original carton, and verify thaw visually. Thawed vials may be held at room temperature for approximately 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 - Prepare 10 mL of 100 mcg/mL ELZONRIS- Using sterile 10 mL syringe, transfer 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 sterile mL syringe, withdraw mL of thawed ELZONRIS from the product vial.- Transfer the mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection. Gently invert the vial at least times to mix the contents. Do not shake vigorously.- Following dilution the final concentration of ELZONRIS is 100 mcg/mL. Step - Prepare the ELZONRIS infusion set.- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patients weight.- Draw up the required volume into new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step with second vial of ELZONRIS). Label the ELZONRIS syringe.- Prepare separate syringe with at least mL of 0.9% Sodium Chloride Injection, USP (saline flush) to be used to flush the administration set once the ELZONRIS dose is delivered.- Label the saline flush syringe.- Connect the saline 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 saline flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with saline). Re-clamp the Y-connector line on the saline 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 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.. One empty 10 mL sterile vial 0.9% Sodium Chloride Injection, USP (sterile saline)Three 10 mL sterile syringesOne mL sterile syringe One mini-bifuse Y-connector Microbore tubing One 0.2 micron polyethersulfone in-line filter. One empty 10 mL sterile vial 0.9% Sodium Chloride Injection, USP (sterile saline). Three 10 mL sterile syringes. One 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 clear, colorless liquid that may contain few white to translucent particles.. Prior to dose preparation thaw at room temperature, between 15C and 25C (59F and 77F), for 15 to 30 minutes in original carton, and verify thaw visually. Thawed vials may be held at room temperature for approximately hour prior to dosage preparation. Do not force thaw. Do not refreeze vial once thawed.. Use aseptic technique for preparation of the ELZONRIS dose.. 2-step process is required for preparation of the final ELZONRIS dose:- Step - Prepare 10 mL of 100 mcg/mL ELZONRIS- Using sterile 10 mL syringe, transfer 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 sterile mL syringe, withdraw mL of thawed ELZONRIS from the product vial.- Transfer the mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection. Gently invert the vial at least times to mix the contents. Do not shake vigorously.- Following dilution the final concentration of ELZONRIS is 100 mcg/mL. Step - Prepare the ELZONRIS infusion set.- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patients weight.- Draw up the required volume into new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step with second vial of ELZONRIS). Label the ELZONRIS syringe.- Prepare separate syringe with at least mL of 0.9% Sodium Chloride Injection, USP (saline flush) to be used to flush the administration set once the ELZONRIS dose is delivered.- Label the saline flush syringe.- Connect the saline 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 saline flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with saline). Re-clamp the Y-connector line on the saline 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. - Step - Prepare 10 mL of 100 mcg/mL ELZONRIS- Using sterile 10 mL syringe, transfer 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 sterile mL syringe, withdraw mL of thawed ELZONRIS from the product vial.- Transfer the mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection. Gently invert the vial at least times to mix the contents. Do not shake vigorously.- Following dilution the final concentration of ELZONRIS is 100 mcg/mL. - Using sterile 10 mL syringe, transfer 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 sterile mL syringe, withdraw mL of thawed ELZONRIS from the product vial.. Transfer the mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection. Gently invert the vial at least times to mix the contents. Do not shake vigorously.. Following dilution the final concentration of ELZONRIS is 100 mcg/mL.. Step - Prepare the ELZONRIS infusion set.- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patients weight.- Draw up the required volume into new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step with second vial of ELZONRIS). Label the ELZONRIS syringe.- Prepare separate syringe with at least mL of 0.9% Sodium Chloride Injection, USP (saline flush) to be used to flush the administration set once the ELZONRIS dose is delivered.- Label the saline flush syringe.- Connect the saline 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 saline flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with saline). Re-clamp the Y-connector line on the saline 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. - Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patients weight.. Draw up the required volume into new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step with second vial of ELZONRIS). Label the ELZONRIS syringe.. Prepare separate syringe with at least mL of 0.9% Sodium Chloride Injection, USP (saline flush) to be used to flush the administration set once the ELZONRIS dose is delivered.. Label the saline flush syringe.. Connect the saline 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 saline flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with saline). Re-clamp the Y-connector line on the saline 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 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.. 2.4Administration. 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 syringe pump to deliver the entire dose and the saline 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 saline flush syringe in the syringe pump.Open the clamp on the saline 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.. 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 syringe pump to deliver the entire dose and the saline 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 saline flush syringe in the syringe pump.. Open the clamp on the saline 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 1,000 mcg in mL clear colorless solution in single-dose vial.. Injection: 1,000 mcg in mL in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on its mechanism of action, ELZONRIS may cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy Testing:Conduct pregnancy testing in females of reproductive potential within days prior to initiating ELZONRIS treatment. Contraception:Advise females to use acceptable contraceptive methods during ELZONRIS treatment and for at least week after the last dose of ELZONRIS.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 94 patients who received ELZONRIS at the labeled dose in STML-401-0114, 23% were 75 years and older. The older patients experienced higher incidence of altered mental status (including confusional state, delirium, mental status changes, dementia, and encephalopathy) than younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. ELZONRIS (tagraxofusp-erzs) injection is preservative-free, sterile, clear, colorless, 1,000 mcg in mL solution supplied in single-dose glass vial. Each carton contains one vial (NDC 72187-0401-1).. 16.2 Storage and Handling. Store in freezer between -25C and -15C (-13F and 5F). Protect ELZONRIS from light by storing in the original package until time of use. Thaw vials at room temperature between 15C and 25C (59F and 77F) prior to preparation [see Preparation for Administration (2.3)]. Do not refreeze the vial once thawed. Do not use beyond expiration date on container.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Capillary Leak Syndrome Advise patients of the risk of capillary leak syndrome (CLS), and to contact their health care professional for signs and symptoms associated with CLS including new or worsening edema, weight gain, shortness of breath, and/or hypotension after infusion. Advise patients to weigh themselves daily [see Warnings and Precautions (5.1)]. Hypersensitivity Advise patients of the risk of hypersensitivity reactions, and to contact their healthcare professional for signs and symptoms associated with hypersensitivity reactions including rash, flushing, wheezing and swelling of the face [see Warnings and Precautions (5.2)]. Hepatic ToxicityAdvise patients to report symptoms that may indicate elevated liver enzymes including fatigue, anorexia and/or right upper abdominal discomfort [see Warnings and Precautions (5.3)]. ContraceptionAdvise females to avoid pregnancy and to use acceptable contraceptive methods during ELZONRIS treatment and for at least week after the last dose of ELZONRIS.LactationAdvise women not to breastfeed [see Use in Specific Populations (8.2)].Manufactured and Distributed by:Stemline Therapeutics, Inc.New York, NY 10022US License No. 2088Stemline(R).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been conducted to assess the carcinogenic or genotoxic potential of tagraxofusp. Animal fertility studies have not been conducted with tagraxofusp-erzs.. 13.2 Animal Toxicology and/or Pharmacology. At human equivalent doses greater than or equal to 1.6 times the recommended dose based on body surface area, severe kidney tubular degeneration/necrosis was observed in cynomolgus monkeys. At human equivalent doses equal to the recommended dose, degeneration/necrosis of the choroid plexus in the brain was observed in cynomolgus monkeys. The reversibility of this finding was not assessed at lower doses, but the finding was irreversible and became progressively more severe at human equivalent dose 1.6 times the recommended dose, weeks after dosing stopped.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL NDC: 72187-0401-1 1000 mcg/mL Vial Label. 1000 mcgg/mL Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ELZONRIS for treatment of BPDCN have been established in pediatric patients years of age and older (no data for pediatric patients less than years of age). Use of ELZONRIS in these age groups is supported by evidence from an adequate and well-controlled study of ELZONRIS in adults with BPDCN and additional safety data from three pediatric patients with BPDCN, including child (2 years to 12 years old) and adolescents (12 years to 17 years old), treated with ELZONRIS at the recommended dosage. The safety profile of ELZONRIS in the pediatric patients was similar to that seen in the adults. Efficacy for pediatric patients is extrapolated from the results of STML-401-0114 [see Clinical Studies 14.1, 14.2].

PHARMACODYNAMICS SECTION.

12.2 Pharmacokinetics. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr.mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.DistributionMean (SD) volume of distribution of tagraxofusp-erzs is 5.1 (1.9) in patients with BPDCN.EliminationMean (SD) clearance is 7.1 (7.2) L/hr in patients with BPDCN. Mean (SD) terminal half-life of tagraxofusp-erzs is 0.7 (0.3) hours.Anti-Product Antibody Formation Affecting PharmacokineticsPharmacokinetic data obtained following doses given in Cycle showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp-erzs is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr.mcg/L and Cmax is 80.0 (82.2) mcg/L.Specific PopulationsNo clinically significant differences in the pharmacokinetics of tagraxofusp-erzs were observed based on age (22 to 84 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD), mild (total bilirubin <= ULN and AST >ULN, or total bilirubin to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to times ULN and any AST) hepatic impairment or body weight after adjusting dose by body weight. The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), or severe hepatic impairment (total bilirubin >3 times ULN and any AST) on tagraxofusp-erzs pharmacokinetics is unknown.Drug Interaction StudiesNo drug-drug interaction studies have been conducted with ELZONRIS.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ELZONRIS has the potential for adverse effects on embryo-fetal development [see Clinical Pharmacology (12.1)]. There are no available data on ELZONRIS use in pregnant women to inform drug-associated risk of adverse developmental outcomes. Animal reproduction or developmental toxicity studies have not been conducted with tagraxofusp-erzs. Advise pregnant women of the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have risk of birth defect, loss, or other adverse outcomes. In the US 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.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dose. Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days to of 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.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., ranitidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.Administer Cycle 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 suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for minimum of hours following each infusion.. Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days to of 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.. 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., ranitidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.. Administer Cycle 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 suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for minimum of hours following each infusion.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store in freezer between -25C and -15C (-13F and 5F). Protect ELZONRIS from light by storing in the original package until time of use. Thaw vials at room temperature between 15C and 25C (59F and 77F) prior to preparation [see Preparation for Administration (2.3)]. Do not refreeze the vial once thawed. Do not use beyond expiration date on container.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ELZONRIS has the potential for adverse effects on embryo-fetal development [see Clinical Pharmacology (12.1)]. There are no available data on ELZONRIS use in pregnant women to inform drug-associated risk of adverse developmental outcomes. Animal reproduction or developmental toxicity studies have not been conducted with tagraxofusp-erzs. Advise pregnant women of the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have risk of birth defect, loss, or other adverse outcomes. In the US 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.. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of ELZONRIS in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from ELZONRIS, breast feeding is not recommended during treatment and for week after the last dose. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action, ELZONRIS may cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy Testing:Conduct pregnancy testing in females of reproductive potential within days prior to initiating ELZONRIS treatment. Contraception:Advise females to use acceptable contraceptive methods during ELZONRIS treatment and for at least week after the last dose of ELZONRIS.. 8.4 Pediatric Use. The safety and effectiveness of ELZONRIS for treatment of BPDCN have been established in pediatric patients years of age and older (no data for pediatric patients less than years of age). Use of ELZONRIS in these age groups is supported by evidence from an adequate and well-controlled study of ELZONRIS in adults with BPDCN and additional safety data from three pediatric patients with BPDCN, including child (2 years to 12 years old) and adolescents (12 years to 17 years old), treated with ELZONRIS at the recommended dosage. The safety profile of ELZONRIS in the pediatric patients was similar to that seen in the adults. Efficacy for pediatric patients is extrapolated from the results of STML-401-0114 [see Clinical Studies 14.1, 14.2].. 8.5 Geriatric Use. Of the 94 patients who received ELZONRIS at the labeled dose in STML-401-0114, 23% were 75 years and older. The older patients experienced higher incidence of altered mental status (including confusional state, delirium, mental status changes, dementia, and encephalopathy) than younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: Monitor patients for signs/symptoms and treat appropriately. (5.2)Hepatotoxicity: Monitor ALT and AST. Interrupt ELZONRIS if the transaminases rise to greater than times the upper limit of normal. (5.3). Hypersensitivity: Monitor patients for signs/symptoms and treat appropriately. (5.2). Hepatotoxicity: Monitor ALT and AST. Interrupt ELZONRIS if the transaminases rise to greater than times the upper limit of normal. (5.3). 5.1 Capillary Leak Syndrome. Capillary leak syndrome (CLS), including life-threatening and fatal cases, has been reported among patients treated with ELZONRIS. In patients receiving ELZONRIS in clinical trials, the overall incidence of CLS was 55% (52/94), including Grade or in 46% (43/94), Grade in 6% (6/94), Grade in 1% (1/94) and fatal events (2/94, 2%). Common signs and symptoms (incidence >= 20%) associated with CLS that were reported during treatment with ELZONRIS include hypoalbuminemia, edema, weight gain, and hypotension.Before initiating therapy with ELZONRIS, ensure that the patient has adequate cardiac function and serum albumin is greater than or equal to 3.2 g/dL. During treatment with ELZONRIS, monitor serum albumin levels prior to the initiation of each dose of ELZONRIS and as indicated clinically thereafter, and assess patients for other signs or symptoms of CLS, including weight gain, new onset or worsening edema, including pulmonary edema, hypotension or hemodynamic instability [see Dose Modifications (2.2)].. 5.2 Hypersensitivity Reactions ELZONRIS can cause severe hypersensitivity reactions. In patients receiving ELZONRIS in clinical trials, hypersensitivity reactions were reported in 46% (43/94) of patients treated with ELZONRIS and were Grade >= in 10% (9/94). Manifestations of hypersensitivity reported in >= 5% of patients include rash, pruritus, stomatitis, and wheezing. Monitor patients for hypersensitivity reactions during treatment with ELZONRIS. Interrupt ELZONRIS infusion and provide supportive care as needed if hypersensitivity reaction should occur [see Dose Modifications (2.2)].. 5.3 Hepatotoxicity. Treatment with ELZONRIS was associated with elevations in liver enzymes. In patients receiving ELZONRIS in clinical trials, elevations in liver enzymes occurred in 88% (83/94) of patients, including Grade or in 48% (45/94), Grade in 36% (34/94), and Grade in 4% (4/94). Monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) prior to each infusion with ELZONRIS. Withhold ELZONRIS temporarily if the transaminases rise to greater than times the upper limit of normal and resume treatment upon normalization or when resolved [see Dose Modifications (2.2)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Recommended Dosage (2.1) 10/2022Warnings and Precautions, Capillary Leak Syndrome (5.1) 10/2022Warnings and Precautions, Hepatotoxicity (5.3) 10/2022.