Tagraxofusp-erzs (Monograph)

Brand name: Elzonris
Drug class: Antineoplastic Agents
Chemical name: L-Methionyldiphtheria toxin-(1-386)-peptide (1-387) fusion protein with L-arginyl-L-prolyl-L-histidyl-L-methionyl-[8-L-serine(P>S399)]interleukin-3 (Homo sapiens) (388-524), non-glycosylated
Molecular formula: C₂₅₅₃H₄₀₂₆N₆₉₂O₇₉₈S₁₆
CAS number: 2055491-00-2

Medically reviewed by Drugs.com on Sep 11, 2023. Written by ASHP.

Warning

Capillary leak syndrome, sometimes life-threatening or fatal, reported. (See Capillary Leak Syndrome under Cautions.)
Temporary interruption of therapy may be necessary.

Introduction

Antineoplastic agent; CD123-directed fusion protein consisting of recombinant human interleukin-3 (IL-3) linked to truncated diphtheria toxin.

Uses for Tagraxofusp-erzs

Blastic Plasmacytoid Dendritic Cell Neoplasm

Treatment of blastic plasmacytoid dendritic cell neoplasm (designated an orphan drug by FDA for this use).

Efficacy based on rate of complete response (CR) or clinical complete response (CRc) in patients with previously untreated blastic plasmacytoid dendritic cell neoplasm.

Tagraxofusp-erzs Dosage and Administration

General

Assess vital signs and laboratory parameters (i.e., serum albumin, aminotransferase, and S_cr concentrations) prior to preparation of each dose and as clinically indicated during therapy. For cycle 1 (including at least 24 hours following the last dose of the cycle, monitor in an inpatient setting. For subsequent cycles, administer in a setting where adequate monitoring for patients with hematologic malignancies can be performed for at least 4 hours following each dose.
To minimize the risk of hypersensitivity reactions, premedicate with an antihistamine (e.g., diphenhydramine), H₂-receptor antagonist, systemic corticosteroid (e.g., IV methylprednisolone 50 mg [or equivalent]), and acetaminophen approximately 60 minutes prior to each infusion.
Because of the risk of capillary leak syndrome, confirm adequacy of cardiac function prior to initiation of therapy. Delay initial dose of drug until serum albumin concentration is ≥3.2 g/dL. (See Capillary Leak Syndrome under Cautions.)

Restricted Distribution

Available through designated specialty distributors. Contact manufacturer for additional information.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion. Use a controlled-infusion device (i.e., syringe pump). To ensure complete administration of the drug, flush infusion set with ≥3 mL of 0.9% sodium chloride injection over 15 minutes using a syringe pump.

Must be diluted prior to administration.

Consult manufacturer’s labeling for detailed information on infusion system requirements (e.g., components, set-up) and procedures for IV infusion.

Dilution

Frozen tagraxofusp-erzs concentrate must be completely thawed at room temperature (15–25°C) for 15–30 minutes in original carton prior to dilution. Do not use heat sources or refreeze vial(s). (See Storage under Stability.)

Mix injection concentrate by gently swirling.

Add 9 mL of 0.9% sodium chloride injection followed by 1 mL of tagraxofusp-erzs concentrate (containing 1000 mcg/mL) to an empty sterile 10-mL vial to provide a final concentration of 100 mcg/mL.

Gently invert diluted solution ≥3 times; do not shake.

Withdraw appropriate volume of diluted tagraxofusp-erzs solution into a sterile syringe. Affix product label to syringe.

Affix 0.9% sodium chloride flush label to a separate syringe containing ≥3 mL of 0.9% sodium chloride injection.

Administer immediately following preparation of syringe. If necessary, may store diluted solution at room temperature for ≤4 hours following dose preparation. (See Storage under Stability.)

Discard any partially used vials.

Rate of Administration

Administer by IV infusion over 15 minutes via a controlled-infusion device (i.e., syringe pump).

Dosage

Pediatric Patients

Blastic Plasmacytoid Dendritic Cell Neoplasm

IV

Pediatric patients ≥2 years of age: 12 mcg/kg administered on days 1–5 of each 21-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

Therapy Interruption for Toxicity

IV

Follow recommendations for therapy interruption in adults.

Adults

Blastic Plasmacytoid Dendritic Cell Neoplasm

IV

12 mcg/kg administered on days 1–5 of each 21-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

Therapy Interruption for Toxicity

If toxicities requiring temporary interruption of therapy occur, may extend dosing period up to, but not beyond, day 10 of cycle.

Hypoalbuminemia

For serum albumin concentration <3.5 g/dL or an absolute reduction of ≥0.5 g/dL from the precycle value (value prior to initiation of current cycle), initiate symptomatic treatment for capillary leak syndrome. (See Capillary Leak Syndrome under Cautions.)

Hepatic Effects

For serum ALT and/or AST elevations >5 times the ULN, interrupt therapy until ALT and AST concentrations return to baseline values or decrease to ≤2.5 times the ULN.

Renal Effects

For S_cr concentrations >1.8 mg/dL, interrupt therapy until S_cr concentrations improve to ≤1.8 mg/dL.

For Cl_cr <60 mL/minute, interrupt therapy until Cl_cr improves to ≥60 mL/minute.

Vital sign Abnormalities

If vital sign abnormalities occur, interruption of therapy may be necessary (see Table 1).

Table 1. Recommended Therapy Interruption for Vital Sign Abnormalities.1
Vital Sign	Dosage Modification
Weight increase of ≥1.5 kg from predose weight on the previous treatment day	Follow recommendations for management of capillary leak syndrome (see Capillary Leak Syndrome under Cautions)
SBP ≥160 mm Hg	Interrupt therapy until SBP is <160 mm Hg
SBP ≤80 mm Hg	Interrupt therapy until SBP is >80 mm Hg
Heart rate ≥130 bpm	Interrupt therapy until heart rate is <130 bpm
Heart rate ≤40 bpm	Interrupt therapy until heart rate is >40 bpm
Body temperature ≥38°C	Interrupt therapy until body temperature is <38°C

Capillary Leak Syndrome

Interrupt tagraxofusp therapy and initiate symptomatic treatment if any of the following occur: serum albumin concentration <3.5 g/dL or an absolute reduction of ≥0.5 g/dL from the precycle value (value prior to initiation of current cycle); weight increase of ≥1.5 kg from predose weight on the previous treatment day; or edema, fluid overload, and/or hypotension.

If capillary leak syndrome resolves and treatment for hemodynamic instability was not required, resume tagraxofusp therapy during the same cycle.

If capillary leak syndrome does not resolve or treatment for hemodynamic instability was required (e.g., IV fluids, vasopressor therapy), withhold tagraxofusp therapy for the remainder of the current cycle, even if signs or symptoms resolve following treatment for hemodynamic stability; if all signs or symptoms of capillary leak syndrome resolve, resume tagraxofusp in the next cycle in hemodynamically stable patients.

Hypersensitivity Reactions

If mild or moderate hypersensitivity reactions occur, interrupt infusion and initiate supportive treatment as necessary; resume infusion at same rate once symptoms resolve.

If severe hypersensitivity reactions occur, permanently discontinue drug and initiate supportive treatment as necessary.

Special Populations

Hepatic Impairment

No dosage recommendations at this time. (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No dosage recommendations at this time. (See Absorption: Special Populations, under Pharmacokinetics.)

Geriatric Patients

No dosage recommendations at this time. (See Absorption: Special Populations, under Pharmacokinetics.)

Cautions for Tagraxofusp-erzs

Contraindications

No known contraindications.

Warnings/Precautions

Warnings

Capillary Leak Syndrome

Risk of severe and/or fatal capillary leak syndrome (e.g., hypoalbuminemia, new-onset or worsening edema, pulmonary edema, weight gain, hypotension) if not treated appropriately.

Monitor BP, heart rate, body temperature, weight, and serum albumin concentrations prior to each dose and as clinically indicated during therapy.

Confirm adequate cardiac function prior to initiation of therapy.

Delay initiation of therapy until serum albumin concentrations are ≥3.2 g/dL.

If manifestations of capillary leak syndrome occur, initiate symptomatic treatment as described in Table 2 until the toxicity resolves. Temporary interruption of therapy may be necessary. (See Therapy Interruption for Toxicity under Dosage and Administration.)

Table 2. Recommended Symptomatic Treatment for Capillary Leak Syndrome.1
Manifestation	Symptomatic Treatment
Serum albumin <3.5 g/dL or an absolute reduction of ≥0.5 g/dL from the precycle value (value prior to initiation of current cycle)	Administer albumin 25 g IV every 12 hours or more frequently until serum albumin concentration reaches ≥3.5 g/dL and absolute difference from precycle value is ≤0.5 g/dL
Weight increase of ≥1.5 kg from predose weight on the previous treatment day	Administer albumin 25 g IV every 12 hours or more frequently and manage hemodynamic status (e.g., diuretic therapy if normotensive or hypertensive; IV fluids and vasopressor therapy if hypotensive) as clinically indicated Continue symptomatic treatment until body weight is <1.5 kg above predose weight on previous day
Edema, fluid overload, and/or hypotension	Administer albumin 25 g IV every 12 hours or more frequently until serum albumin concentration reaches ≥3.5 g/dL Administer systemic corticosteroid therapy (e.g., 1 mg/kg of methylprednisolone daily [or equivalent]) as clinically necessary or until manifestations of capillary leak syndrome resolve Intensively manage hemodynamic status (e.g., IV fluids, diuretic therapy) and hypotension, if present, as clinically necessary or until manifestations of capillary leak syndrome resolve

Sensitivity Reactions

Hypersensitivity Reactions

Severe hypersensitivity reactions (e.g., rash, pruritus, stomatitis, wheezing) reported.

Premedicate with an antihistamine, H₂-receptor antagonist, systemic corticosteroid, and acetaminophen prior to each infusion. (See General under Dosage and Administration.)

Monitor for manifestations of hypersensitivity reactions during each infusion.

If hypersensitivity reactions occur, interrupt or permanently discontinue drug and provide supportive care. (See Therapy Interruption for Toxicity under Dosage and Administration.)

Other Warnings and Precautions

Hepatic Toxicity

Elevations in serum ALT or AST concentrations occur frequently.

Monitor serum ALT and AST concentrations prior to each dose.

If ALT and/or AST elevations >5 times the ULN occur, interrupt therapy. Reinitiate therapy after serum ALT and AST concentrations return to baseline values or decrease to <2.5 times the ULN.

Immunogenicity

Potential for immunogenicity. Preexisting anti-tagraxofusp antibodies reported in most patients because of the high rate of primary and booster immunizations against diphtheria; neutralizing antibodies to tagraxofusp also reported in some of these patients.

AUC and peak plasma concentrations decreased and clearance of drug increased in patients with preexisting anti-tagraxofusp antibodies; no dosage adjustment necessary.

Specific Populations

Pregnancy

May cause fetal harm.

Confirm pregnancy status within 7 days prior to initiation of therapy in females of reproductive potential. Avoid pregnancy during therapy. Advise females of reproductive potential to use effective methods of contraception while receiving the drug and for ≥1 week after the last dose.

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Lactation

Not known whether tagraxofusp is distributed into human milk. Potential effects on nursing infants or on milk production not known.

Discontinue nursing during therapy and for 1 week after last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.

Safety and efficacy in pediatric patients with blastic plasmacytoid dendritic cell neoplasm are supported by extrapolation of data from the principal efficacy study (STML-401-0114) evaluating tagraxofusp-erzs in adults and limited data indicating that adverse effects in pediatric patients are similar to those reported in adults.

Geriatric Use

Adverse CNS effects (i.e., confusion, delirium, mental status changes, dementia, encephalopathy) occurred more frequently in geriatric patients.

Hepatic Impairment

Pharmacokinetics not affected by mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times but ≤3 times the ULN, with any AST concentration) hepatic impairment.

Pharmacokinetics not studied in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration).

Renal Impairment

Pharmacokinetics not affected by mild or moderate renal impairment (estimated GFR [eGFR] 30–89 mL/minute per 1.73 m²).

Pharmacokinetics not studied in patients with severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²).

Common Adverse Effects

Capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, weight gain, decreased albumin concentrations, decreased platelet concentrations, decreased hemoglobin concentrations, decreased calcium concentrations, decreased sodium concentrations, elevated glucose concentrations, elevated ALT and/or AST concentrations.

Drug Interactions

No formal drug interaction studies to date.

Tagraxofusp-erzs Pharmacokinetics

Absorption

Bioavailability

AUC and peak plasma concentrations reduced by 34.6 and 50.6%, respectively, in patients with preexisting anti-tagraxofusp antibodies.

Special Populations

Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times but ≤3 times the ULN, with any AST concentration) hepatic impairment: No effect on pharmacokinetics of tagraxofusp-erzs.

Severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration): Not studied.

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No effect on pharmacokinetics of tagraxofusp-erzs.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²): Not studied.

Clearance increased by 1.96-fold in patients with preexisting anti-tagraxofusp antibodies.

Pharmacokinetics not affected by age (range: 22–84 years), sex, or body weight.

Distribution

Extent

Not known whether tagraxofusp is distributed into human milk.

Elimination

Metabolism

Not characterized. Metabolism by CYP isoenzymes not expected.

Half-life

Mean terminal half-life: 0.7 hours.

Stability

Storage

Parenteral

Injection Concentrate

-25 to -15°C in original carton to protect drug from light. Do not heat or refreeze.

Thawed vials: Approximately 1 hour at room temperature.

Diluted infusion solution: Use immediately, but may store at room temperature for ≤4 hours.

Compatibility

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%

Actions

Recombinant DNA-derived CD123-directed fusion protein containing truncated diphtheria toxin and human IL-3; prepared from Escherichia coli cells.
Binds to IL-3 receptor alpha-chain (IL-3R alpha; also known as CD123) on the surface of CD123-expressing cells, the resultant complex is internalized by the cell, and truncated and catalytic domains of the diphtheria toxin are released into cytosol, thereby inhibiting protein synthesis and inducing apoptosis.

Advice to Patients

Risk of capillary leak syndrome. Importance of informing clinician if manifestations of capillary leak syndrome (e.g., new or worsening edema, weight gain, shortness of breath, hypotension) occur after infusion of tagraxofusp.
Risk of hypersensitivity reactions. Importance of informing clinician if symptoms of such reactions, including rash, flushing, wheezing, and swelling of the face, occur.
Risk of hepatotoxicity. Importance of informing clinician if symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper quadrant pain) occur.
Risk of fetal harm. Necessity of advising females of reproductive potential to use an effective method of contraception while receiving the drug and for ≥1 week after the last dose. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Importance of advising women to avoid breast-feeding during tagraxofusp therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., renal impairment).
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of tagraxofusp-erzs is restricted. (See Restricted Distribution under Dosage and Administration.)