Tagraxofusp

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Elzonris: tagraxofusp-erzs 1000 mcg/mL (1 mL)

Pharmacology

Mechanism of Action

Tagraxofusp is a CD123-directed fusion protein which is composed of human interleukin-3 (IL-3) and truncated diphtheria toxin (DT). After binding to CD123, tagraxofusp is internalized, leading to inhibition of protein synthesis and cell death (Sun 2018).

Pharmacokinetics/Pharmacodynamics

Distribution

5.1 L; 21.2 L in patients with preexisting anti-drug antibodies

Excretion

Clearance: 7.1 L/hour; 13.9 L/hour in patients with preexisting anti-drug antibodies

Half-Life Elimination

0.7 hours

Use: Labeled Indications

Blastic plasmacytoid dendritic cell neoplasm: Treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients ≥2 years of age

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Serum albumin should be ≥3.2 g/dL prior the first dose of cycle 1; monitor serum albumin levels prior to each dose and as clinically necessary. Premedicate with an H₁-antagonist (eg, diphenhydramine), an H₂-antagonist (eg, ranitidine), a corticosteroid (eg, 50 mg IV methylprednisolone or equivalent), and acetaminophen ~60 minutes prior to each tagraxofusp infusion.

Blastic plasmacytoid dendritic cell neoplasm: IV: 12 mcg/kg once daily on days 1 to 5 of a 21-day cycle; continue until disease progression or unacceptable toxicity (Pemmaraju 2019). The dosing period may be extended for dose delays up to day 10 of the cycle.

Administer cycle 1 in the inpatient setting; observe patients through at least 24 hours after the last infusion. Subsequent cycles may be administered either inpatient or outpatient (if suitable); ensure appropriate monitoring is available and observe patients for a minimum of 4 hours following each infusion.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Prior to first dose of first cycle, verify serum albumin ≥3.2 g/dL and patient has adequate cardiac function. Administer the first cycle of doses in an inpatient setting; subsequent cycles may be administered in an inpatient setting or an ambulatory outpatient setting equipped with monitoring capabilities for patients with hematopoietic malignancies. Premedicate 60 minutes prior to each infusion with an H₁- and H₂-histamine antagonist (eg, diphenhydramine and ranitidine), corticosteroid (eg, methylprednisolone IV), and acetaminophen.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): Note: Approval in pediatric patients based on extrapolation of experience in adult patients and scant pediatric experience (minimum reported age: 10 years) (Sun 2018); Children ≥2 years and Adolescents: IV: 12 mcg/kg/dose once daily on days 1 to 5 of a 21-day cycle; dosing period may be extended to delays up to day 10 of the 21-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Dosing adjustment for toxicity: Children ≥2 years and Adolescents: Data is scant in pediatric patients (minimum reported age: 10 years); use appropriate age-related parameters for children. Monitor vital signs and obtain serum albumin, transaminases, and creatinine prior to preparing each tagraxofusp dose.

Significantly low or high systolic blood pressure (SBP) (eg, in adults SBP ≤80 mm Hg or ≥160 mm Hg): Withhold therapy until SBP returns to normal (eg, in adults to >80 mm Hg or <160 mm Hg)

Significantly low or high heart rate (HR) (eg, in adults HR ≤40 bpm or ≥130 bpm): Withhold therapy until HR returns to normal (eg, in adults to >40 bpm or <130 bpm)

Body temperature ≥38°C: Withhold therapy until body temperature <38°C

Hypersensitivity reactions:

Mild to moderate: Withhold therapy until resolution of symptoms; resume therapy at the same infusion rate

Severe or life-threatening: Discontinue permanently.

Capillary leak syndrome (CLS): Note: Data is scant in pediatric patients (minimum reported age: 10 years) (Sun 2018); smaller pediatric patients may require dosing adjustment at different parameters (eg, changes in body weight) or symptoms:

Serum albumin <3.5 g/dL: Interrupt therapy; administer IV albumin until serum albumin raised serum albumin to ≥3.5 g/dL and not more than 0.5 g/dL lower than baseline albumin of the current cycle. Resume therapy upon resolution (see following Note).

Predose body weight increase (eg, ≥1.5 kg in adult patients) over previous day's predose weight: Interrupt therapy; administer IV albumin and manage fluid status as applicable until body weight increases have resolved (eg, in adults, any predose body weight increase is <1.5 kg from previous day's predose weight). Resume therapy upon resolution (see following Note).

Edema, fluid overload and/or hypotension: Interrupt therapy; administer IV albumin until serum albumin ≥3.5 g/dL, administer IV methylprednisolone (or equivalent), and aggressively manage fluid status/BP as necessary. Resume therapy upon resolution (see following Note).

Note: When resuming therapy, may resume with the same cycle if any hemodynamic instability did not require interventions to treat; therapy should be withheld for the remainder of a cycle if signs/symptoms of CLS are unresolved or interventions were required to treat hemodynamic instability (even if resolved), and therapy may resume with the next cycle if all CLS signs/symptoms have resolved and hemodynamically stable.

Dosing: Adjustment for Toxicity

Note: Monitor vital signs and obtain serum albumin, transaminases, and creatinine prior to preparing each tagraxofusp dose.

Capillary leak syndrome: Interrupt tagraxofusp therapy for signs/symptoms of capillary leak syndrome (CLS). If tagraxofusp is withheld for signs/symptoms of CLS, may resume tagraxofusp in the same cycle if all CLS signs/symptoms have resolved and hemodynamic instability did not require treatment. Hold tagraxofusp therapy for the remainder of the cycle if CLS signs/symptoms have not resolved or treatment was necessary to manage hemodynamic instability (eg, IV fluid and/or vasopressors to treat hypotension), even if resolved. May resume tagraxofusp in the next cycle only if all CLS signs/symptoms have resolved and the patient is hemodynamically stable.

Prior to first dose of cycle 1: Serum albumin <3.2 g/dL: Do not initiate tagraxofusp until serum albumin is ≥3.2 g/dL.

During tagraxofusp therapy:

Serum albumin <3.5 g/dL or serum albumin reduced by ≥0.5 g/dL from the value measured prior to tagraxofusp dosing initiation of the current cycle: Interrupt tagraxofusp therapy. Administer 25 g IV albumin as clinically necessary until serum albumin is ≥3.5 g/dL and not more than 0.5 g/dL lower than the value measured prior to tagraxofusp dosing initiation of the current cycle.

Predose body weight increased by ≥1.5 kg over the previous day's predose weight: Interrupt tagraxofusp therapy. Administer 25 g IV albumin as clinically necessary and manage fluid status as clinically indicated (eg, IV fluids/vasopressors if hypotensive and diuretics if normotensive or hypertensive) until body weight increase has resolved (eg, body weight is no longer ≥1.5 kg more than the previous day's predose weight).

Edema, fluid overload, and/or hypotension: Interrupt tagraxofusp therapy. Administer 25 g IV albumin as clinically necessary until serum albumin is ≥3.5 g/dL. Administer 1 mg/kg/day methylprednisolone (or equivalent) until resolution of CLS signs/symptoms or as clinically necessary. Manage fluid status and hypotension aggressively until resolution of CLS signs/symptoms or as clinically necessary; IV fluids and/or diuretics or other blood pressure management may be necessary.

Cardiac effects:

Heart rate ≥130 bpm or ≤40 bpm: Withhold tagraxofusp until heart rate is <130 bpm or >40 bpm.

Systolic blood pressure ≥160 mm Hg or ≤80 mm Hg: Withhold tagraxofusp until systolic blood pressure is <160 mm Hg or >80 mm Hg.

Hypersensitivity reactions:

Mild or moderate: Withhold tagraxofusp until resolution; resume tagraxofusp at the same infusion rate.

Severe or life-threatening: Discontinue tagraxofusp permanently.

Pyrexia: Body temperature ≥38°C: Withhold tagraxofusp until body temperature is <38°C.

Reconstitution

Prior to preparation, thaw vials at room temperature (in original carton) between 15°C and 25°C (59°F and 77°F) for 15 to 30 minutes (do not force thaw); verify thaw visually.

Step 1: Using a sterile 10 mL syringe, transfer 9 mL of sodium chloride 0.9% (NS) to an empty sterile 10 mL vial. Gently swirl the tagraxofusp vial; withdraw 1 mL of thawed tagraxofusp and transfer to the vial containing 9 mL NS; final concentration will be 100 mcg/mL. Gently invert the vial at least 3 times; do not shake vigorously.

Step 2: Draw up required volume of diluted tagraxofusp (100 mcg/mL) in a new sterile syringe and label; if more than 10 mL of diluted tagraxofusp is necessary, repeat step 1 with a second vial of thawed tagraxofusp. Prepare a separate second syringe with at least 3 mL NS to flush the administration set after tagraxofusp administration. Connect the saline flush syringe to one arm of a mini-bifuse Y-connector and ensure the clamp is closed. Connect the tagraxofusp syringe to the other arm of the Y-connector; 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 a 0.2 micron polyethersulfone in-line 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 NS); re-clamp the Y-connector line on the saline flush arm. Remove the cap on the terminal end of the 0.2 micron filter (save cap); unclamp the arm of the Y-connector connected to the tagraxofusp syringe and prime the entire infusion set, including the filter. Recap the filter, and re-clamp the Y-connector line on the tagraxofusp side; infusion set is now prepared for tagraxofusp infusion.

Administration

IV: Administer the tagraxofusp dose and the saline flush via infusion syringe pump over a total infusion time of 15 minutes. Establish IV access and maintain with sodium chloride 0.9% (NS).

Use the prepared/primed mini-bifuse Y-connector, infusion set and 0.2 micron polyethersulfone inline filter. Insert the tagraxofusp syringe into the syringe pump, open the clamp on the tagraxofusp side of the Y-connector and deliver the dose. Once the tagraxofusp infusion is completed, remove it from the pump and place the saline flush syringe in the pump. Open the clamp on the saline flush side of the Y-connector and resume infusion at the pre-specified flow to push remaining tagraxofusp dose out of the infusion line. Administer within 4 hours of preparation.

Premedicate with an H₁-antagonist (eg, diphenhydramine), an H₂-antagonist (eg, ranitidine), a corticosteroid (eg, 50 mg IV methylprednisolone or equivalent), and acetaminophen ~60 minutes prior to each tagraxofusp infusion. Administer cycle 1 in the inpatient setting; observe patients through at least 24 hours after the last infusion. Subsequent cycles may be administered either inpatient or outpatient (if suitable); ensure appropriate monitoring is available and observe patients for a minimum of 4 hours following each infusion.

Storage

Store intact vials in freezer between -25°C and -15°C (-13°F and 5°F). Protect from light (store in the original package until time of use). Thawed vials may be stored at room temperature for approximately 1 hour prior to preparation. Do not refreeze the vial once thawed. Prepared solution for infusion should be administered within 4 hours; keep solution diluted for infusion at room temperature prior to administration. Discard any excess solution.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Capillary leak syndrome (55%), peripheral edema (43%), hypotension (29%), tachycardia (17%), hypertension (15%)

Central nervous system: Fatigue (45%), chills (29%), headache (29%), dizziness (20%), insomnia (17%), anxiety (15%), confusion (11%)

Endocrine & metabolic: Increased serum glucose (87%), decreased serum albumin (77%), decreased serum calcium (57%), decreased serum sodium (50%), decreased serum potassium (39%), weight gain (31%), decreased serum phosphate (30%), increased serum potassium (21%), decreased serum magnesium (20%), hypermagnesemia (14%), decreased serum glucose (11%)

Gastrointestinal: Nausea (49%), decreased appetite (24%), constipation (23%), vomiting (21%), diarrhea (20%)

Hematologic & oncologic: Decreased platelet count (67%; grade ≥3: 53%), decreased hemoglobin (60%; grade ≥3: 35%), decreased neutrophils (37%; grade ≥3: 31%), febrile neutropenia (20%; grade ≥3: 18%)

Hepatic: Increased liver enzymes (88%), increased serum alanine aminotransferase (82%), increased serum aspartate aminotransferase (79%), increased serum alkaline phosphatase (26%), increased serum bilirubin (14%)

Hypersensitivity: Hypersensitivity reaction (46%)

Immunologic: Antibody development (68% to 99%; neutralizing: 85%)

Neuromuscular & skeletal: Back pain (20%)

Renal: Increased serum creatinine (27%)

Respiratory: Dyspnea (19%), cough (14%), epistaxis (14%), oropharyngeal pain (12%)

Miscellaneous: Fever (43%)

1% to 10%:

Dermatologic: Pruritus (10%), skin rash (≥5%)

Endocrine & metabolic: Increased serum sodium (10%)

Gastrointestinal: Stomatitis (≥5%)

Genitourinary: Hematuria (10%)

Hematologic & oncologic: Petechia (10%)

Neuromuscular & skeletal: Limb pain (10%)

Respiratory: Wheezing (≥5%)

Warnings/Precautions

Concerns related to adverse effects:

• Capillary leak syndrome: [US Boxed Warning]: Capillary leak syndrome (CLS) which may be life-threatening or fatal, can occur in patients receiving tagraxofusp. Monitor for signs and symptoms of CLS and take actions as recommended. In clinical trials, CLS was observed in over half of patients; approximately half of CLS events were grade 1 or 2; grades 3 and 4 CLS events have also been reported. Signs and symptoms of tagraxofusp-associated CLS include hypoalbuminemia, edema, weight gain, and hypotension. Ensure adequate cardiac function prior to tagraxofusp initiation. Serum albumin should be ≥3.2 g/dL prior to the first tagraxofusp dose in cycle 1; monitor serum albumin levels prior to each dose and as clinically necessary. Monitor for signs/symptoms of CLS, including weight gain, new onset (or worsening) edema, and pulmonary edema, hypotension, or hemodynamic instability. May require additional medical management for the treatment of CLS.
• Hepatotoxicity: Hepatic transaminase elevations (ALT, AST) have been reported in close to 90% of patients. Grade 1 or 2 liver enzyme elevations occurred in almost half of cases, while grade 3 toxicity occurred in approximately one-third of patients; grade 4 elevations were also reported. Monitor ALT and AST prior to each tagraxofusp dose; may require temporary therapy interruption.
• Hypersensitivity: Severe hypersensitivity reactions may occur. In clinical trials, hypersensitivity reactions occurred in close to half of patients; 10% of events were ≥ grade 3. Reactions included rash, pruritus, stomatitis, and wheezing. Monitor for signs/symptoms of hypersensitivity reactions during tagraxofusp therapy; may require temporary infusion interruption or permanent discontinuation. Provide supportive care as clinically necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Patients ≥75 years experienced a higher incidence of altered mental status (eg, confusion, delirium, mental status changes, dementia, encephalopathy) than younger patients.

Monitoring Parameters

Monitor serum albumin, transaminases, and creatinine prior to each dose; evaluate pregnancy status in females of reproductive potential within 7 days prior to initiating tagraxofusp therapy; monitor vital signs (eg, heart rate, blood pressure, weight) prior to each dose; monitor for signs/symptoms of capillary leak syndrome, hepatotoxicity, and hypersensitivity reactions

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted. Based on the mechanism of action, adverse effects on fetal development may occur following in utero exposure to tagraxofusp.

Evaluate pregnancy status within 7 days prior to therapy initiation in females of reproductive potential. Effective contraception should be used during treatment and for at least 1 week after the last tagraxofusp dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, constipation, diarrhea, lack of appetite, loss of strength and energy, weight gain, back pain, painful extremities, nosebleed, difficulty sleeping, or anxiety. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of infection, signs of capillary leak syndrome (abnormal heartbeat; chest pain; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; unable to pass urine or change in amount of urine passed; or blood in the urine), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), severe headache, dizziness, passing out, vision changes, mouth irritation, mouth sores, swelling of arms or legs, shortness of breath, confusion, fast heartbeat, pinpoint red spots on skin, or blood in the urine (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.