Moxetumomab Pasudotox

Dosage Forms

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

Solution Reconstituted, Intravenous [preservative free]:

Lumoxiti: moxetumomab pasudotox-tdfk 1 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Moxetumomab pasudotox is a CD22-directed cytotoxin composed of a recombinant murine immunoglobulin genetically fused to truncated Pseudomonas exotoxin (PE38). Moxetumomab pasudotox binds CD22 on the cell surface of B-cells and is internalized. Moxetumomab pasudotox internalization results in ADP-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptotic cell death.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 6.5 L

Onset of Action

Achievement of hematologic remission: ~1 month (Kreitman 2018). Day 8 circulating CD19+ B cells (surrogate assay for CD22) were reduced 89% (from baseline) following the first 3 infusions.

Duration of Action

Median duration of complete response (for patients with minimal residual disease): 5.9 months (Kreitman 2018). B cell reduction is sustained for at least 1 month after treatment.

Half-Life Elimination

1.4 hours (range: 0.8 to 1.8 hours)

Use in Specific Populations

Special Populations Note

Antibody formation: In patients who were anti-product antibody (ADA)-positive with high titers, the presence of ADA post-baseline was associated with statistically significantly lower PK exposure (C_max) starting at cycle 3 and beyond.

Use: Labeled Indications

Hairy cell leukemia (relapsed or refractory): Treatment of relapsed or refractory hairy cell leukemia (HCL) in adult patients who have received at least 2 prior systemic therapies, including treatment with a purine nucleoside analog.

Limitations of use: Moxetumomab pasudotox is not recommended in patients with severe renal impairment (CrCl ≤29 mL/minute).

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Use actual body weight prior to the first dose of the first treatment cycle to calculate dose. A change in dose should only be made between cycles when the weight changes by >10% from the weight used to calculate the first dose of the first treatment cycle; do not change a dose during a particular cycle.

Hairy cell leukemia (relapsed or refractory): IV: 0.04 mg/kg on days 1, 3, and 5 of each 28-day treatment cycle; continue for a maximum of 6 cycles, or until disease progression or unacceptable toxicity (Kreitman 2018)

Concomitant treatments:

Hydration: Administer 1 L (500 mL for patients <50 kg) of isotonic IV solution over 2 to 4 hours before and after each moxetumomab pasudotox infusion. Patients should adequately hydrate with up to 3 L (2 L for patients <50 kg) of oral fluids (eg, water, milk or juice) per 24 hours on days 1 through 8 of each 28-day treatment cycle. Monitor fluid balance and serum electrolytes to avoid fluid overload and/or electrolyte imbalance.

Premedications: Administer an antihistamine (eg, hydroxyzine or diphenhydramine), an antipyretic (acetaminophen), and a histamine H₂-receptor antagonist (eg, ranitidine, famotidine, or cimetidine) 30 to 90 minutes prior to each moxetumomab pasudotox infusion.

Post-infusion medications: Administer an oral corticosteroid (eg, dexamethasone 4 mg) to decrease nausea and vomiting. Consider oral antihistamines and antipyretics for up to 24 hours following infusion. Maintain adequate oral fluid intake.

Thromboprophylaxis:Consider low-dose aspirin on days 1 through 8 of each 28-day treatment cycle.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Capillary leak syndrome (CLS):

Monitoring: Monitor weight and blood pressure prior to each infusion. If weight increased by 2.5 kg or ≥5% from day 1 of cycle and the patient is hypotensive, promptly monitor for peripheral edema, hypoalbuminemia, and respiratory symptoms, including dyspnea and cough. If CLS is suspected, monitor for decrease in oxygen saturation and evidence of pulmonary edema and/or serosal effusions. Patients who experience Grade 2 or higher CLS should receive appropriate supportive measures, including corticosteroids (oral or IV); monitor weight, albumin levels, and blood pressure until resolution.

Management:

Grade 2 (symptomatic; medical intervention indicated): Delay treatment until recovery of symptoms.

Grade 3 (severe symptoms; medical intervention indicated): Discontinue moxetumomab pasudotox.

Grade 4 (life-threatening consequences; urgent intervention indicated): Discontinue moxetumomab pasudotox.

Hemolytic uremic syndrome (HUS):

Monitoring: Monitor hemoglobin, platelets and serum creatinine prior to each infusion. If HUS is suspected, promptly monitor serum LDH, indirect bilirubin, and blood smear schistocytes for evidence of hemolysis.

Management: Discontinue moxetumomab pasudotox in patients with HUS. Manage with appropriate supportive measures and fluid replacement; monitor CBC, serum chemistries, and renal function until resolution.

Infusion reactions: Interrupt infusion for severe reactions and manage appropriately. Administer a corticosteroid (oral or IV) ~30 minutes prior to resuming infusion and prior to each subsequent infusion.

Reconstitution

Reconstitution: Calculate the dose (mg) and the number of vials (1 mg/vial) to be reconstituted. Do not round down for partial vials. Use only SWFI to reconstitute moxetumomab pasudotox; do not reconstitute with other solutions. Do not reconstitute vials with the IV solution stabilizer. Reconstitute each vial with 1.1 mL SWFI to a reconstituted concentration of 1 mg/mL (this allows for a vial withdrawal volume of 1 mL). Direct the SWFI along the walls of the vial and not directly toward the lyophilized cake/powder. Swirl gently until dissolved completely; invert vial to ensure all cake/powder in vial is dissolved. Do not shake.

Dilution: Add the IV solution stabilizer (packaged separately) to the infusion bag prior to adding reconstituted moxetumomab pasudotox to the infusion bag. Add 1 mL IV solution stabilizer to a 50 mL NS infusion bag. Use only 1 vial of IV solution stabilizer per moxetumomab pasudotox administration. Invert bag gently to mix; do not shake. Withdraw the required volume of reconstituted moxetumomab pasudotox solution from the vial(s) and add to infusion bag containing 50 mL NS and 1 mL IV solution stabilizer. Invert bag gently to mix; do not shake. Discard any partially used vials of moxetumomab pasudotox or IV solution stabilizer.

Administration

IV: Infuse over 30 minutes. Do not infuse with other medications. Flush the infusion line with normal saline (at the same rate as the infusion) following the infusion to ensure entire dose is delivered. Premedicate 30 to 90 minutes prior to each moxetumomab pasudotox infusion with an antihistamine, acetaminophen, and a histamine-2 receptor antagonist. Maintain adequate hydration.

Storage

Store intact vials and IV solution stabilizer at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original carton to protect from light. Do not shake. Use reconstituted solution immediately. Do not store reconstituted vials. Solutions diluted for infusion should be used immediately or after storage at 20°C to 25°C (68°F to 77°F) for up to 4 hours or at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze. Protect from light. Do not shake. If solution diluted for infusion is refrigerated (2°C to 8°C [36°F to 46°F]), allow it to reach room temperature (20°C to 25°C [68°F to 77°F]) for no more than 4 hours prior to administration. Administer solutions diluted for infusion within 24 hours of reconstitution.

Drug Interactions

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

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

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

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

Test Interactions

Moxetumomab pasudotox may interfere with detection of cellular CD22; CD19+ B cells may be used as a surrogate assay.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (5% to 39%), capillary leak syndrome (≤34%), facial edema (14%)

Central nervous system: Fatigue (34%), headache (33%)

Endocrine & metabolic: Hypoalbuminemia (64%), fluid retention (1% to 63%), electrolyte disorder (57%), hypocalcemia (25% to 54%), hypophosphatemia (53%), hyponatremia (41%), hypokalemia (25%), increased gamma-glutamyl transferase (25%), hypomagnesemia (23%), hyperuricemia (21%)

Gastrointestinal: Nausea (35%), constipation (23%), diarrhea (21%), abdominal distention (13%)

Genitourinary: Nephrotoxicity (26%)

Hematologic & oncologic: Decreased hemoglobin (43%; grade 3: 15%), neutropenia (41%; grade 3: 11%; grade 4: 20%), anemia (21%; grade 3: 10%), decreased platelet count (21%; grade 3: 11%; grade 4: 4%)

Hepatic: Increased serum alanine aminotransferase (65%), increased serum aspartate aminotransferase (55%), increased serum bilirubin (30%), increased serum alkaline phosphatase (20%)

Renal: Increased serum creatinine (17% to 96%)

Miscellaneous: Infusion-related reaction (9% to 50%), fever (31%)

1% to 10%:

Cardiovascular: Edema (5%), pericardial effusion (1%)

Endocrine & metabolic: Weight gain (8%), hypervolemia (1%)

Genitourinary: Proteinuria (8%)

Hematologic & oncologic: Hemolytic-uremic syndrome (7%; grade 3: 3%; grade 4: <1%), febrile neutropenia (grades 3/4: ≤5%)

Hepatic: Ascites (1%)

Local: Localized edema (4%)

Ophthalmic: Blurred vision (9%), xerophthalmia (8%), cataract (5%), eye discomfort (≤4%), eye pain (≤4%), ocular edema (≤4%), periorbital edema (≤4%), conjunctival hemorrhage (1%), conjunctivitis (1%), eye discharge (1%)

Renal: Acute renal failure (2%), renal insufficiency (2%)

Respiratory: Pleural effusion (6%)

Frequency not defined: Immunologic: Antibody development

<1%, postmarketing, and/or case reports: Hemoconcentration, hypotension

Warnings/Precautions

Concerns related to adverse effects:

• Capillary leak syndrome: [US Boxed Warning]: Capillary leak syndrome (CLS), including life-threatening cases, has occurred in patients receiving moxetumomab pasudotox. Monitor weight and blood pressure (prior to each infusion and as clinically indicated); monitor labs (including albumin) if CLS is suspected. May require treatment delay or discontinuation. CLS is characterized by hypoalbuminemia, hypotension, fluid overload symptoms, and hemoconcentration. Grade 2 CLS occurred more frequently, although grades 3 and 4 CLS have been observed. Most CLS cases occurred in the first 8 days (range: 1 to 19 days) of a treatment cycle; however, some cases have occurred throughout the treatment cycle. The median time to resolution of CLS was 12 days (range: 1 to 53 days). Monitor for hypoalbuminemia, elevated hematocrit, leukocytosis, and thrombocytosis, and monitor for signs/symptoms of CLS (weight gain [increase of 2.5 kg or ≥5% from day 1 of current cycle], hypotension, peripheral edema, shortness of breath/cough, pulmonary edema, and/or serosal effusions). Patients should be aware to seek immediate medication attention if signs/symptoms of CLS occur; CLS may be life-threatening or fatal if treatment is delayed. Manage CLS with appropriate supportive care, including concomitant oral or intravenous corticosteroids, and hospitalization as clinically indicated. Withhold moxetumomab pasudotox for grade 2 CLS until resolution; permanently discontinue for grade 3 or higher CLS.
• Electrolyte abnormality: Electrolyte abnormalities occurred in over half of patients treated with moxetumomab pasudotox (including grade 3 and 4 events). Hypocalcemia was the most common electrolyte abnormality. Electrolyte abnormalities have commonly occurred within the same treatment cycle as CLS, HUS, fluid retention, or renal toxicity. Monitor serum electrolytes prior to each dose and on day 8 of each treatment cycle; mid-cycle monitoring is also recommended.
• Hemolytic uremic syndrome: [US Boxed Warning]: Hemolytic uremic syndrome (HUS), including life-threatening cases, has occurred in patients receiving moxetumomab pasudotox. Monitor hemoglobin, platelet count, serum creatinine, and ensure adequate hydration. Discontinue moxetumomab pasudotox in patients with HUS. HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure. Grades 3 and 4 HUS have been observed. Most HUS cases occurred in the first 9 days (range: 1 to 16 days) of a treatment cycle; however, cases have been reported throughout the cycle. All cases of HUS resolved, including those where treatment was discontinued. The median time to resolution of HUS was 11.5 days (range: 2 to 44 days). Avoid moxetumomab pasudotox in patients with history of severe thrombotic microangiopathy (TMA) or HUS. Administer prophylactic IV fluids prior to and following moxetumomab pasudotox infusions. In one clinical trial, patients with a platelet count ≥100,000/mm³ received low-dose aspirin for thrombosis prophylaxis on days 1 through 8 of each 28-day treatment cycle. Monitor CBC and serum chemistries prior to each dose and on day 8 of each treatment cycle; mid-cycle monitoring is also recommended. Consider the diagnosis of HUS in patients who develop hemolytic anemia, worsening thrombocytopenia (or sudden onset), increased serum creatinine, bilirubin and/or LDH elevations, and have evidence of hemolysis based on peripheral blood smear schistocytes. HUS events may be life-threatening if treatment is delayed, with increased risk of progressive renal failure requiring dialysis. If HUS is suspected, initiate appropriate supportive measures, including fluid repletion, hemodynamic monitoring, and consider hospitalization as clinically indicated. Discontinue moxetumomab pasudotox in patients with HUS.
• Infusion reactions: Infusion-related reactions have occurred in half of patients who received moxetumomab pasudotox; grade 3 infusion reaction has been reported. Infusion-related reactions may occur during any treatment cycle. Infusion reactions included chills, fever, dizziness, cough, dyspnea, feeling hot, flushing, headache, hyper-/hypotension, myalgia, nausea, vomiting, tachycardia (including sinus tachycardia), or wheezing; the most frequently reported infusion-related events were nausea, vomiting, fever, chills, and headache. Premedicate with antihistamines and antipyretics prior to each moxetumomab pasudotox dose. If a severe infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management; administer a corticosteroid (oral or IV) ~30 minutes before resuming the infusion, and before the next moxetumomab pasudotox infusion.
• Renal toxicity: Renal toxicity has been reported in patients treated with moxetumomab pasudotox, including acute kidney injury (including grade 3 events), renal failure, renal impairment, elevated serum creatinine, and proteinuria. Most renal toxicity events were mild to moderate in severity. Serum creatinine increased by 2 or more grades (from baseline) during treatment, including grade 3 increases, in some patients. Serum creatinine remained elevated (1.5 to 3 times the upper limit of normal) at the end of treatment in a small percentage of patients. Patients ≥65 years of age, with baseline renal impairment, or who experience HUS may be at an increased risk for worsening of renal function following moxetumomab pasudotox treatment. Monitor renal function prior to each infusion and as clinically indicated throughout treatment. Delay dosing in patients with grade 3 or higher serum creatinine elevations or if worsens from baseline by ≥2 grades.

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 ≥65 years of age may have a higher incidence of adverse reactions leading to discontinuation and renal toxicity.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Monitor CBC and serum chemistries prior to each dose and on day 8 of each treatment cycle; mid-cycle monitoring is also recommended. Monitor renal function prior to each infusion and as clinically indicated throughout treatment. Obtain pregnancy test to assess pregnancy status (prior to therapy initiation in females of reproductive potential). Monitor weight and blood pressure (prior to each infusion and as clinically indicated) and monitor labs (including albumin) if CLS is suspected. Monitor for signs/symptoms of CLS (weight gain [increase of 2.5 kg or ≥5% from day 1 of current cycle, hypotension, peripheral edema, shortness of breath/cough, pulmonary edema and/or serosal effusions). In patients suspected to have HUS, monitor for serum creatinine, bilirubin and/or LDH elevations, and for evidence of hemolysis based on peripheral blood smear schistocytes. Monitor for signs/symptoms of infusion reactions, thrombosis, and fluid overload.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and adverse events observed in nonpregnant animal studies, adverse maternal and fetal events may be expected if exposure occurs during pregnancy.

Evaluate pregnancy status prior to use. The manufacturer recommends females of reproductive potential use effective contraception during treatment and for at least 30 days after the last dose of moxetumomab pasudotox.

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, loss of strength and energy, constipation, diarrhea, or dry eyes. Have patient report immediately to prescriber signs of infusion reaction, 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 Hemolytic-uremic syndrome (unable to pass urine; loss of strength and energy; signs of bleeding or bruising; fever; or swelling of the face, hands, feet or body), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite,or severe nausea or vomiting), severe headache, severe dizziness, passing out, vision changes, edema, tingling, numbness, or signs of infection (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.