Moxetumomab pasudotox, a CD22-directed antibody-fusion protein consisting of a recombinant murine monoclonal antibody (moxetumomab) covalently linked to a cytotoxic bacterial protein toxin ( Pseudomonas exotoxin A [PE38]), is an antineoplastic agent; the drug also is referred to as an immunotoxin.1, 4, 5, 6, 7, 11
Moxetumomab pasudotox-tdfk is used for the treatment of relapsed or refractory hairy cell leukemia in patients who previously received at least 2 systemic therapies, including a purine nucleoside analog (e.g., cladribine, pentostatin).1, 3, 5 The current indication is based on durable (lasting longer than 180 days) complete response rate.1, 3 Moxetumomab pasudotox-tdfk has been designated an orphan drug by FDA for the treatment of hairy cell leukemia.2
The current indication for moxetumomab pasudotox-tdfk in the treatment of previously treated relapsed or refractory hairy cell leukemia is based principally on results of an open-label, multicenter, noncomparative phase 3 study (Study 1053) in 80 adults with relapsed or refractory hairy cell leukemia or a hairy cell leukemia-variant previously treated with at least 2 systemic therapies.1, 3, 5 Prior systemic therapy must have included 2 courses of a purine nucleoside analog or a single course of rituximab or a b-Raf serine-threonine kinase (BRAF) inhibitor following a single course of a purine nucleoside analog.3 In this study, patients received moxetumomab pasudotox-tdfk 0.04 mg/kg by IV infusion over 30 minutes on days 1, 3, and 5 of each 28-day cycle.1, 3 Therapy was continued for a maximum of 6 cycles or until complete response was achieved or disease progression or unacceptable toxicity occurred.1, 3 The median duration of moxetumomab pasudotox-tdfk treatment was 5.7 months.1 The primary measure of efficacy was durable complete response (as assessed by a blinded independent review committee) lasting longer than 180 days.1, 3 Complete response was defined as the absence of hairy cells in bone marrow without evidence of disease (i.e., splenomegaly, hepatomegaly, lymphadenopathy) on radiographic imaging and with full recovery of peripheral blood cell counts (absolute neutrophil count [ANC] of at least 1500/mm3, platelet count of at least 100,000/mm3, hemoglobin concentration of at least 11 g/dL) without growth factor support or transfusions for at least 4 weeks.1, 3
In this study, the median age of patients was 60 years (range: 34-84 years); 94% of these patients were Caucasian, 79% were male, 98% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 33% had hemoglobin concentrations less than 10 g/dL, 68% had an ANC less than 1000/mm3, 84% had platelet counts less than 100,000/mm3, and approximately 35% had baseline splenomegaly (spleen size of 14 cm or greater).1 Patients enrolled in this study had received a median of 3 prior therapies (range: 2-11); all patients received a purine nucleoside analog, 29% received a purine nucleoside analog in combination with rituximab, 51% received rituximab monotherapy, 25% received interferon alfa, and 18% received a BRAF inhibitor.1
At a median follow-up of 16.7 months, the overall response rate in patients treated with moxetumomab pasudotox-tdfk was 75%; complete response was achieved in 41% of patients.1, 3 The median duration of response had not been reached at the time of analysis; however, 30% of patients who achieved a complete response had a durable response lasting more than 180 days.1, 3 The median time to overall or complete response was 5.7 (range 1.8-12.9) or 5.9 (range: 1.8-13.2) months, respectively.1 Recovery of peripheral blood cell counts was achieved in 80% of patients; median time to hematologic response was 1.1 months.1, 3 At the time of the analysis, the median duration of hematologic response had not been reached.1, 3
To minimize the risk of infusion-related reactions associated with moxetumomab pasudotox, the manufacturer recommends premedication with an antihistamine (e.g., diphenhydramine hydrochloride, hydroxyzine), acetaminophen, and a histamine H2-receptor antagonist (e.g. ranitidine, famotidine, cimetidine) administered 30-90 minutes prior to each infusion of moxetumomab pasudotox.1 Administration of an oral antihistamine and acetaminophen for up to 24 hours after each moxetumomab pasudotox infusion also may be considered.1 Patients who experience a severe infusion-related reaction should receive an oral or IV corticosteroid approximately 30 minutes prior to subsequent infusions of moxetumomab pasudotox.1 (See Infusion-related Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
To minimize the risk of hemolytic uremic syndrome associated with moxetumomab pasudotox, adequate fluid volume status should be maintained during moxetumomab pasudotox therapy, and patients should be monitored for fluid overload, manifestations of thrombosis, and electrolyte abnormalities.1 For patients weighing 50 kg or more , the manufacturer recommends IV hydration with 1 L of 5% dextrose in 0.45% sodium chloride injection, 5% dextrose in 0.9% sodium chloride injection, or an appropriate isotonic IV solution administered by IV infusion over 2-4 hours before and after each dose of moxetumomab pasudotox; oral hydration also should be maintained on days 1-8 of each 28-day cycle with up to 12 glasses (3 L) of fluids (e.g., water, milk, juice).1 For patients weighing less than 50 kg , the manufacturer recommends IV hydration with 500 mL of 5% dextrose in 0.45% sodium chloride injection, 5% dextrose in 0.9% sodium chloride injection, or an appropriate isotonic IV solution administered by IV infusion over 2-4 hours before and after each dose of moxetumomab pasudotox; oral hydration also should be maintained on days 1-8 of each 28-day cycle with up to 8 glasses (2 L) of fluids (e.g., water, milk, juice).1 Thromboprophylaxis with low-dose aspirin (81 mg daily) may be considered on days 1-8 of each 28-day cycle.1, 8 (See Hemolytic Uremic Syndrome under Warnings/Precautions: Warnings, in Cautions.)
To reduce the incidence and/or severity of nausea and vomiting associated with moxetumomab pasudotox, an oral corticosteroid (e.g., dexamethasone 4 mg) is recommended after each dose of moxetumomab pasudotox.1
Moxetumomab pasudotox-tdfk is administered by IV infusion over 30 minutes.1 To ensure administration of a full dose of moxetumomab pasudotox-tdfk, the IV administration line should be flushed with 0.9% sodium chloride injection after each dose using the same infusion rate.1
Prior to administration, moxetumomab pasudotox-tdfk lyophilized powder for injection must be reconstituted and diluted.1 Strict aseptic technique must be observed in preparing and administering moxetumomab pasudotox-tdfk solutions since the powder for injection contains no preservative.1 Moxetumomab pasudotox-tdfk should not be admixed with or administered as an infusion with any other drug.1
Based on the indicated dosage of moxetumomab pasudotox-tdfk, the appropriate number of vials of the drug should be reconstituted; the dosage of moxetumomab pasudotox-tdfk should not be rounded down for partial vials.1
Each vial labeled as containing 1 mg of moxetumomab pasudotox-tdfk is reconstituted by adding 1.1 mL of sterile water for injection to provide a solution containing 1 mg/mL.1 The diluent should be directed toward the inside wall of the vial and not directly at the cake or powder.1 The vial should then be gently swirled and inverted until complete dissolution of the cake or powder occurs, and then inspected visually for particulate matter and discoloration prior to dilution and administration.1 The resulting solution should not be shaken.1
The reconstituted solution should be clear to slightly opalescent, colorless to slightly yellow, and free of visible particulates; the drug should be discarded if the solution is cloudy, discolored, or contains precipitates.1
Reconstituted solutions of the drug must be diluted immediately since the powder for injection contains no preservative.1
For preparation of the final diluted moxetumomab pasudotox-tdfk solution for infusion, 1 mL of the manufacturer-provided IV solution stabilizer (containing citric acid monohydrate, polysorbate 80, and sodium citrate dihydrate in sterile water for injection) should be added to an infusion bag containing 50 mL of 0.9% sodium chloride injection prior to addition of the reconstituted moxetumomab pasudotox-tdfk solution.1 The IV solution stabilizer should not be used to reconstitute moxetumomab pasudotox-tdfk powder for injection.1 Only one vial of the IV solution stabilizer is necessary for each infusion of the drug.1 The infusion bag should be gently inverted to mix the 0.9% sodium chloride injection and IV solution stabilizer and should not be shaken.1
The appropriate volume of the appropriate number of reconstituted vials of moxetumomab pasudotox-tdfk containing 1 mg/mL should then be added to the infusion bag containing 0.9% sodium chloride injection and the IV solution stabilizer.1 The final diluted moxetumomab pasudotox-tdfk solution for infusion should be mixed by gentle inversion and should not be shaken.1
Following dilution, moxetumomab pasudotox-tdfk infusion solution should be administered immediately; if not used immediately, the solution may be stored at room temperature (20-25°C) for up to 4 hours or may be stored under refrigeration (2-8°C) for up to 24 hours.1 Diluted solutions of the drug stored under refrigeration should be allowed to equilibrate at room temperature for no more than 4 hours prior to the start of the infusion.1 Diluted solutions of the drug should be protected from light and should not be frozen.1
Commercially available moxetumomab pasudotox-tdfk lyophilized powder for injection and IV solution stabilizer contain no preservatives and are intended for single use; vials containing unused portions of the reconstituted solution or IV solution stabilizer should be immediately discarded.1
IV infusions of moxetumomab pasudotox-tdfk should be administered over 30 minutes.1
Dosage of moxetumomab pasudotox-tdfk should be based on actual body weight at baseline prior to initiation of therapy.1 Dosage adjustments should not be made during a treatment cycle based on changes in body weight.1 However, if body weight changes more than 10% from baseline, dosage of moxetumomab pasudotox-tdfk can be adjusted based on the current weight before starting the next treatment cycle.1
For the treatment of relapsed or refractory hairy cell leukemia in patients who have received at least 2 prior systemic therapies, the recommended adult dosage of moxetumomab pasudotox-tdfk is 0.04 mg/kg on days 1, 3, and 5 of each 28-day cycle.1 Therapy should be continued for a maximum of 6 28-day cycles or until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If symptomatic grade 2 capillary leak syndrome requiring medical management occurs, moxetumomab pasudotox therapy should be interrupted until the toxicity has resolved.1 (See Capillary Leak Syndrome under Warnings/Precautions: Warnings, in Cautions.)
If grade 3 or 4 capillary leak syndrome requiring medical management occurs, moxetumomab pasudotox should be permanently discontinued.1
If hemolytic uremic syndrome occurs, moxetumomab pasudotox should be discontinued.1 (See Hemolytic Uremic Syndrome under Warnings/Precautions: Warnings, in Cautions.)
If grade 2 or greater elevations (exceeding 1.5 times baseline values or the upper limit of normal [ULN]) of serum creatinine concentrations occur in patients with baseline serum creatinine concentrations within the normal range, moxetumomab pasudotox therapy should be interrupted until the toxicity has resolved to grade 1 or less (1.5 times or less baseline values or the ULN).1 (See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If grade 3 or greater elevations (exceeding 3 times baseline values or the ULN) of serum creatinine concentrations occur in patients with baseline grade 1 or 2 elevations of serum creatinine, moxetumomab pasudotox therapy should be interrupted until the toxicity has resolved to baseline or lower.1
If a severe infusion-related reaction occurs, the moxetumomab pasudotox infusion should be interrupted and appropriate treatment should be provided.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Dosage adjustment is not necessary in patients with hepatic impairment.5 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance of 30 mL/minute or greater).5 The manufacturer states that use of the drug in patients with severe renal impairment (creatinine clearance of 29 mL/minute or less) is not recommended.1 (See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that there are no known contraindications to the use of moxetumomab pasudotox.1
Capillary leak syndrome, sometimes life-threatening, has been reported in patients receiving moxetumomab pasudotox.1 Characteristic manifestations of capillary leak syndrome include hypotension, hypoalbuminemia, edema, and hemoconcentration.1
In a combined safety database of moxetumomab pasudotox-tdfk in patients with hairy cell leukemia, capillary leak syndrome occurred in 44 of 129 (34%) patients receiving the drug; grade 2, 3, or 4 capillary leak syndrome occurred in 23, 1.6, or 2%, respectively, of patients receiving moxetumomab pasudotox-tdfk.1 Onset of capillary leak syndrome generally occurred during the initial 8 days (range: 1-19 days) of a treatment cycle; however, some cases have been reported on other days throughout a cycle.1 The median time to resolution of capillary leak syndrome was 12 days (range: 1-53 days).1
Blood pressure and weight should be assessed prior to each moxetumomab pasudotox infusion and as clinically indicated during therapy.1 Patients also should be monitored for manifestations of capillary leak syndrome (e.g., weight gain, hypotension, peripheral edema, shortness of breath, cough, pulmonary edema, serosal effusions, hypoalbuminemia, elevated hematocrit, leukocytosis, thrombocytosis).1 Patients experiencing hypotension and weight gain (i.e., increase in weight of 2.5 kg or 5% or more from day 1 of the current treatment cycle) should be promptly evaluated for peripheral edema, hypoalbuminemia, and respiratory symptoms (i.e., shortness of breath, cough).1 If capillary leak syndrome is suspected, oxygen saturation and manifestations of pulmonary edema and/or serosal effusions should be assessed.1
Capillary leak syndrome may be life-threatening or fatal if treatment is delayed.1 Patients who develop grade 2 or greater capillary leak syndrome, which may require hospitalization, should be monitored (e.g., weight, blood pressure, serum albumin concentrations) and receive symptomatic treatment (i.e., oral or IV corticosteroids), until the toxicity resolves.1 Temporary interruption or discontinuance of moxetumomab pasudotox therapy may be necessary.1 (See Capillary Leak Syndrome under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Hemolytic uremic syndrome, sometimes life-threatening, has been reported in patients receiving moxetumomab pasudotox.1 Hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure.1, 8, 10
In a combined safety database of moxetumomab pasudotox-tdfk in patients with hairy cell leukemia, hemolytic uremic syndrome occurred in 9 of 129 (7%) patients receiving the drug; grade 3 or 4 hemolytic uremic syndrome occurred in 3 or 0.8%, respectively, of patients receiving moxetumomab pasudotox-tdfk.1 Onset of hemolytic uremic syndrome generally occurred during the initial 9 days (range: 1-16 days) of a treatment cycle; however, some cases have been reported on other days throughout a cycle.1 The median time to resolution of hemolytic uremic syndrome was 11.5 days (range: 2-44 days).1 Hemolytic uremic syndrome resolved in all patients, including those requiring discontinuance of the drug.1
Moxetumomab pasudotox should be avoided in patients with a history of severe thrombotic microangiopathy or hemolytic uremic syndrome.1 Appropriate prophylactic measures (e.g., adequate hydration, low-dose aspirin) should be used, and patients should be monitored for fluid overload, manifestations of thrombosis, and electrolyte abnormalities.1 (See Dosage and Administration: General.) In the principal efficacy study (Study 1053), patients with a platelet count of 100,000/mm3 or greater received thromboprophylaxis with low-dose aspirin (81 mg daily) on days 1-8 of each 28-day cycle.1, 8
Complete blood counts (CBCs) (including hemoglobin concentrations and platelet counts) and blood chemistries (i.e., serum creatinine concentrations) should be monitored prior to each dose and on day 8 of each cycle; additional monitoring of CBCs and blood chemistries on day 14 of each cycle also is recommended.1 The possible diagnosis of hemolytic uremic syndrome should be considered in patients who develop hemolytic anemia, sudden onset or worsening of thrombocytopenia, elevated concentrations of serum creatinine, elevated concentrations of serum bilirubin and/or LDH, or evidence of microangiopathic hemolytic anemia (presence of schistocytes on peripheral blood smear).1
Hemolytic uremic syndrome may be life-threatening and/or result in renal failure requiring dialysis if treatment is delayed.1 If hemolytic uremic syndrome is suspected, hemodynamic parameters, peripheral blood smear, serum LDH concentrations, and indirect bilirubin concentrations should be monitored, and supportive treatment (i.e., hydration), which may also include a need for hospitalization, should be initiated.1 If hemolytic uremic syndrome is confirmed, moxetumomab pasudotox therapy should be discontinued and supportive treatment (i.e., hydration) should be initiated; renal function, CBCs and blood chemistries also should be monitored until the toxicity resolves.1
Other Warnings and Precautions
Renal toxicity, manifested as deterioration of renal function, acute kidney injury, renal failure, or laboratory abnormalities (i.e., elevated concentrations of serum creatinine, proteinuria) has been reported in patients receiving moxetumomab pasudotox.1
In a combined safety database of moxetumomab pasudotox-tdfk in patients with hairy cell leukemia, renal toxicity occurred in 34 of 129 (26%) patients receiving the drug; elevated concentrations of serum creatinine, proteinuria, acute kidney injury, renal failure, or renal impairment occurred in 17, 8, 2.3, 2.3, or 1.6%, respectively, of patients receiving moxetumomab pasudotox-tdfk.1 Most adverse renal effects were mild to moderate in severity; however, grade 3 acute kidney injury occurred in 1.6% of patients receiving moxetumomab pasudotox-tdfk.1 Elevations of serum creatinine concentrations by at least 2 grades from baseline occurred in 29 of 129 (22%) patients receiving moxetumomab pasudotox-tdfk; grade 3 elevations of serum creatinine occurred in 1.6% of patients receiving the drug.1 Following completion of moxetumomab pasudotox-tdfk therapy, elevation of serum creatinine concentrations 1.5-3 times the upper limit of normal (ULN) was reported in 5% of patients.1
Patients who develop hemolytic uremic syndrome, those with baseline renal impairment, and those 65 years of age or older may be at increased risk for worsening renal function following therapy with moxetumomab pasudotox.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Moxetumomab pasudotox should not be used in patients with severe renal impairment (creatinine clearance of 29 mL/minute or less).1
Renal function should be monitored prior to each dose of moxetumomab pasudotox-tdfk and as clinically indicated during therapy.1 Temporary interruption of moxetumomab pasudotox may be necessary if elevations in serum creatinine concentrations occur during therapy with the drug.1 (Renal Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Infusion-related reactions have been reported in patients receiving moxetumomab pasudotox.1 Infusion-related reactions may occur during any treatment cycle.1
In the principal efficacy study, infusion-related reactions associated with at least one characteristic manifestation (e.g., nausea, pyrexia, chills, vomiting, headache, cough, wheezing, dizziness, dyspnea, feeling hot, flushing, hypertension, hypotension, myalgia, tachycardia) on the day of infusion occurred in 40 of 80 (50%) patients receiving moxetumomab pasudotox-tdfk; grade 3 infusion-related reactions occurred in 11% of patients receiving the drug.1 The most common infusion-related reactions reported in patients receiving moxetumomab pasudotox-tdfk were nausea, pyrexia, chills, vomiting, and headache.1
To minimize the risk of infusion-related reactions, patients receiving moxetumomab pasudotox should be premedicated with acetaminophen, an antihistamine, and a histamine H2-receptor antagonist prior to each infusion of the drug.1 (See Dosage and Administration: General.)
In patients experiencing severe infusion-related reactions, the moxetumomab pasudotox infusion should be interrupted and appropriate treatment should be provided.1 An oral or IV corticosteroid should be administered approximately 30 minutes prior to resuming the infusion and prior to subsequent infusions.1 (See Infusion-related Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Electrolyte abnormalities (e.g., hypocalcemia) have been reported in patients receiving moxetumomab pasudotox.1
In a combined safety database of moxetumomab pasudotox-tdfk in patients with hairy cell leukemia, electrolyte abnormalities occurred in 73 of 129 (57%) patients receiving the drug; grade 3 or 4 electrolyte abnormalities occurred in 14 or 0.8%, respectively, of patients receiving moxetumomab pasudotox-tdfk.1 The most common electrolyte abnormality reported in patients receiving moxetumomab pasudotox-tdfk was hypocalcemia.1 Electrolyte abnormalities occurred in the same cycle as capillary leak syndrome, hemolytic uremic syndrome, fluid retention, or renal toxicity in 48 of 129 (37%) patients receiving moxetumomab pasudotox-tdfk.1
Serum electrolytes should be monitored prior to each dose and on day 8 of each cycle; additional monitoring on day 14 of each cycle also is recommended.1
There is potential for immunogenicity with moxetumomab pasudotox therapy.1
In the principal efficacy study, preexisting anti-moxetumomab pasudotox antibodies were detected by electrochemiluminescence (ECL) in 45 of 76 (59%) patients.1, 5 Anti-moxetumomab pasudotox antibody formation was detected at any point during treatment in 70 of 80 (88%) patients receiving moxetumomab pasudotox-tdfk.1 Neutralizing antibodies to moxetumomab pasudotox were detected in 96% of patients who tested positive for antibody formation at any point during treatment.1 The majority (99%) of patients who developed neutralizing antibodies to moxetumomab pasudotox had anti-moxetumomab pasudotox antibodies specific for the PE38 binding domain; 54% also had anti-moxetumomab pasudotox antibodies specific for the CD22 binding domain.1 Among patients who developed neutralizing antibodies to moxetumomab pasudotox, 82% of patients experienced an increase in antibody titers by a median of 640-fold compared with baseline values.5
In patients who tested positive for antibody formation with high titers, peak plasma concentrations of moxetumomab pasudotox were substantially decreased during cycle 3 and beyond in the presence of anti-moxetumomab pasudotox antibodies post-baseline;1 durable complete response rates also were lower in patients with high titers of anti-moxetumomab pasudotox antibodies in cycle 5 compared with those with lower anti-moxetumomab pasudotox antibody titers.5
There are no available data on moxetumomab pasudotox use in pregnant women; however, based on its mechanism of action and findings in nonpregnant animals, moxetumomab pasudotox may cause fetal and maternal harm.1
Animal reproductive and developmental studies have not been conducted with moxetumomab pasudotox.1 Degeneration of heart tissue has been demonstrated in nonpregnant cynomolgus monkeys receiving moxetumomab pasudotox at dosages exceeding 3 times the recommended human dosage and gliosis in the brain, axonal degeneration in the spinal cord, and body tremors occurred at dosages exceeding 10 times the recommended human dosage.1
Pregnancy should be avoided during moxetumomab pasudotox therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of moxetumomab pasudotox therapy in women of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving moxetumomab pasudotox and for at least 30 days after the last dose of the drug.1
If moxetumomab pasudotox is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
It is not known whether moxetumomab pasudotox is distributed into human milk.1 Effects of the drug on the breast-fed infant or milk production also are not known.1 Low amounts of moxetumomab are expected to distribute into human milk since the drug is a large molecule.11
The benefits of breast-feeding and the woman's clinical need for moxetumomab pasudotox should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1
Safety and efficacy of moxetumomab pasudotox have not been established in pediatric patients.1
In a combined safety database, 31% of patients with hairy cell leukemia receiving moxetumomab pasudotox-tdfk were 65 years of age or older and 8% were 75 years of age or older.1 Exploratory analysis suggests that renal toxicity (40 versus 20%) and adverse effects resulting in discontinuance of therapy (23 versus 7%) occurred more frequently in geriatric patients compared with younger adults.1
Clinical studies evaluating moxetumomab pasudotox-tdfk did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1
In population pharmacokinetic analyses, mild hepatic impairment (total bilirubin concentrations not exceeding the ULN and AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding the ULN, but not more than 1.5 times the ULN, with any AST concentration) did not have clinically important effects on the pharmacokinetics of moxetumomab pasudotox.1, 5
The effect of moderate or severe hepatic impairment (total bilirubin concentrations exceeding 1.5 times the ULN) on the pharmacokinetics of moxetumomab pasudotox is unknown.1
In population pharmacokinetic analyses, mild or moderate renal impairment (creatinine clearance 30-89 mL/minute) did not have clinically important effects on the pharmacokinetics of moxetumomab pasudotox.1, 5
The effect of severe renal impairment (creatinine clearance of 29 mL/minute or less) on the pharmacokinetics of moxetumomab pasudotox is unknown; therefore, moxetumomab pasudotox is not recommended in patients with severe renal impairment.1 (See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Adverse effects reported in 20% or more of patients receiving moxetumomab pasudotox-tdfk include infusion-related reactions,1 peripheral edema,1, 3 nausea,1, 3 fatigue,1, 3 headache,1, 3 pyrexia,1, 3 constipation,1, 3 anemia,1, 3 and diarrhea.1, 3 Laboratory abnormalities reported in 20% or more of patients receiving moxetumomab pasudotox-tdfk include elevated concentrations of serum creatinine,1 elevated concentrations of aminotransferases (i.e., AST, ALT),1, 3 hypoalbuminemia,1, 3 hypocalcemia,1 hypophosphatemia,1 decreased concentrations of hemoglobin,1 neutropenia,1 hyponatremia,1 elevated concentrations of bilirubin,1 hypokalemia,1 elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP),1 hypomagnesemia,1 thrombocytopenia,1 hyperuricemia,1 elevated concentrations of serum alkaline phosphatase,1 and decreased concentrations of lymphocytes.3
Moxetumomab pasudotox, a CD22-directed antibody-fusion protein consisting of a recombinant murine monoclonal antibody (moxetumomab) covalently linked to a cytotoxic bacterial protein toxin ( Pseudomonas exotoxin A [PE38]), is an antineoplastic agent that also is referred to as an immunotoxin.1, 4, 5, 6, 7, 11 The drug is produced by recombinant DNA technology in Escherichia coli and consists of variable fragments of antibodies to CD22 genetically fused to fragments of PE38.1, 4, 5, 7
The anticancer activity of moxetumomab pasudotox appears to be produced by binding of the antibody-fusion protein to CD22-expressing tumor cells.1, 4, 8 The antibody portion of moxetumomab pasudotox recognizes and binds specifically to antigen CD22, a transmembrane glycoprotein expressed in most B-cell lymphoma and leukemia, including hairy cell leukemia, cells.1, 4, 5, 7, 8, 9 Following binding of moxetumomab pasudotox to CD22-expressing tumor cells, the resultant complex is internalized by the cell.1, 4, 7 The bacterial toxin PE38 then inactivates adenosine diphosphate (ADP)-ribosylation of elongation factor 2 causing inhibition of protein synthesis and subsequent apoptosis.1, 4, 5, 7, 8, 10 Although kanamycin is included in the nutrient medium used during the fermentation process, it is undetectable in the final preparation of moxetumomab pasudotox.1
An initial decrease in CD+ B-cell counts and redistribution of peripheral T cells and natural killer cells are observed in patients with hairy cell leukemia receiving moxetumomab pasudotox therapy.1 Moxetumomab pasudotox decreased peripheral CD19+ B-cell counts (surrogate marker for peripheral B-cells) by 89% from baseline on day 8 following the initial 3 doses of moxetumomab pasudotox in such patients.1, 5 Decreased CD19+ B-cell counts persisted for at least 1 month following discontinuance of the drug and for 6 months following discontinuance of the drug in patients who achieved a complete or partial response.1, 3 Median CD3+ T-cell, CD4+ T-cell, CD8+ T-cell, and CD16+/CD56 natural killer cell counts decreased by 21, 20, 23, and 47%, respectively, on day 8 of the first treatment cycle and returned to or remained above baseline values on day 29 and thereafter.1
Systemic exposure to moxetumomab pasudotox is proportional to dose following repeated administration of the drug over the dosage range of 0.005-0.05 mg/kg.1 When moxetumomab pasudotox-tdfk is administered IV on days 1, 3, and 5 of a 28-day cycle, no systemic accumulation of the drug occurs.1 The metabolic pathway of moxetumomab pasudotox has not been characterized.1 As with other therapeutic proteins, the drug is expected to be degraded into small peptides and amino acids via catabolic pathways.1 Population pharmacokinetic modeling suggests that clearance of moxetumomab pasudotox decreases over time; however, the decrease in clearance suggests that moxetumomab pasudotox undergoes target-mediated drug disposition.1, 5 The mean elimination half-life of moxetumomab pasudotox is 1.4 hours.1
Pharmacokinetic parameters of moxetumomab pasudotox do not appear to be affected by age (range of 36-84 years), sex, race (white versus non-white), and body weight (42-152 kg).1
Importance of advising patients to read the manufacturer's medication guide before beginning treatment and each time moxetumomab pasudotox is administered.1
Risk of capillary leak syndrome.1 Importance of informing clinician immediately if manifestations of capillary leak syndrome (e.g., hypotension, generalized edema, dyspnea, rapid weight gain) occur.1
Risk of hemolytic uremic syndrome.1 Importance of monitoring blood chemistries frequently.1 Importance of informing clinician immediately if manifestations of hemolytic uremic syndrome (e.g., decreased urination, hematuria, unusual bleeding or bruising, stomach pain, vomiting, fever, fatigue, mood or behavior changes, confusion, seizures, difficulty breathing, tachycardia) occur.1 Importance of advising patients to maintain adequate hydration during moxetumomab pasudotox therapy.1 (See Dosage and Administration: General.)
Risk of infusion-related reactions.1 Importance of informing clinician immediately if signs or symptoms of such reactions, including fever, chills, difficulty breathing, wheezing, cough, dizziness, flushing, tachycardia, headache, blood pressure changes, muscle pain, nausea, or vomiting, occur during infusion of moxetumomab pasudotox-tdfk.1
Risk of renal impairment.1 Importance of informing clinician if changes in urination occur.1
Risk of electrolyte abnormalities (e.g., hypokalemia).1 Importance of informing clinician immediately if symptoms of electrolyte abnormalities (e.g., seizure, irregular or fast heartbeat, muscle cramping, paresthesia, nausea) occur.1
Risk of fetal harm.1 Necessity of advising women of reproductive potential that they should use an effective method of contraception while receiving the drug and for at least 30 days after the last dose of the drug.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women to avoid breast-feeding during moxetumomab pasudotox therapy.1
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).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 1 mg |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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