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Inotuzumab Ozogamicin

Class: Antineoplastic Agents
Brands: Besponsa

Warning

Warning: Hepatotoxicity, including Hepatic Veno-occlusive Disease (VOD; also known as Sinusoidal Obstruction Syndrome) and Increased Risk of Post-Hematopoietic Stem Cell Transplant (HSCT) Non-relapse Mortality1

See full prescribing information for complete boxed warning.1

  • Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received inotuzumab ozogamicin.1

  • A higher post-HSCT non-relapse mortality rate occurred in patients receiving inotuzumab ozogamicin.1

Introduction

Inotuzumab ozogamicin is an antineoplastic agent.

Uses for Inotuzumab Ozogamicin

Inotuzumab ozogamicin has the following uses:

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).1

Inotuzumab Ozogamicin Dosage and Administration

General

Inotuzumab ozogamicin is available in the following dosage form(s) and strength(s):

For injection: 0.9 mg lyophilized powder in a single-dose vial for reconstitution and further dilution.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Premedicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions.1

  • Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below (see Table 1). See full prescribing information for dosing details.1

For patients who achieve a CR (complete remission) or a CRi (complete remission with incomplete hematologic recovery), and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21).

Table 1. Inotuzumab Ozogamicin Dosage Regimen for Cycle 1 and Subsequent Cycles Depending on Response to Treatment

Day 1

Day 8

Day 15

Dosing regimen for Cycle 1

All patients:

Dose

0.8 mg/m2

0.5 mg/m2

0.5 mg/m2

Cycle length

21 days

Dosing regimen for subsequent cycles depending on response to treatment

Patients who have achieved a CR or CRi:

Dose

0.5 mg/m2

0.5 mg/m2

0.5 mg/m2

Cycle length

28 days

Patients who have not achieved a CR or CRi:

Dose

0.8 mg/m2

0.5 mg/m2

0.5 mg/m2

Cycle length

28 days

  • See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug.1

Cautions for Inotuzumab Ozogamicin

Contraindications

None.1

Warnings/Precautions

Hepatotoxicity, including Hepatic Veno-occlusive Disease (VOD; also known as Sinusoidal Obstruction Syndrome)

In the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD, was observed in 23/164 patients (14%) in the inotuzumab ozogamicin arm during or following treatment or following a hematopoietic stem cell transplant (HSCT) after completion of treatment. VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3–57 days). In the inotuzumab ozogamicin arm, among the 79 patients who proceeded to a subsequent HSCT, VOD was reported in 18/79 patients (23%), and among all 164 patients treated, VOD was reported in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT.1

The risk of VOD was greater in patients who underwent HSCT after inotuzumab ozogamicin treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with inotuzumab ozogamicin included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of inotuzumab ozogamicin treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with inotuzumab ozogamicin.1

Monitor closely for signs and symptoms of VOD; these may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with inotuzumab ozogamicin is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) and minimal residual disease (MRD) negativity after 2 cycles. (See Dosage and Administration: Dosage.) For patients who proceed to HSCT, monitor liver tests closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.1

In the INO-VATE ALL trial, increases in liver tests were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively.1

In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of inotuzumab ozogamicin. Elevations of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin.1

Increased Risk of Post-Hematopoietic Stem Cell Transplant (HSCT) Non-relapse Mortality

In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving inotuzumab ozogamicin compared to the investigator's choice of chemotherapy arm, resulting in a higher day 100 post-HSCT mortality rate.1

Overall, 79/164 patients (48%) in the inotuzumab ozogamicin arm and 35/162 patients (22%) in the investigator's choice of chemotherapy arm had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the inotuzumab ozogamicin arm compared to the investigator's choice of chemotherapy arm, respectively.1

In the inotuzumab ozogamicin arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the inotuzumab ozogamicin arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection).1

Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.1

Myelosuppression

In the INO-VATE ALL trial, myelosuppression was observed in patients receiving inotuzumab ozogamicin.1

Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, was reported in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to >50,000/mm3 was later than 45 days after the last dose in 15/164 patients (9%) who received inotuzumab ozogamicin and 3/162 patients (2%) who received investigator's choice of chemotherapy.1

Complications associated with myelosuppression (including infections and bleeding/hemorrhagic events) were observed in patients receiving inotuzumab ozogamicin. Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 patients (5%). Bacterial, viral, and fungal infections were reported.1

Hemorrhagic events were reported in 54/164 patients (33%). Grade 3 or 4 hemorrhagic events were reported in 8/164 patients (5%). One Grade 5 (fatal) hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 patients (1%). The most common hemorrhagic event was epistaxis which was reported in 24/164 patients (15%).1

Monitor complete blood counts prior to each dose of inotuzumab ozogamicin and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with inotuzumab ozogamicin. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with inotuzumab ozogamicin. Management of severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin.1

Infusion Related Reactions

In the INO-VATE ALL trial, infusion related reactions were observed in patients who received inotuzumab ozogamicin. Infusion related reactions (all Grade 2) were reported in 4/164 patients (2%). Infusion related reactions generally occurred in Cycle 1 shortly after the end of the inotuzumab ozogamicin infusion and resolved spontaneously or with medical management.1

Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing.1

Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue inotuzumab ozogamicin.1

QT Interval Prolongation

In the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥60 msec from baseline were measured in 4/162 patients (3%). No patients had QTcF values greater than 500 msec. Grade 2 QT prolongation was reported in 2/164 patients (1%). No ≥Grade 3 QT prolongation or events of torsades de pointes were reported.1

Administer inotuzumab ozogamicin with caution in patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances. Obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.1

Embryo-fetal Toxicity

Based on its mechanism of action and findings from animal studies, inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 8 months after the final dose of inotuzumab ozogamicin. Advise males with female partners of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose of inotuzumab ozogamicin. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with inotuzumab ozogamicin.1

Specific Populations

Pregnancy

Risk Summary: Based on its mechanism of action and findings from animal studies, inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on inotuzumab ozogamicin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥0.4 times the exposure in patients at the maximum recommended dose, based on AUC. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.1

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively.1

Animal Data: In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥0.11 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).1

In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo-fetal development.1

Lactation

There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with inotuzumab ozogamicin and for at least 2 months after the last dose.1

Females And Males Of Reproductive Potential

Based on its mechanism of action and findings from animal studies, inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating inotuzumab ozogamicin.1

Advise females of reproductive potential to avoid becoming pregnant while receiving inotuzumab ozogamicin. Advise females of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 8 months after the last dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose.1

Based on findings in animals, inotuzumab ozogamicin may impair fertility in females of reproductive potential.1

Based on findings in animals, inotuzumab ozogamicin may impair fertility in males of reproductive potential.1

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.1

Geriatric Use

In the INO-VATE ALL trial, 30/164 patients (18%) treated with inotuzumab ozogamicin were ≥65 years of age. No differences in responses were identified between older and younger patients.1

Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age.1

Hepatic Impairment

Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced.1

No adjustment to the starting dose is required when administering inotuzumab ozogamicin to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert's syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN.1

Common Adverse Effects

The most common (≥20%) adverse reactions are thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism Of Action

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.1

Advice to Patients

Hepatotoxicity, including Hepatic Veno-occlusive Disease (VOD; also known as Sinusoidal Obstruction Syndrome)

Inform patients that liver problems, including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during inotuzumab ozogamicin treatment. Inform patients that they should seek immediate medical advice if they experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and abdominal swelling that may be painful. Inform patients that they should carefully consider the benefit/risk of inotuzumab ozogamicin treatment if they have a prior history of VOD or serious ongoing liver disease.1

Increased Risk of Post-Hematopoietic Stem Cell Transplant (HSCT) Non-Relapse Mortality

Inform patients that there is an increased risk of post-HSCT non-relapse mortality after receiving inotuzumab ozogamicin, and that the most common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients to report signs and symptoms of infection.1

Myelosuppression

Inform patients that decreased blood counts, which may be life-threatening, may develop during inotuzumab ozogamicin treatment and that complications associated with decreased blood counts may include infections, which may be life-threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported during treatment with inotuzumab ozogamicin.1

Infusion Related Reactions

Advise patients to contact their health care provider if they experience symptoms such as fever, chills, rash, or breathing problems during the infusion of inotuzumab ozogamicin.1

QT Interval Prolongation

Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and the use of all medications to their healthcare provider.1

Embryo-fetal Toxicity

Advise males and females of reproductive potential to use effective contraception during inotuzumab ozogamicin treatment and for at least 5 and 8 months after the last dose, respectively. Advise females of reproductive potential to avoid becoming pregnant while receiving inotuzumab ozogamicin. Advise women to contact their healthcare provider if they become pregnant, of if pregnancy is suspected, during treatment with inotuzumab ozogamicin. Inform the patient of the potential risk to the fetus.1

Lactation

Advise women against breastfeeding while receiving inotuzumab ozogamicin and for 2 months after the last dose.1

Additional Information

AHFS First Release. For additional information 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 uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Inotuzumab Ozogamicin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Powder, Lyophilized, for Solution

0.25 mg /1 mL

Besponsa

Wyeth Pharmaceuticals Inc. a subsidiary of Pfizer Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions September 11, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.. Besponsa (inotuzumab ozogamicin) INTRAVENOUS prescribing information. 2017 Aug.

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