Inotuzumab ozogamicin

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# Black Box Warning

# Overview
Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) that is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Inotuzumab Ozogamicin is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
- Pre-medicate before each dose.
- For the first cycle, the recommended total dose of Inotuzumab Ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity.
- For subsequent cycles:
- In patients who achieve a CR or CRi, the recommended total dose of Inotuzumab Ozogamicin is 1.5 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 4 weeks in duration.
- In patients who do not achieve a CR or CRi, the recommended total dose of Inotuzumab Ozogamicin is 1.8 mg/m2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 4 weeks in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
- For patients proceeding to hematopoietic stem cell transplant (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 CR or CRi and minimal residual disease (MRD) negativity after 2 cycles.
- For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
- Modify the dose of Inotuzumab Ozogamicin for toxicities (see Tables 24). Inotuzumab Ozogamicin doses within a treatment cycle (i.e., Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for non-hematologic toxicities. If the dose is reduced due to Inotuzumab Ozogamicin-related toxicity, the dose must not be re-escalated.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Inotuzumab Ozogamicin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Inotuzumab Ozogamicin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Inotuzumab ozogamicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Inotuzumab Ozogamicin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Inotuzumab Ozogamicin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- 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 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: 357 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.
- 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.
- 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 or CRi and MRD negativity after 2 cycles. 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.
- In the INO-VATE ALL trial, myelosuppression was observed in patients receiving Inotuzumab Ozogamicin.
- 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.
- 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.
- 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%).
- 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.
- 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.
- Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing.
- 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.
- In the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia's formula (QTcF) of  to 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 Torsade de Pointes were reported.
- 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.
- 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.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The adverse reactions described in this section reflect exposure to Inotuzumab Ozogamicin in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of Inotuzumab Ozogamicin versus Investigator's choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor , mitoxantrone + cytarabine , or high dose cytarabine ) (INO-VATE ALL Trial ).
- Of the 164 patients who received Inotuzumab Ozogamicin, the median age was 47 years (range: 1878 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.
- In patients who received Inotuzumab Ozogamicin, the median duration of treatment was 8.9 weeks (range: 0.126.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.115.6 weeks), with a median of 1 treatment cycle started in each patient.
- In patients who received Inotuzumab Ozogamicin, the most common ( 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.
- In patients who received Inotuzumab Ozogamicin, the most common ( 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.
- In patients who received Inotuzumab Ozogamicin, the most common ( 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common ( 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common ( 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).
- VOD was reported in 23/164 patients (14%) who received Inotuzumab Ozogamicin during or following treatment or following a HSCT after completion of treatment.
- Table 6 shows the adverse reactions with  10% incidence reported in patients with relapsed or refractory ALL who received Inotuzumab Ozogamicin or Investigator's choice of chemotherapy.
- Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with Inotuzumab Ozogamicin included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).
- Table 7 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received Inotuzumab Ozogamicin or Investigator's choice of chemotherapy.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Inotuzumab Ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- In clinical studies of Inotuzumab Ozogamicin in patients with relapsed or refractory ALL, the immunogenicity of Inotuzumab Ozogamicin was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-Inotuzumab Ozogamicin antibodies. For patients whose sera tested positive for anti-Inotuzumab Ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.
- In clinical studies of Inotuzumab Ozogamicin in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-Inotuzumab Ozogamicin antibodies. No patients tested positive for neutralizing anti-Inotuzumab Ozogamicin antibodies. In patients who tested positive for anti-Inotuzumab Ozogamicin antibodies, the presence of anti-Inotuzumab Ozogamicin antibodies did not affect clearance following Inotuzumab Ozogamicin treatment.

## Postmarketing Experience
There is limited information regarding Inotuzumab ozogamicin Postmarketing Experience in the drug label.

# Drug Interactions
- Drugs That Prolong the QT Interval
- Concomitant use of Inotuzumab Ozogamicin with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc interval prolongation. Discontinue or use alternative concomitant drugs that do not prolong QT/QTc interval while the patient is using Inotuzumab Ozogamicin. When it is not feasible to avoid concomitant use of drugs known to prolong QT/QTc, obtain 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
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.
- 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 24% and 1520%, respectively.
Data (Animal)
- 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).
- 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Inotuzumab ozogamicin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Inotuzumab ozogamicin during labor and delivery.

### Nursing Mothers
Risk Summary
- 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.

### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.

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

### Gender
There is no FDA guidance on the use of Inotuzumab ozogamicin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Inotuzumab ozogamicin with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Inotuzumab ozogamicin in patients with renal impairment.

### 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 1.01.5  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 1.53  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.
- 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.

### Females of Reproductive Potential and Males
Pregnancy Testing
- 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.
Contraception
Females
- 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.
Males
- 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.
Infertility
Females
- Based on findings in animals, Inotuzumab Ozogamicin may impair fertility in females of reproductive potential.
Males
- Based on findings in animals, Inotuzumab Ozogamicin may impair fertility in males of reproductive potential.

### Immunocompromised Patients
There is no FDA guidance one the use of Inotuzumab ozogamicin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- See TABLE 5 for storage times and conditions for prior to and during administration of the diluted solution.
- Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-,or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
- Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (2025C; 6877F). Infusion lines made of PVC (DEHP- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.
- Table 5 shows the storage times and conditions for reconstitution, dilution, and administration of Inotuzumab Ozogamicin.

### Monitoring
- Resolution or improvement of disease-related signs (reduction of blasts in the bone marrow and peripheral blood, recovery of blood counts, and resolution of extramedullary disease) may indicate efficacy.
- Total bilirubin and liver function tests (LFTs): prior to and following each dose; in patients proceeding to hemopoietic stem cell transplant (HSCT), monitor LFTs closely in the first month after HSCT, then according to standard medical practice.
- Signs and symptoms of hepatic venoocclusive disease, including rapid weight gain, ascites, and hepatomegaly (possibly painful).
- Toxicity, including signs and symptoms of hepatic venoocclusive disease and infection: Post-HSCT.
- Signs and symptoms of infection , bleeding, or hemorrhage, and other signs of myelosuppression: During therapy.
- CBC: prior to each dose.
- Electrolytes and ECG: prior to the start of therapy, after initiation of any drug known to prolong the QTc interval, and periodically as clinically indicated during therapy.
- Infusion related reactions (including symptoms such as fever, chills, rash, or breathing problems): During and for 1 hour following infusion.

# IV Compatibility
There is limited information regarding the compatibility of Inotuzumab ozogamicin and IV administrations.

# Overdosage
There is limited information regarding Inotuzumab ozogamicin overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## 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.

## Structure

## Pharmacodynamics
- During the treatment period, the pharmacodynamic response to Inotuzumab Ozogamicin was characterized by the depletion of CD22-positive leukemic blasts.
Cardiac Electrophysiology
- In a randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of  60 msec from baseline were measured in 4/162 patients (3%) in the Inotuzumab Ozogamicin arm and 3/124 patients (2%) in the Investigator's choice of chemotherapy arm. Increases in QTcF of > 500 msec were observed in none of the patients in the Inotuzumab Ozogamicin arm and 1/124 patients (1%) in the Investigator's choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the Inotuzumab Ozogamicin arm.

## Pharmacokinetics
- The mean Cmax of Inotuzumab Ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ngh/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, a 5.3 times accumulation of Inotuzumab Ozogamicin was predicted by Cycle 4.
Distribution
- N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of Inotuzumab Ozogamicin was approximately 12 L.
Elimination
- The pharmacokinetics of Inotuzumab Ozogamicin was well characterized by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of Inotuzumab Ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t12) was 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of Inotuzumab Ozogamicin was predicted by Cycle 4.
Metabolism
- In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.
Specific Populations
- The effect of intrinsic factors on Inotuzumab Ozogamicin pharmacokinetics was assessed using a population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race (Asian versus non-Asian ) had no clinically significant effect on the pharmacokinetics of Inotuzumab Ozogamicin. Body surface area was found to significantly affect Inotuzumab Ozogamicin disposition. Inotuzumab Ozogamicin is dosed based on body surface area.
Patients with Renal Impairment
- The clearance of Inotuzumab Ozogamicin in patients with mild renal impairment (creatinine clearance  6089 mL/min; n=237), moderate renal impairment (CLcr 3059 mL/min; n=122), or severe renal impairment (CLcr 1529 mL/min; n=4) was similar to patients with normal renal function (CLcr 90 mL/min; n=402). The safety and efficacy of Inotuzumab Ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.
Patients with Hepatic Impairment
- The clearance of Inotuzumab Ozogamicin in patients with mild hepatic impairment (total bilirubin ULN and AST > ULN, or total bilirubin >1.01.5  ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST ULN; n=611). There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).
Drug Interactions
- In vitro
- Effect of Metabolic Pathways and Transporter Systems on Inotuzumab Ozogamicin
- N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp).
- At clinically relevant concentrations, N-acetyl-gamma-calicheamicin dimethylhydrazide had a low potential to:
- Inhibit cytochrome P450 (CYP 450) Enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
- Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
- Inhibit UGT Enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.
- Inhibit Drug Transporters: P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.
- At clinically relevant concentrations, Inotuzumab Ozogamicin had a low potential to:
- Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
- Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.

## Nonclinical Toxicology
- Formal carcinogenicity studies have not been conducted with Inotuzumab Ozogamicin. In toxicity studies, rats were dosed weekly for 4 or 26 weeks with Inotuzumab Ozogamicin at doses up to 4.1 mg/m2 and 0.73 mg/m2, respectively. After 26 weeks of dosing, rats developed hepatocellular adenomas in the liver at 0.73 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC).
- Inotuzumab Ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single doses 1.1 mg/m2. This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from Inotuzumab Ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.
- In a female fertility and early embryonic development study, female rats were administered daily intravenous doses of Inotuzumab Ozogamicin up to 0.11 mg/m2 for 2 weeks before mating through Day 7 of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos and gravid uterine weights were observed at the 0.11 mg/m2 dose level (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were nonreversible following a 4-week nondosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at 0.07 mg/m2 in male rats and at 0.73 mg/m2 in female monkeys.

# Clinical Studies
- The safety and efficacy of Inotuzumab Ozogamicin were evaluated in INO-VATE ALL (NCT01564784) a randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL. Patients were stratified at randomization based on duration of first remission (< 12 months or  12 months, salvage treatment (Salvage 1 or 2) and patient age at randomization (< 55 or  55 years). Eligible patients were  18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have  5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy. Table 1 shows the dosing regimen used to treat patients.
- Among all 326 patients who were randomized to receive Inotuzumab Ozogamicin (N=164) or Investigator's choice of chemotherapy (N=162), 215 patients (66%) had received 1 prior treatment regimen for ALL and 108 patients (33%) had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 1879 years), 276 patients (85%) had Philadelphia chromosome-negative ALL, 206 patients (63%) had a duration of first remission < 12 months, and 55 patients (17%) had undergone a HSCT prior to receiving Inotuzumab Ozogamicin or Investigator's choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics.
- All evaluable patients had B-cell precursor ALL that expressed CD22, with  90% of evaluable patients exhibiting  70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory.
- The efficacy of Inotuzumab Ozogamicin was established on the basis of CR, the duration of CR, and proportion of MRD-negative CR (< 1  10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized. CR, duration of remission (DoR), and MRD results in the initial 218 randomized patients were consistent with those seen in all 326 randomized patients.
- Among the initial 218 randomized patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved CR/CRi in Cycles 1 and 2, respectively, in the Inotuzumab Ozogamicin arm, and 29/32 (91%) and 1/32 (3%) of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the Investigator's choice of chemotherapy arm.
- Table 8 shows the efficacy results from this study.
- Among the initial 218 patients, as per EAC assessment, 32/109 patients (29%) in the Inotuzumab Ozogamicin arm achieved complete remission with partial hematologic recovery (CRh; defined as  0.5  109/L, and platelet counts > 50  109/L but not meeting full recovery of peripheral blood counts) versus 6/109 patients (6%) in the Investigator's choice of chemotherapy arm, and 71/109 patients (65%) in the Inotuzumab Ozogamicin arm achieved CR/CRh versus 25/109 patients (23%) in the Investigator's choice of chemotherapy arm.
- 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.
- Figure 1 shows the analysis of overall survival (OS). The analysis of OS did not meet the pre-specified boundary for statistical significance.

# How Supplied
- Inotuzumab Ozogamicin (Inotuzumab Ozogamicin) for Injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. Each vial delivers 0.9 mg Inotuzumab Ozogamicin. Each carton (NDC 0008-0100-01) contains one single-dose vial.

## Storage
- Refrigerate (28C; 3646F) Inotuzumab Ozogamicin vials and store in the original carton to protect from light. Do not freeze.
- Inotuzumab Ozogamicin is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
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.
Increased Risk of Post-HSCT Non-Relapse Mortality
- Inform patients that there is an increased risk of post-HSCT non-relapse mortality after receiving Inotuzumab Ozogamicin, that the most common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients to report signs and symptoms of infection.
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.
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.
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.
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, or if pregnancy is suspected, during treatment with Inotuzumab Ozogamicin. Inform the patient of the potential risk to the fetus.
Lactation
- Advise women against breastfeeding while receiving Inotuzumab Ozogamicin and for 2 months after the last dose.

# Precautions with Alcohol
Alcohol-Inotuzumab ozogamicin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Besponsa

# Look-Alike Drug Names
There is limited information regarding Inotuzumab ozogamicin Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price