Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate approved for the treatment of adult and pediatric patients aged 1 year and older with relapsed or refractory, CD22-positive, B-cell precursor acute lymphoblastic leukemia. Severe or life-threatening hepatotoxicity including veno-occlusive disease/sinusoidal obstruction syndrome has been reported. Patients who undergo a hematopoietic stem-cell transplant following inotuzumab ozogamicin therapy may have a higher risk for nonrelapse mortality.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 1
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Inotuzumab ozogamicin is available as a single-dose 0.9-mg lyophilized powder vial.
-Dilution is required prior to administration.
-Premedication with a corticosteroid, an antipyretic agent (e.g., acetaminophen), and an antihistamine prior to each dose is recommended.
-Do not mix with or administer as an infusion with other drugs.
Reconstitution
-After calculating the dose and number of vials needed, add 4 mL of Sterile Water for Injection to each vial for a final vial concentration of 0.25 mg/mL (0.9 mg in 3.6 mL).
-Gently swirl the vial to dissolve powder but do not shake.
-The reconstitution solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter.
-Storage of reconstituted vials: If not further diluted immediately, vials may be stored in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F) for up to 4 hours after reconstitution; protect from light and do not freeze.
Dilution
-Add the required dose/volume from the reconstituted vial(s) to an infusion container (i.e., infusion bag or syringe) and dilute with 0.9% Sodium Chloride Injection as follows:
--For calculated doses of 0.5 mg or more: In an infusion bag, dilute to a final concentration of 0.01 mg/mL to 0.1 mg/mL in a total volume of 50 mL.
-For calculated doses less than 0.5 mg: In a syringe, dilute to a final concentration of 0.025 mg/mL to 0.1 mg/mL in a total volume between 2 mL to 50 mL.
-Gently invert to mix the diluted solution but do not shake.
-Discard any unused portion left in the vial.
-Storage of diluted solution: If not infused immediately, the diluted solution may be stored at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or refrigerated for up to 6 hours; protect from light and do not freeze.
Intravenous (IV) Infusion
-Allow refrigerated diluted solutions to warm to room temperature for approximately 1 hour prior to administration.
-Administer the diluted solution as an IV infusion over 1 hour.
-Use a syringe pump and micro-bore IV tubing for syringe infusions.
-Flush the IV line with 0.9% Sodium Chloride Injection following administration to ensure complete medication delivery.
-The diluted solution does not need to be filtered; if it is filtered, use polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulfone (HPS)-based filters.
-Do not use filters made of nylon or mixed cellulose ester (MCE).
-The inotuzumab ozogamicin infusion should be completed within 8 hours of vial reconstitution.
-Observe patients during and for at least 1 hour after the end of the infusion for symptoms of infusion-related reactions.
Severe or life-threatening hepatotoxicity including veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) was reported in 14% of adult patients (n = 164) and 15% of pediatric patients (n = 53) who received inotuzumab ozogamicin in clinical trials. Monitor liver function tests (LFTs) including total bilirubin and alkaline phosphatase levels prior to and following each inotuzumab ozogamicin dose. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop liver function test abnormalities. Closely monitor patients for signs and symptoms of VOD/SOS including hepatomegaly, rapid weight increases, and ascites. Permanently discontinue therapy in patients who develop VOD/SOS; treat according to standard medical practice. In patients who undergo a hematopoietic stem-cell transplant (HSCT), monitor LFTs at least weekly during the first month post-HSCT; thereafter, continue to monitor LFTs less frequently as indicated. Elevated hepatic enzymes/increased transaminase levels (26%; grade 3 or higher, 7%), increased gamma-glutamyl transferase (GGT) level (21%; grade 3 or higher, 10%), increased alkaline phosphatase level (13%; grade 3 or higher, 2%), hyperbilirubinemia (21%; grade 3 or higher, 5%), and ascites (4%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. In 79 adult patients who received a hematopoietic stem-cell transplant (HSCT) after inotuzumab ozogamicin therapy, 18 patients (23%) experienced VOD/SOS. The median time from HSCT to onset of VOD/SOS was 15 days (range, 3 to 57 days). Elevated hepatic enzymes, including increased AST (87; grade 3 or 4, 21%), ALT (83%; grade 3 or 4, 21%), GGT (79%; grade 3 or 4, 27%), and alkaline phosphatase (28%) levels, increased bilirubin level (30%; grade 3 or 4, 9%), and hyperbilirubinemia (9%; grade 3 or 4, 8%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53). In 26 pediatric patients who received a HSCT after inotuzumab ozogamicin therapy, 5 patients (19%) experienced VOD/SOS.
Severe myelosuppression has been reported with inotuzumab ozogamicin therapy in a clinical trial. Monitor complete blood counts prior to each dose of inotuzumab ozogamicin. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe myelosuppression. Thrombocytopenia (51%; grade 3 or higher, 42%), neutropenia (49%; grade 3 or higher, 48%), anemia (36%; grade 3 or higher, 24%), leukopenia (35%; grade 3 or higher, 33%), febrile neutropenia (grade 3 or higher, 26%), lymphopenia (18%; grade 3 or higher, 16%), and pancytopenia (2%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Recovery of platelet counts to greater than 50,000 cells/mm3 was later than 45 days after the last dose in 9% of patients treated with of inotuzumab ozogamicin. Decreased platelet count (100%; grade 3 or 4, 85%), thrombocytopenia (grade 3 or 4, 45%), decreased neutrophil count (98%; grade 3 or 4, 96%), neutropenia (grade 3 or 4, 40%), decreased hemoglobin level (96%; grade 3 or 4, 42%), anemia (45%; grade 3 or 4, 38%), decreased white blood count (98%; grade 3 or 4, 89%), febrile neutropenia (grade 3 or higher, 28%), and decreased lymphocyte count (87%; grade 3 or 4, 73%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Serious infection (e.g., bacterial, viral, and fungal infection) was reported in patients who received inotuzumab ozogamicin therapy in a clinical trial; some cases were fatal. Monitor for signs and symptoms of infection during therapy. Administer prophylactic anti-infective agents as appropriate. Infection was reported in 48% (grade 3 or higher, 28%) of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Fatal infections (e.g., pneumonia, neutropenic sepsis, sepsis, and septic shock) were reported in 5% of inotuzumab ozogamicin-treated patients. Infection occurred in 43% (grade 3 or higher, 23%) of pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53); fatal cases of lung infection and sepsis were reported. The term infection included sepsis, encephalitis, candidiasis, influenza, rhinitis, sepsis, sinusitis, and skin infection.
Serious bleeding was reported in patients who received inotuzumab ozogamicin in a clinical trial. Monitor for signs and symptoms of bleeding during therapy. Bleeding (33%; grade 3 or higher, 5%) including epistaxis (15%) occurred in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial; 1 patient experienced fatal intra-abdominal/GI bleeding. Bleeding (42%; grade 3 or higher, 6%) including hematoma (15%) mouth hemorrhage (11%), and epistaxis (11%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53). The term bleeding included conjunctival bleeding, contusion, ecchymosis, epistaxis, eyelid bleeding, GI bleeding, hemorrhagic gastritis, gingival bleeding, hemoptysis, hematemesis, hematochezia, hematotympanum, hematuria, intracranial bleeding, subcutaneous bleeding or hematoma, bleeding hemorrhoids, intra-abdominal bleeding, mesenteric bleeding, thrombotic thrombocytopenic purpura (TTP), metrorrhagia, mouth or lip bleeding, muscle bleeding, oral mucosa hematoma, petechiae, post-procedural hematoma, rectal bleeding, hemorrhagic shock, subdural hematoma, and vaginal bleeding.
QT prolongation was reported with inotuzumab ozogamicin therapy in a clinical trial. Obtain an electrocardiogram (ECG) and monitor serum electrolytes prior to the start of treatment and periodically during therapy as clinically indicated. Grade 2 QT prolongation was reported in 1% of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. In this trial, 3% of patients had a corrected QT interval that increased by 60 milliseconds (msec) or more from baseline; prolonged QT interval on ECG occurred in 1% of patients. Increased QTcF values of more than 60 msec from baseline (14%) and more than 500 msec (6%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Decreased appetite/anorexia (12%; grade 3 or higher, 1%), nausea (31%; grade 3 or higher, 2%), abdominal pain (23%; grade 3 or higher, 3%), diarrhea (17%; grade 3 or higher, 1%), constipation (16%), vomiting (15%; grade 3 or higher, 1%), abdominal distension (6%), and stomatitis (13%; grade 3 or higher, 2%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. In this trial, the term stomatitis included aphthous ulcer, mucosal inflammation, mouth/oral ulceration, oral pain, and oropharyngeal pain.Vomiting (45%; grade 3 or higher, 2%), nausea (32%), abdominal pain (25%; grade 3 or higher, 2%), constipation (19%; grade 3 or higher, 2%), stomatitis (17%; grade 3 or higher, 6%), diarrhea (11%), and decreased appetite (11%; grade 3 or higher, 4%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Headache was reported in 28% (grade 3 or higher, 2%) of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. In this trial, the term headache included migraine and sinus headache. Headache occurred in 21% of pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Fatigue/asthenia was reported in 35% (grade 3 or higher, 5%) of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Fatigue occurred in 17% of pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Fever (32%; grade 3 or higher, 3%) and chills (11%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Fever (49%; grade 3 or higher, 4%) and chills (8%) occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Increased lipase level (9%) and increased amylase level/hyperamylasemia (5%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Increased lipase (23%; grade 3 or 4, 4%) and amylase (14%) levels occurred in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Hyperuricemia (4%) and tumor lysis syndrome (TLS) (2%) were reported in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. TLS occurred in 11% of pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Antibody formation was reported in 3% of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 236) in clinical trials; antibody formation did not affect the clearance of inotuzumab ozogamicin. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. There were no reports of antibody formation in pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Infusion-related reactions were reported with inotuzumab ozogamicin therapy; symptoms may include fever, chills, rash (unspecified), or breathing problems. Premedicate patients with a corticosteroid, antipyretic, and antihistamine prior to each infusion and monitor patients closely during and for at least 1 hour after the end of infusion. Therapy interruption or permanent discontinuation may be necessary in patients who develop infusion-related reactions; initiate appropriate medical management as necessary including steroids and antihistamines. Grade 2 infusion-related reactions were reported in 2% of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (n = 164) in a randomized trial. Most reactions occurred in cycle 1 after the end of the infusion and resolved spontaneously or with medical intervention. Infusion-related reactions, including hypersensitivity, occurred in 8% of pediatric patients (age range, 1 to 17 years) with ALL who received inotuzumab ozogamicin in a clinical study (n = 53).
Fatal encephalopathy has been reported in pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Pain in extremity (19%; grade 3 or higher, 2%), back pain (6%), neck pain (6%), muscular weakness (6%), and pain (15%; grade 3 or higher, 2%) occurred in pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Edema occurred in 19% of pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Hypotension (6%; grade 3 or higher, 4%) and sinus tachycardia (6%; grade 3 or higher, 2%) occurred in pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Rash (19%; grade 3 or higher, 4%), pruritus (9%), and hyperhidrosis (6%) occurred in pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Cough (17%), dyspnea (8%; grade 3 or higher, 2%), and hypoxia (8%; grade 3 or higher, 4%) occurred in pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Weight gain occurred in 8% (grade 3 or higher, 2%) of pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Anxiety occurred in 6% of pediatric patients (age range, 1 to 17 years) with acute lymphoblastic leukemia who received inotuzumab ozogamicin in a clinical study (n = 53).
Severe or life-threatening hepatotoxicity including veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) has been reported with inotuzumab ozogamicin therapy. Additionally, adolescents and children who received inotuzumab ozogamicin had a higher incidence of elevated hepatic enzymes (increased AST/ALT levels, 21% vs. 4%) and hyperbilirubinemia (9% vs. 5%) compared with adult patients. Monitor liver function tests (LFTs) including total bilirubin and alkaline phosphatase levels prior to and following each inotuzumab ozogamicin dose. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop liver function test abnormalities. Closely monitor patients for signs and symptoms of VOD/SOS including hepatomegaly, rapid weight gain, and ascites. Permanently discontinue therapy in patients who develop VOD/SOS; treat according to standard medical practice. In patients who undergo a hematopoietic stem-cell transplant (HSCT), monitor LFTs frequently during the first month post-HSCT; thereafter, continue to monitor LFTs but less often. The median time from HSCT to onset of VOD/SOS was 15 days (range, 3 to 57 days). The risk of VOD/SOS may be greater in patients who receive a HSCT or a conditioning regimen that contains 2 alkylating agents prior to HSCT and in patients who have an increased total bilirubin level prior to a HSCT; other risk factors include hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis), a prior HSCT, increased age, later salvage lines, and a greater number of inotuzumab ozogamicin treatment cycles.
Patients who underwent a hematopoietic stem-cell transplant (HSCT) had a higher 100-day post-HSCT nonrelapse mortality rate following inotuzumab ozogamicin therapy compared with an investigator choice regimen (39% vs. 23%) in a randomized trial. Additionally, post-HSCT death occurred in 27% of 26 pediatric patients who received a HSCT after inotuzumab ozogamicin therapy in a clinical trial. Monitor patients closely for post-HSCT toxicity. The most common causes of post-HSCT death were veno-occlusive disease/sinusoidal obstruction syndrome and infectious complications.
Severe myelosuppression/bone marrow suppression (e.g., neutropenia, thrombocytopenia) have been reported with inotuzumab ozogamicin therapy. Monitor complete blood counts prior to each dose of inotuzumab ozogamicin. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe myelosuppression. Serious infection and bleeding have also occurred in patients who received inotuzumab ozogamicin; some cases were fatal. Monitor for signs and symptoms of infection and bleeding during therapy. Administer prophylactic anti-infective agents as appropriate.
QT prolongation has been reported with inotuzumab ozogamicin therapy. Obtain an electrocardiogram (ECG) and monitor serum electrolytes prior to the start of treatment and periodically during therapy as clinically indicated. Use inotuzumab ozogamicin with caution in patients with a history of QT prolongation. Avoid concomitant use with other medications known to prolong the QT interval; if coadministration is unavoidable, monitor ECGs and serum electrolytes during coadministration. Use inotuzumab ozogamicin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause an electrolyte imbalance. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Infusion-related reactions were reported with inotuzumab ozogamicin therapy; symptoms may include fever, chills, rash, or breathing problems. Premedicate patients with a corticosteroid, antipyretic, and antihistamine prior to each infusion and monitor patients closely during and for at least 1 hour after the end of infusion. Therapy interruption or permanent discontinuation may be necessary in patients who develop infusion-related reactions. Initiate medical management as necessary including steroids and antihistamines. Most reactions occurred in cycle 1 after the end of the infusion and resolved spontaneously or with medical intervention.
Inotuzumab ozogamicin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Patients of reproductive potential should avoid becoming pregnant while taking inotuzumab ozogamicin. Discuss the potential hazard to the fetus if inotuzumab ozogamicin is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including increased resorptions, fetal growth retardation, and delayed skeletal ossification were observed when inotuzumab ozogamicin was administered to pregnant rats during organogenesis at doses resulting in exposures of approximately 2-times the exposure in humans (at the maximum recommended dose). Additionally, fetal growth retardation occurred in at inotuzumab ozogamicin doses resulting in exposures approximately 0.4-times the exposure in humans.
Counsel patients about the reproductive risk and contraception requirements during inotuzumab ozogamicin treatment. Pregnancy testing prior to starting inotuzumab ozogamicin therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for 8 months after the last inotuzumab ozogamicin dose. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for 5 months after inotuzumab ozogamicin therapy. Based on information from animal studies, infertility may occur in females or males of reproductive potential.
It is not known if inotuzumab ozogamicin or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Because there is a potential for serious adverse reactions in nursing children from inotuzumab ozogamicin, patients should discontinue breast-feeding during inotuzumab ozogamicin therapy and for at least 2 months after the last dose.
For the treatment of acute lymphocytic leukemia (ALL):
-for the treatment of relapsed or refractory, CD22-positive, B-cell precursor ALL:
NOTE: Inotuzumab ozogamicin is designated as an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults: 0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15 on cycle 1. The length of cycle 1 is 21 days but may be extended to 28 days in patients who achieve a complete remission (CR) or a complete remission with incomplete hematologic recovery (CRi) or to allow for recovery from toxicity. In patients who do not achieve a CR or CRi, give inotuzumab ozogamicin at the same dosage (0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15) repeated every 28 days; discontinue treatment if a CR or CRi is not achieved after 3 cycles. In patients who achieve a CR or CRi, give inotuzumab ozogamicin 0.5 mg/m2 IV on days 1, 8, and 15 repeated every 28 days. In patients who proceed to hematopoietic stem cell transplant (HSCT), administer 2 cycles of therapy; consider a third cycle in patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles. Patients not proceeding to HSCT should receive a maximum of 6 cycles of therapy. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity. Premedicate patients with a corticosteroid, an antipyretic agent (e.g., acetaminophen), and an antihistamine prior to each inotuzumab ozogamicin dose. Administer cytoreduction therapy with a combination of hydroxyurea, steroids, and/or vincristine prior to giving the first dose of inotuzumab ozogamicin in patients with a peripheral blast count greater than 10,000 cells/mm3. The median progression-free survival time (5 months vs. 1.8 months; hazard ratio (HR) = 0.45; 97.5% CI, 0.34 to 0.61; p less than 0.001) was significantly improved with inotuzumab ozogamicin compared with standard therapy in patients with relapsed or refractory CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative ALL in an open-label, randomized, phase 3 trial (n = 326; the INO-VATE trial). In this study, 66% of patients had received 1 prior regimen (range, 1 to 3 regimens) for ALL; and 17% of patients had undergone a prior HSCT. The median overall survival time was significantly improved in the inotuzumab ozogamicin arm compared with the standard-therapy group (7.7 months vs. 6.2 months; HR = 0.75; 95% CI, 0.57 to 0.99) at a median follow-up time of 29.6 months (range, 1.7 to 49.7 months).
Children and Adolescents: 0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15 on cycle 1. The length of cycle 1 is 21 days but may be extended to 28 days in patients who achieve a complete remission (CR) or a complete remission with incomplete hematologic recovery (CRi) or to allow for recovery from toxicity. In patients who do not achieve a CR or CRi, give inotuzumab ozogamicin at the same dosage (0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15) repeated every 28 days; discontinue treatment if a CR or CRi is not achieved after 3 cycles. In patients who achieve a CR or CRi, give inotuzumab ozogamicin 0.5 mg/m2 IV on days 1, 8, and 15 repeated every 28 days. In patients who proceed to hematopoietic stem cell transplant (HSCT), administer 2 cycles of therapy; consider a third cycle in patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles. Patients not proceeding to HSCT should receive a maximum of 6 cycles of therapy. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity. Premedicate patients with a corticosteroid, an antipyretic agent (e.g., acetaminophen), and an antihistamine prior to each inotuzumab ozogamicin dose. Administer cytoreduction therapy with a combination of hydroxyurea, steroids, and/or vincristine prior to giving the first dose of inotuzumab ozogamicin in patients with a peripheral blast count greater than 10,000 cells/mm3. The complete response (CR) rate was 42% in 53 pediatric patients (median age, 9 years; range, 1 to 17 years) with relapsed or refractory CD22-positive, B-cell precursor ALL who received inotuzumab ozogamicin in a single-arm, phase 1b (ITCC-059) trial. The median duration of CR was 8.2 months. Additionally, 95.5% of patients who achieved a CR did not have minimal residual disease (MDR), evaluated using flow cytometry or polymerase chain reaction (PCR); the MRD negativity rate was 86.4% when evaluated with real-time quantitative reverse transcriptase PCR in patients who achieved a CR. Patients in this study received a median of 2 (range, 1 to 4) cycles of inotuzumab ozogamicin in combination with a modified UKALL-R3 regimen containing vincristine, dexamethasone, and intrathecal therapy.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
NOTE: Do not interrupt doses within a treatment cycle (i.e., day 8 or day 15 dose) for neutropenia or thrombocytopenia. Dosing interruptions within a cycle are recommended for nonhematologic toxicity. If a dose reduction is necessary, do not re-escalate the dose.
Hematologic Toxicity
Absolute neutrophil count (ANC) of 1 X 109 cells/L or greater prior to initiating inotuzumab ozogamicin therapy: if the ANC decreases, hold the next cycle of therapy until recovery of the ANC to 1 X 109 cells/L or greater. Discontinue therapy if low ANC lasts longer than 28 days and is suspected to be due to inotuzumab ozogamicin.
Platelet count of 50 X 109 cells/L or greater prior to initiating inotuzumab ozogamicin therapy: if platelet count decreases, hold the next cycle of therapy until the platelet count recovers to 50 X 109 cells/L or greater. Discontinue therapy if low platelet count lasts longer than 28 days and is suspected to be due to inotuzumab ozogamicin.
ANC was less than 1 X 109 cells/L and/or platelet count was less than 50 X 109 cells/L prior to initiating inotuzumab ozogamicin therapy: if the ANC or platelet count decreases, hold the next cycle of therapy until at least 1 of the following occurs:
-the ANC and platelet counts recover to at least baseline levels for the prior cycle
-the ANC recovers to 1 X 109 cells/L or greater and the platelet count recovers to 50 x 109 cells/L or greater
-the patient has stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease and not inotuzumab ozogamicin-related toxicity.
Infusion-Related Reactions
Mild to moderate reactions: hold the infusion and start appropriate medical management. Consider discontinuing the infusion or administer steroids and antihistamines depending on the severity of the reaction.
Severe or life-threatening reactions: stop the infusion and permanently discontinue therapy.
Nonhematologic Toxicity
Evaluate patients for toxicity prior to each dose. For grade 2 or higher toxicity, hold therapy until the toxicity recovers to grade 1 or less (or pretreatment grade level). Dose modifications depend on duration of dosing interruption as follows:
Less than 7 days (within a cycle): hold the next dose; maintain a minimum of 6 days between doses.
7 days or greater: omit the next dose within the cycle.
14 days or greater: after recovery, decrease the total dose by 25% for the subsequent cycle. If further dose modification is required, reduce the number of doses to 2 per cycle for subsequent cycles. If a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, permanently discontinue therapy.
Greater than 28 days: consider permanent discontinuation of therapy.
Maximum Dosage Limits:
-Adults
0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15.
-Geriatric
0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15.
-Adolescents
0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15.
-Children
0.8 mg/m2 IV on day 1 and 0.5 mg/m2 IV on days 8 and 15.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Treatment-Related Hepatotoxicity
Evaluate patients for toxicity prior to each dose. Dosing interruptions within a cycle are recommended for hepatic impairment. If a dose reduction is necessary, do not re-escalate the dose.
Total bilirubin level of 1.5-times the upper limit of normal (ULN) or less and AST/ALT level of 2.5-times the ULN or less: no dose adjustment is necessary.
Total bilirubin level greater than 1.5-times the ULN and AST/ALT level greater than 2.5-times the ULN: hold therapy until the total bilirubin level is 1.5-times the ULN or less and the AST/ALT level is 2.5-times the ULN or less unless hyperbilirubinemia is due to Gilbert's syndrome or hemolysis. Dose modifications depend on duration of dosing interruption as follows:
Less than 7 days (within a cycle): hold the next dose; maintain a minimum of 6 days between doses.
7 days or greater: omit the next dose within the cycle.
14 days or greater: after recovery, decrease the total dose by 25% for the subsequent cycle. If further dose modification is required, reduce the number of doses to 2 per cycle for subsequent cycles. If a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, permanently discontinue therapy.
Greater than 28 days: permanently discontinue therapy.
Hepatic Veno-Occlusive Disease (VOD)/Sinusoidal obstruction syndrome (SOS) or Other Severe Liver Toxicity
Permanently discontinue therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adagrasib: (Major) Concomitant use of adagrasib and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Alfuzosin: (Major) Avoid coadministration of inotuzumab ozogamicin with alfuzosin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Concomitant use of amiodarone and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of inotuzumab with amisulpride due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Amisulpride causes dose- and concentration- dependent QT prolongation. Inotuzumab has been associated with QT interval prolongation.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Anagrelide: (Major) Avoid coadministration of inotuzumab ozogamicin with anagrelide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Additionally, monitor patients for cardiovascular effects during concomitant therapy and evaluate as necessary. Inotuzumab has been associated with QT interval prolongation. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects taking anagrelide.
Apomorphine: (Major) Avoid coadministration of inotuzumab ozogamicin with apomorphine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Major) Avoid coadministration of inotuzumab ozogamicin with aripiprazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
Arsenic Trioxide: (Major) Avoid coadministration of inotuzumab ozogamicin with arsenic trioxide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. TdP, QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of inotuzumab ozogamicin with artemether; lumefantrine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Artemether; lumefantrine is also associated with QT interval prolongation.
Asenapine: (Major) Avoid coadministration of inotuzumab ozogamicin with asenapine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and asenapine have been associated with QT prolongation.
Atomoxetine: (Major) Avoid coadministration of inotuzumab ozogamicin with atomoxetine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
Azithromycin: (Major) Avoid coadministration of inotuzumab ozogamicin with azithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Avoid any non-essential QT prolonging drugs and correct electrolyte imbalances. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
Bedaquiline: (Major) Avoid coadministration of inotuzumab ozogamicin with bedaquiline due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during therapy (at least 2, 12, and 24 weeks after starting bedaquiline therapy). Inotuzumab has been associated with QT interval prolongation. Bedaquiline has also been reported to prolong the QT interval.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine: (Major) Avoid coadministration of inotuzumab ozogamicin with buprenorphine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Buprenorphine; Naloxone: (Major) Avoid coadministration of inotuzumab ozogamicin with buprenorphine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ceritinib: (Major) Avoid coadministration of inotuzumab ozogamicin with ceritinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Inotuzumab has been associated with QT interval prolongation. Concentration-dependent QT prolongation has been reported with ceritinib.
Chloroquine: (Major) Avoid coadministration of chloroquine with inotuzumab due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Inotuzumab has also been associated with QT interval prolongation.
Chlorpromazine: (Major) Avoid coadministration of inotuzumab ozogamicin with chlorpromazine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Coadministration of inotuzumab ozogamicin with cisapride is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
Citalopram: (Major) Avoid coadministration of inotuzumab ozogamicin with citalopram due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes at baseline, after treatment initiation, and periodically during therapy. Inotuzumab has been associated with QT interval prolongation. Citalopram causes dose-dependent QT interval prolongation.
Clarithromycin: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Clofazimine: (Major) Concomitant use of clofazimine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clozapine: (Major) Avoid coadministration of inotuzumab ozogamicin with clozapine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Codeine; Promethazine: (Major) Concomitant use of promethazine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Crizotinib: (Major) Avoid coadministration of inotuzumab ozogamicin with crizotinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Inotuzumab has been associated with QT interval prolongation. Crizotinib has also been associated with concentration-dependent QT prolongation.
Dasatinib: (Major) Avoid coadministration of inotuzumab ozogamicin with dasatinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of inotuzumab ozogamicin with degarelix due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desflurane: (Major) Avoid coadministration of inotuzumab ozogamicin with halogenated anesthetics due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, monitor the ECG and electrolytes. Inotuzumab has been associated with QT interval prolongation. Halogenated anesthetics can also prolong the QT interval.
Deutetrabenazine: (Major) Avoid coadministration of inotuzumab with deutetrabenazine due to the potential for additive QT interval prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of inotuzumab treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of inotuzumab ozogamicin with quinidine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Quinidine administration is also associated with QT prolongation and TdP.
Disopyramide: (Major) Avoid coadministration of inotuzumab ozogamicin with disopyramide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Disopyramide administration is associated with QT prolongation and TdP.
Dofetilide: (Major) Avoid coadministration of inotuzumab with dofetilide due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
Dolasetron: (Major) Avoid coadministration of inotuzumab ozogamicin with dolasetron due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an ECG.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) Avoid coadministration of inotuzumab ozogamicin with donepezil due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
Donepezil; Memantine: (Major) Avoid coadministration of inotuzumab ozogamicin with donepezil due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
Dronedarone: (Contraindicated) Coadministration of inotuzumab with dronedarone is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of inotuzumab ozogamicin with droperidol due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Additionally, initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Inotuzumab has been associated with QT interval prolongation. Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Efavirenz: (Major) Avoid coadministration of inotuzumab ozogamicin with efavirenz due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of inotuzumab ozogamicin with efavirenz due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of inotuzumab ozogamicin with efavirenz due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QTc prolongation has been observed with the use of efavirenz.
Eliglustat: (Major) Avoid coadministration of inotuzumab ozogamicin with eliglustat due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid coadministration of encorafenib and inotuzumab due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Inotuzumab has also been associated with QT interval prolongation.
Entrectinib: (Major) Avoid coadministration of inotuzumab with entrectinib due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Both entrectinib and inotuzumab have been associated with QT prolongation.
Eribulin: (Major) Avoid coadministration of inotuzumab ozogamicin with eribulin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment; closely monitor the patient for QT interval prolongation. Both inotuzumab and eribulin have been associated with QT prolongation.
Erythromycin: (Major) Avoid coadministration of inotuzumab ozogamicin with erythromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Erythromycin is associated with QT prolongation and TdP.
Escitalopram: (Major) Avoid coadministration of inotuzumab ozogamicin with escitalopram due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Escitalopram has been associated with a risk of QT prolongation and TdP.
Etrasimod: (Major) Concomitant use of etrasimod and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Fexinidazole: (Major) Concomitant use of fexinidazole and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Avoid coadministration of inotuzumab ozogamicin with fingolimod due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Specifically, overnight monitoring with continuous ECG in a medical facility is advised after the first fingolimod dose. Inotuzumab has been associated with QT interval prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of inotuzumab ozogamicin with flecainide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) Avoid coadministration of inotuzumab ozogamicin with fluconazole due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Fluoxetine: (Major) Avoid coadministration of inotuzumab ozogamicin with fluoxetine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been reported in patients treated with fluoxetine.
Fluphenazine: (Minor) Coadministration of inotuzumab ozogamicin with fluphenazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Fluphenazine is also associated with a possible risk for QT prolongation.
Fluvoxamine: (Major) Avoid coadministration of inotuzumab ozogamicin with fluvoxamine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Inotuzumab has been associated with QT prolongation. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment.
Foscarnet: (Major) Avoid coadministration of inotuzumab ozogamicin with foscarnet due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet.
Fostemsavir: (Major) Avoid coadministration of inotuzumab with fostemsavir due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of inotuzumab ozogamicin with gemifloxacin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Gemifloxacin may prolong the QT interval in some patients. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gilteritinib: (Major) Avoid coadministration of inotuzumab with gilteritinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with inotuzumab due to the potential for additive QT prolongation. If coadministration cannot be avoided, obtain ECGs prior to the start of treatment and increase the frequency of ECG monitoring during concurrent use. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Inotuzumab has also been associated with QT interval prolongation.
Goserelin: (Major) Avoid coadministration of inotuzumab with goserelin due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of inotuzumab ozogamicin with granisetron due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes at baseline, after treatment initiation, and periodically during therapy as clinically indicated. Both inotuzumab and granisetron have been associated with QT prolongation.
Halogenated Anesthetics: (Major) Avoid coadministration of inotuzumab ozogamicin with halogenated anesthetics due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, monitor the ECG and electrolytes. Inotuzumab has been associated with QT interval prolongation. Halogenated anesthetics can also prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of inotuzumab ozogamicin with haloperidol due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of inotuzumab with histrelin due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of inotuzumab and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of inotuzumab and hydroxyzine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibutilide: (Major) Avoid coadministration of inotuzumab ozogamicin with ibutilide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Iloperidone: (Major) Avoid coadministration of inotuzumab ozogamicin with iloperidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and iloperidone have been associated with QT prolongation.
Isoflurane: (Major) Avoid coadministration of inotuzumab ozogamicin with halogenated anesthetics due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, monitor the ECG and electrolytes. Inotuzumab has been associated with QT interval prolongation. Halogenated anesthetics can also prolong the QT interval.
Itraconazole: (Major) Avoid coadministration of inotuzumab ozogamicin with itraconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and itraconazole have been associated with QT prolongation.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with inotuzumab due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Inotuzumab has been associated with QT interval prolongation.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and inotuzumab due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Lapatinib: (Major) Avoid coadministration of inotuzumab with lapatinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment; also monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Inotuzumab has been associated with QT interval prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with inotuzumab as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG before and during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Inotuzumab has been associated with QT interval prolongation.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with inotuzumab due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Inotuzumab has also been associated with QT interval prolongation.
Leuprolide: (Major) Avoid coadministration of inotuzumab with leuprolide due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., leuprolide ) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of inotuzumab with leuprolide due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., leuprolide ) may prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of levofloxacin and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and inotuzumab due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lithium: (Major) Avoid coadministration of inotuzumab ozogamicin with lithium due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and lithium have been associated with QT interval prolongation.
Lofexidine: (Major) Avoid coadministration of lofexidine and inotuzumab due to the potential for additive QT prolongation. If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Inotuzumab has been associated with QT interval prolongation.
Loperamide: (Major) Avoid coadministration of inotuzumab ozogamicin with loperamide due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of inotuzumab ozogamicin with loperamide due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with inotuzumab due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as inotuzumab. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Inotuzumab has been associated with QT interval prolongation.
Maprotiline: (Major) Avoid coadministration of inotuzumab ozogamicin with maprotiline due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Mefloquine: (Major) Avoid coadministration of inotuzumab ozogamicin with mefloquine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Methadone: (Major) Avoid coadministration of inotuzumab ozogamicin with methadone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) Concomitant use of metronidazole and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) Avoid coadministration of inotuzumab ozogamicin with midostaurin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and midostaurin have been associated with QT prolongation.
Mifepristone: (Major) Concomitant use of inotuzumab and mifepristone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirtazapine: (Major) Concomitant use of inotuzumab and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mobocertinib: (Major) Concomitant use of mobocertinib and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Avoid coadministration of inotuzumab ozogamicin with moxifloxacin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and moxifloxacin have been associated with QT prolongation. Although extremely rare, TdP has also been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nilotinib: (Major) Avoid coadministration of inotuzumab ozogamicin with nilotinib due to the potential for additive QT prolongation and risk of torsade de pointes. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment; closely monitor for evidence of QT prolongation during concurrent use. Inotuzumab has been associated with QT interval prolongation. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy.
Ofloxacin: (Major) Concomitant use of ofloxacin and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of inotuzumab ozogamicin with fluoxetine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) Concomitant use of ondansetron and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Avoid coadministration of inotuzumab with osilodrostat due to the potential for additive QT prolongation. If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of inotuzumab with osimertinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment; monitor electrolytes. An interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Inotuzumab has been associated with QT interval prolongation, and concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Avoid coadministration of inotuzumab ozogamicin with oxaliplatin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Correct electrolyte abnormalities prior to treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and ventricular arrhythmias including, fatal TdP, have been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) Avoid coadministration of inotuzumab with ozanimod due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Pacritinib: (Major) Concomitant use of pacritinib and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of inotuzumab ozogamicin with paliperidone if possible due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Both inotuzumab and paliperidone have been associated with QT interval prolongation; TdP and ventricular fibrillation have been reported in the setting of paliperidone overdose. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Close monitoring is essential for patients with known risk factors for cardiac disease or arrhythmias.
Panobinostat: (Major) Avoid coadministration of inotuzumab ozogamicin with panobinostat due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and panobinostat have been associated with QT interval prolongation.
Pasireotide: (Major) Avoid coadministration of inotuzumab ozogamicin with pasireotide due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of inotuzumab ozogamicin with pazopanib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and pazopanib have been associated with QT interval prolongation.
Pentamidine: (Major) Avoid coadministration of inotuzumab ozogamicin with pentamidine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Systemic pentamidine has also been associated with QT prolongation.
Perphenazine: (Minor) Coadministration of inotuzumab ozogamicin with perphenazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Perphenazine is also associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Coadministration of inotuzumab ozogamicin with perphenazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Perphenazine is also associated with a possible risk for QT prolongation.
Pimavanserin: (Major) Avoid coadministration of inotuzumab ozogamicin with pimavanserin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Coadministration of inotuzumab ozogamicin with pimozide is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Inotuzumab has also been associated with QT interval prolongation.
Pitolisant: (Major) Avoid coadministration of inotuzumab with pitolisant due to the potential for additive QT prolongation and torsade de pointes. If coadministration cannot be avoided, monitor ECG before and during treatment. Inotuzumab has been associated with QT interval prolongation. Pitolisant also prolongs the QT interval.
Ponesimod: (Major) Avoid coadministration of inotuzumab and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment and monitor for signs and symptoms of infection. Inotuzumab has been associated with QT interval prolongation. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Major) Avoid coadministration of inotuzumab ozogamicin with posaconazole in due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Posaconazole has also been associated with QT interval prolongation as well as rare cases of TdP.
Primaquine: (Major) Avoid coadministration of inotuzumab ozogamicin with primaquine in due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and primaquine have been associated with QT interval prolongation.
Procainamide: (Major) Avoid coadministration of inotuzumab ozogamicin with procainamide due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Procainamide is associated with a well-established risk of QT prolongation and TdP.
Prochlorperazine: (Minor) Coadministration of inotuzumab ozogamicin with prochlorperazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation.
Promethazine: (Major) Concomitant use of promethazine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quetiapine: (Major) Concomitant use of quetiapine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) Avoid coadministration of inotuzumab ozogamicin with quinidine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Quinidine administration is also associated with QT prolongation and TdP.
Quinine: (Major) Avoid coadministration of inotuzumab ozogamicin with quinine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Quinine has been associated with QT prolongation and rare cases of TdP.
Quizartinib: (Major) Concomitant use of quizartinib and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Avoid coadministration of inotuzumab ozogamicin with ranolazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) Avoid coadministration of inotuzumab with relugolix due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of inotuzumab with relugolix due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Ribociclib: (Major) Avoid coadministration of inotuzumab ozogamicin with ribociclib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
Ribociclib; Letrozole: (Major) Avoid coadministration of inotuzumab ozogamicin with ribociclib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
Rilpivirine: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) Avoid coadministration of inotuzumab ozogamicin with risperidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Romidepsin: (Major) Avoid coadministration of inotuzumab ozogamicin with romidepsin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Romidepsin has also been reported to prolong the QT interval.
Saquinavir: (Major) Avoid coadministration of inotuzumab ozogamicin with saquinavir due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Avoid coadministration of inotuzumab with selpercatinib due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of sertraline and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of inotuzumab ozogamicin with halogenated anesthetics due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, monitor the ECG and electrolytes. Inotuzumab has been associated with QT interval prolongation. Halogenated anesthetics can also prolong the QT interval.
Siponimod: (Major) Avoid coadministration of siponimod and inotuzumab due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Iloperidone has been associated with QT prolongation. Inotuzumab has been associated with QT interval prolongation.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of inotuzumab ozogamicin with solifenacin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has also been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with inotuzumab due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT interval prolongation.
Sotalol: (Major) Concomitant use of sotalol and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sunitinib: (Major) Avoid coadministration of inotuzumab with sunitinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Sunitinib can also cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including TdP.
Tacrolimus: (Major) Avoid coadministration of inotuzumab ozogamicin with tacrolimus due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and tacrolimus have been associated with QT interval prolongation.
Tamoxifen: (Major) Concomitant use of tamoxifen and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Avoid coadministration of inotuzumab ozogamicin with telavancin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and telavancin have been associated with QT interval prolongation.
Tetrabenazine: (Major) Avoid coadministration of inotuzumab ozogamicin with tetrabenazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Coadministration of inotuzumab ozogamicin with thioridazine is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. Inotuzumab has also been associated with QT interval prolongation.
Tolterodine: (Major) Avoid coadministration of inotuzumab ozogamicin with tolterodine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of inotuzumab ozogamicin with toremifene due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and closely monitor during treatment. Correct hypokalemia or hypomagnesemia prior to administration of toremifene. Inotuzumab has been associated with QT interval prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trazodone: (Major) Concomitant use of trazodone and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Coadministration of inotuzumab ozogamicin with trifluoperazine may increase the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Trifluoperazine is also associated with a possible risk for QT prolongation.
Triptorelin: (Major) Avoid coadministration of inotuzumab with triptorelin due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vandetanib: (Major) Avoid coadministration of vandetanib with inotuzumab due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and electrolytes at baseline and periodically during treatment; correct any electrolyte abnormalities. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Inotuzumab has also been associated with QT interval prolongation.
Vardenafil: (Major) Concomitant use of vardenafil and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid coadministration of inotuzumab ozogamicin with vemurafenib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and vemurafenib have been associated with QT interval prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voclosporin: (Major) Avoid concomitant use of inotuzumab and voclosporin due to the risk of additive QT prolongation. If concomitant use is necessary, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Voriconazole: (Major) Avoid coadministration of inotuzumab ozogamicin with voriconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Vorinostat: (Major) Avoid coadministration of inotuzumab ozogamicin with vorinostat due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and vorinostat have been associated with QT interval prolongation.
Ziprasidone: (Major) Avoid coadministration of inotuzumab ozogamicin with ziprasidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP.
Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate. CD22 is expressed on pre-B-cells and mature B-cells. Inotuzumab ozogamicin consists of a cytotoxic agent, N-acetyl-gamma-calicheamicin, covalently linked to a humanized anti-CD22 IgG4 monoclonal antibody. N-acetyl-gamma-calicheamicin is a natural product of Micromonospora echinospora; it induces double-strand DNA breaks resulting in cell cycle arrest and apoptotic cell death. Inotuzumab ozogamicin binds to CD22-expressing tumor cells where it becomes internalized in the B-cell and N-acetyl-gamma-calicheamicin dimethylhydrazide is released via hydrolytic cleavage of the link.
Inotuzumab ozogamicin is administered intravenously. Its volume of distribution is approximately 12 L. N-acetyl-gamma-calicheamicin dimethylhydrazide, the cytotoxic component of inotuzumab ozogamicin, is about 97% bound to human plasma proteins in vitro. The steady-state clearance was 0.0333 L/hour and the terminal half-life was 12.3 days in 234 patients with relapsed or refractory acute lymphoblastic leukemia who received inotuzumab ozogamicin in clinical trials. N-acetyl-gamma- calicheamicin is metabolized by nonenzymatic reduction in vitro; serum levels were usually below the limit of detection in humans.
Affected cytochrome P450 isoenzymes and transporters: P-gp
N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-gp.
-Route-Specific Pharmacokinetics
Intravenous Route
The mean Cmax and AUC values were 308 ng/mL and 100,000 ng X hour/mL respectively, in patients with relapsed or refractory acute lymphoblastic leukemia who received Inotuzumab; the steady-state drug concentration was achieved by cycle 4. Additionally, a 5.3-times accumulation of inotuzumab ozogamicin was predicted by cycle 4.
-Special Populations
Hepatic Impairment
The inotuzumab ozogamicin clearance was similar in 150 patients with mild hepatic impairment (defined as a total bilirubin level of the upper limit of normal (ULN) or less and an AST level greater than the ULN OR a total bilirubin level greater than 1- to 1.5-times the ULN and any AST level) compared with 611 patients with normal hepatic function. There is insufficient pharmacokinetic data in patients with moderate and severe hepatic impairment (defined as a total bilirubin level greater than 1.5-times the ULN).
Renal Impairment
The inotuzumab ozogamicin clearance values were similar in patients with mild (n = 237; creatinine clearance (CrCl), 60 to 89 mL/min), moderate (n = 122; CrCl, 30 to 59 mL/min), and severe (n = 4; CrCl, 15 to 29 mL/min) renal impairment compared with 402 patients with normal renal function. The safety and efficacy of inotuzumab ozogamicin have not been established in patients with end stage renal disease with or without hemodialysis.
Pediatrics
At the recommended dosage, the AUC value of inotuzumab ozogamicin was increased by approximately 30% in pediatric patients 1 year and older compared with adults.
Geriatric
Age (range, 18 to 92 years) had no clinically significant impact on the pharmacokinetic (PK) parameters of inotuzumab ozogamicin in a population PK analysis.
Gender Differences
Gender had no clinically significant impact on the pharmacokinetic (PK) parameters of inotuzumab ozogamicin in a population PK analysis.
Ethnic Differences
Ethnicity had no clinically significant impact on the pharmacokinetic (PK) parameters of inotuzumab ozogamicin in a population PK analysis.
Obesity
Body surface area (BSA) does significantly affect the disposition of inotuzumab ozogamicin; therefore, drug dosing is based on BSA.