Drug information of Inotuzumab‎

Mechanism of effect

Inotuzumab ozogamicin is comprised of cytotoxic antibiotic N-acetyl-gamma-calicheamicin dimethylhydrazide attached to a humanized monoclonal IgG4 antibody via 4-(4 acetylphenoxy) butanoic acid (acetyl butyrate) linker. The drug exerts a potent cytotoxic effect against CD22+ B-cell lymphoma when the antibody binds to the CD22 receptor on the surface of B cells .

The drug-CD22 complex is rapidly internalized into the cell, forming an endosome which subsequently fuses with lysosomes. N-acetyl-gamma-calicheamicin dimethylhydrazide is then intracellularly released into the acidic environment. N-acetyl-gamma-calicheamicin dimethylhydrazide is a calicheamicin derivative, which is naturally produced by the bacterium Micromonospora echinospora, and is toxic to the body when not bound to the antibody.

 It mediates apoptosis of the cell by binding to the minor groove of DNA in a sequence-specific manner and undergoing a structural change to generate diradicals . These changes abstract hydrogen ions from the phosphodiester bonds of double-stranded DNA, resulting in breaks and cell apoptosis.

Pharmacodynamic

Inotuzumab ozogamicin is an antineoplastic agent that targets CD22 antigen expressed on immature B-cell lymphocytes and blocks further growth of tumor cells. The drug aims to restore normal blood counts and achieve complete remission from the disease. QT interval prolongation was observed in patients receiving inotuzumab ozogamicin.

Pharmacokinetics

• Peak plasma concentration: 308 ng/mL
• AUC: 100,000 ng·h/mL
• Steady-state drug concentration was achieved by cycle 4
• Protein bound: 97%
• Vd: ~12 L
• Metabolism: N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction
• Clearance, steady state: 0.0333 L/h
• Half-life: 12.3 days

Dosage

Adult

Acute Lymphoblastic Leukemia

Cycle 1 for all patients

• Total dose of inotuzumab: 1.8 mg/m² per 21-day cycle, administered as 3 divided doses
• Day 1: 0.8 mg/m²
• Day 8 and 15: 0.5 mg/m²
• Duration of cycle 1 is 21 days; may extend to 28 days (eg, 7-day treatment-free interval starting on day 21) if patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity
• CR is defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 10^9/L and absolute neutrophil counts [ANC] ≥ 1 × 10^9/L) and resolution of any extramedullary disease
• CRi is defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 10^9/L and/or ANC < 1 × 10^9/L) and resolution of any extramedullary disease

Patients who achieve a CR or CRi

• Total dose of inotuzumab is 1.5 mg/m² per 28-day cycle, including a 7-day treatment-free interval starting on day 21, administered as 3 divided doses
• Day 1, 8, and 15: 0.5 mg/m² IV

Patients who do not achieve a CR or CRi

• Total dose of inotuzumab is 1.8 mg/m² per 28-day cycle, including a 7-day treatment-free interval starting on day 21 administered as 3 divided doses
• Day 1: 0.8 mg/m² IV
• Day 8 and 15: 0.5 mg/m² IV
• Patients who do not achieve a CR or CRi ≤3 cycles should discontinue treatment

Pediatric

Safety and efficacy not established

Side effects

anemia , Infection , Diarrhea , Headache , nausea , vomiting , fever , hemorrhage , Hyperbilirubinemia , tiredness , Abdominal pain , Leukopenia , thrombocytopenia , Febrile Neutropenia

Interactions

formoterol , Dolasetron , vandetanib , Chloroquine , sparfloxacin , Procainamide , Dofetilide , Amiodarone , Erythromycin , Ofloxacin , Ondansetron , Propafenone , Pimozide , Arsenic trioxide , Artemether , lumefantrine , Lopinavir , Telithromycin , Droperidol , chlorpropamide , Goserelin , Anagrelide , Ranolazine , Pentamidine , Quetiapine , Quinidine , Histrelin , Apomorphine , Voriconazole , Clarithromycin , Chlorpromazine , Chloroquine phosphate , Clozapine , Flecainide , Granisetron , Levofloxacin , Methadone , Moxifloxacin , Nilotinib , Haloperidol , Sorafenib , Ciprofloxacin , Citalopram , Cisapride , Fluconazole , Fingolimod , Tetrabenazine , Trazodone , Triptorelin , Thioridazine , Gemifloxacin , Sotalol , Halofantrine , Grepafloxacin , Arformoterol , Alfuzosin , Paliperidone , Pazopanib , Pimavanserin , lenvatinib , Crizotinib , Entrectinib , Bepridil , bedaquiline , Gemtuzumab , Remdesivir , vemurafenib , Meningococcal conjugate vaccine , alirocumab , Halaven

Alerts

Liver problems have happened with inotuzumab ozogamicin. Sometimes, this has been life-threatening or deadly. The chance of liver problems is higher in people who had a stem cell transplant after treatment with inotuzumab ozogamicin. It is also higher in people who have already had liver problems, who have had more treatments with inotuzumab ozogamicin, and in older patients.

Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Points of recommendation

• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will need an ECG before starting inotuzumab ozogamicin. You may also need to have an ECG while using inotuzumab ozogamicin. Talk with your doctor.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 5 months after care ends. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant within 5 months after your care has ended, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting inotuzumab ozogamicin. Talk with your doctor.
• Use birth control that you can trust to prevent pregnancy while taking inotuzumab ozogamicin and for 8 months after your last dose.
• If you get pregnant while taking inotuzumab ozogamicin or within 8 months after your last dose, call your doctor right away.

Pregnancy level

HAVE NOT BEEN ESTABLISHED

Related drugs

Blinatumomab , Gemtuzumab