Gemtuzumab

Indications

Gemtuzumab is used for: Acute Myeloid Leukemia

Adult Dose

Acute Myeloid Leukemia Newly Diagnosed CD33-positive AML Indicated for newly diagnosed CD33-positive AML in adults Combination Regimen Induction cycle: 3 mg/m² IV (up to one 4.5-mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine For patients requiring a second induction cycle, do not administer gemtuzumab during second induction cycle Consolidation: 3 mg/m² IV on Day 1 (up to one 4.5-mg vial) in combination with daunorubicin and cytarabine Monotherapy Treatment course consists of 1 cycle of induction and up to 8 cycles of continuation therapy Induction: 6 mg/m² IV on Day 1, and 3 mg/m² on Day 8 Continuation therapy: 2 mg/m² IV on Day 1 q4weeks Relapsed or Refractory CD33-positive AML Indicated for relapsed/refractory CD33-positive AML in adults 3 mg/m² on Days 1, 4, and 7 for 1 cycle Hepatic impairment Mild (total bilirubin <1.5X ULN): No dosage adjustment necessary Moderate (total bilirubin >1.5-3.0X ULN) or severe (total bilirubin >3X ULN): Unknown Total bilirubin >2X ULN, or AST and/or ALT >2.5X ULN Hold treatment until total bilirubin to <2X ULN and AST/ALT to <2.5X ULN prior to each dose Omit scheduled dose if delayed >2 days between sequential infusions

Child Dose

Acute Myeloid Leukemia (AML) Indicated for relapsed/refractory CD33-positive AML in adults and children aged ?2 years <2 years: Safety and efficacy not established >2 years: 3 mg/m² IV on Days 1, 4, and 7 for 1 cycle

Renal Dose

Administration

IV Preparation Cytotoxic drug; follow applicable special handling and disposal procedures Reconstitution Calculate dose in mg and determine number of vials required Before reconstitution, allow vials to reach ambient temperature for ~5 minutes Reconstitute each vial with 5 mL sterile water for injection to obtain a concentration of 1 mg/mL (each vial delivers 4.5 mL [4.5 mg]) Do not shake; gently swirl vial to aid dissolution Inspect reconstituted solution for particulates and discoloration Reconstituted solution may contain small white to off-white, opaque-to-translucent, and amorphous to fiber like particles Contains no bacteriostatic preservatives Use solution immediately to further dilute or refrigerate (see Storage) Further dilution required Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area Withdraw this amount from the vial(s) using a syringe; discard unused reconstituted solution Remove a volume of 0.9% NaCl from the prefilled bag equal to the volume of product (mL) calculated above Add the reconstituted solution to infusion container with 0.9% NaCl to make a total volume of 50 mL or 100 mL, depending on dose Do not shake; gently invert infusion container to mix diluted solution See storage information listed below if not used immediately IV Administration Must use an in-line 0.2 micron polyethersulfone (PES) filter for infusion Protect IV bag from light using a light-blocking cover during infusion; the infusion line does not need to be protected from light Infuse diluted solution IV over 2 hr Do not mix or coadminister gemtuzumab with other medicinal products

Contra Indications

Hypersensitivity to the active substance in gemtuzumab or any of its components or to any of the excipients

Precautions

Hepatotoxicity, including severe or fatal VOD also known as SOS, has been reported; see Black Box Warnings For patients being treated with gemtuzumab in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available consider whether the potential benefit of continuing treatment outweighs the risks for the individual patient Animal data report gemtuzumab may cause embryo-fetal harm when administered to pregnant women; see Pregnancy Lactation No data on the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production Owing to potential for adverse reactions in breastfed infants, women should not breastfeed during treatment and for at least 1 month after the final dose

Pregnancy-Lactation

Pregnancy Based on animal data, gemtuzumab can cause embryo-fetal harm when administered to a pregnant woman No available data on gemtuzumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage In rat embryo-fetal development studies, gemtuzumab ozogamicin caused embryofetal toxicity at maternal systemic exposures that ?0.4 times the exposure in patients at the maximum recommended dose, based on AUC For patients who are pregnant, or become pregnant during treatment, advise the patient of the potential risk to a fetus Verify the pregnancy status of females of reproductive potential prior to initiating treatment Gemtuzumab may impair fertility in male or females of reproductive potential Contraception Advise females of reproductive potential to avoid becoming pregnant while receiving gemtuzumab Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after last dose Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after last dose Lactation No data on the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production Owing to potential for adverse reactions in breastfed infants, women should not breastfeed during treatment and for at least 1 month after the final dose

Interactions

Adverse Effects

Side effects of Gemtuzumab : >10% (Newly diagnosed plus Daunorubicin and Cytarabine) Hypophosphatemia, grade 3 or higher (64%) Hypokalemia, grade 3 or higher (57%) Infection, grade 3 or higher (47-55%) Hyponatremia, grade 3 or higher (44%) Prolonged thrombocytopenia (19-35%) Hemorrhage, grade 3 or higher (5-18%) AST increased, grade 3 or higher (14%) Alkaline phosphatase increased, grade 3 or higher (13%) >10% (Monotherapy for Relapsed) Fever, all grades (79%) Infection, all grades (42%) Increased AST, all grades (40%) Bleeding, all grades (23%) Nausea and vomiting, all grades (21%) Constipation, all grades (21%) Mucositis, all grades (21%) Headache, all grades (19%) Increased ALT, all grades (16%) Rash, all grades (16%) Sepsis, grade 3 (32%) Fever, grade 3 (16%) Rash, grade 3 (11%) 1-10% (Newly diagnosed plus Daunorubicin and Cytarabine) ALT increased, grade 3 or higher (10%) Blood bilirubin increased, grade 3 or higher (8%) Prolonged neutropenia (2-3%) Veno-occlusive disease, grade 3 or higher (2%) 1-10% (Monotherapy for Relapsed) Hyperbilirubinemia (7%) Pneumonia, grade 3 (7%) Bleeding, grade 3 (7%) Mucositis, grade 3 (4%) Pain, grade 3 (4%) Diarrhea, grade 3 (2%) Headaches, grade 3 (2%) Tachycardia, grade 3 (2%) Lung edema, grade 3 (2%)

Mechanism of Action

CD33-directed antibody-drug conjugate (ADC); the antibody portion (hP67.6) recognizes human CD33 antigen and the small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker Nonclinical data suggest that the anticancer activity results from ADC binding to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex, and intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death