Class: Antineoplastic Agents
Chemical Name: Methyl [(1R,4Z,8S,13E)-[8-[[2-O-[4-(acetylethylamino)-2,4-dideoxy-3-O-methyl-α-L-threo-pentopyranosyl]-4,6-dideoxy-4-[[[2,6-dideoxy-4-S-[4-[6-deoxy-3-O-methyl-α-L-mannopyranosyl)oxy]-3-iodo-5,6-dimethoxy-2-methylbenzoyl]-4-thio-β-D-ribo-hexopyranosyl]oxy]amino]-β-D-glucopyranosyl]oxy]-13-[2-[[3-[[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazino]-1,1-dimethyl-3-oxopropyl]-dithio]ethylidene]-1-hydroxy-11-oxobicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-10-yl]carbamate conjugate dimer disulfide with human-mouse monoclonal hP67.6 κ-chain anti-(human CD33 (antigen)) (human-mouse monoclonal hP67.6 γ4-chain, immunoglobulin G4
CAS Number: 220578-59-6
Risk of hepatotoxicity, including hepatic veno-occlusive disease (VOD; also known as sinusoidal obstruction syndrome); may be life-threatening or fatal. (See Hepatotoxicity under Cautions.)
Reported in patients receiving the drug as monotherapy or as part of a combination chemotherapy regimen.
Monitor frequently for manifestations of hepatic VOD.
Antineoplastic agent; CD33-directed antibody-drug conjugate consisting of an anti-CD33 monoclonal antibody covalently linked to a cytotoxic calicheamicin derivative (N-acetyl-γ-calicheamicin).
Uses for Gemtuzumab
Acute Myeloid Leukemia (AML)
Used in combination with daunorubicin and cytarabine for induction and consolidation therapy in adults with newly diagnosed CD33-positive de novo AML. Subgroup analysis suggests possible lack of clinical benefit in patients with unfavorable cytogenetics. (See Decreased Efficacy in Patients with Unfavorable Cytogenetics under Cautions.)
Used alone (i.e., as single agent) for induction and continuation therapy in adults with newly diagnosed CD33-positive AML.
Used as single-agent therapy for relapsed or refractory CD33-positive AML in adults and children ≥2 years of age.
Designated an orphan drug by FDA for treatment of AML.
Gemtuzumab Dosage and Administration
To minimize risk of infusion-related reactions in adults, premedicate with acetaminophen 650 mg and diphenhydramine hydrochloride 50 mg 1 hour prior to each infusion, followed by methylprednisolone 1 mg/kg (or equivalent) within 30 minutes prior to infusion. (See Infusion-related Effects under Cautions.)
To minimize risk of infusion-related reactions in pediatric patients, premedicate with acetaminophen 15 mg/kg (up to maximum dose of 650 mg), diphenhydramine hydrochloride 1 mg/kg (up to maximum dose of 50 mg), and methylprednisolone 1 mg/kg (or equivalent) 1 hour prior to each infusion; may administer additional doses of acetaminophen and diphenhydramine hydrochloride every 4 hours.
If WBC counts ≥30,000/mm3, cytoreduction prior to administration is recommended.
Take appropriate measures to prevent tumor lysis syndrome.
Consult specialized references for procedures for proper handling and disposal of antineoplastics.
For solution compatibility information, see Compatibility under Stability.
Administer by IV infusion using a 0.2-μm polyethersulfone inline filter.
Must reconstitute powder for injection and dilute to an appropriate concentration prior to administration.
Do not admix with or infuse simultaneously through the same IV line with other drugs.
Protect drug from light during storage and administration; only the infusion container (syringe or bag) must be protected from light during infusion.
Vials are intended for single use only; discard any partially used vials.
Prior to reconstitution, allow vials to stand at room temperature for approximately 5 minutes.
Reconstitute vial containing 4.5 mg of gemtuzumab ozogamicin with 5 mL of sterile water for injection to provide a solution containing 1 mg/mL. Gently swirl vial to dissolve powder. Do not shake.
Reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particulates.
If not used immediately, may store reconstituted drug according to manufacturer's storage instructions. (See Storage under Stability.)
Withdraw appropriate volume of reconstituted solution and dilute to final concentration of 0.075–0.234 mg/mL prior to IV infusion.
Prepare final diluted solution in a syringe or IV bag depending on dose. For doses ≥3.9 mg, may prepare in either a syringe or infusion bag; for doses <3.9 mg, must prepare in a syringe to reduce potential for drug adsorption.
Gently invert infusion container to mix solution; do not shake.
Immediate administration recommended. If not used immediately, may store infusion solution according to manufacturer's storage instructions. (See Storage under Stability.) If diluted solution was previously refrigerated, bring to room temperature for 1 hour prior to administration.
Rate of Administration
Administer by IV infusion over 2 hours.
Relapsed or Refractory CD33-Positive AML
Treatment consists of a single course of therapy.
Pediatric patients ≥2 years of age: 3 mg/m2 (up to a maximum dose of 4.5 mg) on days 1, 4, and 7 for one cycle.
Dosage Modification for Toxicity
Follow recommendations for dosage modification in adults.
Combination Therapy for Newly Diagnosed CD33-positive AML
Full treatment course consists of 1–2 cycles of induction therapy and 2 cycles of consolidation therapy.
3 mg/m2 (up to maximum dose of 4.5 mg) on days 1, 4, and 7 in combination with daunorubicin and cytarabine.
If complete remission not achieved, may consider a second induction cycle consisting of only daunorubicin and cytarabine.
3 mg/m2 (up to maximum dose of 4.5 mg) on day 1 in combination with daunorubicin and cytarabine for 2 cycles.
Administer consolidation therapy 14 days after CBCs recover from previous cycle.
If platelet counts do not recover to ≥100,000/mm3 and ANC counts do not recover to >500/mm3 within 14 days after the planned start date of consolidation therapy, omit gemtuzumab ozogamicin from consolidation cycles.
Single-agent Therapy for Newly Diagnosed CD33-positive AML
Full treatment course consists of 1 cycle of induction therapy and up to 8 cycles of continuation therapy.
6 mg/m2 on day 1 followed by 3 mg/m2 on day 8.
2 mg/m2 on day 1 of each 4-week cycle, up to 8 cycles.
Single-agent Therapy for Relapsed or Refractory CD33-positive AML
Treatment consists of a single course of therapy.
3 mg/m2 (up to a maximum dose of 4.5 mg) on days 1, 4, and 7 for one cycle.
Dosage Modification for Toxicity
If treatment-related toxicities occur, monitor CBCs and blood chemistries at least 3 times per week until resolution of the toxicity.
If thrombocytopenia or neutropenia occurs in patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine, discontinuance of gemtuzumab ozogamicin during consolidation therapy may be necessary. (See Combination Therapy for Newly Diagnosed CD33-positive AML under Dosage and Administration.)
If serum ALT and/or AST concentrations increase to >2.5 times the ULN or total bilirubin concentrations >2 times the ULN, interrupt therapy until ALT and AST recover to ≤2.5 times the ULN and total bilirubin concentrations recover to ≤2 times the ULN. If therapy is withheld for >2 days between sequential doses, omit scheduled dose.
If hepatic VOD or other severe hepatotoxicity occurs, discontinue therapy.
If infusion-related reactions occur, interrupt infusion and institute appropriate treatment (e.g., acetaminophen, diphenhydramine, and/or methylprednisolone) and supportive care.
Upon resolution of a mild or moderate infusion-related reaction, may resume infusion but consider reducing infusion rate by at least 50%. If the infusion-related reaction recurs, interrupt infusion again and follow same recommendations.
If a severe or life-threatening infusion-related reaction (i.e., anaphylaxis, severe respiratory symptoms, clinically important hypotension) occurs, permanently discontinue therapy.
Other Nonhematologic ToxicityIV
If other severe or life-threatening nonhematologic toxicity occurs, interrupt therapy until toxicity improves to no more than mild in severity. If therapy is withheld for >2 days between sequential doses, omit scheduled dose.
Relapsed or Refractory CD33-positive AML
Pediatric patients ≥2 years of age: Maximum dose of 4.5 mg.
Newly Diagnosed CD33-positive AML
Combination therapy with daunorubicin and cytarabine: Maximum dose of 4.5 mg.
Relapsed or Refractory CD33-positive AML
Maximum dose of 4.5 mg.
No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)
No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)
No special dosage recommendations at this time. (See Geriatric Use under Cautions.)
Cautions for Gemtuzumab
Known hypersensitivity to gemtuzumab ozogamicin or any ingredient in the formulation.
Hepatotoxicity, including life-threatening or fatal hepatic VOD, reported. (See Boxed Warning.) Median time to onset 9 days (range: 2–298 days); generally occurs within 28 days following any dose.
Risk of hepatic VOD is increased in patients receiving higher dosages (e.g., 9 mg/m2 for 2 doses administered 14 days apart) as a single agent, those with preexisting moderate or severe hepatic impairment, and those receiving the drug before or after hematopoietic stem cell transplantation (HSCT).
An interval of at least 2–3.5 months between the last dose of gemtuzumab ozogamicin and HSCT recommended.
Closely monitor for manifestations of hepatic VOD (e.g., elevated aminotransferase and/or total bilirubin concentrations, hepatomegaly, rapid weight gain, ascites).
Liver function test abnormalities also reported. Assess liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase) prior to each dose; more frequent monitoring may be necessary during the post-HSCT period in patients proceeding to HSCT following therapy with gemtuzumab ozogamicin. If liver function test abnormalities occur, monitor liver function tests and clinical manifestations of hepatotoxicity more frequently.
If hepatotoxicity occurs, temporary interruption of therapy or drug discontinuance may be necessary. (See Hepatotoxicity under Dosage and Administration.)
If hepatic VOD occurs, discontinue drug and institute treatment according to standard practices.
Other Warnings and Precautions
Life-threatening or fatal infusion-related reactions (e.g., pyrexia, chills, hypotension, tachycardia, hypoxia, respiratory failure) reported, generally during or within 24 hours following an infusion.
Premedicate with acetaminophen, an antihistamine (e.g., diphenhydramine), and a corticosteroid prior to each infusion. Monitor patient during and for at least 1 hour following completion of infusion. Also monitor vital signs frequently.
If manifestations of an infusion-related reaction occur, especially dyspnea, bronchospasm, or hypotension, immediately interrupt infusion and monitor patient until resolution. Provide appropriate treatment and supportive care; reduction in infusion rate or permanent discontinuance of therapy may be required. (See Infusion-related Effects under Dosage and Administration.)
Prolonged thrombocytopenia (platelet counts <50,000/mm3 lasting longer than 42 days in the absence of active disease), resulting in serious or fatal hemorrhage (e.g., cerebral, intracranial, and subdural hematoma) reported. Risk of prolonged thrombocytopenia increased following each treatment phase in patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine.
Monitor CBC counts prior to each dose, and more frequently following therapy until resolution of cytopenias. Monitor for manifestations of bleeding during therapy. If hemorrhage or prolonged thrombocytopenia occurs, institute supportive care; treatment delay or discontinuance of therapy may be required. (See Hematologic Toxicity under Dosage and Administration.)
Prolongation of QT Interval
Prolongation of QT interval reported in patients receiving other antibody-drug conjugates containing calicheamicin.
Monitor ECG and serum electrolytes prior to initiation of therapy and as clinically indicated in patients with a history of or predisposition to QT interval prolongation (e.g., those with electrolyte abnormalities or receiving concomitant drugs known to prolong the QT interval).
Decreased Efficacy in Patients with Unfavorable Cytogenetics
Subgroup analysis suggests a lack of clinical benefit for the drug in combination with standard therapy versus standard therapy alone in patients with unfavorable cytogenetics.
Consider potential benefits and risks of continuing gemtuzumab ozogamicin in combination with daunorubicin and cytarabine in patients with newly diagnosed de novo AML following availability of cytogenetic test results.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.
Confirm pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Women of childbearing potential and men who are partners of such women should use effective contraceptive methods while receiving gemtuzumab ozogamicin and for ≥6 and ≥3 months, respectively, after the drug is discontinued.
If used during pregnancy, apprise of potential fetal hazard.
Impairment of Fertility
May impair male and female fertility.
Immunogenic potential not evaluated.
Animal studies suggest possible fetal harm if used during pregnancy; no available data in pregnant women. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether distributed into human milk. Effects on nursing infants and milk production also unknown. Discontinue nursing during therapy and for ≥1 month after drug discontinuance.
Safety and efficacy not established in pediatric patients with newly diagnosed AML.
Use of gemtuzumab ozogamicin monotherapy for relapsed or refractory AML in pediatric patients ≥2 years of age is supported by a noncomparative study that included 13 patients 2 years to <12 years of age and 15 patients 12–18 years of age; only 1 patient was <2 years of age. No overall differences in safety and efficacy relative to age group observed.
In the principal clinical trial evaluating gemtuzumab ozogamicin in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, no overall differences in safety or efficacy in geriatric patients (≥65 years of age) relative to younger adults observed.
In the principal clinical study evaluating gemtuzumab ozogamicin monotherapy for newly diagnosed AML, all patients were ≥60 years of age; no overall differences in safety or efficacy based on age observed.
In the principal clinical trial evaluating gemtuzumab ozogamicin monotherapy for relapsed or refractory AML, no overall differences in safety or efficacy in geriatric patients (≥65 years of age) relative to younger adults observed; however, pyrexia and infection of severe or greater severity occurred more frequently in geriatric patients.
Pharmacokinetics not affected by mild hepatic impairment. (See Special Populations under Pharmacokinetics.)
Pharmacokinetics not affected by mild or moderate renal impairment. (See Special Populations under Pharmacokinetics.)
Common Adverse Effects
Combination therapy with daunorubicin and cytarabine in patients with newly diagnosed de novo AML: Hemorrhage, infection, prolonged thrombocytopenia (platelet counts <50,000/mm3 lasting >42 days in absence of active disease), anemia, neutropenia, hypophosphatemia, hypokalemia, hyponatremia, elevated alkaline phosphatase concentrations, elevated ALT and/or AST concentrations.
Monotherapy in patients with newly diagnosed AML: Hepatotoxicity, fatigue, infection, cardiac effects, hemorrhage, febrile neutropenia, metabolic abnormalities.
Monotherapy in patients with relapsed or refractory AML: Pyrexia, infection, elevated ALT and/or AST concentrations, hemorrhage, nausea and vomiting, constipation, mucositis, headache, rash, sepsis.
Interactions for Gemtuzumab
In vitro, gemtuzumab ozogamicin unlikely to inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 at clinically relevant concentrations.
In vitro, calicheamicin derivative of the antibody-drug conjugate unlikely to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 inhibit UGT 1A1, 1A4, 1A6, 1A9, and 2B7, or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.
Calicheamicin derivative of the antibody-drug conjugate unlikely to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, organic anion transport protein (OATP) 1B1, and OATP1B3.
No formal drug interaction studies have been performed to date.
Drugs that Prolong QT Interval
Potential additive effect on QT-interval prolongation; manufacturer recommends ECG and electrolyte monitoring during concomitant use. (See Prolongation of QT Interval under Cautions.)
Formal pharmacokinetic studies not performed for fractionated doses of gemtuzumab ozogamicin (e.g., 3 mg/m2 on days 1, 4, and 7).
Simulations suggest reduced peak plasma concentrations and systemic exposure of gemtuzumab ozogamicin when given in a fractionated dosing regimen (3 mg/m2 on days 1, 4, and 7) compared with an unfractionated regimen (9 mg/m2 for 2 doses administered 14 days apart).
Hepatic impairment: No clinically meaningful effect on pharmacokinetics in patients with mild hepatic impairment. Data not available for moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN).
Renal impairment: No clinically meaningful effect on pharmacokinetics in patients with mild or moderate renal impairment (Clcr 30–89 mL/minute). Data not available for severe renal impairment (Clcr 15–29 mL/minute).
Not known whether gemtuzumab ozogamicin is distributed into milk.
Plasma Protein Binding
Calicheamicin derivative: Approximately 97%.
Calicheamicin derivative extensively metabolized, primarily by nonenzymatic reduction.
Unconjugated gemtuzumab: 62 and 90 hours following first and second doses, respectively, of antibody-drug conjugate.
Powder for Injection
2–8°C in original package to protect from light. Do not freeze.
Reconstituted drug: 2–8°C for ≤1 hour. Protect from light. Do not freeze.
Diluted infusion solution: If not used immediately, may store at 2–8°C for ≤12 hours (including 1-hour storage of reconstituted solution in refrigerator, if needed, prior to dilution) and at room temperature (15–25°C) for ≤6 hours (including 2-hour infusion time and an additional 1 hour, if needed, to allow refrigerated diluted solution to reach room temperature prior to administration). Protect from light. Do not freeze.
For information on systemic interactions resulting from concomitant use, see Interactions.
Sodium chloride 0.9%
Antibody-drug conjugate consisting of an anti-CD33 antibody (recombinant humanized IgG4 kappa immunoglobulin) conjugated with the cytotoxic antitumor antibiotic N-acetyl-γ-calicheamicin.
Formulation consists of both conjugated and unconjugated antibody; on average, approximately 2–3 moles of the calicheamicin derivative are attached to each mole of antibody.
The antibody-drug conjugate binds to antigen CD33, a transmembrane glycoprotein expressed on leukemic blasts in >80% of patients with AML; resultant complex is internalized by the cell and the calicheamicin derivative is released via hydrolytic cleavage. The released calicheamicin derivative binds to DNA in the minor groove causing double-strand breaks and subsequent cell cycle arrest and apoptosis.
Saturation of a high percentage of antigen CD33 required for maximum delivery of calicheamicin to leukemic blast cells. Near maximal saturation of antigen CD33 in peripheral blood observed with doses ≥2 mg/m2.
Advice to Patients
Risk of hepatotoxicity, including severe, life-threatening, or fatal hepatic VOD. Importance of informing patients that the risk of developing hepatic VOD may be increased in patients who have previously undergone or plan to undergo HSCT. Importance of regular monitoring for signs and symptoms of hepatotoxicity (e.g., rapid weight gain, right upper-quadrant abdominal pain or tenderness, hepatomegaly, ascites) during therapy.
Risk of thrombocytopenia and hemorrhage. Importance of informing clinicians if signs and symptoms of bleeding occur.
Risk of infusion-related reactions. Importance of reporting signs and symptoms of such reactions, including fever, chills, rash, or breathing difficulty.
Risk of fetal harm. Necessity of advising women of childbearing potential and men who are partners of such women that they should use an effective method of contraception while receiving the drug and for ≥6 and ≥3 months, respectively, after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Importance of advising women to discontinue nursing during therapy and for ≥1 month after discontinuance of the drug.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injection, for IV infusion
AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 15, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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