Drug information of Gemtuzumab

Gemtuzumab


Gemtuzumab ozogamicin is used to treat a certain type of acute myeloid leukemia, and is sometimes given when this condition has come back or has not responded after prior chemotherapy.

Mechanism of effect

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

Pharmacodynamic

Used for the treatment of acute myeloid leukemia (AML), mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives mylotarg the selectivity needed to target leukemic cells.

Pharmacokinetics

Peak plasma concentration: 3 mg/mL (first dose); 3.6 mg/mL (second dose)

Protein bound: 97% (N-acetyl gamma calicheamicin dimethyl hydrazide)

Vd: ~21.4 L (hP67.6 antibody)

Metabolism:N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulfide moiety

Half-life (hP67.6 antibody): 62 hr (first dose); 90 hr (second dose)

Clearance (hP67.6 antibody): 0.35 L/hr (first dose); 0.15 L/hr (second dose)

Drug indications

Acute Myeloid Leukemia

Acute Myeloid Leukemia

Dosage

-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

3 mg/m2 on Days 1, 4, and 7 for 1 cycle

PEDIATRIC                         

-Newly Diagnosed Acute Myeloid Leukemia

Indicated for newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients aged ≥1 month

 

<1 month: Safety and efficacy not established

≥1 month

Body surface area (BSA) <0.6 m2: 0.1 mg/kg IV

BSA ≥0.6 m2: 3 mg/m2 IV

First induction cycle: Give once in combination with standard chemotherapy

Second induction cycle: No gemtuzumab given

First intensification cycle: No gemtuzumab given

Second intensification cycle: Give once in combination with standard chemotherapy; consider risks and potential benefits before giving gemtuzumab

Third intensification cycle: No gemtuzumab given

-Relapse or refractory AML

Indicated for relapsed or refractory CD33-positive AML in adults and pediatric patients ≥2 years

3 mg/m2 (up to one 4.5-mg vial) on Days 1, 4, and 7 for 1 cycle

Drug contraindications

Hypersensitivity to this drug

Hypersensitivity to drug or any ingredient

Side effects

herpes simplex , Infection , Diarrhea , Headache , fever , hemorrhage , Hyperbilirubinemia , pneumonia , Hypophosphatemia , Mucositis , Rash

Hypophosphatemia, grade 3 or higher -Hypokalemia, grade 3 or higher -Hyponatremia, grade 3 or higher -Prolonged thrombocytopenia -AST increased, grade 3 or higher -Alkaline phosphatase increased, grade 3 or higher -Fever, all grades -Infection, all grades -Bleeding, all grades -Nausea and vomiting, all grades -Constipation, all grades-Mucositis, all grades -Headache, all grades -Increased ALT, all grades -Rash, all grades-Sepsis, grade 3 -Blood bilirubin increased, grade 3 or higher -Prolonged neutropenia -Veno-occlusive disease, grade 3 or higher -Pneumonia, grade 3 -Pain, grade 3 -Diarrhea, grade 3 -Headaches, grade 3 -Tachycardia, grade 3 -Lung edema, grade 3

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Alerts

-Hepatotoxicity, including severe or fatal veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of gemtuzumab

- 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

- Life-threatening or fatal infusion related-reactions can occur during or within 24 hr following gemtuzumab infusion

- Risk of fatal or life-threatening hemorrhage owing to prolonged thrombocytopenia

- QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin

- Patients with hyperleukocytosis (leukocyte count ≥30 Gi/L): Cytoreduction is recommended prior to gemtuzumab administration

 

Points of recommendation

-Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each gemtuzumab dose

- Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation

- Interrupt infusion immediately for patients who are suspected of infusion-related reaction, especially dyspnea, bronchospasm, or hypotension

-Monitor patients during and for ≥1 hr after infusion completed or until signs/symptoms completely resolve

-Discontinue gemtuzumab use in patients who develop signs or symptoms of anaphylaxis (eg, severe respiratory symptoms or clinically significant hypotension)

- Assess blood cell counts prior to each gemtuzumab dose; monitor frequently after treatment until resolution of cytopenias

-Monitor patients for signs/symptoms of bleeding during treatment; manage severe bleeding, hemorrhage,

- Obtain ECG and electrolytes before initiating drug and during treatment as needed in patients with history of or predisposition for QTc prolongation, who are taking drugs known to prolong QT interval, or with electrolyte disturbances

- Use appropriate measures to prevent tumor lysis syndrome

Pregnancy level

Forbidden

Based on animal data, gemtuzumab can cause embryo-fetal harm when administered to a pregnant woman

Gemtuzumab may impair fertility in male or females of reproductive potential

For patients who are pregnant, or become pregnant during treatment, advise the patient of the potential risk to a fetus

Advise females of reproductive potential to avoid becoming pregnant while receiving gemtuzumab

Breast feeding warning

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

Related drugs

Inotuzumab‎

Drug forms

Mylotarg

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