gemtuzumab (Rx)

>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%)

Contraindications

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

Cautions

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

Infusion-related reactions

• Life-threatening or fatal infusion related-reactions can occur during or within 24 hr following gemtuzumab infusion
• Premedicate prior to gemtuzumab infusion
• Monitor vital signs frequently during infusion
• 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)

Hemorrhage

• Risk of fatal or life-threatening hemorrhage owing to prolonged thrombocytopenia
• Proportion of patients with persistent thrombocytopenia increased with progressive treatment phases and was higher in patients treated with combination therapy plus gemtuzumab than with chemotherapy alone
• 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, or persistent thrombocytopenia by treatment interruption or discontinuation and provide appropriate medical care

QT interval prolongation

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

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

Absorption

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

Distribution

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

Elimination

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)

IV Compatibilities

0.9% NaCl

IV Preparation

Cytotoxic drug; follow applicable special handling and disposal procedures

Reconstitution

• Calculate dose in mg and determine number of vials required
• 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
• 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 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

Premedication

Children and adolescents

• Premediate 1 hr before with acetaminophen and diphenhydramine, then 30 min before with methylprednisolone
• Acetaminophen 15 mg/kg (not to exceed 650 mg/dose) PO AND
• Diphenhydramine 1 mg/kg (not to exceed 50 mg/dose) PO/IV AND
• Methylprednisolone 1 mg/kg PO/IV
• Additional doses of acetaminophen and diphenhydramine may be administered q4hr after the initial pretreatment dose
• Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction (eg, fever, chills, hypotension, or dyspnea) during the infusion or within 4 hr afterwards

Adults

• Premediate 1 hr before with acetaminophen and diphenhydramine, then 30 min before with methylprednisolone
• Acetaminophen 650 mg PO AND
• Diphenhydramine 50 mg PO/IV AND
• Methylprednisolone 1 mg/kg IV or an equivalent dose of an alternative corticosteroid
• Additional doses of acetaminophen and diphenhydramine may be administered q4hr after the initial pretreatment dose
• Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction (eg, fever, chills, hypotension, or dyspnea) during the infusion or within 4 hr afterwards

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 infuse gemtuzumab with other medicinal products
• Cytotoxic drug; follow applicable special handling and disposal procedures

Storage

Protect from light

Do not freeze

Unopened vials

• Refrigerate at 2-8°C (36-46°F) store in the original carton

Reconstituted solution

• Refrigerate at 2-8°C (36-46°F) for up to 1 hr

Diluted solution

• Store at room temperature 15-25°C (59-77°F) for up to 6 hr; the 6-hr timeframe includes the 2-hr infusion time and 1 hr, if needed, to allow the refrigerated diluted solution to equilibrate to room temperature
• Refrigerate at 2-8°C (36-46°F) for up to 12 hr, which includes up to 1 hr in the vial following reconstitution