gemtuzumab (Rx)

Brand and Other Names:Mylotarg
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized cake powder for reconstitution

  • 4.5 mg/single-dose vial
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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 and children aged ≥2 years
  • 3 mg/m² on Days 1, 4, and 7 for 1 cycle

Premedication

  • 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

Dosing Modifications

Veno-occlusive disease (VOD): Discontinue treatment

Renal impairment

  • Mild-moderate (CrCl: 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl: 15-29 mL/min): Safety and efficacy unknown

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

Infusion-related reactions

  • Interrupt infusion and institute appropriate medical management
  • Administer acetaminophen, diphenhydramine, and/or methylprednisolone, if needed
  • Provide supportive care measures as needed
  • Consider resuming the infusion at less than or half the rate at which the reaction occurred once symptoms resolve
  • Repeat the procedure above in the event of recurrence of symptoms
  • Permanently discontinue gemtuzumab if a severe infusion reaction occurs or for any life-threatening infusion reaction

Other severe/life-threatening nonhematologic toxicities

  • Hold treatment until reaction severity is no more than mild
  • Omit scheduled dose if delayed more than 2 days between sequential infusions

Combination therapy only

  • Persistent thrombocytopenia
    • If platelet count does not recover to greater than 100 Gi/L ≤14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue gemtuzumab
    • Do not administer gemtuzumab in the consolidation cycle
  • Persistent neutropenia
    • If neutrophil count does not recover to greater than 0.5 Gi/L ≤14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue gemtuzumab
    • Do not administer gemtuzumab in the consolidation cycle

Dosing Considerations

Use appropriate measures to prevent tumor lysis syndrome

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

Monitor blood cell counts frequently through resolution of cytopenias

Monitor blood cell counts and chemistries <3X/week through recovery from treatment-related toxicities

Dosage Forms & Strengths

injection, lyophilized cake powder for reconstitution

  • 4.5-mg/single-dose vial
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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

Premedication

  • 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

Dosing Modifications

Veno-occlusive disease (VOD): Discontinue treatment

Renal impairment

  • Mild-moderate (CrCl: 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl: 15-29 mL/min): Safety and efficacy unknown

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 improves to ≤2X ULN and AST/ALT to ≤2.5X ULN prior to each dose
  • Omit scheduled dose if delayed >2 days between sequential infusions

Infusion-related reactions

  • Interrupt infusion and institute appropriate medical management
  • Administer acetaminophen, diphenhydramine, and/or methylprednisolone, if needed
  • Provide supportive care measures as needed
  • Consider resuming the infusion at less than or half the rate at which the reaction occurred once symptoms resolve
  • Repeat the procedure above in the event of recurrence of symptoms
  • Permanently discontinue gemtuzumab if a severe infusion reaction occurs or for any life-threatening infusion reaction

Other severe/life-threatening nonhematologic toxicities

  • Hold treatment until reaction severity is no more than mild
  • Omit scheduled dose if delayed more than 2 days between sequential infusions

Dosing Considerations

Use appropriate measures to prevent tumor lysis syndrome

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

Monitor blood cell counts frequently through resolution of cytopenias

Monitor blood cell counts and chemistries <3X/week through recovery from treatment-related toxicities

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Interactions

Interaction Checker

and gemtuzumab

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >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%)

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            Warnings

            Black Box Warnings

            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

            In clinical trials, the risk of VOD was higher in adults who received higher gemtuzumab doses as monotherapy, in patients with moderate/severe hepatic impairment prior to treatment, in patients treated with gemtuzumab after HSCT, and in patients who underwent hematopoietic stem cell transplantation (HSCT), after treatment with gemtuzumab

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

            Monitor frequently for signs/symptoms of VOD (eg, elevations in ALT, AST, total bilirubin, hepatomegaly, rapid weight gain, ascites) after treatment; monitoring only total bilirubin may not identify all patients at risk of VOD

            Patients who develop abnormal liver tests: More frequent monitoring of liver tests and clinical signs/symptoms of hepatotoxicity is recommended

            Patients who proceed to HSCT: Monitor liver tests frequently during the post-HSCT period, as appropriate

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

            In patients who experience VOD, discontinue treatment and treat according to standard medical practice

            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
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            Pregnancy

            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.

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            Pharmacology

            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)

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            Administration

            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
            • 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

            Storage

            Protect from light

            Do not freeze

            Unopened vials

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

            Reconstituted solution

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

            Diluted solution

            • May 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
            • May be refrigerated at 2-8°C (36-46°F) for up to 12 hr, which includes up to 1 hr in the vial following reconstitution
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            Formulary

            FormularyPatient Discounts

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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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