Gemtuzumab Ozogamicin

Class: Antineoplastic Agents
VA Class: AN900
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
Brands: Mylotarg

Warning(s)

Special Alerts:

  • Withdrawal from US Market
  • On June 21, 2010, Pfizer announced the voluntary withdrawal of gemtuzumab ozogamicin from the US market effective October 15, 2010, because a required postapproval study had failed to confirm clinical benefit and had raised new concerns about safety.11 12

  • Because the drug became commercially available in the US in 2000 under FDA’s accelerated review policy, the manufacturer was required to submit additional data confirming clinical benefit.11 12 However, interim data from the study conducted to fulfill this requirement (Southwest Oncology Group [SWOG] S0106) indicated that addition of gemtuzumab ozogamicin to standard therapy for acute myeloid leukemia (AML) did not improve survival but was associated with an increased risk of fatal adverse events.11 12 (See Acute Myeloid Leukemia [AML] under Uses.)

  • In June 2010, Pfizer stated that the drug would remain available for a limited time so that patients currently receiving the drug would have the option, after consultation with their clinician, of completing their planned course of therapy.11 12 Pfizer recommended that gemtuzumab ozogamicin not be newly prescribed for additional patients in the US.11 12

  • Any future use of the drug in the US requires submission of an Investigational New Drug (IND) application to FDA.11 12

  • For additional information concerning use of the drug, contact the manufacturer at 800-438-1985 or .12

Warning(s)

  • Experience of Supervising Clinician
  • Use under supervision of a qualified clinician experienced in treatment of acute leukemia in facilities equipped to monitor and treat leukemia patients.1

  • Combined Therapy
  • Use only as single-agent chemotherapy and not in combination chemotherapy regimens outside of clinical trial setting.1 Controlled trials have failed to demonstrate efficacy and safety in combination with other chemotherapeutic agents.1 (See Acute Myeloid Leukemia [AML] under Uses.)

  • Myelosuppression
  • Risk of severe myelosuppression at recommended dosages.1 (See Myelosuppression under Cautions.)

  • Hypersensitivity
  • Possible severe, potentially fatal hypersensitivity reactions (e.g., anaphylaxis); strongly consider discontinuance if anaphylaxis develops.1

  • Infusion Reactions
  • Possible infusion reactions, including severe, potentially fatal pulmonary events; most infusion-related symptoms occur during infusion or within 24 hours of administration and resolve.1 Interrupt infusion in patients experiencing dyspnea or clinically important hypotension;1 monitor until manifestations completely resolve.1 Strongly consider discontinuance if pulmonary edema or acute respiratory distress syndrome develops.1 (See Pulmonary Reactions under Cautions.)

  • Leukoreduction
  • Risk for pulmonary events and tymor lysis syndrome may be greater in patients with high peripheral blast counts; consider leukoreduction with hydroxyurea or leukapheresis to reduce peripheral leukocyte count to <30,000/mm3 prior to administration.1

  • Hepatotoxicity
  • Possible hepatotoxicity; risk for developing hepatic veno-occlusive disease (VOD), including severe VOD, is increased in patients who receive gemtuzumab ozogamicin either before or after hematopoietic stem-cell transplant (HSCT), patients with underlying hepatic disease or hepatic impairment, and patients receiving gemtuzumab ozogamicin in combination with other chemotherapy.1 Hepatic failure and VOD have been fatal in some cases.1 Monitor carefully for manifestations, particularly VOD (e.g., rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and/or liver enzymes); however, careful monitoring may not identify all patients at risk or prevent complications.1 (See Hepatotoxicity under Cautions.)

Introduction

Antineoplastic agent; recombinant DNA-derived humanized anti-CD33 monoclonal antibody.1 2 3 4 5 6

Uses for Gemtuzumab Ozogamicin

Acute Myeloid Leukemia (AML)

Treatment of CD33-positive AML in first relapse in patients who are ≥60 years of age and are not considered candidates for cytotoxic chemotherapy (designated an orphan drug by FDA for this use).1 2 7 9

Safety and efficacy in patients with poor performance status and organ dysfunction not established.1

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FDA granted approval based on overall response rate in noncomparative, open-label studies in patients with CD33-positive AML in first relapse.2 10 12

Interim data from a subsequent randomized, open-label, phase 3 trial (SWOG S0106) in patients 18–60 years of age with previously untreated AML indicated that addition of gemtuzumab ozogamicin to daunorubicin/cytarabine induction therapy did not improve response rate or relapse-free survival, and administration as postconsolidation therapy did not improve relapse-free survival, postconsolidation disease-free survival, or overall survival.1 12 13 Fatal induction-related adverse events (e.g., hemorrhage, infection, ARDS) were more common with the gemtuzumab ozogamicin-containing induction regimen than with daunorubicin/cytarabine (5.7 versus 1.4%).1 12 13 (See Special Alerts.)

Gemtuzumab Ozogamicin Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.1

  • To minimize risk of tumor lysis syndrome and infusion-related reactions (severe, sometimes fatal, sensitivity reactions or pulmonary events), treat with hydroxyurea or leukapheresis to reduce the peripheral leukocyte count to <30,000/mm3 before gemtuzumab ozogamicin administration.1

  • Take appropriate measures (e.g., allopurinol, hydration) to prevent hyperuricemia.1

  • To minimize risk of hypersensitivity reactions and infusion-related events, premedicate with acetaminophen 650–1000 mg and diphenhydramine hydrochloride 50 mg orally 1 hour prior to each dose.1 Fever and chills are common despite acetaminophen and antihistamine premedication, but generally resolve within 2–4 hours with supportive therapy (acetaminophen, antihistamines, IV fluids).1 If needed, give 2 additional doses of acetaminophen 650–1000 mg at 4-hour intervals.1 (See Infusion Reactions under Cautions.)

  • Administration of methylprednisolone prior to gemtuzumab ozogamicin administration may ameliorate infusion-related symptoms.1

Administration

Administer by IV infusion only; do not administer by rapid IV injection.1 2

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer through a separate IV line using an inline low-protein-binding filter (consult manufacturer’s labeling for filter specifications) into either a central or peripheral vein.1

Protect from direct and indirect sunlight and unshielded fluorescent light during preparation and administration.1 Only the IV bag must be protected from light during the infusion.1

Complete the infusion within 20 hours following reconstitution (i.e., infuse over 2 hours after storing reconstituted solution in vial for no more than 2 hours and storing infusion solution in IV bag for no more than 16 hours) (See Reconstitution and also see Dilution, under Dosage and Administration).1

Reconstitution

Reconstitute and prepare in a laminar flow hood with shielded fluorescent light.1

Reconstitute by adding 5 mL of sterile water for injection to provide a solution containing 1 mg/mL.1 Gently swirl and inspect vial to ensure complete dissolution.1 Must be diluted further before IV infusion.1

May store reconstituted drug in vial at room temperature or under refrigeration and protected from light for up to 2 hours before further dilution.1

Reconstituted solution may appear hazy because of normal light scattering from the protein.1

Vials are for single use only.1

Dilution

For IV infusion, withdraw appropriate dose and dilute in 100 mL of 0.9% sodium chloride in either a PVC or non-PVC (ethylene/polypropylene copolymer) IV bag covered by an ultraviolet (UV) light protector.1

Do not dilute with other electrolyte solutions or with 5% dextrose injection; do not admix with other drugs.1

Infusion solution may appear hazy because of normal light scattering from the protein.1

May store the infusion solution at room temperature and protected from light for up to 16 hours prior to administration.1

Rate of Administration

Administer by IV infusion over 2 hours.1

Dosage

Adults

AML
IV

9 mg/m2 with a repeated dose in 14 days (2 doses total).1 2 Complete recovery from adverse hematologic effects (e.g., myelosuppression, thrombocytopenia) not required for administration of second dose.1

Prescribing Limits

Adults

AML
IV

Doses >9 mg/m2 have not been evaluated to date.1

Cautions for Gemtuzumab Ozogamicin

Contraindications

  • Known hypersensitivity to gemtuzumab ozogamicin or any of its components (e.g., anti-CD33 antibody [hP67.6], calicheamicin derivatives) or to any ingredient in the formulation.1

Warnings/Precautions

Warnings

Use under supervision of a qualified clinician experienced in treatment of acute leukemia in facilities equipped to monitor and treat leukemia patients.1

Do not use in combination therapy outside of clinical trial setting; controlled trials have failed to demonstrate efficacy and safety in combination with other chemotherapeutic agents.1 (See Acute Myeloid Leukemia [AML] under Uses.)

Myelosuppression

Severe myelosuppression occurs in all patients receiving the recommended dosage.1 4 In clinical studies, grade 3 or 4 neutropenia developed in 98% of patients; median time for ANC recovery to 500/mm3 in responding patients was 40–43 days.1 Carefully monitor hematologic function and promptly treat systemic infections.1 8

Pulmonary Reactions

Risk of severe adverse pulmonary events, including dyspnea, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, and acute respiratory distress syndrome as sequelae of infusion reactions; infrequently fatal.1 Risk may be increased in patients with symptomatic intrinsic pulmonary disease (e.g., asthma, COPD) or leukocyte count >30,000/mm3 (see General under Dosage and Administration and see Boxed Warning).1

Hepatotoxicity

Risk of severe hepatotoxicity, including hepatic VOD and hepatic failure, sometimes fatal.1 Hepatotoxicity reported in patients receiving the drug as monotherapy, as part of a combination chemotherapy regimen, and in patients without a history of hepatic disease or HSCT.1 (See Boxed Warning.)

Risk of grade 3 or 4 hyperbilirubinemia and elevations in serum ALT and AST.1 Use with extra caution in patients with hepatic impairment.1 Not studied in patients with bilirubin >2 mg/dL.1

In clinical trials, VOD occurred in 22% of patients who received gemtuzumab ozogamicin after undergoing HSCT, 15% of those who underwent HSCT after receiving gemtuzumab ozogamicin, and 1% of those who received the drug but did not undergo HSCT.1

AUC of total calicheamicin is correlated with additional risk of hepatomegaly and with risk of VOD; however, no evidence that reducing the drug dose will reduce risk of VOD (see Plasma Concentrations under Pharmacokinetics).1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Sensitivity Reactions

Infusion Reactions

Risk of severe infusion-related effects, infrequently fatal.1 Possible acute infusion reactions (e.g., shaking chills, fever, nausea, vomiting, headache, hypotension, hypertension, hypoxia, dyspnea, hyperglycemia) during first 24 hours after administration;1 2 4 5 occur more frequently with first dose.1 Premedicate and monitor vital signs during and for 4 hours after infusion.1 (See General under Dosage and Administration and see Boxed Warning.)

Anaphylaxis

Possible anaphylaxis, infrequently fatal.1 (See Boxed Warning.)

Major Toxicities

Hematologic Effects

Possible grade 3 or 4 thrombocytopenia, anemia, or bleeding (e.g., epistaxis, cerebral hemorrhage, disseminated intravascular coagulation, intracranial hemorrhage, hematuria, melena, petechiae).1 Grade 3 or 4 bleeding more common in nonresponders than in responders.1

Infectious Complications

Risk of grade 3 or 4 infection-related events (e.g., sepsis, pneumonia, shock), including opportunistic infections, during and immediately after treatment.1

GI Effects

Possible oral mucositis or stomatitis.1

Renal Effects

Renal failure secondary to tumor lysis syndrome, hypersensitivity reactions, anaphylaxis, or pulmonary events reported.1

General Precautions

Tumor Lysis Syndrome

May occur as result of leukemia treatment.1 Take appropriate preventive measures.1 (See General under Dosage and Administration.)

Therapy Monitoring

Monitor electrolytes, liver function tests, CBCs, and platelet counts during therapy.1 Monitor vital signs during and for 4 hours after infusion.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.1 Due to potential risk in nursing infant, discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 (See Hepatotoxicity under Cautions.)

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Abdominal pain, asthenia, back pain, chills, fever, headache, neutropenic fever, pain, sepsis, hemorrhage, hypertension, hypotension, tachycardia, anorexia, constipation, diarrhea, dyspepsia, liver function test abnormalities, nausea, stomatitis, vomiting, anemia, ecchymosis, leukopenia, petechiae, thrombocytopenia, bilirubinemia, hyperglycemia, hypocalcemia, hypokalemia, increased LDH, peripheral edema, dizziness, insomnia, increased cough, dyspnea, epistaxis, pharyngitis, pneumonia, herpes simplex, rash.1

In clinical trials, overall mortality rate within 28 days of the last gemtuzumab ozogamicin dose was 14% in patients <60 years of age and 17% in those ≥60 years of age.1

Interactions for Gemtuzumab Ozogamicin

No formal drug interaction studies to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Interactions with drugs affected by CYP enzymes cannot be excluded.1

Gemtuzumab Ozogamicin Pharmacokinetics

Absorption

Plasma Concentrations

AUC of total calicheamicin following the second 9-mg/m2 dose is about twice that following the first dose.1 AUC of total calicheamicin is correlated with additional risk of hepatomegaly and with risk of VOD; however, no evidence that reducing gemtuzumab ozogamicin dose will reduce risk of VOD.1 (See Hepatotoxicity under Cautions.)

AUC of unconjugated calicheamicin is increased by 30% following the second dose.1

Distribution

Extent

Not known whether gemtuzumab ozogamicin is distributed into milk.1

Elimination

Metabolism

Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin.1 Many metabolites of the calicheamicin derivative were identified after in vitro incubation in human hepatic microsomes and cytosol and in HL-60 promyelocytic leukemia cells.1 Isozymes involved in metabolism not determined.1

Half-life

Total calicheamicin: 41 hours after first dose; 64 hours after second dose.1 (See Plasma Concentrations under Pharmacokinetics.)

Unconjugated calicheamicin: 143 hours afer first dose.1 (See Plasma Concentrations under Pharmacokinetics.)

Special Populations

Pharmacokinetics not affected by age, gender, body surface area, or weight.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C; protect from light.1

May store reconstituted drug in vial at room temperature or under refrigeration and protected from light for up to 2 hours.1

May store infusion solution at room temperature and protected from light for up to 16 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1

Sodium chloride 0.9%

Actions

  • Antibody component is an IgG4 kappa immunoglobulin conjugated with the cytotoxic antitumor antibiotic calicheamicin.1 2

  • Antibody portion binds specifically to antigen CD33, a sialic acid-dependent adhesion protein expressed on leukemic blasts in >80% of patients with AML;1 2 3 4 5 6 8 also expressed on normal and leukemic myeloid colony-forming cells but not on pluripotent hematopoietic stem cells or nonhematopoietic cells.1 2 3 4 5 6 8

  • Following binding of antibody portion to antigen CD33, complex is formed that is internalized by the myeloid cell.1 2 5 Calicheamicin is released within lysosomes of the myeloid and binds to DNA in the minor groove, resulting in double strand breaks and cell death.1 4 5

Advice to Patients

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy during therapy.1 Apprise pregnant women of risk to fetus.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Gemtuzumab Ozogamicin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

5 mg

Mylotarg

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 30, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Wyeth Pharmaceuticals. Mylotarg (gemtuzumab ozogamicin for injection) prescribing information. Philadelphia, PA; 2010 Apr.

2. Anon. Gemtuzumab for relapsed acute myeloid leukemia. Med Lett Drugs Ther. 2000; 42:67-8. [PubMed 10908423]

3. Rowe JM. Treatment of acute myelogenous leukemia in older adults. Leukemia. 2000; 14:480-7. [PubMed 10720146]

4. Bernstein ID. Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. Leukemia. 2000; 14:474-5. [PubMed 10720144]

5. Appelbaum FR. Antibody-targeted therapy for myeloid leukemia. Semin Hematol. 1999; 36(Suppl 6):2-8. [PubMed 10530710]

6. Sievers EL, Applebaum FR, Spielberger RT et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood. 1999; 93:3678-84. [IDIS 427265] [PubMed 10339474]

7. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2000 Aug 3. From FDA web site.

8. Wyeth-Ayerst, St. Davids, PA: Personal communication. 1

9. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

10. Wyeth-Ayerst. Mylotarg (gemtuzumab ozogamicin for injection) prescribing information. Philadelphia, PA; 2001 Jul 19.

11. Food and Drug Administration. Mylotarg (gemtuzumab ozogamicin): market withdrawal. Rockville, MD; 2010 Jun 21. From FDA website (). Accessed 2010 Jul 26.

12. Shapiro M. Dear healthcare professional letter: Pfizer prepares for voluntary withdrawal of US New Drug Application and for discontinuation of commercial availability of Mylotarg for relapsed acute myelogenous leukemia. New York, NY: Pfizer; 2010 Jun 21. Available at .

13. Report of study: SO106 Phase III. Presented at Southwest Oncology Group Spring Group Meeting. San Francisco, CA: 2010 Apr 17. Available at .

14. Burnett AK, Hills RK, Milligan D et al. Identification of Patients With Acute Myeloblastic Leukemia Who Benefit From the Addition of Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial. J Clin Oncol. 2010; :.

15. Petersdorf S, Kopecky K, Stuart RK et al. Preliminary results of Southwest Oncology Group study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Paper presented at 51st American Society of Hematology Annual Meeting and Exposition. New Orleans, LA: 2009 Dec 7. Abstract No. 790. Available at: .

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