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

Special Alerts:

[Posted 06/21/2010]

ISSUE: FDA notified healthcare professionals that results from a recent clinical trial raised new concerns about the product’s safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

BACKGROUND: Gemtuzumab ozogamicin (Mylotarg), indicated for treatment of acute myeloid leukemia (AML), a bone marrow cancer, was approved in May 2000 under the FDA’s accelerated approval program. A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding gemtuzumab ozogamicin to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received gemtuzumab ozogamicin compared with those receiving chemotherapy alone.

RECOMMENDATION: Gemtuzumab ozogamicin will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving gemtuzumab ozogamicin of the product’s potential safety risks. Any future use of gemtuzumab ozogamicin in the United States will require submission of an investigational new drug application to the FDA.

For more information visit the FDA website at: and .

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 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

  
  

• 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 severe hepatic veno-occlusive disease (VOD) may be increased in patients who receive gemtuzumab ozogamicin either before or after hematopoietic stem-cell transplant, 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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Acute Myeloid Leukemia

Treatment of CD33-positive acute myeloid leukemia (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 US FDA for this use).^{1 2 7}

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

Gemtuzumab Ozogamicin Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

• 
  

  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 If needed, give 2 additional doses of acetaminophen 650–1000 mg at 4-hour intervals.¹ (See Infusion Reactions under Cautions.)

  
  


• 
  

  Consider procedures for handling and disposal of antineoplastic drugs.¹

  
  

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

IV Administration

Administer by a separate IV line using a low protein-binding terminal filter (1.2 mcgm) into either a central or peripheral vein.¹

Protect from direct and indirect sunlight and unshielded fluorescent light during preparation and administration.¹

Reconstitution

Prior to reconstitution, allow vial containing gemtuzumab ozogamicin powder for injection to reach room temperature.¹

Reconstitute and prepare in a laminar flow hood with fluorescent light turned off.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 for evidence of particulates.¹ Must be diluted further before IV infusion.¹

Dilution

For IV infusion, withdraw appropriate dose and dilute in 100 mL of 0.9% sodium chloride.¹

Following dilution, cover IV container with a UV protectant bag and use immediately.¹

Rate of Administration

Administer by IV infusion over 2 hours.^{1 1}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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; efficacy and safety in combination with other chemotherapeutic agents not demonstrated.¹

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; responding patients recovered ANCs by a median of 40.5 days after the first dose.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 hematopoietic stem-cell transplantation.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

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).¹

Infectious Complications

Risk of grade 3 or 4 infections (e.g., sepsis, pneumonia), 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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 Hepatotoxicty under Cautions.)

Renal Impairment

Not studied in patients with renal impairment.¹

Common Adverse Effects

Fever, chills, nausea, vomiting, asthenia, diarrhea, abdominal pain, headache, stomatitis, dyspnea, epistaxis, hypokalemia, anorexia, sepsis, constipation, local reaction, herpes simplex, rash, neutropenic fever, pain, hypertension, hypotension, increased cough, petechiae, peripheral edema, back pain, dizziness, insomnia, pharyngitis, ecchymosis, increased LDH, vaginal hemorrhage, tachycardia, dyspepsia, pulmonary physical findings, hemorrhage, hypomagnesemia, pneumonia, rhinitis, hematuria.¹

Interactions for Gemtuzumab Ozogamicin

No formal drug interaction studies to date.¹

Gemtuzumab Ozogamicin Pharmacokinetics

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

Approximately 45 and 100 hours, respectively, for total and unconjugated calicheamicin after first dose.¹ Half-life of total calicheamicin increases to approximately 60 hours after second dose but remains unchanged for unconjugated calicheamicin.

Stability

Storage

Parenteral

Powder for Injection

2–8°C; protect from light.¹

May store reconstituted drug in vial at 2–8°C and protected from light for up to 8 hours.¹

Following dilution, cover IV container with a UV protectant bag and use immediately.¹

Compatibility

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

Parenteral

Solution Compatibility

Compatible1
Sodium chloride 0.9%

ActionsActions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  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.

  
  


• 
  

  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.

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Gemtuzumab Ozogamicin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	5 mg	Mylotarg	Wyeth

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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

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 From FDA web site.

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

a. Wyeth-Ayerst. Mylotarg (gemtuzumab ozogamicin for injection) prescribing information. Philadelphia, PA; 2003 Jul.

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