Professional Drug Information > Gemtuzumab Ozogamicin

Gemtuzumab Ozogamicin (Systemic)

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Mylotarg™.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antineoplastic—

Monoclonal antibody—

Indications

Accepted

Leukemia, acute myeloid (treatment)—Gemtuzumab ozogamicin is indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.^{01}{02}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Recombinant DNA-derived humanized monoclonal antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora sp. calichensis.^{01}
Molecular weight—
    151 to 153 kilodaltons^{01}

Mechanism of action/Effect:

Gemtuzumab ozogamicin is cytotoxic to the CD33 positive HL-60 human leukemia cell line.^{01} Gemtuzumab ozogamicin binds to the CD33 antigen expressed by hematopoietic cells which results in formation of a complex that is internalized.^{01} Once internalized, the calicheamicin derivative is released inside the lysosomes of the myeloid cell and binds to DNA which results in DNA double strand breaks and cell death.^{01} This results in significant inhibition of colony formation in cultures of adult leukemic bone marrow cells.^{01}

Half-life:

Elimination—45 and 100 hours, total and unconjugated calicheamicin, respectively, after the first recommended 9 mg/m ²dose given over 2 hours.^{01} After a second 9 mg/m²dose, the half-life of total calicheamicin increases to 60 hours while the half-life of unconjugated calicheamicin remains unchanged.^{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to anti-CD33 antibody or calicheamicin derivatives may also be sensitive to gemtuzumab ozogamicin^{01} .

Carcinogenicity/Mutagenicity

No long-term studies in animals have been performed to evaluate the carcinogenic potential of gemtuzumab ozogamicin. Gemtuzumab ozogamicin was clastogenic in the mouse in vivomicronucleus test.^{01} This positive result is consistent with the known ability of calicheamicin to cause double-stranded breaks in DNA^{01}.

Pregnancy/Reproduction
Fertility—
Formal fertility studies have not been conducted in animals.^{01} When given weekly for 6 doses to rats, gemtuzumab ozogamicin caused atrophy of the seminiferous tubules, oligospermia, desquamated cells in the epididymis, and hyperplasia of the interstitial cells at the dose of 1.2 mg/kg/week (approximately 0.9 times the human dose on a mg/m² basis). These findings did not resolve following a 5–week recovery period^{01}.

Pregnancy—
Gemtuzumab ozogamicin crosses the placenta and has been shown to cause adverse effects on the fetus.^{01} Risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective.^{01} Gemtuzumab ozogamicin may cause fetal harm when administered to a pregnant woman^{01}. There are no adequate and well-controlled studies in pregnant women. If gemtuzumab ozogamicin is used in pregnancy or if the patient becomes pregnant while receiving it, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with gemtuzumab ozogamicin ^{01} . Daily treatment of pregnant rats with gemtuzumab ozogamicin during organogenesis caused dose-related decreases in fetal weight in association with dose-related decreases in fetal skeletal ossification beginning at 0.025 mg/kg/day. Doses of 0.060 mg/kg/day (approximately 0.04 times the recommended human single dose on a mg/m² basis) produced increased embryo-fetal mortality (increased numbers of resorptions and decreased numbers of live fetuses per litter).^{01} Gross external, visceral, and skeletal alterations at the 0.060 mg/kg/day dose level included digital malformations in one or both hind feet, absences of the aortic arch, wavy ribs, anomalies of the long bones in the forelimb(s), misshapen scapula, absence of vertebral centrum, and fused sternebrae.^{01} This dose was also associated with maternal toxicity (decreased weight gain, decreased food consumption)^{01}.

FDA Pregnancy Category D^{01}.

Breast-feeding

It is not known if gemtuzumab ozogamicin is distributed into breast milk^{01}. Because many drugs, including immunoglobulins, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from gemtuzumab ozogamicin, a decision should be made whether to discontinue nursing or to discontinue gemtuzumab ozogamicin, taking into account the importance of the drug to the mother^{01}.

Pediatrics

No information is available on the relationship of age to the effects of gemtuzumab ozogamicin in the pediatric population. Safety and efficacy have not been established^{01}.


Geriatrics


Elderly patients are more likely to have laboratory parameters associated with hepatic dysfunction. It is recommended that bilirubin, AST, and ALT levels be closely monitored^{01}.


Pharmacogenetics

There have been no clinically important differences in treatment-emergent adverse events between female and male patients^{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood dyscrasia–causing medications (see Appendix II )    (anemic and/or thrombocytopenic effects of gemtuzumab ozogamicin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of gemtuzumab ozogamicin, if necessary, should be based on blood counts )


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively )


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by gemtuzumab ozogamicin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year )


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by gemtuzumab ozogamicin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the gemtuzumab ozogamicin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Previous allergic reaction to gemtuzumab ozogamicin or any of its components, including anti-CD33 antibody and calicheamicin derivatives^{01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression, existing or
» Infection    (gemtuzumab ozogamicin will cause severe bone marrow depression in all patients when given at the recommended dose. Hematologic monitoring is required and systemic infections should be treated^{01})


» Caution should be used also in patients who have had previous cytotoxic drug or radiation therapy
Caution should be used in patients that have had or are planning to have a hematopoietic stem-cell transplant    (increased risk of developing severe hepatic veno-occlusive disease)

^{02}
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Hepatic function impairment    (gemtuzumab ozogamicin has not been studied in patients with bilirubin >2 mg/dL. Caution should be exercised when administering gemtuzumab ozogamicin in patients with hepatic impairment^{01}; increased risk of developing severe hepatic veno-occlusive disease^{02})


High peripheral blast counts    (risk of pulmonary events and tumor lysis syndrome may be increased; consider leukoreduction or leukapheresis prior to starting gemtuzumab ozogamicin therapy )

^{02}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Electrolytes    (recommended during therapy with gemtuzumab ozogamicin due to possible occurrences of hypokalemia, hypomagnesia, and increased lactic dehydrogenase^{01})


» Alanine aminotransferase (ALT [SGPT]) values and
» Aspartate aminotransferase (AST [SGOT]) values and
» Total bilirubin concentrations, serum    (recommended to monitor for abnormalities of liver function^{01})


» Complete blood counts and
» Platelet counts    (recommended to monitor for myelosuppression, anemia, and thrombocytopenia^{01})


» Vital signs    (recommended during infusion and for the four hours following infusion due to possible post-infusion symptom complex^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia^{01} (pale skin; troubled breathing, exertional; unusual bleeding or bruising; unusual tiredness or weakness)
    
bleeding events, including epistaxis^{01} (unexplained nosebleeds)
    
cerebral hemorrhage^{01} (blurred vision; headache sudden and severe; inability to speak; seizures; slurred speech; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe)
    
disseminated intravascular coagulation^{01} (blood in stools; blood in urine; bluish color of fingernails, lips, skin, palms, or nail beds; bruising; excessive sweating; persistent bleeding or oozing from puncture sites, mouth, or nose)
    
intracranial hemorrhage^{01} ( headache, sudden severe; weakness, sudden )
    
hematuria^{01} (blood in urine; lower back pain; pain or burning while urinating)
    
ecchymosis^{01} (bruising; large, flat, blue or purplish patches in the skin)
    
hepatotoxicity, including hyperbilirubinemia and hepatic veno-occlusive disease^{02}{01} (yellow eyes or skin; upper abdominal pain; rapid weight gain)
    
abnormal levels in ALT and AST^{01}
    
and concurrent elevations in transaminases and bilirubin^{01}
    
hypokalemia^{01} (convulsions; decreased urine; dry mouth; irregular heartbeat; increased thirst ; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in hands, feet, or lips ; shortness of breath; unusual tiredness or weakness)
    
hypomagnesemia^{01} (muscle trembling or twitching)
    
infections, including sepsis^{01} (chills; confusion; delirium; dizziness ; light-headedness ; fainting; fast heartbeat; fever; rapid, shallow breathing)
    
pneumonia^{01} (chest pain; cough ; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest ; wheezing)
    
and Herpes simplex^{01} (burning or stinging of skin; painful cold sores or blisters on lips, nose, eyes, or genitals)
    
infusion-related reactions, including chills ^{01}
fever ^{01}
nausea or vomiting^{01}
dyspnea ^{01} (troubled breathing), headache ^{01}
hypotension ^{01} (dizziness; fainting), hypertension^{01} ( blurred vision; dizziness; severe or continuing dull nervousness; headache; pounding in the ears; slow or fast heartbeat), hypoxia^{01}
and hyperglycemia^{01} ( blurred vision dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; loss of consciousness; nausea; stomachache; sweating; troubled breathing; vomiting)
    
lactic dehydrogenase increased^{01}
    
mucositis or stomatitis (cracked lips; diarrhea; difficulty in swallowing; sores, ulcers, or white spots on lips, tongue, or inside mouth; swelling or inflammation of the mouth)
    
myelosuppression^{01} ( black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin ; unusual bleeding or bruising)
    
neutropenic fever^{01}
    
peripheral edema^{01} (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet; unusual weight gain or loss)
    
petechiae^{01} ( small red or purple spots on skin)
    
renal failure (lower back or side pain ; decreased frequency or amount of urine ; bloody urine ; increased thirst; loss of appetite ; nausea ; vomiting, unusual tiredness, or weakness; swelling of face, fingers, lower legs ; weight gain; troubled breathing,; increased blood pressure)—secondary to tumor lysis syndrome
    
tachycardia^{01} (fainting; fast, pounding, or irregular heartbeat or pulse; palpitations)
    
thrombocytopenia^{01} (black, tarry stools; chest pain; chills; cough; fever; painful or difficult urination ; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising ; unusual tiredness or weakness)
    
tumor lysis syndrome (joint pain; lower back or side pain; stomach pain ; swelling of feet or lower legs)
    
vaginal hemorrhage^{01} (heavy nonmenstrual vaginal bleeding)

Note: Severe myelosuppression occurs in all patients when gemtuzumab ozogamicin is used at recommended doses.
Infusion-reaction symptoms generally occur after the end of the 2–hour intravenous infusion and resolve after 2 to 4 hours with supportive therapy including acetaminophen, diphenhydramine, and intravenous fluids. Fewer infusion-related events are observed after the second dose^{01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdomen enlarged ^{01}(swelling of abdominal or stomach area; full or bloated feeling or pressure in the stomach )
    
abdominal pain ^{01}
    
anorexia ^{01}(loss of appetite; weight loss )
    
arthralgia ^{01}( pain, swelling, or redness in joints; muscle pain or stiffness ; difficulty in moving)
    
asthenia ^{01}(lack or loss of strength)
    
back pain ^{01}
    
constipation ^{01}
    
cough increased ^{01}
    
depression ^{01}(mood or mental changes )
    
diarrhea ^{01}( increase in bowel movements; loose stools; soft stools)
    
dizziness ^{01}
    
dyspepsia ^{01}(acid or sour stomach; belching; heartburn; indigestion; stomach discomfort upset)
    
insomnia ^{01}(sleeplessness; trouble sleeping ; unable to sleep)
    
local skin reactions ^{01}(dry, red, hot, or irritated skin)
    
nonspecific skin rash ^{01}
    
pain ^{01}
    
pharyngitis ^{01}
    
pulmonary physical finding, including
    
rales
    
rhonchi
    
and changes in breath sounds ^{01}
    
rhinitis ^{01}(stuffy nose; runny nose; sneezing )

Incidence less frequent
    
Antibody formation



Those not indicating need for medical attention
Incidence less frequent
    
immune response ^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
General supportive measures should be followed in case of overdose. Blood pressure and blood counts should be carefully monitored. Gemtuzumab ozogamicin is not dialyzable^{01}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Gemtuzumab ozogamicin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to gemtuzumab ozogamicin or any of its components: anti-CD33 antibody, calicheamicin derivatives, or inactive ingredients

Pregnancy—Use is not recommended because of potential harm to fetus; advisability of using contraception and informing physician immediately if pregnancy is suspected.





Breast-feeding—Not recommended because of potential serious adverse effects.





Use in the elderly—Patients 60 years old and older may more consistently have laboratory parameters associated with hepatic dysfunction than patients less than 60 years old while receiving gemtuzumab ozogamicin.
Other medications, especially other bone marrow depressants or previous cytotoxic drug or radiation therapy
Other medical problems, especially bone marrow depression, infection, chickenpox, and herpes zoster

Proper use of this medication

» Proper dosing

Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs

» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
Signs of potential side effects, especially anemia, bleeding events (including epistaxis), cerebral hemorrhage, disseminated intravascular coagulation, intracranial hemorrhage, hematuria, ecchymosis, hepatotoxicity (including hyperbilirubinemia, hepatic veno-occlusive disease, and abnormal levels in ALT and AST), hypokalemia, hypomagnesemia, infections (including sepsis, pneumonia, and Herpes simplex), infusion-related reactions (including chills, fever, nausea or vomiting, dyspnea, headache, hypotension, hypertension, hypoxia, and hyperglycemia), increased lactic dehydrogenase, mucositis or stomatitis, myelosuppression, neutropenic fever, peripheral edema, petechiae, renal failure, tachycardia, thrombocytopenia, tumor lysis syndrome, or vaginal hemorrhage


General Dosing Information
Gemtuzumab ozogamicin may be given peripherally or through a central line. A separate IV line equipped with a low protein-binding 1.2–micron terminal filter must be used for administration of the drug^{01}.

To reduce the incidence of post-infusion symptom complex, patients should receive diphenhydramine 50 mg orally and acetaminophen 650 to 1000 mg orally one hour prior to gemtuzumab ozogamicin administration; thereafter, two additional doses of acetaminophen 650 to 1000 mg orally every 4 hours as needed should be given^{01}.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of gemtuzumab ozogamicin. These may include: extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool and secretions for occult blood; care in use of toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Tumor lysis syndrome may be a consequence of leukemia treatment. Appropriate measures (e.g., hydration and allopurinol), must be taken to prevent hyperuricemia.^{01}
Procedures for handling and disposal of anticancer drugs should be considered^{01}. There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include
   • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves, goggles, gowns, and masks.
   • Pregnant personnel should not come in contact with antineoplastic medication containers or mixing supplies.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampules, and unused medication.
   • Use of proper technique in handling spills, including the use of dilute sodium hypochlorite solution (1% active chlorine) and water, and proper disposal of waste.


Parenteral Dosage Forms

GEMTUZUMAB OZOGAMICIN FOR INJECTION

Note: Gemtuzumab ozogamicin should not be administered as an intravenous push or bolus^{01}. Gemtuzumab ozogamicin should be administered under the supervision of physicians experienced in the treatment of acute leukemia and in facilities equipped to monitor and treat leukemia patients. ^{02}


Note: Physicians should consider leukoreduction with hydroxyurea or leukopheresis to reduce the white blood count to below 30,000 per microliter prior to administration^{02}


Usual Adult Dose
Leukemia, acute myeloid (treatment)
Intravenous infusion, 9 mg per square meter (mg/m²) administered over 2 hours^{01}. The recommended treatment course with gemtuzumab ozogamicin is a total of 2 doses with 14 days between the doses. Full recovery from hematologic toxicities is not a requirement for administration of the second dose^{01}.


Usual Pediatric Dose
Safety and efficacy have not been established^{01}.

Usual Geriatric Dose
See Usual adult dose.

Size(s) usually available:
U.S.—


5 mg of lyophilized powder per 20 mL single-vial package (Rx) [Mylotarg™ (dextran 40) ( sucrose) (sodium chloride) ( monobasic and dibasic sodium phosphate)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from light.^{01}

Preparation of dosage form:
All preparation of gemtuzumab ozogamicin should take place in a biologic safety hood with the fluorescent light off. Prior to reconstitution, allow drug vials to come to room temperature. Reconstitute the contents of the vial with 5 mL Sterile Water for Injection, USP, using sterile syringes. Gently swirl each vial. Each vial should be inspected for complete solution and for particulate matter. The final concentration of drug in the vial is 1 mg per mL. Withdraw the desired volume from each vial and inject into a 100 mL IV bag of 0.9% Sodium Chloride Injection. Place the 100–mL IV bag into an UV protection bag^{01}.

Stability:
While in the vial, the reconstituted drug may be stored in the refrigerator and protected from light for up to 8 hours. The diluted drug solution in the IV bag should be used immediately^{01}.

Incompatibilities:
No physical biochemical compatibility studies have been conducted to evaluate the coadministration of gemtuzumab ozogamicin with other agents. Gemtuzumab ozogamicin should not be infused concomitantly in the same intravenous line with other agents.

Auxiliary labeling:
   • Keep from heat and light.

Developed: 08/28/2000
Revised: 08/22/2002

References

1. Product Information: Mylotarg™, gemtuzumab ozogamicin. Wyeth Laboratories, Philadelphia, PA, (PI revised 5/2000) reviewed 7/2000.
   

2. Product Information: Mylotarg™, gemtuzumab ozogamicin. Wyeth Laboratories, Philadelphia, PA, (PI revised 4/2001) reviewed 6/2001.
   

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