Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin is an antineoplastic agent.1

General

Gemtuzumab ozogamicin is available in the following dosage form(s) and strength(s):

For injection: 4.5 mg as a lyophilized cake or powder in a single-dose vial for reconstitution and dilution.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Newly diagnosed de novo AML (combination regimen):

• Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine. 1

• Consolidation: 3 mg/m2 (up to one 4.5 mg vial) on Day 1 in combination with daunorubicin and cytarabine.1

Newly diagnosed AML (single-agent regimen):

• Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8.1

• Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks.1

Relapsed or refractory AML (single-agent regimen):

• 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7.1

Premedicate with a corticosteroid, antihistamine, and acetaminophen 1 hour prior to gemtuzumab ozogamicin.1

Contraindications

Hypersensitivity to gemtuzumab ozogamicin or any of its components.1

Warnings/Precautions

Hepatotoxicity, Including Veno-occlusive Liver Disease

Hepatotoxicity, including life-threatening and sometimes fatal hepatic veno-occlusive liver disease (VOD) events, have been reported in patients receiving gemtuzumab ozogamicin as a single agent or as part of a combination chemotherapy regimen.1

In ALFA-0701, VOD events were reported in 6/131 (5%) patients during or following treatment with gemtuzumab ozogamicin, or following later hematopoietic stem cell transplantation (HSCT). The median time from the gemtuzumab ozogamicin dose to onset of VOD was 9 days (range: 2–298 days), with 5 events occurring within 28 days of any dose of gemtuzumab ozogamicin and 1 event occurring greater than 28 days after the last dose of gemtuzumab ozogamicin. Three of the 6 VOD events were fatal. VOD was also reported in 2 patients in the control arm of ALFA-0701 after receiving gemtuzumab ozogamicin as a therapy for relapsed AML. 1

In MyloFrance-1 (gemtuzumab ozogamicin 3 mg/m2On Days 1, 4 and 7), VOD events were reported in none of the 57 patients during or following treatment, or following HSCT after completion of gemtuzumab ozogamicin treatment.1

Based on an analysis across trials, the risk of VOD was higher in adult patients who received higher doses of gemtuzumab ozogamicin as monotherapy, in patients with moderate or severe hepatic impairment prior to receiving gemtuzumab ozogamicin, in patients treated with gemtuzumab ozogamicin after HSCT, and in patients who underwent HSCT after treatment with gemtuzumab ozogamicin. Patients who had moderate/severe hepatic impairment prior to treatment with gemtuzumab ozogamicin were 8.7 times more likely to develop VOD compared to patients without moderate/severe hepatic impairment at baseline. Patients treated with gemtuzumab ozogamicin for relapse after HSCT were 2.6 times more likely to develop VOD compared to patients without prior HSCT. Patients who underwent HSCT following gemtuzumab ozogamicin treatment were 2.9 times more likely to develop VOD after HSCT compared to patients without HSCT following gemtuzumab ozogamicin treatment. Although no relationship was found between VOD and time of HSCT relative to higher gemtuzumab ozogamicin monotherapy doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of gemtuzumab ozogamicin and HSCT. In MyloFrance-1, no patients underwent HSCT within 3.5 months of gemtuzumab ozogamicin therapy. 1

Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of gemtuzumab ozogamicin. After treatment with gemtuzumab ozogamicin, monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate.1

Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of gemtuzumab ozogamicin. In patients who experience VOD, discontinue gemtuzumab ozogamicin and treat according to standard medical practice.1

Infusion-Related Reactions (Including Anaphylaxis)

Life-threatening or fatal infusion related-reactions can occur during or within 24 hours following infusion of gemtuzumab ozogamicin. Signs and symptoms of infusion-related reactions may include fever, chills, hypotension, tachycardia, hypoxia and respiratory failure.1

Premedicate prior to gemtuzumab ozogamicin infusion. Monitor vital signs frequently during infusion. Interrupt infusion immediately for patients who develop evidence of infusion reaction, especially dyspnea, bronchospasm, or hypotension. Monitor patients during and for at least 1 hour after the end of the infusion or until signs and symptoms completely resolve. Discontinue use of gemtuzumab ozogamicin in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension.1

Hemorrhage

Gemtuzumab ozogamicin is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia. In ALFA-0701, (gemtuzumab ozogamicin in combination with chemotherapy), all grades and Grade 3–4 bleeding events were reported in 118/131 (90%) and 27/131 (21%) patients, respectively. Fatal bleeding events (including cerebral hematoma, intracranial hematoma, and subdural hematoma) occurred in 4/131 (3%) patients. Thrombocytopenia with platelet counts less than 50,000/mm3 persisting more than 42 days occurred in 19 (19%) patients in the induction phase. The proportion of patients with persistent thrombocytopenia increased with progressive treatment phases and was higher in patients treated with gemtuzumab ozogamicin plus chemotherapy than with chemotherapy alone.1

In AML-19 (gemtuzumab ozogamicin monotherapy at 6 mg/m2 Day 1 and 3 mg/m2 Day 8), all grades and Grade 3 or higher bleeding were reported in 28/111 (25%) and 14/111 (13%) patients, respectively. Fatal bleeding occurred in 1/111 (1%). In MyloFrance-1 (gemtuzumab ozogamicin 3 mg/m2 as monotherapy), Grade 3 bleeding was reported in 4/57 (7%) patients, but no patient experienced Grade 4 hemorrhage. 1

Assess blood counts prior to each dose of gemtuzumab ozogamicin and monitor blood counts frequently after treatment with gemtuzumab ozogamicin until resolution of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with gemtuzumab ozogamicin. Manage severe bleeding, hemorrhage or persistent thrombocytopenia using dose delay or permanent discontinuation of gemtuzumab ozogamicin, and provide supportive care per standard practice.1

QT Interval Prolongation

QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. When administering gemtuzumab ozogamicin to patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances, obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment and as needed during administration.1

Use in AML with Adverse-Risk Cytogenetics

In subgroup analyses in ALFA-0701, the addition of gemtuzumab ozogamicin to standard combination chemotherapy did not improve event-free survival in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). For patients being treated with gemtuzumab ozogamicin 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 with gemtuzumab ozogamicin outweighs the risks for the individual patient.1

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, gemtuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, gemtuzumab ozogamicin caused embryo-fetal toxicity, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with gemtuzumab ozogamicin and for at least 6 months after the final dose of gemtuzumab ozogamicin. Advise males with female partners of reproductive potential to use effective contraception during treatment with gemtuzumab ozogamicin and for at least 3 months after the last dose of gemtuzumab ozogamicin. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with gemtuzumab ozogamicin.1

Specific Populations

Based on its mechanism of action and findings from animal studies, gemtuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on gemtuzumab ozogamicin 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 embryo-fetal toxicity at maternal systemic exposures that were greater than or equal to 0.4 times the exposure in patients at the maximum recommended dose, based on AUC. If gemtuzumab ozogamicin is used during pregnancy, or if the patient becomes pregnant while taking gemtuzumab ozogamicin, advise the patient of the potential risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.1

In an embryo-fetal development study in rats, pregnant animals received daily intravenous doses up to 1.2 mg/m2/day gemtuzumab ozogamicin during the period of organogenesis. Embryo-fetal toxicities including fetal growth retardation as evidenced by decreased live fetal weights, incidence of fetal wavy ribs and delayed skeletal ossification were observed at greater than or equal to 0.15 mg/m2/day. Increased embryo-fetal lethality and fetal morphological anomalies (digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae) were observed at greater than or equal to 0.36 mg/m2/day. All doses with embryo-fetal effects were observed in the presence of maternal toxicity that included decreases in gestational body weight gain, food consumption, and gravid uterine weight. The lowest dose at which embryo-fetal effects were observed in rats (0.15 mg/m2/day) was 0.4 times the exposure in patients at the maximum recommended human dose, based on AUC.1

There are 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. Because of the potential for adverse reactions in breastfed infants, women should not breastfeed during treatment with gemtuzumab ozogamicin and for at least 1 month after the final dose.1

Based on animal studies, gemtuzumab ozogamicin can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating gemtuzumab ozogamicin.1

Advise females of reproductive potential to avoid becoming pregnant while receiving gemtuzumab ozogamicin. Advise females of reproductive potential to use effective contraception during treatment with gemtuzumab ozogamicin and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with gemtuzumab ozogamicin and for at least 3 months after the last dose.1

Based on findings in animals, gemtuzumab ozogamicin may impair fertility in females of reproductive potential. Based on findings in animals, gemtuzumab ozogamicin may impair fertility in males of reproductive potential.1

The safety and efficacy of gemtuzumab ozogamicin in combination with daunorubicin and cytarabine have not been established in the pediatric patients with newly diagnosed de novo AML. 1

The safety and efficacy of gemtuzumab ozogamicin as a single agent in the pediatric patients with relapsed or refractory AML is supported by a single-arm trial in 29 patients in the following age groups: 1 patient 1 month to less than 2 years old, 13 patients 2 years to less than 12 years old, and 15 patients 12 years to 18 years old. A literature review included an additional 96 patients with ages ranging from 0.2 to 21 years. No differences in efficacy and safety were observed by age.1

Use of gemtuzumab ozogamicin in combination with daunorubicin and cytarabine in newly diagnosed adult patients with de novo AML is supported by a randomized, controlled trial that included 50 patients greater than or equal to 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Use of gemtuzumab ozogamicin monotherapy in newly diagnosed adult patients with AML is supported by a randomized controlled trial with 118 patients treated with gemtuzumab ozogamicin. All patients were over the age of 60 years and 65% of patients were above 75 years. No overall differences in effectiveness were observed by age. 1

Use of gemtuzumab ozogamicin as single-agent treatment of relapsed or refractory AML is supported by a single-arm trial that included 27 patients 65 years or older. No overall differences in effectiveness were observed between these patients and younger patients. Elderly patients experienced a higher rate of fever and severe or greater infections. 1

Common Adverse Effects

The most common adverse reactions (greater than 15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor. Rarely, some bleeding problems have been deadly.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Talk with your doctor before getting any vaccines. Use with gemtuzumab ozogamicin may either raise the chance of an infection or make the vaccine not work as well.
• Infusion reactions have happened with this medicine. Sometimes, these could be very bad or life-threatening. Talk with the doctor.
• Infusion reactions can happen up to 24 hours after gemtuzumab ozogamicin is given.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 3 months after care ends. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant while you take gemtuzumab ozogamicin or within 3 months after your last dose, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this medicine. Talk with your doctor.
• Use birth control that you can trust to prevent pregnancy while taking gemtuzumab ozogamicin and for 6 months after stopping this medicine.
• If you get pregnant while taking gemtuzumab ozogamicin or within 6 months after your last dose, call your doctor right away.

Call your doctor for instructions if you miss an appointment for your gemtuzumab ozogamicin injection.

Gemtuzumab ozogamicin can cause a serious heart problem, especially if you use certain medicines at the same time, such as antibiotics, antifungal medicine, antidepressants, anti-malaria medicine, asthma inhalers, antipsychotic medicine, certain HIV/AIDS medicine, heart or blood pressure medicine, or medicine to prevent vomiting. Tell your doctor about all your current medicines and any medicine you start or stop using.

Other drugs may interact with gemtuzumab ozogamicin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.