Included as part of the PRECAUTIONS section.
Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD)
Hepatotoxicity, including life-threatening and sometimes fatal hepatic VOD events, have been reported in patients receiving MYLOTARG as a single agent or as part of a combination chemotherapy regimen [see ADVERSE REACTIONS].
In ALFA-0701, VOD events were reported in 6/131 (5%) patients during or following treatment with MYLOTARG, or following later hematopoietic stem cell transplantation (HSCT). The median time from the MYLOTARG dose to onset of VOD was 9 days (range: 2-298 days), with 5 events occurring within 28 days of any dose of MYLOTARG and 1 event occurring greater than 28 days after the last dose of MYLOTARG. Three of the 6 VOD events were fatal. VOD was also reported in 2 patients in the control arm of ALFA-0701 after receiving MYLOTARG as a therapy for relapsed AML.
In MyloFrance-1 (MYLOTARG 3 mg/m² on 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 MYLOTARG treatment.
Based on an analysis across trials, the risk of VOD was higher in adult patients who received higher doses of MYLOTARG as monotherapy, in patients with moderate or severe hepatic impairment prior to receiving MYLOTARG, in patients treated with MYLOTARG after HSCT, and in patients who underwent HSCT after treatment with MYLOTARG. Patients who had moderate/severe hepatic impairment prior to treatment with MYLOTARG were 8.7 times more likely to develop VOD compared to patients without moderate/severe hepatic impairment at baseline. Patients treated with MYLOTARG for relapse after HSCT were 2.6 times more likely to develop VOD compared to patients without prior HSCT. Patients who underwent HSCT following MYLOTARG treatment were 2.9 times more likely to develop VOD after HSCT compared to patients without HSCT following MYLOTARG treatment. Although no relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT. In MyloFrance-1, no patients underwent HSCT within 3.5 months of MYLOTARG therapy.
Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of MYLOTARG. After treatment with MYLOTARG, 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.
Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of MYLOTARG [see DOSAGE AND ADMINISTRATION]. In patients who experience VOD, discontinue MYLOTARG and treat according to standard medical practice.
Infusion-Related Reactions (Including Anaphylaxis)
Life-threatening or fatal infusion related-reactions can occur during or within 24 hours following infusion of MYLOTARG [see ADVERSE REACTIONS]. Signs and symptoms of infusion-related reactions may include fever, chills, hypotension, tachycardia, hypoxia and respiratory failure.
Premedicate prior to MYLOTARG infusion [see DOSAGE AND ADMINISTRATION]. 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 MYLOTARG in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension [see DOSAGE AND ADMINISTRATION].
MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia. In ALFA-0701, (MYLOTARG 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 Gi/L persisting more than 42 days occurred in 19 (19%) patients in the induction phase [see ADVERSE REACTIONS]. The proportion of patients with persistent thrombocytopenia increased with progressive treatment phases and was higher in patients treated with MYLOTARG plus chemotherapy than with chemotherapy alone [see ADVERSE REACTIONS].
In AML-19 (MYLOTARG 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 (MYLOTARG 3 mg/m² as monotherapy), Grade 3 bleeding was reported in 4/57 (7%) patients, but no patient experienced Grade 4 hemorrhage.
Assess blood counts prior to each dose of MYLOTARG and monitor blood counts frequently after treatment with MYLOTARG until resolution of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with MYLOTARG. Manage severe bleeding, hemorrhage or persistent thrombocytopenia using dose delay or permanent discontinuation of MYLOTARG [see DOSAGE AND ADMINISTRATION], and provide supportive care per standard practice.
QT Interval Prolongation
QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. When administering MYLOTARG 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.
Use In AML With Adverse-Risk Cytogenetics
In subgroup analyses in ALFA-0701, the addition of MYLOTARG 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 MYLOTARG 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 MYLOTARG outweighs the risks for the individual patient.
Based on its mechanism of action and findings from animal studies, MYLOTARG 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 MYLOTARG and for at least 6 months after the final dose of MYLOTARG. Advise males with female partners of reproductive potential to use effective contraception during treatment with MYLOTARG and for at least 3 months after the last dose of MYLOTARG. 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 MYLOTARG [see Use In Specific Populations, CLINICAL PHARMACOLOGY, and Nonclinical Toxicology].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies, rats were dosed weekly for 6 weeks with gemtuzumab ozogamicin at doses up to 7.2 mg/m²/week. After 6 weeks of dosing, rats developed oval cell hyperplasia in the liver, which is considered a potentially preneoplastic finding, at 7.2 mg/m²/week (approximately 16 times the exposure in patients at the maximum recommended dose, based on AUC). Other preneoplastic or neoplastic changes observed with other antibody-calicheamicin conjugates in rats included basophilic and/or eosinophilic altered cell foci and hepatocellular adenomas. The relevance of these animal findings to humans is uncertain.
Gemtuzumab ozogamicin was clastogenic in vivo in the bone marrow of mice that received single doses greater than or equal to 22.1 mg/m². This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl gamma calicheamicin dimethyl hydrazide (the released cytotoxic agent) was mutagenic in the bacterial reverse mutation assay and clastogenic in the in vitro micronucleus assay in human TK6 cells.
In a female fertility study, female rats were administered daily intravenous doses of gemtuzumab ozogamicin up to 1.08 mg/m² for 14 days before mating with untreated male rats. Significant decreases in the numbers of corpora lutea and implants were observed at 1.08 mg/m², and dose-related decreases and increases in the number of live and dead embryos were observed at doses tested (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC). Increased embryofetal lethality at ≥0.36 mg/m² was observed in the presence of maternal toxicity that included decreases in gestational body weight and food consumption. Additional findings in female reproductive organs (ovarian atrophy and decreased numbers of follicles associated with atrophy of the uterus, vagina and mammary glands) occurred in rats and monkeys after dosing with other antibody-calicheamicin conjugates.
Fertility was assessed in male rats administered daily intravenous doses of gemtuzumab ozogamicin from 0.12 to 1.08 mg/m² for 28 days, followed by mating with untreated females, either at the end of the dosing period or after a 9-week drug-free period. Male fertility index was decreased at doses ≥0.12 mg/m² (approximately 1.2 times the exposure in patients at the maximum recommended dose, based on AUC). Effects on testes and epididymides occurred at ≥0.12 mg/m², including smaller size and lower weights in addition to adverse effects on sperm. Partial recovery was noted for some effects. Additional effects in male reproductive organs occurred in repeat-dose toxicology studies and included effects on mammary gland, testes, and epididymides in rats at ≥2.4 mg/m²/week and effects on testes and epididymides in monkeys at 21.6 mg/m²/week. Testicular effects in male monkeys with other antibody-calicheamicin conjugates included degeneration of seminiferous tubules and decreased epididymidal sperm, which did not reverse following a 6-week drug-free period.
Use In Specific Populations
Based on its mechanism of action and findings from animal studies [see CLINICAL PHARMACOLOGY and Nonclinical Toxicology], MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on MYLOTARG 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 (see Data). If MYLOTARG is used during pregnancy, or if the patient becomes pregnant while taking MYLOTARG, 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.
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.
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 MYLOTARG and for at least 1 month after the final dose.
Females And Males Of Reproductive Potential
Based on animal studies, MYLOTARG can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations and Nonclinical Toxicology]. Verify the pregnancy status of females of reproductive potential prior to initiating MYLOTARG.
Advise females of reproductive potential to avoid becoming pregnant while receiving MYLOTARG. Advise females of reproductive potential to use effective contraception during treatment with MYLOTARG and for at least 6 months after the last dose [see Nonclinical Toxicology].
Advise males with female partners of reproductive potential to use effective contraception during treatment with MYLOTARG and for at least 3 months after the last dose [see Nonclinical Toxicology].
Based on findings in animals, MYLOTARG may impair fertility in females of reproductive potential [see Nonclinical Toxicology]. Males Based on findings in animals, MYLOTARG may impair fertility in males of reproductive potential [see Nonclinical Toxicology].
The safety and efficacy of MYLOTARG in combination with daunorubicin and cytarabine have not been established in the pediatric patients with newly-diagnosed de novo AML.
The safety and efficacy of MYLOTARG 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.
Use of MYLOTARG 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 MYLOTARG monotherapy in newly-diagnosed adult patients with AML is supported by a randomized controlled trial with 118 patients treated with MYLOTARG. 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.
Use of MYLOTARG 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.