Gemtuzumab Ozogamicin

MYLOTARG is a CD33-directed antibody and cytotoxic drug conjugate indicated for:

• treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients 1 month and older ( 1.1 ).
• treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years and older ( 1.2 ).

1.1 Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML) MYLOTARG is indicated for the treatment of newly-diagnosed CD33-positive acute myeloid leukemia in adults and pediatric patients 1 month and older.

1.2 Relapsed or Refractory CD33-positive AML MYLOTARG is indicated for the treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and pediatric patients 2 years and older.

For injection: 4.5 mg as a white to off-white lyophilized cake or powder in a single-dose vial for reconstitution and further dilution. For Injection: 4.5 mg as a lyophilized cake or powder in a single-dose vial for reconstitution and dilution ( 3 ).

MYLOTARG is contraindicated in patients with a history of hypersensitivity to the active substance in MYLOTARG or any of its components or to any of the excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . Hypersensitivity to MYLOTARG or any of its components ( 4 ).

• Infusion-related reactions (including anaphylaxis): Premedicate with a corticosteroid, acetaminophen, and diphenhydramine. Monitor patients during and for at least 1 hour after the end of the infusion. Interrupt the infusion, administer steroids or antihistamines, or permanently discontinue treatment as necessary ( 2.1 , 5.2 , 6 ).
• Hemorrhage: Severe, including fatal, hemorrhage may occur when MYLOTARG is used at recommended doses. Monitor platelet counts frequently ( 5.3 , 6.1 ).
• Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3 ).

5.1 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 (6) ]. In ALFA-0701, VOD events were reported in 6/131 (5%) adult 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/m 2 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. In AAML0531, VOD events were reported in 25/520 (5%) pediatric patients in the MYLOTARG arm. VOD was fatal in 2 patients. Among 187 pediatric patients who underwent HSCT in the MYLOTARG arm, VOD occurred within 30 days post-HSCT in 20 (11%) patients. 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 (2.3) ] . In patients who experience VOD, discontinue MYLOTARG and treat according to standard medical practice.

5.2 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 (6) ] . 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 (2.1) ] . 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 (2.2) ] .

5.3 Hemorrhage 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 (6) ] . 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 (6) ] . In AAML0531, fatal bleeding occurred in 3/520 (<1%) of the pediatric patients. Grade 3 or 4 bleeding was reported in 66/520 (13%) of the pediatric patients in the MYLOTARG arm. In AML-19 (MYLOTARG monotherapy at 6 mg/m 2 Day 1 and 3 mg/m 2 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/m 2 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 (2.2) ] , and provide supportive care per standard practice. 5.4 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.

5.5 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.

5.6 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. […]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity, including VOD [see Warnings and Precautions (5.1) ]
• Infusion-related reactions [see Warnings and Precautions (5.2) ]
• Hemorrhage [see Warnings and Precautions (5.3) ] The most common adverse reactions (greater than 15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, mucositis, febrile neutropenia, and decreased appetite ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Combination Therapy in Newly-Diagnosed De Novo CD33-positive AML The safety of MYLOTARG in first-line combination therapy was evaluated in two prospective clinical trials, Study ALFA-0701 in adults and Study AAML0531 in pediatric patients. Study ALFA-0701 The safety evaluation of MYLOTARG (3 mg/m 2 Day 1, 4 and 7 in combination with daunorubicin and cytarabine [DA]) in adults is based on data from ALFA-0701 for 131 patients treated with MYLOTARG plus DA and in 137 patients treated with DA alone [see Clinical Studies (14.1) ]. In this study, 123 patients received all 3 fractionated doses of MYLOTARG and 7 patients missed at least 1 dose, with a mean total dose administered during induction of 14.51 mg (range: 4.6–18.0). MYLOTARG was received by 91 (70%) patients in the MYLOTARG arm during Consolidation 1 and 64 (49%) patients in the MYLOTARG arm during Consolidation 2. Safety data consisting of selected TEAEs considered most important for understanding the safety profile of MYLOTARG as well as all adverse events (AEs) that led to the permanent discontinuation of treatment were retrospectively collected. The selected TEAEs consisted of all grades hemorrhages, all grades VOD, and severe infections. Discontinuation due to any adverse reaction occurred in 31% of patients in the MYLOTARG arm versus 7% in the DA arm. The most frequent (greater than or equal to 1%) adverse reactions for patients treated with MYLOTARG that led to permanent discontinuation were thrombocytopenia (15%), VOD (3%), and septic shock (2%). Fatal adverse reactions occurred in 8 patients (6%) in the MYLOTARG arm versus 3 patients (2%) in the DA arm. In the MYLOTARG arm, 3 patients died of VOD, 4 patients died of hemorrhage-related events (CNS hemorrhage, hemorrhagic shock), and 1 patient died of suspected cardiac cause. In the DA arm, 3 patients died of sepsis. Table 2. Selected Grade 3 and Higher Adverse Reactions in Patients with Newly-Diagnosed De Novo AML in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine (n, %) Daunorubicin + Cytarabine (n, %) Abbreviations: AML=acute myeloid leukemia; N=number of patients; PT=preferred term. Induction N = 131 N = 137 Infection Infection is a grouped term consisting of multiple preferred terms. 61 (47%) 53 (39%) Hemorrhage Hemorrhage is a grouped term consisting of multiple preferred terms. 24 (18%) 12 (9%) Veno-occlusive liver disease Veno-occlusive liver disease includes the following reported PTs: Veno-occlusive liver disease, veno-occlusive disease. 3 (2%) 0 Consolidation 1 N = 91 N = 103 Infection 50 (55%) 43 (42%) Hemorrhage 5 (5%) 0 Veno-occlusive liver disease 0 0 Consolidation 2 N = 64 N = 107 Infection 32 (50%) 54 (50%) Hemorrhage 4 (6%) 0 Veno-occlusive liver disease 0 0 All patients in ALFA-0701 developed severe neutropenia, thrombocytopenia and anemia. The incidence of Grade 3–4 thrombocytopenia that was prolonged in the absence of active leukemia was higher in patients treated with MYLOTARG (Table 3). Table 3. Prolonged Cytopenias Platelets less than 50 Gi/L or neutrophils less than

0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia. in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine (n/N, %) Daunorubicin + Cytarabine (n/N, %) Induction Prolonged thrombocytopenia 19/101 (19%) 7/97 (7%) Prolonged neutropenia 3/106 (3%) 0/101 (0%) Consolidation 1 Prolonged thrombocytopenia 21/87 (24%) 6/91 (7%) Prolonged neutropenia 3/88 (3%) 1/97 (1%) Consolidation 2 Prolonged thrombocytopenia 22/62 (35%) 25/103 (24%) Prolonged neutropenia 1/62 (2%) 2/105 (2%) Table 4 summarizes shifts in selected chemistry abnormalities by treatment arm for patients treated in ALFA-0701. Table 4. Chemistry Laboratory Values: Shifts in Subjects with Baseline Grade 2 or Lower Values in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine Daunorubicin + Cytarabine Laboratory Abnormality Subjects (n) with baseline Grade less than or equal to 2 Progressed to Grade greater than or equal to 3 (n, %) Subjects (n) with baseline Grade less than or equal to 2 Progressed to Grade greater than or equal to 3 (n, %) Hypophosphatemia 117 75 (64%) 127 52 (41%) Hypokalemia 127 73 (57%) 133 41 (31%) Hyponatremia 129 57 (44%) 134 36 (27%) Alkaline phosphatase increased 120 16 (13%) 128 7 (5%) Aspartate aminotransferase increased 126 18 (14%) 132 11 (8%) Alanine aminotransferase increased 124 13 (10%) 132 20 (15%) Blood bilirubin increased 119 9 (8%) 126 5 (4%) Study AAML0531 The safety evaluation of MYLOTARG in combination with chemotherapy in pediatric patients is based on data from AAML0531 [see Clinical Studies (14.1) ] in randomized and treated patients (N = 520 MYLOTARG and chemotherapy and N = 517 chemotherapy alone). In the MYLOTARG arm of this study, 520 patients received Induction 1 and 326 patients received Intensification 2. Safety data collected included only Grade 3 and 4 nonhematologic adverse events, deaths, VOD/SOS, and prolongation of neutropenia and thrombocytopenia. Table 5 shows the Grade 3 or 4 adverse reactions (≥5%) in the MYLOTARG + chemotherapy or chemotherapy alone arms in patients with newly-diagnosed de novo AML in AAML0531. In the MYLOTARG + chemotherapy arm, fatal adverse reactions (by grouped terms) were infection (14 [3%]), multi-organ failure (5 [1%]), anemia (1 [<1%]), and hemorrhage (3 [<1%]). In the chemotherapy arm, fatal adverse reactions included infection (7 [1%]), multi-organ failure (6 [1%]), hepatic failure (1 [<1%]), hypotension (3 [<1%]), and hemorrhage (3 [<1%]). Table 5. Grade 3 and Higher Adverse Reactions (≥5%) in Patients with Newly-Diagnosed De Novo AML in AAML0531 During Treatment Cycles with MYLOTARG Induction 1 Intensification 2 MYLOTARG + Chemotherapy N = 520 n (%) Chemotherapy alone N = 517 n (%) MYLOTARG + Chemotherapy N = 326 n (%) Chemotherapy alone N = 304 n (%) Infection Grouped term consisting of multiple preferred terms 186 (36%) 181 (35%) 220 (67%) 211 (69%) Febrile neutropenia 167 (32%) 157 (30%) 79 (24%) 68 (22%) Decreased appetite 78 (15%) 79 (15%) 61 (19%) 36 (12%) Hyperglycemia 59 (11%) 55 (11%) 36 (11%) 28 (9%) Mucositis 55 (11%) 64 (12%) 25 (8%) 15 (5%) Hypoxia 35 (7%) 26 (5%) 19 (6%) 22 (7%) Hemorrhage 36 (7%) 19 (4%) 19 (6%) 9 (3%) Transaminase Increased 33 (6%) 24 (5%) 23 (7%) 13 (4%) Diarrhea 21 (4%) 36 (7%) 15 (5%) 10 (3%) Nausea 21 (4%) 18 (4%) 23 (7%) 10 (3%) Hypotension 16 (3%) 26 (5%) 28 (9%) 23 (8%) The addition of MYLOTARG to chemotherapy was associated with a higher incidence of prolonged thrombocytopenia and neutropenia particularly when used in Intensification 2. During Intensification 2, prolonged thrombocytopenia (platelets <50 Gi/L lasting past cycle Day 42 in the absence of active leukemia) was reported in 64% (190/297) of patients in the MYLOTARG + chemotherapy arm compared with 55% (146/264) in the chemotherapy alone arm. Prolonged neutropenia (neutrophils <0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia) occurred in 47% (142/300) versus 43% (118/275) of patients, respectively. […]

Lactation: Advise not to breastfeed ( 8.2 ).

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] , MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on MYLOTARG use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, gemtuzumab ozogamicin caused embryo-fetal toxicity, including structural abnormalities and alterations to growth, 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 ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received daily intravenous doses up to 1.2 mg/m 2 /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/m 2 /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/m 2 /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/m 2 /day) was 0.4 times the exposure in patients at the maximum recommended human dose, based on AUC.

8.2 Lactation Risk Summary 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 serious adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with MYLOTARG and for at least 1 month after the final dose.

8.3 Females and Males of Reproductive Potential MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating MYLOTARG. Contraception Females 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 (13.1) ] . Males 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 (13.1) ] . Infertility Females Based on findings in animals, MYLOTARG may impair female fertility [see Nonclinical Toxicology (13.1) ] . Males Based on findings in animals, MYLOTARG may impair male fertility [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of MYLOTARG in combination with standard chemotherapy have been established in pediatric patients 1 month and older with newly-diagnosed de novo AML. The use of MYLOTARG for this indication is supported by evidence of effectiveness from adequate and well-controlled studies in adults with supportive data on safety and effectiveness in Study AAML0531 (NCT00372593) [see Adverse Reactions (6.1) , Clinical Studies (14.1) ]. AAML0531 included patients in the following age groups: 2 patients less than 27 days old, 94 patients 28 days to less than 2 years old, 225 patients 2 years to less than 12 years old, 175 patients 12 years old to less than 18 years old, and 36 patients 18 years or older in the MYLOTARG plus chemotherapy arm. The safety and effectiveness of MYLOTARG with standard chemotherapy in pediatric patients less than 1 month of age with newly-diagnosed de novo AML have not been established. The safety and effectiveness of MYLOTARG as a single agent in pediatric patients with newly-diagnosed AML have not been established. The safety and effectiveness 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. The information on this use is discussed throughout the labeling. The safety and effectiveness of MYLOTARG as a single agent in pediatric patients less than 2 years of age with relapsed or refractory AML have not been established.

8.5 Geriatric Use 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.

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.