CD33-directed Immunoconjugate

Mylotarg

Approved 1 Sept 2017Single-doseVial

Indications

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 ).

1.1Newly-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.

1.2Relapsed 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.

Contraindications

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 ).

Warnings and precautions

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 ).

Indications

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 ).

1.1Newly-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.

1.2Relapsed 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.

Contraindications

Warnings and precautions

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 ).

Pregnancy and breastfeeding

8.1Pregnancy 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.

Adverse reactions

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 .

6.1Clinical 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.

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Mylotarg

Indications

1.1Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML)

1.2Relapsed or Refractory CD33-positive AML

Contraindications

Warnings and precautions

Two medicines in one question?

Mylotarg

Indications

1.1Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML)

1.2Relapsed or Refractory CD33-positive AML

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD)

5.2Infusion-Related Reactions (Including Anaphylaxis) Life-threatening

5.3Hemorrhage

5.4QT Interval Prolongation

5.5Use in AML with Adverse-Risk Cytogenetics

5.6Embryo-Fetal Toxicity Based

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information

At a glance