What is mechanism of action?

mechanism of action is CD33-directed Antibody Interactions [MoA]

Mylotarg

(Gemtuzumab Ozogamicin)

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Dosage & Administration

* •Newly-diagnosed, de novo AML (combination regimen)

Adults

:
* -

Induction:

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

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG

[see Clinical Studies (14.2)]

).
* -

Consolidation:

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

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).

*

Pediatric patients 1 month and older

:
* -3 mg/m² for patients with body surface area (BSA) 0.6 m² or greater (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).
* -0.1 mg/kg for patients with BSA less than 0.6 m² (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).
* -See Full Prescribing Information for complete dosing information (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).

* •Newly-diagnosed AML (single-agent regimen):

Adults

:
* -

Induction:

6 mg/m² (not limited to one 4.5 mg vial) on Day 1 and 3 mg/m² (not limited to one 4.5 mg vial) on Day 8 (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).
* -

Continuation:

For patients without evidence of disease progression following induction, up to 8 continuation courses of MYLOTARG 2 mg/m² (not limited to one 4.5 mg vial) on Day 1 every 4 weeks (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).

* •Relapsed or refractory AML (single-agent regimen):
* Adults and pediatric patients 2 years and older:
* -3 mg/m² (up to one 4.5 mg vial) on Days 1, 4, and 7 (

2.2 Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Adults

[see Clinical Studies (14.1)]

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine

For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.

For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is:

* •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
* •0.1 mg/kg for patients with BSA less than 0.6 m²

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle

[see Clinical Studies (14.1)].

[see Adverse Reactions (6.1)]

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy

[see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

[see Clinical Studies (14.2)]

).

* •Premedicate with a corticosteroid, antihistamine, and acetaminophen (

2.1 Premedication and Special Considerations

* •Premedicate adults with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or intravenously 1 hour prior to MYLOTARG dosing and 1 mg/kg methylprednisolone or an equivalent dose of an alternative corticosteroid within 30 minutes prior to infusion of MYLOTARG.
* •Premedicate pediatric patients 1 month and older with acetaminophen 15 mg/kg (maximum of 650 mg) and diphenhydramine 1 mg/kg (maximum of 50 mg) 1 hour prior to MYLOTARG dosing, and 1 mg/kg methylprednisolone orally or intravenously within 30 minutes prior to infusion of MYLOTARG; additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pretreatment dose. Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction, such as fever, chills, hypotension, or dyspnea during the infusion or within 4 hours afterwards

[see Warnings and Precautions (5.2)]

.
* •Use appropriate measures to prevent tumor lysis syndrome.
* •For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to administration of MYLOTARG.

Mylotarg Prescribing Information

Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of MYLOTARG as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for signs and symptoms of VOD after treatment with MYLOTARG. (

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/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 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.

and

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/m²Day 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
InfectionInfection is a grouped term consisting of multiple preferred terms.	61 (47%)	53 (39%)
HemorrhageHemorrhage is a grouped term consisting of multiple preferred terms.	24 (18%)	12 (9%)
Veno-occlusive liver diseaseVeno-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 CytopeniasPlatelets 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 (%)
InfectionGrouped 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. The prolonged cytopenias were associated with more deaths in remission in the MYLOTARG + chemotherapy arm (29 [5%]) compared to the chemotherapy alone arm (15 [3%]).

VOD events were reported in 25 (5%) patients in the MYLOTARG + chemotherapy arm as well as 25 (5%) of the chemotherapy alone arm. VOD was fatal in 2 (<1%) and 7 (1%) patients in the MYLOTARG + chemotherapy arm and chemotherapy alone arm, respectively.

Monotherapy for Newly-Diagnosed CD33-positive AML

The safety evaluation of MYLOTARG (6 mg/m²then 3 mg/m², with 7 days between the doses) as monotherapy is based on a randomized, open-label, Phase 3 trial of MYLOTARG (N=118) versus best supportive care (BSC) (N=119) in patients with previously untreated AML who were considered ineligible for intensive chemotherapy in Study AML-19

[see Clinical Studies (14.1)].

The overall incidence of any Grade adverse reactions reported in AML-19 was 87% in the MYLOTARG arm and 90% in the BSC arm. The incidence of Grade greater than or equal to 3 adverse reactions was 61% in the MYLOTARG arm and 68% in the BSC arm. Death due to any Adverse Event was reported in the MYLOTARG arm of 19 (17%) compared to the BSC arm of 23 (20%).

Table 6. Selected Adverse Reactions in AML-19
	MYLOTARG n=111		Best Supportive Care n=114
	Any Grade	Grade ≥3	Any Grade	Grade ≥3
Liver	57 (51%)	8 (7%)	52 (46%)	7 (6%)
Fatigue	51 (46%)	13 (12%)	69 (61%)	24 (21%)
Infection	49 (44%)	39 (35%)	48 (42%)	39 (34%)
Cardiac	31 (28%)	7 (6%)	37 (33%)	16 (14%)
Bleeding	28 (25%)	14 (13%)	34 (30%)	14 (12%)
Febrile neutropenia	20 (18%)	20 (18%)	27 (24%)	27 (24%)
Metabolic	18 (16%)	4 (4%)	17 (15%)	7 (6%)
Renal	7 (6%)	4 (4%)	9 (8%)	5 (4%)

Monotherapy for Relapsed or Refractory CD33-positive AML

The adverse reactions described in this section reflect exposure to MYLOTARG 3 mg/m²on Days 1, 4 and 7 as monotherapy in 57 patients with relapsed AML treated on MyloFrance-1

[see Clinical Studies (14.1)]

. All 57 (100%) patients received the 3 planned doses of MYLOTARG.

During the treatment period, Grade 3 treatment-emergent adverse events (TEAEs) that occurred in greater than 1% patients included sepsis (32%), fever (16%), rash (11%), pneumonia (7%), bleeding (7%), mucositis (4%), pain (4%), diarrhea (2%), headaches (2%), tachycardia (2%), and lung edema (2%). No Grade 4 toxicity was observed. All grade TEAEs that occurred in greater than 15% of patients included fever (79%), infection (42%), increased AST (40%), bleeding (23%), nausea and vomiting (21%), constipation (21%), mucositis (21%), headache (19%), increased ALT (16%), and rash (16%). No infectious deaths occurred. Grade 1 or 2 hyperbilirubinemia developed in 4 (7%) patients. No episodes of VOD occurred. Seven patients received HSCT after MYLOTARG treatment. Three patients received an allogeneic BMT and 4 patients were treated with autologous BMT. No patients developed VOD following HSCT.

)

MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Calculate the dose (mg) and number of vials of MYLOTARG required.

Prior to reconstitution, allow drug product vials to reach

room temperature (up to 30°C)

for approximately 5 minutes.

Reconstitute each vial with 5 mL of Sterile Water for Injection, USP to obtain a concentration of 1 mg/mL of MYLOTARG that delivers 4.5 mL (4.5 mg).

Gently swirl the vial to aid dissolution. DO NOT SHAKE.

Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particles.

MYLOTARG contains no bacteriostatic preservatives.

If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 16 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) or up to 3 hours at room temperature (up to 30°C).

PROTECT FROM LIGHT. DO NOT FREEZE

Dilution

Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial(s) using a syringe. PROTECT FROM LIGHT. Discard any unused reconstituted solution left in the vial.

Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:

Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with 0.9% Sodium Chloride Injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.

Doses greater than or equal to 3.9 mg are to be diluted in a syringe or a polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP), non-PVC polyolefin, or ethylene vinyl acetate intravenous infusion bag in an appropriate volume of 0.9% Sodium Chloride Injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.

Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.

Following dilution with 0.9% Sodium Chloride Injection, MYLOTARG solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) and for up to 6 hours at room temperature (up to 30°C). The allowed time at room temperature (up to 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and the 2 hours needed to administer to the patient. PROTECT FROM LIGHT and DO NOT FREEZE.

Administration

Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG.

Protect the intravenous bag from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light.

Infuse the diluted solution over 2 hours using an infusion set made of polyvinyl chloride (PVC) with DEHP, PVC non-DEHP, polyethylene, or polyurethane. The infusion must be completed prior to the end of the allowed 6-hour storage of the diluted solution at room temperature (up to 30°C).

Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

)

•
Dosage and Administration, Instructions for Reconstitution, Dilution, and Administration ( 2.4 Instructions for Reconstitution, Dilution, and Administration Use appropriate aseptic technique for the reconstitution and dilution procedures. Protect the reconstituted and diluted MYLOTARG solution from light. Reconstitution
08/2021

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 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.
).
•treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years 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.
).

•Newly-diagnosed, de novo AML (combination regimen)

Adults
:
- -
  Induction:
  3 mg/m² (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
- -
  Consolidation:
  3 mg/m² on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
Pediatric patients 1 month and older
:
- -3 mg/m² for patients with body surface area (BSA) 0.6 m² or greater (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
- -0.1 mg/kg for patients with BSA less than 0.6 m² (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
- -See Full Prescribing Information for complete dosing information (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
•Newly-diagnosed AML (single-agent regimen):

Adults
:
- -
  Induction:
  6 mg/m² (not limited to one 4.5 mg vial) on Day 1 and 3 mg/m² (not limited to one 4.5 mg vial) on Day 8 (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
- -
  Continuation:
  For patients without evidence of disease progression following induction, up to 8 continuation courses of MYLOTARG 2 mg/m² (not limited to one 4.5 mg vial) on Day 1 every 4 weeks (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
•Relapsed or refractory AML (single-agent regimen):
Adults and pediatric patients 2 years and older:
- -3 mg/m² (up to one 4.5 mg vial) on Days 1, 4, and 7 (
  2.2 Recommended Dosage
  Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
  Adults
  The recommended dose of MYLOTARG in adults is 3 mg/m². A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles
  [see Clinical Studies (14.1)]
  .
  For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
  .
  For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
  For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m²on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
  Pediatric Patients 1 Month and Older
  The recommended dose of MYLOTARG in pediatric patients 1 month and older is:
  •3 mg/m²for patients with body surface area (BSA) greater than or equal to 0.6 m²
  •0.1 mg/kg for patients with BSA less than 0.6 m²
  For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle
  [see Clinical Studies (14.1)].
  No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2
  [see Adverse Reactions (6.1)]
  .
  Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
  A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy
  [see Clinical Studies (14.1)].
  For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m²(not limited to one 4.5 mg vial) on Day 8.
  For continuation, the recommended dose of MYLOTARG is 2 mg/m²(not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
  Relapsed or Refractory CD33-positive AML (Single-agent Regimen)
  The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m²(up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG
  [see Clinical Studies (14.2)]
  .
  ).
•Premedicate with a corticosteroid, antihistamine, and acetaminophen (
2.1 Premedication and Special Considerations
- •Premedicate adults with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or intravenously 1 hour prior to MYLOTARG dosing and 1 mg/kg methylprednisolone or an equivalent dose of an alternative corticosteroid within 30 minutes prior to infusion of MYLOTARG.
- •Premedicate pediatric patients 1 month and older with acetaminophen 15 mg/kg (maximum of 650 mg) and diphenhydramine 1 mg/kg (maximum of 50 mg) 1 hour prior to MYLOTARG dosing, and 1 mg/kg methylprednisolone orally or intravenously within 30 minutes prior to infusion of MYLOTARG; additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pretreatment dose. Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction, such as fever, chills, hypotension, or dyspnea during the infusion or within 4 hours afterwards
  [see Warnings and Precautions (5.2)]
  .
- •Use appropriate measures to prevent tumor lysis syndrome.
- •For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to administration of MYLOTARG.
).

Lactation: Advise not to breastfeed (

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.

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