Dosage & Administration
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.
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.
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.
Premedication and Special Considerations
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- 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.
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- 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)].
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- Use appropriate measures to prevent tumor lysis syndrome.
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- For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to administration of MYLOTARG.
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/m2 on 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:
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- 3 mg/m2 for patients with body surface area (BSA) greater than or equal to 0.6 m2
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- 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)].
Dosage Modifications for Toxicities
Monitor blood counts frequently through resolution of cytopenias. Monitor blood counts and chemistries at least three times per week through recovery from treatment-related toxicities. Management of some adverse reactions [see Warnings and Precautions (5), Adverse Reactions (6)] may require dose interruptions or permanent discontinuation of MYLOTARG. Table 1 shows the dose modification guidelines for hematologic and nonhematologic toxicities.
| Hematologic and Nonhematologic Toxicities | Recommended Action |
|---|---|
| Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; VOD=veno-occlusive disease; ULN=upper limit of normal. | |
For patients receiving MYLOTARG in combination therapy | |
Persistent thrombocytopenia |
|
Persistent neutropenia |
|
For all patients receiving MYLOTARG (Monotherapy or in Combination) | |
VOD |
|
Total bilirubin greater than 2 × ULN, or AST and/or ALT greater than 2.5 × ULN |
|
Infusion-related reactions |
|
Other severe or life-threatening non-hematologic toxicities |
|
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
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- MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
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- Calculate the dose (mg) and number of vials of MYLOTARG required.
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- Prior to reconstitution, allow drug product vials to reach room temperature (up to 30°C) for approximately 5 minutes.
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- 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).
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- Gently swirl the vial to aid dissolution. DO NOT SHAKE.
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- 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.
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- MYLOTARG contains no bacteriostatic preservatives.
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- 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
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- 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:
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- 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.
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- 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.
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- Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.
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- 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
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- Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG.
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- Protect the intravenous bag from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light.
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- 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).
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- Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.
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.
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/m2/day gemtuzumab ozogamicin during the period of organogenesis. Embryo-fetal toxicities including fetal growth retardation as evidenced by decreased live fetal weights, incidence of fetal wavy ribs and delayed skeletal ossification were observed at greater than or equal to 0.15 mg/m2/day. Increased embryo-fetal lethality and fetal morphological anomalies (digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae) were observed at greater than or equal to 0.36 mg/m2/day. All doses with embryo-fetal effects were observed in the presence of maternal toxicity that included decreases in gestational body weight gain, food consumption, and gravid uterine weight. The lowest dose at which embryo-fetal effects were observed in rats (0.15 mg/m2/day) was 0.4 times the exposure in patients at the maximum recommended human dose, based on AUC.
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.
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)].
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.
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.
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)].