Mylotarg

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

• If you have an allergy to gemtuzumab ozogamicin or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take Mylotarg or for 1 month after you stop this medicine.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Mylotarg with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Hard stools (constipation).
• Mouth irritation or mouth sores.
• Headache.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

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 children with acetaminophen 15 mg/kg (maximum of 650 mg), diphenhydramine 1 mg/kg (maximum of 50 mg), and 1 mg/kg methylprednisolone orally or intravenously; 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.

Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (combination regimen)

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.

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 as a single agent on Day 1, and 3 mg/m2 on Day 8.

For continuation, the recommended dose of Mylotarg is 2 mg/m2 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 of relapsed or refractory CD33-positive AML is 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 [see Clinical Studies (14.1)].

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) and Adverse Reactions (6)] may require dose interruptions or permanent discontinuation of Mylotarg Table 1 shows the dose modification guidelines for hematologic and nonhematologic 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

• 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 ambient temperature 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.
• Use reconstituted solution immediately or after being refrigerated at 2–8°C (36–46°F) for up to 1 hour. 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.
• Remove a volume of 0.9% Sodium Chloride Injection from the prefilled bag equal to the volume of Mylotarg product (mL) calculated above.
• Add the reconstituted solution to an infusion container with 0.9% Sodium Chloride Injection to make a total volume of 50 mL or 100 mL, depending on dose. 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, store at room temperature (15–25°C; 59–77°F) for up to 6 hours, which includes the 2-hour infusion time and 1-hour, if needed, to allow the refrigerated diluted solution to equilibrate to room temperature. The diluted solution can be refrigerated at 2–8°C (36–46°F) for up to 12 hours which includes up to 1-hour in the vial post-reconstitution. 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.
• 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.

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%) patients during or following treatment with Mylotarg, or following later hematopoietic stem cell transplantation (HSCT). The median time from the Mylotarg dose to onset of VOD was 9 days (range: 2–298 days), with 5 events occurring within 28 days of any dose of Mylotarg and 1 event occurring greater than 28 days after the last dose of Mylotarg. Three of the 6 VOD events were fatal. VOD was also reported in 2 patients in the control arm of ALFA-0701 after receiving Mylotarg as a therapy for relapsed AML.

In MyloFrance-1 (Mylotarg 3 mg/m2 on Days 1, 4 and 7), VOD events were reported in none of the 57 patients during or following treatment, or following HSCT after completion of Mylotarg treatment.

Based on an analysis across trials, the risk of VOD was higher in adult patients who received higher doses of Mylotarg as monotherapy, in patients with moderate or severe hepatic impairment prior to receiving Mylotarg, in patients treated with Mylotarg after HSCT, and in patients who underwent HSCT after treatment with Mylotarg. Patients who had moderate/severe hepatic impairment prior to treatment with Mylotarg were 8.7 times more likely to develop VOD compared to patients without moderate/severe hepatic impairment at baseline. Patients treated with Mylotarg for relapse after HSCT were 2.6 times more likely to develop VOD compared to patients without prior HSCT. Patients who underwent HSCT following Mylotarg treatment were 2.9 times more likely to develop VOD after HSCT compared to patients without HSCT following Mylotarg treatment. Although no relationship was found between VOD and time of HSCT relative to higher Mylotarg monotherapy doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of Mylotarg and HSCT. In MyloFrance-1, no patients underwent HSCT within 3.5 months of Mylotarg therapy.

Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of Mylotarg. After treatment with Mylotarg, monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate.

Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of Mylotarg [see Dosage and Administration (2.3)]. In patients who experience VOD, discontinue Mylotarg and treat according to standard medical practice.

Infusion-Related Reactions (Including Anaphylaxis)

Life-threatening or fatal infusion related-reactions can occur during or within 24 hours following infusion of Mylotarg [see Adverse Reactions (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)].

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 AML-19 (Mylotarg monotherapy at 6 mg/m2 Day 1 and 3 mg/m2 Day 8), all grades and Grade 3 or higher bleeding were reported in 28/111 (25%) and 14/111 (13%) patients, respectively. Fatal bleeding occurred in 1/111 (1%). In MyloFrance-1 (Mylotarg 3 mg/m2 as monotherapy), Grade 3 bleeding was reported in 4/57 (7%) patients, but no patient experienced Grade 4 hemorrhage.

Assess blood counts prior to each dose of Mylotarg and monitor blood counts frequently after treatment with Mylotarg until resolution of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with Mylotarg. Manage severe bleeding, hemorrhage or persistent thrombocytopenia using dose delay or permanent discontinuation of Mylotarg [see Dosage and Administration (2.2)], and provide supportive care per standard practice.

QT Interval Prolongation

QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. When administering Mylotarg to patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances, obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment and as needed during administration.

Use in AML with Adverse-Risk Cytogenetics

In subgroup analyses in ALFA-0701, the addition of Mylotarg to standard combination chemotherapy did not improve event-free survival in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). For patients being treated with Mylotarg in combination with daunorubicin and cytarabine for newly-diagnosed de novo AML, when cytogenetics testing results become available consider whether the potential benefit of continuing treatment with Mylotarg outweighs the risks for the individual patient.

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. In animal studies, gemtuzumab ozogamicin caused embryo-fetal toxicity, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with Mylotarg and for at least 6 months after the final dose of Mylotarg. Advise males with female partners of reproductive potential to use effective contraception during treatment with Mylotarg and for at least 3 months after the last dose of Mylotarg. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with Mylotarg [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)].

Newly-Diagnosed CD33-positive AML

Study ALFA-0701

Mylotarg in combination with chemotherapy was investigated in ALFA-0701 (NCT00927498), a multicenter, randomized, open-label Phase 3 study of 271 patients with newly-diagnosed de novo AML age 50 to 70 years. Patients were randomized (1:1) to receive induction therapy consisting of daunorubicin (60 mg/m2 on Days 1 to 3) and cytarabine (200 mg/m2 on Days 1 to 7) (DA) with (n=135) or without (n=136) Mylotarg 3 mg/m2 (up to maximum of one vial) on Days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone. Patients with response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on Day 1 of consolidation course 1; 60 mg/m2 on Days 1 and 2 of consolidation course 2) and cytarabine (1 g/m2 every 12 hours on Days 1 to 4) with or without Mylotarg 3 mg/m2 (up to a maximum of one vial) on Day 1 according to their initial randomization. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of Mylotarg and transplantation was recommended.

The median age of the patients was 62 years (range, 50–70), 137 female and 134 male, and 88% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender as a higher percentage of males were enrolled in the Mylotarg arm (55%) than in the DA alone arm (44%). Overall, 59%, 65%, and 70% of patients had documented favorable/intermediate risk and 33%, 27%, and 21% had poor/adverse disease by the National Comprehensive Cancer Network (NCCN), European LeukemiaNet (ELN), and cytogenetic risk classifications, respectively. CD33 expression on AML blasts by flow cytometry harmonized from local laboratory results was determined in 194/271 (72%) patients overall. Few patients (14%) had low CD33 expression (less than 30% of blasts), and none had no expression of CD33.

Efficacy was established on the basis of event-free survival (EFS), measured from the date of randomization until induction failure, relapse, or death by any cause. Per protocol, induction failure was defined as failure to achieve CR or CRp in induction, and date of induction failure was defined as date of marrow evaluation after the last course of induction. Median EFS was 17.3 months in the Mylotarg arm versus 9.5 months in the control arm; hazard ratio (HR) 0.56 (95% CI: 0.42–0.76); 2-sided p less than 0.001 by log-rank test.

In an exploratory analysis of EFS defined as failure to achieve CR in induction, relapse, or death from any cause and using the date of randomization as the date of induction failure, median EFS was 13.6 months for Mylotarg + DA and 8.8 months for DA with HR 0.68 (95% CI: 0.51–0.91).

The Kaplan-Meier plot for per-protocol EFS is shown in Figure 1. There was no statistically significant difference between treatment arms in overall survival.

Figure 1. Kaplan-Meier Plot of Event-Free Survival (mITT Population) ALFA-0701 Trial

Abbreviations: C=cytarabine; D=daunorubicin; GO=gemtuzumab ozogamicin; mITT=modified intent-to-treat.

Study AML-19

Mylotarg single-agent therapy was evaluated in Study AML-19 (NCT00091234), a multicenter, randomized, open-label Phase 3 study comparing Mylotarg to best supportive care (BSC) for patients with newly-diagnosed AML who were a) greater than 75 years of age or b) 61 to 75 years of age with a World Health Organization performance status (WHO PS) greater than 2 or were unwilling to receive intensive chemotherapy. Patients were randomized 1:1 and stratified by age (61–75 vs 76–80 years vs ≥ 81 years), CD33 positivity of bone marrow blasts (less than 20 % vs 20–80% vs greater than 80% vs unknown), initial white blood cell count (less than 30 vs greater than or equal to 30 × 109/L), WHO PS (0–1 vs 2 vs 3–4), and institution.

During induction, Mylotarg 6 mg/m2 was given on Day 1 and Mylotarg 3 mg/m2 was given on Day 8. Patients with no evidence of disease progression or significant toxicities after Mylotarg induction received continuation therapy as outpatients with up to 8 courses of treatment including Mylotarg 2 mg/m2 on Day 1 every 4 weeks. Patients continued therapy if they did not experience significant toxicities, relapse, or disease progression. BSC included standard supportive care measures and hydroxyurea or other anti-metabolites for palliative purposes.

In total, 118 patients were randomized to treatment with Mylotarg and 119 patients to BSC. Overall, the median age of patients was 77 years (range, 62–88 years), and most patients (65%) had a WHO PS of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender and cytogenetics. Compared to the BSC arm, the Mylotarg arm had a higher percentage of females (52% vs 39%) and patients with favorable/intermediate risk cytogenetics (50% vs 38%). The proportion with adverse cytogenetics was similar between arms (28% vs 27%). Fewer patients on the Mylotarg arm had missing cytogenetics data (22% vs 35%). CD33 expression on AML blasts by flow cytometry at a centralized location was determined in 235/237 (99%) patients; 10% had CD33 expression less than 20%.

The efficacy of Mylotarg was established on the basis of improvement in overall survival (OS). The hazard ratio (HR) for OS was 0.69 (95% CI: 0.53–0.90) (2-sided p=0.005 by log-rank test). Median OS was 4.9 months in the Mylotarg arm versus 3.6 months in the control arm.

Relapsed or refractory CD33-positive AML

Study MyloFrance-1

The efficacy of Mylotarg as a single agent was evaluated in MyloFrance-1 a phase 2, single-arm, open-label study in adults with CD33-positive AML in first relapse. Patients with secondary leukemia or a prior autologous or allogeneic stem cell transplantation were excluded. Study treatment included a single course of Mylotarg 3 mg/m2 on Days 1, 4, and 7. Consolidation therapy consisted of cytarabine intravenously every 12 hours for 3 days. The cytarabine dose was 3 g/m2 for patients less than 55 years old and 1 g/m2 for patients 55 years or older and/or patients with a creatinine clearance below 50 mL/minute. Hematopoietic stem cell transplantation (HSCT) was allowed after treatment with Mylotarg, but it was recommended to delay HSCT by at least 90 days following Mylotarg.

There were 57 patients treated with Mylotarg. Overall, the median age of patients was 64 years (range 22–80 years). The median duration of first remission was 10 months. Forty-four (78%) patients had intermediate-risk and 12 (22%) poor-risk cytogenetics.

The efficacy of Mylotarg was established on the basis of complete remission (CR) rate and duration of remission. Fifteen (26%; 95% CI 16% – 40%) patients achieved CR following a single course of Mylotarg. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.

Pfizer

NDC 0008-4510-01
Rx only

Mylotarg™
(gemtuzumab ozogamicin)
for Injection

4.5 mg/vial

For Intravenous Infusion Only

Single-dose vial.

No Preservatives
Discard unused portion.

Gemtuzumab ozogamicin is injected into a vein through an IV. A healthcare provider will give you this injection. Gemtuzumab ozogamicin is sometimes given in combination with other cancer medicines.

You will be given other medications to help prevent serious side effects or an infusion reaction. Start and keep taking these medications exactly as your doctor has prescribed.

Gemtuzumab ozogamicin must be given slowly, and the infusion can take at least 2 hours to complete.

You will be watched closely for at least 1 hour after receiving this medicine, to make sure you do not have an infusion reaction.

Gemtuzumab ozogamicin is given in a treatment cycle, and you will receive it only on certain days of each cycle. Your doctor will determine how long to treat you with this medicine.

Gemtuzumab ozogamicin may cause serious or life-threatening liver problems, including veno-occlusive disease (blocked blood vessels in the liver that can lead to liver damage).

You will need frequent medical tests to be sure this medicine is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.