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MYLOTARG™ (gemtuzumab ozogamicin) Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

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/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.

In AAML0531, VOD events were reported in 25/520 (5%) pediatric patients in the MYLOTARG arm. VOD was fatal in 2 patients. Among 187 pediatric patients who underwent HSCT in the MYLOTARG arm, VOD occurred within 30 days post-HSCT in 20 (11%) patients.

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

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

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

5.2 Infusion-Related Reactions (Including Anaphylaxis)

Life-threatening or fatal infusion-related-reactions can occur during or within 24 hours following infusion of MYLOTARG [see Adverse Reactions (6)]. Signs and symptoms of infusion-related reactions may include fever, chills, hypotension, tachycardia, hypoxia and respiratory failure.

Premedicate prior to MYLOTARG infusion [see Dosage and Administration (2.1)]. Monitor vital signs frequently during infusion. Interrupt infusion immediately for patients who develop evidence of infusion reaction, especially dyspnea, bronchospasm, or hypotension. Monitor patients during and for at least 1 hour after the end of the infusion or until signs and symptoms completely resolve. Discontinue use of MYLOTARG in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension [see Dosage and Administration (2.2)].

5.3 Hemorrhage

MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia. In ALFA-0701, (MYLOTARG in combination with chemotherapy), all grades and Grade 3–4 bleeding events were reported in 118/131 (90%) and 27/131 (21%) patients, respectively. Fatal bleeding events (including cerebral hematoma, intracranial hematoma, and subdural hematoma) occurred in 4/131 (3%) patients. Thrombocytopenia with platelet counts less than 50 Gi/L persisting more than 42 days occurred in 19 (19%) patients in the induction phase [see Adverse Reactions (6)]. The proportion of patients with persistent thrombocytopenia increased with progressive treatment phases and was higher in patients treated with MYLOTARG plus chemotherapy than with chemotherapy alone [see Adverse Reactions (6)].

In AAML0531, fatal bleeding occurred in 3/520 (<1%) of the pediatric patients. Grade 3 or 4 bleeding was reported in 66/520 (13%) of the pediatric patients in the MYLOTARG arm.

In AML-19 (MYLOTARG monotherapy at 6 mg/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.

5.4 QT Interval Prolongation

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

5.5 Use in AML with Adverse-Risk Cytogenetics

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

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MYLOTARG and for at least 6 months after the final dose. 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 Use in Specific Populations (8.1, 8.3)].

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