Mylotarg (Gemtuzumab Ozogamicini) - Warnings and Precautions

WARNINGS

Mylotarg should be administered under the supervision of physicians experienced in the treatment of acute leukemia and in facilities equipped to monitor and treat leukemia patients.

There are no controlled trials demonstrating efficacy and safety using Mylotarg in combination with other chemotherapeutic agents. Therefore, Mylotarg should only be used as single agent chemotherapy and not in combination chemotherapy regimens outside clinical trials.

Myelosuppression: Severe myelosuppression will occur in all patients given the recommended dose of this agent. Careful hematologic monitoring is required. Systemic infections should be treated.

Hypersensitivity Reactions Including Anaphylaxis, Infusion Reactions, Pulmonary Events: Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis), and other infusion-related reactions which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal. In most cases, infusion-related symptoms occurred during the infusion or within 24 hours of administration of Mylotarg and resolved.

Mylotarg infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of further Mylotarg treatment should be strongly considered for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome. Since patients with high peripheral blast counts may be at greater risk for such reactions, physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to below 30,000/μL prior to administration of Mylotarg.

Infusion Reactions: Mylotarg can produce a post-infusion symptom complex of fever and chills, and less commonly hypotension and dyspnea that may occur during the first 24 hours after administration. Grade 3 or 4 non-hematologic infusion-related adverse events included chills, fever, hypotension, hypertension, hyperglycemia, hypoxia, and dyspnea. Most patients received the following prophylactic medications before administration: diphenhydramine 50 mg po and acetaminophen 650-1000 mg po; thereafter, two additional doses of acetaminophen 650-1000 mg po, one every 4 hours as needed. Vital signs should be monitored during infusion and for the four hours following infusion.

In clinical studies, these symptoms generally occurred after the end of the 2-hour intravenous infusion and resolved after 2 to 4 hours with a supportive therapy of acetaminophen, diphenhydramine, and IV fluids. Fewer infusion-related events were observed after the second dose.

Pulmonary Events: Severe pulmonary events leading to death have been reported infrequently with the use of Mylotarg in the postmarketing setting. Signs, symptoms and clinical findings include dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, and acute respiratory distress syndrome. These events occur as sequelae of infusion reactions; patients with WBC counts≥ 30,000/μL may be at increased risk. (See Infusion Reactions section of WARNINGS.) Physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to below 30,000/μL prior to administration of Mylotarg. Patients with symptomatic intrinsic lung disease may also be at greater risk of severe pulmonary reactions.

Hepatotoxicity: Hepatotoxicity, including severe VOD, has been reported in association with the use of Mylotarg as a single agent, as part of a combination chemotherapy regimen, and in patients without a history of liver disease or HSCT. Patients who receive Mylotarg either before or after HSCT, patients with underlying hepatic disease or abnormal liver function, and patients receiving Mylotarg in combinations with other chemotherapy may be at increased risk for developing VOD, including severe VOD. Patients who had received HSCT before Mylotarg were at a higher risk of VOD (22%) than patients who had not been transplanted (1%). Patients who had received HSCT following Mylotarg were at a higher risk of VOD (15%) than patients who had not been transplanted (1%). Death from liver failure and from VOD has been reported in patients who received Mylotarg. Physicians should monitor their patients carefully for symptoms of hepatotoxicity, particularly VOD. These symptoms can include: rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and/or liver enzymes. However, careful monitoring may not identify all patients at risk or prevent the complications of hepatotoxicity. (See ADVERSE REACTIONS section.)

Use in Patients with Hepatic Impairment: Mylotarg has not been studied in patients with bilirubin > 2 mg/dL. Extra caution should be exercised when administering Mylotarg in patients with hepatic impairment (see ADVERSE REACTIONS section).

Tumor Lysis Syndrome (TLS): TLS may be a consequence of leukemia treatment with any chemotherapeutic agent including Mylotarg. Renal failure secondary to TLS has been reported in association with the use of Mylotarg. Appropriate measures, (e.g. hydration and allopurinol), must be taken to prevent hyperuricemia. Physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood count to < 30,000/μL prior to administration of Mylotarg (see CLINICAL STUDIES section).

Pregnancy: Mylotarg may cause fetal harm when administered to a pregnant woman. Daily treatment of pregnant rats with gemtuzumab ozogamicin during organogenesis caused dose-related decreases in fetal weight in association with dose-related decreases in fetal skeletal ossification beginning at 0.025 mg/kg/day. Doses of 0.060 mg/kg/day (approximately 0.04 times the recommended human single dose on a mg/m² basis) produced increased embryo-fetal mortality (increased numbers of resorptions and decreased numbers of live fetuses per litter). Gross external, visceral, and skeletal alterations at the 0.060 mg/kg/day dose level included digital malformations (ectrodactyly, brachydactyly) in one or both hind feet, absence of the aortic arch, wavy ribs, anomalies of the long bones in the forelimb(s) (short/thick humerus, misshapen radius and ulna, and short/thick ulna), misshapen scapula, absence of vertebral centrum, and fused sternebrae. This dose was also associated with maternal toxicity (decreased weight gain, decreased food consumption). There are no adequate and well-controlled studies in pregnant women. If Mylotarg is used in pregnancy, or if the patient becomes pregnant while taking it, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Mylotarg.

PRECAUTIONS

DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS

General