SIDE EFFECTS

Mylotarg (gemtuzumab ozogamicin for injection) has been administered to 277 patients with relapsed AML at 9 mg/m² . Mylotarg (gemtuzumab ozogamicin for injection) was generally given as two intravenous infusions separated by 14 days.

Acute Infusion-Related Events (Table 3)

TABLE 3: NUMBER AND PERCENTAGE OF PATIENTS REPORTED TO HAVE ACUTE INFUSION-RELATED ADVERSE EVENTS (N = 277)

Fever and chills were commonly reported despite prophylactic treatment with acetaminophen and antihistamines (see WARNINGS section). Generally, these symptoms occurred at the end of the 2 hour infusion and resolved after 2 to 4 hours with supportive therapy including acetaminophen, diphenhydramine, and intravenous fluids. These events all occurred on the same day as gemtuzumab ozogamicin infusion. Fewer infusion-related events were observed after the second dose. Methylprednisolone given prior to Mylotarg (gemtuzumab ozogamicin for injection) infusion may ameliorate infusion-related symptoms.

Antibody Formation: Antibodies to gemtuzumab ozogamicin were not detected in any of the 277 patients, including the 20 patients who received more than 1 course of study drug, in the Phase 2 clinical studies. Two patients in a Phase 1 study developed antibody titers against the calicheamicin/calicheamicin-linker portion of gemtuzumab ozogamicin after three doses. One patient experienced transient fever, hypotension and dyspnea; the other patient had no clinical symptoms. No patient developed antibody responses to the hP67.6 antibody portion of Mylotarg (gemtuzumab ozogamicin for injection) .

Myelosuppression: Severe myelosuppression is the major toxicity associated with Mylotarg (gemtuzumab ozogamicin for injection) .

Neutropenia: During the treatment phase, 267/272 (98%) patients experienced Grade 3 or Grade 4 neutropenia. For all patients, the median times to ANC recovery at 500/μL for the CR and CRp patients were 40.0 and 43.0 days, respectively.

Anemia, Thrombocytopenia: During the treatment phase, 143/276 (52%) patients experienced Grade 3 or Grade 4 anemia and 272/276 (99%) patients experienced Grade 3 or Grade 4 thrombocytopenia. A summary of the platelet recovery for responding patients is provided in Table 4.

TABLE 4: MEDIAN TIME TO RECOVERY OF PLATELET COUNTS FOR ALL CR AND CRp PATIENTS (DAYS)

Infection: During the treatment phase, 84/277 (30%) patients experienced Grade 3 or Grade 4 infections, including opportunistic infections. The most frequent Grade 3 or Grade 4 infection-related treatment-emergent adverse events (TEAEs) were sepsis (17%), pneumonia (8%), shock (4%), infection (3%), stomatitis (2%), and herpes simplex (2%).

Bleeding: During the treatment phase, 36/277 (13%) patients experienced Grade 3 or Grade 4 bleeding. The most common bleeding events for all patients were epistaxis (3%), cerebral hemorrhage (2%), intracranial hemorrhage (1%), melena (1%), petechiae (1%), hematuria (1%), and disseminated intravascular coagulation (1%).

A greater proportion of NR patients (15%) experienced NCI grade 3 or 4 bleeding events compared with OR patients (7%). Among CR patients, 1 grade 3 bleeding event, epistaxis, was experienced. Bleeding events occurred in 1/35 CR patients and 4/36 CRp patients.

Transfusions: During the treatment phase, more transfusions were required in the NR and CRp patients compared with the CRs (Table 5):

TABLE 5: NUMBER OF TRANSFUSIONS BY RESPONSE GROUP

Mucositis: A total of 69/277 (25%) patients were reported to have a TEAE consistent with oral mucositis or stomatitis. During the treatment phase, 9/277 (3%) patients experienced Grade 3 or 4 stomatitis/mucositis after the first dose.

Hepatotoxicity: In clinical studies, 80/274 (29%) patients experienced Grade 3 or Grade 4 hyperbilirubinemia. 26/274 (9%) of patients experienced Grade 3 or Grade 4 abnormalities in levels of ALT, and 49/274 (18%) patients experienced Grade 3 or Grade 4 abnormalities in levels of AST. One patient died with liver failure in the setting of tumor lysis syndrome and multisystem organ failure 22 days after treatment. Another patient died after an episode of persistent jaundice and hepatosplenomegaly 156 days after treatment. Ascites, an event that can be associated with liver damage, was observed in 8 patients. Abnormalities of liver function were often transient and reversible.

VOD: A total of 299 courses of Mylotarg (gemtuzumab ozogamicin for injection) were administered in 277 relapsed patients and 16 episodes of VOD (in 15 patients) were identified (16/299, 5%). The incidence of VOD in patients treated with Mylotarg (gemtuzumab ozogamicin for injection) who had no prior or subsequent HSCT was 1.0%. The risk of developing VOD was 20% for patients with a history of HSCT prior to Mylotarg (gemtuzumab ozogamicin for injection) administration. In patients who received HSCT after Mylotarg (gemtuzumab ozogamicin for injection) administration, the risk of developing VOD was 15%. (See Table 6). In the 15 patients that developed VOD, 9 patients had fatal VOD or ongoing VOD at the time of death:

TABLE 6: INCIDENCE OF VOD REPORTED BY TREATMENT GROUPS

Skin:Pruritus was reported in 18/277 (6%) patients, while rash occurred in 51/277 (18%) patients. Cutaneous herpes simplex was reported in 59/277 (21%) patients. No patient experienced alopecia.

Early Mortality in Clinical Studies

The overall mortality rate within 28 days of last dose was 16% (44/277). The mortality rate was 14% (17/120) for patients who were < 60 years old, and 17% (27/157) for patients who were ≥ 60 years old.

Retreatment Events: Twenty (20) patients received additional courses of Mylotarg (gemtuzumab ozogamicin for injection) in the studies. One (1) patient received a total of 4 courses of treatment.

Dose Relationship for Adverse Events: Dose-relationship data were generated from a small dose-escalation study. The most common clinical adverse event observed in this study was an infusion-related symptom complex of fever and chills. In general, the severity of fever, but not chills, increased as the dose level increased. Only one dose level of Mylotarg (gemtuzumab ozogamicin for injection) was studied in the Phase 2 clinical trials in relapsed AML.

Treatment-Emergent Adverse Events (TEAE): TEAEs (Grades 1-4) that occurred in ≥ 10% of the patients regardless of causality are listed in Table 7.

TABLE 7: COMMONLY REPORTED ( ≥ 10%) TREATMENT-EMERGENT ADVERSE EVENTS BY AGE GROUP: NUMBER (%) OF PATIENTS

TEAEs of NCI grade 3 or 4 severity that occurred in part I of studies with an incidence of ≥ 10% in at least 1 age subgroup, are presented in Table 8.

TABLE 8: NUMBER (%) OF PATIENTS REPORTING NCI GRADE 3 OR 4 TREATMENT-EMERGENT ADVERSE EVENTS DURING PART I BY AGE GROUP: EVENTS WITH INCIDENCE ≥ 10%

Clinically important laboratory abnormalities with a Grade 3 or 4 severity are listed in Table 9

TABLE 9: NUMBER (%^a) OF PATIENTS WITH LABORATORY TEST RESULTS OF GRADE 3 OR 4 SEVERITY^b

There were considered to be no clinically important differences in TEAEs between patients < 60 years of age and those patients ≥ 60.

There were considered to be no clinically important differences in TEAEs between female and male patients.

Other Clinical Experience

In postmarketing experience and other clinical trials, additional cases of VOD have been reported, some in association with the use of other chemotherapeutic agents, underlying hepatic disease/abnormal liver function, or a history of prior or subsequent HSCT. Renal failure, renal failure secondary to TLS, renal impairment, hypersensitivity reactions (including bradycardia), anaphylaxis, pulmonary events, pulmonary hemorrhage, gastrointestinal hemorrhage, Budd Chiari Syndrome, portal vein thrombosis, and neutropenic sepsis have also been reported in association with the use of Mylotarg. (See WARNINGS section).

Observational Study: A prospective postmarketing registry study is being conducted to assess the safety of Mylotarg (gemtuzumab ozogamicin for injection) under conditions of routine clinical practice. The primary objectives is to estimate the incidence of hepatic veno-occlusive disease (VOD) among patients treated with Mylotarg (gemtuzumab ozogamicin for injection) . In an interim analysis of 225 patients, SAEs are presented according to an “events of special interest” (ESI) classification comprised of hepatic (including VOD), renal, infusion-related, pulmonary, and hypersensitivity events (Table 10).

There were 816 SAEs reported in 197/225 patients (87.6% of all patients). Of the SAEs, 159 were also ESIs reported in 64 (28.4%) patients. The percentage of patients experiencing a serious ESI was 9.8% (hepatic), 6.7% (renal), 8.0% (infusion-related), and 12.9% (pulmonary). Among the 816 SAEs, 225 (27.6%) were fatal events (multiple concurrent fatal events could be reported for a patient) reported in 134 (59.6%) patients. Using the ESI classification, there were 30 fatal ESIs reported in 19 (8.4%) patients.

In this registry, the incidence of VOD based on an independent review is 10.2% (23/225). Among patients with HSCT before or after Mylotarg (gemtuzumab ozogamicin for injection) infusion the incidence of VOD was 14.9% (10/67 patients). For patients without HSCT the VOD incidence was 8.2% (12/146 patients). HSCT status was not reported in 8.3% (19/225) of patients.

TABLE 10: SERIOUS ADVERSE EVENTS REPORTED IN THE MYLOTARG (gemtuzumab ozogamicin for injection) PROSPECTIVE OBSERVATIONAL STUDY (N=225)^a

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