In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Eribulin Mesylate Injection and monitor these electrolytes periodically during therapy. Avoid Eribulin Mesylate Injection in patients with congenital long QT syndrome.
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
The following adverse reactions are discussed in detail in other sections of the labeling:
In clinical trials, Eribulin Mesylate Injection has been administered to 1963 patients including 467 patients exposed to Eribulin Mesylate Injection for 6 months or longer. The majority of the 1963 patients were women (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%).
Metastatic Breast Cancer
The most common adverse reactions (≥25%) reported in patients receiving Eribulin Mesylate Injection were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving Eribulin Mesylate Injection were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of Eribulin Mesylate Injection was peripheral neuropathy (5%).
The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either Eribulin Mesylate Injection (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received Eribulin Mesylate Injection and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving Eribulin Mesylate Injection and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.
Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received Eribulin Mesylate Injection in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony- stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received Eribulin Mesylate Injection.
Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received Eribulin Mesylate Injection. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.
Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of Eribulin Mesylate Injection-treated patients experienced Grade 2 or greater ALT elevation. One Eribulin Mesylate Injection-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to Eribulin Mesylate Injection.
Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the Eribulin Mesylate Injection-treated group:
Liposarcoma
The safety of Eribulin Mesylate Injection was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either Eribulin Mesylate Injection 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m2 (20%), 1000 mg/m2 (64%), or 1200 mg/m2 (16%) every 3 weeks. A total of 223 patients received Eribulin Mesylate Injection and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving Eribulin Mesylate Injection [see Clinical Studies (14.2)].
The most common adverse reactions (≥25%) reported in patients receiving Eribulin Mesylate Injection were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving Eribulin Mesylate Injection were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving Eribulin Mesylate Injection were neutropenia (4.9%) and pyrexia (4.5%). Permanent discontinuation of Eribulin Mesylate Injection for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of Eribulin Mesylate Injection were fatigue and thrombocytopenia (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%).
Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in the Eribulin Mesylate Injection-treated arm in Study 2.
Other clinically important adverse reactions occurring in ≥10% of the Eribulin Mesylate Injection-treated patients were:
Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in ≥5% to <10% of the Eribulin Mesylate Injection-treated group: