Frequently asked questions about HALAVEN® for metastatic breast cancer (mBC)

HALAVEN (eribulin mesylate) Injection is indicated for the treatment of patients with metastatic breast cancer (mBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Warnings and Precautions

Neutropenia: Severe neutropenia (ANC <500/mm3) lasting >1 week occurred in 12% of patients with metastatic breast cancer (mBC). Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days.

Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.

QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

Adverse Reactions

In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).

Use in Specific Populations

Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

Find out additional safety information for HALAVEN

The pivotal trial for HALAVEN is the Phase III, randomized, open-label, multicenter, multinational Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin) (EMBRACE) trial of HALAVEN vs Treatment of Physician’s Choice (TPC) in patients with metastatic breast cancer (mBC) (N=762). The primary endpoint was overall survival. Patients were randomized (2:1) to receive either HALAVEN 1.4 mg/m2 intravenously (IV) for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all breast cancer patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [including paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, and 10% other chemotherapy) and 3% hormonal therapy.1,2

HALAVEN is administered at 1.4 mg/m2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of HALAVEN in patients with metastatic breast cancer (mBC) with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2. For patients with mBC with moderate hepatic impairment (Child-Pugh B), the recommended dose of HALAVEN is 0.7 mg/m2. Finally, for patients with mBC with moderate or severe renal impairment, defined as having a creatinine clearance of 15 mL/min to 49 mL/min, the recommended dose of HALAVEN is 1.1 mg/m2 over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.1

Patients with metastatic breast cancer (mBC) should be assessed for peripheral neuropathy, and complete blood cell counts should be obtained prior to each dose.1

HALAVEN should not be administered on Days 1 or 8 for an absolute neutrophil count (ANC) of less than 1,000/mm3, platelets less than 75,000/mm3, or Grade 3 or 4 nonhematologic toxicities. The Day 8 dose may be delayed for a maximum of 1 week. However, if toxicities do not resolve or improve to Grade 2 or less in severity by Day 15, omit the dose. If toxicities resolve or improve to Grade 2 or less in severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.1

If a dose has been delayed for toxicities and toxicities have recovered to ≤Grade 2, HALAVEN may be resumed at a permanently reduced dose of 1.1 mg/m2 if any of the following occur: ANC is less than 500/mm3 for more than 7 days, ANC is less than 1,000/mm3 with fever or infection, platelets are less than 25,000/mm3, platelets are less than 50,000/mm3 requiring transfusion, nonhematologic Grade 3 or 4 toxicities, or omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity.1

For any event requiring permanent dose reduction while receiving the 1.1 mg/m2 dose, HALAVEN may be resumed at a permanently reduced dose of 0.7 mg/m2 once toxicities have recovered to ≤Grade 2. Discontinue HALAVEN for any event requiring permanent dose reduction while receiving the 0.7 mg/m2 dose.1

Based on preclinical studies, with its distinct binding profile, HALAVEN causes irreversible mitotic blockage resulting in apoptosis, leading to the destruction of many tumor cells. Additionally, based on preclinical studies in human breast cancer models, HALAVEN causes vascular remodeling, reducing hypoxic conditions within the tumor and promoting the epithelial phenotype. This ultimately inhibits the migration and invasive capacity of residual breast cancer cells.1,3-9

The HALAVEN $0 Co-Pay Program assists eligible commercially insured patients with the out-of-pocket costs of HALAVEN (co-payments and co-insurances). The $0 Co-Pay Program is part of the Eisai Assistance Program (EAP), which offers information about reimbursement and patient assistance programs. To learn more about the $0 Co-Pay Program and the EAP for HALAVEN, visit www.eisaireimbursement.com/hcp/halaven or call 1.866.61.EISAI (1.866.613.4724) to speak with an EAP hotline agent (Monday to Friday, 8 AM to 8 PM, ET).

For questions about HALAVEN, e-mail Eisai Medical Information at medinfo@eisai.com or call 1.888.274.2378

Indications

Metastatic Breast Cancer

HALAVEN (eribulin mesylate) Injection is indicated for the treatment of patients with metastatic breast cancer (mBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Liposarcoma

HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.

Important Safety Information

Warnings and Precautions

Neutropenia: Severe neutropenia (ANC <500/mm3) lasting >1 week occurred in 12% of patients with mBC and liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Febrile neutropenia occurred in 0.9% of patients with liposarcoma or leiomyosarcoma, and fatal neutropenic sepsis occurred in 0.9% of patients. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days.

Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC. Grade 3 peripheral neuropathy occurred in 3.1% of patients with liposarcoma and leiomyosarcoma receiving HALAVEN and neuropathy lasting more than 60 days occurred in 58% (38/65) of patients who had neuropathy at the last treatment visit. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.

QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

Adverse Reactions

In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).

In patients with liposarcoma and leiomyosarcoma receiving HALAVEN, the most common adverse reactions (≥25%) reported in patients receiving HALAVEN were fatigue (62%), nausea (41%), alopecia (35%), constipation (32%), peripheral neuropathy (29%), abdominal pain (29%), and pyrexia (28%). The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia (32%), hypokalemia (5.4%), and hypocalcemia (5%). Neutropenia (4.9%) and pyrexia (4.5%) were the most common serious adverse reactions. The most common adverse reactions resulting in discontinuation were fatigue and thrombocytopenia (0.9% each).

Use in Specific Populations

Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

Hepatic and Renal Impairment: A reduction in starting dose is recommended for patients with mild or moderate hepatic impairment and/or moderate or severe renal impairment.

References: 1. HALAVEN [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2016. 2. Cortes J, O'Shaughnessy J, Loesch D, et al; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923. 3. Towle MJ, Salvato KA, Wels BF, et al. Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res. 2011;71(2):496-505. 4. Kuznetsov G, Towle MJ, Cheng H, et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res. 2004;64(16):5760-5766. 5. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005;4(7):1086-1095. 6. Funahashi Y, Okamoto K, Adachi Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 2014;105(10):1334-1342. 7. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res. 2015;21(11):2445-2452. 8. Jiang J, Tang YL, Liang XH. EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther. 2011;11(8):714-723. 9. Yoshida T, Ozawa Y, Kimura T, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states. Br J Cancer. 2014;110(6):1497-1505.

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