Halaven

HALAVEN- eribulin mesylate injection
Eisai Inc.

1 INDICATIONS AND USAGE

1.1 Me tastatic Breast Cancer

HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two 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 [see Clinical Studies (14.1)].

1.2 Liposarcoma

HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [ see Use in Specific Populations (8.6)].

The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [ see Use in Specific Populations (8.6)].

The recommended dose of HALAVEN in patients with moderate or severe renal impairment (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [ see Use in Specific Populations (8.7)].

2.2 Dose Modification

Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays

  • Do not administer HALAVEN on Day 1 or Day 8 for any of the following:
    – ANC < 1,000/mm3
    – Platelets < 75,000/mm3
    – Grade 3 or 4 non-hematological toxicities.
  • The Day 8 dose may be delayed for a maximum of 1 week.
    – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
    – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions

  • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.
  • Do not re-escalate HALAVEN dose after it has been reduced.
Table 1: Recommended Dose Reductions
Event Description Recommended HALAVEN Dose
Permanently reduce the 1.4 mg/m 2 HALAVEN dos e for any of the following: 1.1 mg/m2
ANC <500/mm3 for >7 days
ANC <1,000 /mm3 with fever or infection
Platelets <25,000/mm3
Platelets <50,000/mm3 requiring transfusion
Non-hematologic Grade 3 or 4 toxicities
Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity
Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2
Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN
ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE) version 3.0.

2.3 Instructions for Preparation and Administration

Aseptically withdraw the required amount of HALAVEN from the single-dose vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.

Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products.

Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration at 4°C (40°F). Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration at 4°C (40°F).

Discard unused portions of the vial.

3 DOSAGE FORMS AND STRENGTHS

Injection: 1 mg/2 mL (0.5 mg/mL) eribulin mesylate is a clear, colorless, sterile solution in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Neutropenia

In Study 1, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients. Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse Reactions (6.1)].

In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

In Study 2, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)].

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days [ see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy

In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1. Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days).

In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: 3.5 months to 9 months). Neuropathy lasting more than 60 days occurred in 58% (38/65) of patients. Sixty three percent (41/65) had not recovered within a median follow-up duration of 6.4 months (range: 27 days to 29 months).

Monitor patients closely 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 [ see Dosage and Administration (2.2)].

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