Eribulin Mesylate

Eribulin mesylate injection is a microtubule inhibitor 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. (
  1.1

  Me

  tastatic Breast Cancer

  Eribulin mesylate injection 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)

  ]

  .
  )
• Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. (
  1.2

  Liposarcoma

  Eribulin mesylate injection 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)

  ]

  .
  )

• Administer 1.4 mg/m² intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (
  2.1

  Recommended Dose

  The recommended dose of eribulin mesylate injection is 1.4 mg/m²administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

  The recommended dose of eribulin mesylate injection in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m²administered 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 eribulin mesylate injection in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m²administered 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 eribulin mesylate injection in patients with moderate or severe renal impairment (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m²administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle

  [

  see

  Use in Specific Populations (8.7)

  ]

  .
  )
• Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (
  2.1

  Recommended Dose

  The recommended dose of eribulin mesylate injection is 1.4 mg/m²administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

  The recommended dose of eribulin mesylate injection in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m²administered 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 eribulin mesylate injection in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m²administered 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 eribulin mesylate injection in patients with moderate or severe renal impairment (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m²administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle

  [

  see

  Use in Specific Populations (8.7)

  ]

  .
  )
• Do not mix with other drugs or administer with dextrose-containing solutions. (
  2.3

  Instructions for Preparation and Administration

  Aseptically withdraw the required amount of eribulin mesylate injection 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 eribulin mesylate injection 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 eribulin mesylate injection 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.
  )

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

• Lactation:  Do not breastfeed. (
  8.2

  Lactation

  Risk Summary

  There is no information regarding the presence of eribulin mesylate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies in animals were conducted.  Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with eribulin mesylate and for 2 weeks after the final dose.
  )
  
  
• Hepatic Impairment:  A lower starting dose is recommended for patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) were not studied. (
  8.6

  Hepatic Impairment

  Administration of eribulin mesylate at a dose of 1.1 mg/m²to patients with mild hepatic impairment and 0.7 mg/m²to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m²to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m²is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m²is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin mesylate was not studied in patients with severe hepatic impairment (Child-Pugh C)

  [see

  Dosage and Administration (2.1)

  ,

  Clinical Pharmacology (12.3)

  ]

  .
  )
  
  
• Renal Impairment: A lower starting dose is recommended for patients with moderate (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (
  8.7

  Renal Impairment

  For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting dose to 1.1 mg/m²

  [see

  Dosage and Administration (2.1)

  ,

  Clinical Pharmacology (12.3)

  ]

  .
  )

• Neutropenia
  :  Monitor peripheral blood cell counts and adjust dose as appropriate. (
  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 eribulin mesylate 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 eribulin mesylate 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 eribulin mesylate did not include patients with baseline neutrophil counts below 1,500/mm³.
  )
• Peripheral Neuropathy
  :  Monitor for signs of neuropathy. Manage with dose delay and adjustment. (
  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 eribulin mesylate (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 eribulin mesylate-treated patients. Peripheral neuropathy led to discontinuation of eribulin mesylate 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 eribulin mesylate in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to Grade 2 or less

  [

  see

  Dosage and Administration (2.2)

  ]

  .
  )
• Embryo-Fetal Toxicity
  :  Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (
  5.3

  Embryo

  -

  Fetal Toxicity

  Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman.  There are no adequate and well-controlled studies of eribulin mesylate in pregnant women. In animal reproduction studies, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate 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 eribulin mesylate and for 3.5 months following the final dose

  [see

  Use in Specific Populations (8.1)

  ]

  .
  ,
  8.1

  Pregnancy

  Risk Summary

  Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman

  [see

  Clinical Pharmacology (12.1)

  ]

  . There are no available data on the use of eribulin mesylate during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose

  [see Data]

  .  Advise pregnant women of the potential risk to a fetus.

  The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. Increased abortion and severe fetal external or soft tissue malformations, including the absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m²based on body surface area. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at doses at or above a maternally toxic dose of approximately 0.43 times the recommended human dose.
  ,
  8.3

  Females and Males of Reproductive Potential

  Contraception

  Females

  Based on findings from an animal reproduction study and its mechanism of action, eribulin mesylate can cause fetal harm when administered to a pregnant woman

  [see

  Use in Specific Populations (8.1)

  ]

  .  Advise females of reproductive potential to use effective contraception during treatment with eribulin mesylate and for at least 2 weeks following the final dose

  .

  Males

  Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with eribulin mesylate and for 3.5 months following the final dose.

  Infertility

  Males

  Based on animal data, eribulin mesylate may result in damage to male reproductive tissues leading to impaired fertility of unknown duration

  [see

  Nonclinical Toxicology (13.1)

  ].
  )
• QT Prolongation
  :  Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome. (
  5.4

  QT Prolongation

  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 and monitor these electrolytes periodically during therapy. Avoid eribulin mesylate in patients with congenital long QT syndrome.
  )