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|drugClass=[[antineoplastic agent]] and [[mitotic Inhibitor]]
|drugClass=[[antineoplastic agent]] and [[mitotic Inhibitor]]
|indicationType=treatment
|indicationType=treatment
|indication=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
|indication=patients with [[breast cancer|metastatic breast cancer]] who have previously received at least two [[Chemotherapeutic agent|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.
|adverseReactions=[[alopecia]], Weight loss, [[constipation]], [[anorexia]], [[nausea]], [[anemia]], [[neutropenia]], [[ALT]]/[[SGPT]], [[arthralgia]], [[myalgia]], [[asthenia]], [[headache]], [[peripheral neuropathy]], [[fatigue]], [[fever]]
|adverseReactions=[[alopecia]], [[weight loss]], [[constipation]], [[anorexia]], [[nausea]], [[anemia]], [[neutropenia]], [[ALT]]/[[SGPT]] elevation, [[arthralgia]], [[myalgia]], [[asthenia]], [[headache]], [[peripheral neuropathy]], [[fatigue]], [[fever]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=====Recommended Dose====
|fdaLIADAdult=====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 Eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.  


====Dose Modification====
====Dose Modification====
Assess for [[peripheral neuropathy]] and obtain complete [[blood cell counts]] prior to each dose.
*Assess for [[peripheral neuropathy]] and obtain [[complete blood cell counts]] prior to each dose.


=====Recommended dose delays=====
=====Recommended dose delays=====
*Do not administer HALAVEN on Day 1 or Day 8 for any of the following:
'''Do not administer Eribulin on Day 1 or Day 8 for any of the following:'''
**[[ANC]] < 1,000/mm3  
*[[ANC]] < 1,000/mm3  
**[[Platelets]] < 75,000/mm3  
*[[Platelets]] < 75,000/mm3  
**Grade 3 or 4 non-hematological toxicities.
*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.
'''The Day 8 dose may be delayed for a maximum of 1 week.'''
**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.
*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 Eribulin at a reduced dose and initiate the next cycle no sooner than 2 weeks later.


=====Recommended dose reductions=====
=====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.
*If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume Eribulin at a reduced dose as set out in Table 1.
Do not re-escalate HALAVEN dose after it has been reduced.
*Do not re-escalate Eribulin dose after it has been reduced.


[[file:Dose modification Eribulin.png|none|400px]]
[[file:Dose modification Eribulin.png|none|400px]]


====Instructions for Preparation and Administration====
====Instructions for Preparation and Administration====
*Aseptically withdraw the required amount of HALAVEN from the single-use vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
*Aseptically withdraw the required amount of Eribulin from the single-use 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.  
*Do not dilute in or administer through an intravenous line containing solutions with dextrose.  
*Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C).  Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration.
*Do not administer in the same intravenous line concurrent with the other medicinal products.  
*Store undiluted Eribulin in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C).  Store diluted solutions of Eribulin for up to 4 hours at room temperature or up to 24 hours under refrigeration.
*Discard unused portions of the vial.
*Discard unused portions of the vial.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Eribulin in adult patients.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Eribulin in adult patients.
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|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Eribulin in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Eribulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Eribulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Eribulin in pediatric patients.
|contraindications=None
|contraindications=*None
|warnings=====Neutropenia====
|warnings=====Neutropenia====
Severe [[neutropenia]] ([[ANC]] < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with [[alanine aminotransferase]] or [[aspartate aminotransferase]] > 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]].
*Severe [[neutropenia]] ([[ANC]] < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with [[alanine aminotransferase]] or [[aspartate aminotransferase]] > 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]].
 
*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 and reduce subsequent doses in patients who experience [[febrile neutropenia]] or Grade 4 [[neutropenia]] lasting longer than 7 days.  Clinical studies of Eribulin did not include patients with baseline [[neutrophil]] counts below 1,500/mm3.
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.  Clinical studies of HALAVEN did not include patients with baseline [[neutrophil counts]] below 1,500/mm3.


====Peripheral Neuropathy====
====Peripheral Neuropathy====
Grade 3 [[peripheral neuropathy]] occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. [[Peripheral neuropathy]] was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). [[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). Monitor patients closely for signs of [[peripheral motor neuropathy]] and [[sensory neuropathy]].  Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral [[neuropathy]] until resolution to Grade 2 or less.  
*Grade 3 [[peripheral neuropathy]] occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.
*[[Peripheral neuropathy]] was the most common toxicity leading to discontinuation of Eribulin (5% of patients; 24/503).  
*[[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).
*Monitor patients closely for signs of [[peripheral motor neuropathy]] and [[sensory neuropathy]].   
*Withhold Eribulin in patients who experience Grade 3 or 4 peripheral [[neuropathy]] until resolution to Grade 2 or less.  


====Embryo-Fetal Toxicity====
====Embryo-Fetal Toxicity====
There are no adequate and well-controlled studies of HALAVEN in pregnant women.  HALAVEN is a [[microtubule inhibitor]]; therefore, it is expected to cause fetal harm when administered to a pregnant woman.  Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area.  If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.
*There are no adequate and well-controlled studies of Eribulin in pregnant women.   
*Eribulin is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman.   
*Embryo-fetal toxicity and [[teratogenicity]] occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area.   
*If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.


====Prolongation====
====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 antiarrhythmics]] and [[Class III antiarrhythmics]], and [[electrolyte abnormalities]]. Correct [[hypokalemia]] or [[hypomagnesemia]] prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital [[long QT syndrome]].
*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 [[antiarrhythmics|Class Ia antiarrhythmics]] and [[antiarrhythmics|Class III antiarrhythmics]], and [[electrolyte abnormalities]]. Correct [[hypokalemia]] or [[hypomagnesemia]] prior to initiating Eribulin and monitor these electrolytes periodically during therapy. Avoid Eribulin in patients with congenital [[long QT syndrome]].
|clinicalTrials=The following adverse reactions are discussed in detail in other sections of the labeling:
|clinicalTrials=The following adverse reactions are discussed in detail in other sections of the labeling:
*[[Neutropenia]].  
*[[Neutropenia]].  
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*[[QT interval prolongation]].
*[[QT interval prolongation]].


The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were [[neutropenia]], [[anemia]], [[asthenia]]/[[fatigue]], [[alopecia]], [[peripheral neuropathy]], [[nausea]], and [[constipation]]. The most common serious adverse reactions reported in patients receiving HALAVEN were [[febrile neutropenia]] (4%) and [[neutropenia]] (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was [[peripheral neuropathy]] (5%).  
*The most common adverse reactions (≥25%) reported in patients receiving Eribulin were [[neutropenia]], [[anemia]], [[asthenia]]/[[fatigue]], [[alopecia]], [[peripheral neuropathy]], [[nausea]], and [[constipation]]. The most common serious adverse reactions reported in patients receiving Eribulin were [[febrile neutropenia]] (4%) and [[neutropenia]] (2%). The most common adverse reaction resulting in discontinuation of Eribulin was [[peripheral neuropathy]] (5%).  
 
<br>
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.  
<i>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.</i>
 
*In clinical trials, Eribulin has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to Eribulin for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years).  The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years).  The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
*The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either Eribulin (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  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 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.
 
The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (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 HALAVEN, 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 HALAVEN 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.


[[file:Eribulin AR1.png|none|400px]]
[[file:Eribulin AR1.png|none|400px]]


====Cytopenias====
====Cytopenias====
Grade 3 [[neutropenia]] occurred in 28% (143/503) of patients who received HALAVEN 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 HALAVEN.   
*Grade 3 neutropenia occurred in 28% (143/503) of patients who received Eribulin 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.   


====Peripheral Neuropathy====
====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 HALAVEN. 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]].
*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.  
*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====
====Liver Function Test Abnormalities====
Among patients with Grade 0 or 1 [[ALT]] levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater [[ALT]] elevation. One HALAVEN-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 HALAVEN.
*Among patients with Grade 0 or 1 [[ALT]] levels at baseline, 18% of Eribulin-treated patients experienced Grade 2 or greater [[ALT]] elevation. *One Eribulin-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.


====Less Common Adverse Reactions====
====Less Common Adverse Reactions====
The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group:
'''The following additional adverse reactions were reported in ≥5% to <10% of the Eribulin-treated group:'''
 
*Eye Disorders: increased [[lacrimation]]
*Eye Disorders: increased [[lacrimation]]
*Gastrointestinal Disorders: [[dyspepsia]], [[abdominal pain]], [[stomatitis]], [[dry mouth]]
*Gastrointestinal Disorders: [[dyspepsia]], [[abdominal pain]], [[stomatitis]], [[dry mouth]]
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*Psychiatric Disorders: [[insomnia]], [[depression]]
*Psychiatric Disorders: [[insomnia]], [[depression]]
*Skin and Subcutaneous Tissue Disorders: [[rash]]
*Skin and Subcutaneous Tissue Disorders: [[rash]]
|postmarketing=The following adverse drug reactions have been identified during post-approval of HALAVEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
|postmarketing=<i>The following adverse drug reactions have been identified during post-approval of Eribulin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</i>
 
*Blood and Lymphatic System Disorders: [[lymphopenia]]
*Blood and Lymphatic System Disorders: [[lymphopenia]]
*Gastrointestinal Disorders: [[pancreatitis]]
*Gastrointestinal Disorders: [[pancreatitis]]
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*Respiratory, thoracic and mediastinal disorders: [[interstitial lung disease]]
*Respiratory, thoracic and mediastinal disorders: [[interstitial lung disease]]
*Skin and Subcutaneous Tissue Disorders: [[pruritus]]
*Skin and Subcutaneous Tissue Disorders: [[pruritus]]
|drugInteractions=====Effects of Other Drugs on HALAVEN====
|drugInteractions=====Effects of Other Drugs on Eribulin====
No drug-drug interactions are expected with [[CYP3A4 inhibitors]], [[CYP3A4 inducers]] or [[P-glycoprotein]] ([[P-gp]]) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when HALAVEN was administered with or without [[ketoconazole]] (a strong inhibitor of [[CYP3A4]] and a [[P-gp inhibitor]]) and when HALAVEN was administered with or without [[rifampin]] (a [[CYP3A4 inducer]]).
*No drug-drug interactions are expected with [[CYP3A4 inhibitors]], [[CYP3A4 inducers]] or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when Eribulin was administered with or without [[ketoconazole]] (a strong inhibitor of [[CYP3A4]] and a P-gp inhibitor) and when Eribulin was administered with or without [[rifampin]] (a [[CYP3A4 inducer]]).


====Effects of HALAVEN on Other Drugs====
====Effects of Eribulin on Other Drugs====
Eribulin does not inhibit [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]] or [[CYP3A4]] enzymes or induce [[CYP1A2]], [[CYP2C9]], [[CYP2C19]] or [[CYP3A4]] enzymes at relevant clinical concentrations.  Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
*Eribulin does not inhibit [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]] or [[CYP3A4]] enzymes or induce [[CYP1A2]], [[CYP2C9]], [[CYP2C19]] or [[CYP3A4]] enzymes at relevant clinical concentrations.  Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
|overdose=Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 [[neutropenia]] lasting seven days and a Grade 3 [[hypersensitivity reaction]] lasting one day. There is no known antidote for HALAVEN overdose.
|FDAPregCat=D
|useInPregnancyFDA=*There are no adequate and well-controlled studies with Eribulin in pregnant women.  Eribulin is a [[microtubule inhibitor]], therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
*In a 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 (mg/m2).  Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.
*Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.
|useInNursing=*It is not known whether Eribulin is excreted into human milk.  No studies in humans or animals were conducted to determine if Eribulin is excreted into milk.  Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from Eribulin, a decision should be made whether to discontinue nursing or to discontinue Eribulin taking into account the importance of the drug to the mother.
|useInPed=*The safety and effectiveness of Eribulin in pediatric patients below the age of 18 years have not been established.
|useInGeri=*Study 1 did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.  Of the 827 subjects who received the recommended dose and schedule of Eribulin in clinical studies, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.
|useInRenalImpair=*For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal [[renal function]]. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate [[renal impairment]]. The safety of Eribulin was not studied in patients with severe [[renal impairment]] ([[CrCl]] < 30 mL/min)
|useInHepaticImpair=*Administration of Eribulin at a dose of 1.1 mg/m2 to patients with mild [[hepatic impairment]] and 0.7 mg/m2 to patients with moderate [[hepatic impairment]] resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment ([[Child-Pugh]] A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment ([[Child-Pugh]] B). Eribulin was not studied in patients with severe hepatic impairment ([[Child-Pugh]] C)
|overdose=*Overdosage of Eribulin has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 [[neutropenia]] lasting seven days and a Grade 3 [[hypersensitivity reaction]] lasting one day. There is no known antidote for Eribulin overdose.
|drugBox={{Drugbox2
|drugBox={{Drugbox2
| Verifiedfields = changed
| Verifiedfields = changed
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<!--Clinical data-->
<!--Clinical data-->
| tradename = Halaven
| tradename = Eribulin
| Drugs.com = {{drugs.com|CDI|eribulin}}
| Drugs.com = {{drugs.com|CDI|eribulin}}
| MedlinePlus = a611007
| MedlinePlus = a611007
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| StdInChIKey = VEPHOPLDBFLPDL-KVWSPMLQSA-N
| StdInChIKey = VEPHOPLDBFLPDL-KVWSPMLQSA-N
}}
}}
|mechAction=Eribulin inhibits the growth phase of [[microtubules]] without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to [[G2]]/[[M]] [[cell-cycle]] block, disruption of [[mitotic spindles]], and, ultimately, [[apoptotic cell death]] after prolonged mitotic blockage.
|mechAction=*Eribulin inhibits the growth phase of [[microtubules]] without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to [[G2]]/[[M]] [[cell-cycle]] block, disruption of [[mitotic spindles]], and, ultimately, [[apoptotic cell death]] after prolonged mitotic blockage.
|structure=It has a molecular weight of 826.0 (729.9 for free base).  The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:
|structure=*It has a molecular weight of 826.0 (729.9 for free base).  The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:
[[file:Eribulin Structure.png|none|400px]]
[[file:Eribulin Structure.png|none|400px]]
|PK=The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2  to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of  0.25 mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin  at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%  Eribulin exposure after multiple dosing is comparable to that following a single dose.  No accumulation of eribulin is observed with weekly administration.  
|PK=*The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2  to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of  0.25 mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin  at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%  Eribulin exposure after multiple dosing is comparable to that following a single dose.  No accumulation of eribulin is observed with weekly administration.  


=====Metabolism=====
=====Metabolism=====
Unchanged eribulin was the major circulating species in plasma following administration of 14C‑eribulin to patients.  Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.  Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.
*Unchanged eribulin was the major circulating species in plasma following administration of 14C‑eribulin to patients.  Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.  Cytochrome P450 3A4 ([[CYP3A4]]) negligibly metabolizes eribulin in vitro.


=====Elimination=====
=====Elimination=====
Eribulin is eliminated primarily in feces unchanged.  After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.
*Eribulin is eliminated primarily in feces unchanged.  After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
Carcinogenicity studies have not been conducted with eribulin mesylate.


|alcohol=Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse [[lymphoma]] mutagenesis assays, and was [[clastogenic]] in an in vivo rat [[bone marrow]] micronucleus assay.
}}
__NOTOC__
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 461094948
| IUPAC_name = 2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9''H'',15''H''-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4''H'')-one
| image = Eribulin.svg
| width = 300


<!--Clinical data-->
The effects of Eribulin on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals.  However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of [[seminiferous epithelium]] with [[hypospermia]]/[[aspermia]]) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.
| tradename = Halaven
|clinicalStudies=*Study 1 was an open-label, randomized, multicenter trial of 762 patients with [[metastatic breast cancer]] who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen.  Patients were required to receive prior [[anthracycline]]- and [[taxane]]- based chemotherapy for adjuvant or [[metastatic disease]]. Patients were randomized (2:1) to receive Eribulin (n=508) or a single agent therapy selected prior to randomization (control arm, n=254).  Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. Eribulin was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle.  Eribulin-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% [[vinorelbine]], 18% [[gemcitabine]], 18% [[capecitabine]], 16% [[taxane]], 9% [[anthracycline]], 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
| Drugs.com = {{drugs.com|CDI|eribulin}}
*Patient demographic and baseline characteristics were comparable between the treatment arms.  The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa.  Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including [[estrogen receptor]] status (positive: 67%, negative: 28%), [[progesterone receptor]] status (positive: 49%, negative: 39%), [[HER2]]/[[neu]] receptor status (positive: 16%, negative: 74%), triple negative status ([[ER]]-,[[PR]]-,[[HER2]]/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the Eribulin and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
| MedlinePlus = a611007
*In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the Eribulin arm compared to the control arm (see Table 3).  An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to Eribulin, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).
| licence_EU = <!-- EMEA requires brand name -->
| licence_US = Eribulin
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = D
| pregnancy_category =  
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = Rx-only
| legal_status =  
| routes_of_administration = Intravenous
 
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =  


<!--Identifiers-->
[[file:Eribulin CS.png|none|400px]]
| CAS_number_Ref = {{cascite|changed|??}}
|howSupplied=*Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.
| CAS_number = 253128-41-5
|storage=*Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.
| ATC_prefix = L01
|packLabel=[[file:Eribulin Package.png|none|400px]]
| ATC_suffix = XX41
[[file:Eribulin Appearance.png|none|400px]]
| ATC_supplemental =  
|alcohol=*Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
| PubChem = 17755248
|brandNames=* Halaven
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =   
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21396142
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = LR24G6354G
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1237028
 
<!--Chemical data-->
| chemical_formula =  
| C=40 | H=59 | N=1 | O=11
| molecular_weight = 729.90 g/mol
| smiles = NC[C@@H](O)C[C@H]5O[C@H]4C[C@H]9O[C@@H](CC[C@@H]1O[C@H](CC1=C)CC[C@@]32O[C@@H]6[C@@H]8O[C@H](C2)[C@H](O3)[C@@H]8O[C@H]7CC[C@H](CC(=O)O[C@@H]4[C@H]5OC)O[C@H]67)C[C@@H](C)C9=C
| InChI = 1/C39H57NO12/c1-18-11-22-5-7-25-19(2)12-24(44-25)9-10-39-16-30-35(51-39)36-37(49-30)38(52-39)33-26(48-36)8-6-23(46-33)14-31(42)50-34-29(15-27(45-22)20(18)3)47-28(32(34)43-4)13-21(41)17-40/h18,21-30,32-38,41H,2-3,5-17,40H2,1,4H3/t18-,21+,22+,23-,24+,25+,26+,27-,28-,29+,30-,32+,33+,34+,35+,36+,37-,38+,39+/m1/s1
| InChIKey = VEPHOPLDBFLPDL-KVWSPMLQBN
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C39H57NO12/c1-18-11-22-5-7-25-19(2)12-24(44-25)9-10-39-16-30-35(51-39)36-37(49-30)38(52-39)33-26(48-36)8-6-23(46-33)14-31(42)50-34-29(15-27(45-22)20(18)3)47-28(32(34)43-4)13-21(41)17-40/h18,21-30,32-38,41H,2-3,5-17,40H2,1,4H3/t18-,21+,22+,23-,24+,25+,26+,27-,28-,29+,30-,32+,33+,34+,35+,36+,37-,38+,39+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VEPHOPLDBFLPDL-KVWSPMLQSA-N
}}
}}
{{SI}}
[[Category: Drug]]
{{CMG}}
[[Category: Chemotherapeutic agents]]
==Overview==
'''Eribulin''' is an anticancer drug marketed by [[Eisai Co.]] under the trade name '''Halaven'''. Eribulin [[mesylate]] was approved by the [[U.S. Food and Drug Administration]] on November 15, 2010, to treat patients with [[metastatic breast cancer]] who have received at least two prior chemotherapy regimens for late-stage disease, including both [[anthracycline]]- and [[taxane]]-based [[chemotherapy|chemotherapies]].<ref>{{cite press release | title = FDA approves new treatment option for late-stage breast cancer | publisher = USFDA | date = 2010-11-15 | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm | accessdate = November 15, 2010}}</ref> It was approved by [[Health Canada]] on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. <ref> [http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/nd_ad_2012_halaven_141946-eng.php Notice of Decision for HALAVEN]</ref>
 
Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including [[non-small cell lung cancer]], [[prostate cancer]] and [[sarcoma]].<ref>http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389</ref>
 
Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.
 
==Structure and mechanism==
Structurally, eribulin is a fully synthetic macrocyclic ketone [[analog (chemistry)|analogue]] of the marine sponge natural product [[halichondrin B]],<ref name="pmid11221827">{{cite journal | author = Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, [[Kishi Y]], Yu MJ, Littlefield BA | title = In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B | journal = Cancer Res. | volume = 61 | issue = 3 | pages = 1013–21 | year = 2001 | month = February | pmid = 11221827 | doi = | url =  }}</ref><ref name="isbn0-8493-1863-7">{{cite book | editor = Newman DJ, Kingston DGI, Cragg, GM | authorlink = | others = | title = Anticancer agents from natural products | edition = | language = | publisher = Taylor & Francis | location = Washington, DC | year = 2005 | chapter = Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B | author = Yu MJ, [[Kishi Y]], Littlefield BA | quote = | isbn = 0-8493-1863-7 | oclc = | doi = | url = | accessdate = }}</ref> the latter being a potent naturally-occurring [[mitotic inhibitor]] with a unique [[mechanism of action]] found in the ''[[Halichondria]]'' genus of [[demosponge|sponge]]s.<ref name="Hirata_1986">{{ cite journal | author = Hirata Y, Uemura D | title=Halichondrins - antitumor polyether macrolides from a marine sponge | journal=Pure Appl. Chem. | year = 1986 | volume = 58 | issue = 5 | pages = 701–710 | doi = 10.1351/pac198658050701}}</ref><ref name="pmid1874739">{{cite journal | author = Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E | title = Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data | journal = J. Biol. Chem. | volume = 266 | issue = 24 | pages = 15882–9 | year = 1991 | month = August | pmid = 1874739 | doi = | url =  }}</ref> Eribulin is a mechanistically-unique [[microtubule#Chemical effects on microtubule dynamics|inhibitor of microtubule dynamics]],<ref name="pmid16020666">{{cite journal | author = Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L | title = The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth | journal = Mol. Cancer Ther. | volume = 4 | issue = 7 | pages = 1086–95 | year = 2005 | month = July | pmid = 16020666 | doi = 10.1158/1535-7163.MCT-04-0345 | url =  }}</ref><ref name="pmid18645010">{{cite journal | author = Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA | title = Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase | journal = Mol. Cancer Ther. | volume = 7 | issue = 7 | pages = 2003–11 | year = 2008 | month = July | pmid = 18645010 | pmc = 2562299 | doi = 10.1158/1535-7163.MCT-08-0095 | url =  }}</ref> binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.<ref name="pmid20030375">{{cite journal | author = Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA | title = Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability | journal = Biochemistry | volume = 49 | issue = 6 | pages = 1331–7 | year = 2010 | month = February | pmid = 20030375 | pmc = 2846717 | doi = 10.1021/bi901810u | url =  }}</ref> Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.<ref name="pmid15313917">{{cite journal | author = Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, [[Kishi Y]], Yu MJ, Littlefield BA | title = Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389 | journal = Cancer Res. | volume = 64 | issue = 16 | pages = 5760–6 | year = 2004 | month = August | pmid = 15313917 | doi = 10.1158/0008-5472.CAN-04-1169 | url =  }}</ref><ref name="pmid21127197">{{cite journal | author = Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA | title = Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions | journal = Cancer Res. | volume = 71 | issue = 2 | pages = 496–505 | year = 2011 | month = January | pmid = 21127197 | doi = 10.1158/0008-5472.CAN-10-1874 | url =  }}</ref>
 
A new synthetic route to E7389 was published in 2009.<ref name="pmid19807076">{{cite journal | author = Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, [[Kishi Y]] | title = New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach | journal = J. Am. Chem. Soc. | volume = 131 | issue = 43 | pages = 15636–41 | year = 2009 | month = November | pmid = 19807076 | doi = 10.1021/ja9058475 | url =  }}</ref>
 
==References==
{{reflist|2}}
 
== External links ==
* [http://newdrugreview.com/index.php/anticancer-drugs/halaven-injection Eribulin Mesylate - Halaven (Brand Name Drug) (Original Approval Date FDA: November 15, 2010)]
 
{{Intracellular chemotherapeutic agents}}
 
[[Category:Antineoplastic drugs]]
 
{{antineoplastic-drug-stub}}
 
[[de:Eribulin]]
[[ja:エリブリン]]
[[pl:Eribulina]]

Latest revision as of 20:31, 18 August 2015

Eribulin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Eribulin is an antineoplastic agent and mitotic Inhibitor that is FDA approved 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.. Common adverse reactions include alopecia, weight loss, constipation, anorexia, nausea, anemia, neutropenia, ALT/SGPT elevation, arthralgia, myalgia, asthenia, headache, peripheral neuropathy, fatigue, fever..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dose

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

Dose Modification

Recommended dose delays

Do not administer Eribulin 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 Eribulin 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 Eribulin at a reduced dose as set out in Table 1.
  • Do not re-escalate Eribulin dose after it has been reduced.

Instructions for Preparation and Administration

  • Aseptically withdraw the required amount of Eribulin from the single-use 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 in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of Eribulin for up to 4 hours at room temperature or up to 24 hours under refrigeration.
  • Discard unused portions of the vial.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Eribulin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in pediatric patients.

Contraindications

  • None

Warnings

Neutropenia

Peripheral Neuropathy

  • Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.
  • Peripheral neuropathy was the most common toxicity leading to discontinuation of Eribulin (5% of patients; 24/503).
  • 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).
  • Monitor patients closely for signs of peripheral motor neuropathy and sensory neuropathy.
  • Withhold Eribulin in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity

  • There are no adequate and well-controlled studies of Eribulin in pregnant women.
  • Eribulin is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman.
  • Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area.
  • If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

Prolongation

Adverse Reactions

Clinical Trials Experience

The following adverse reactions are discussed in detail in other sections of the labeling:


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.

  • In clinical trials, Eribulin has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to Eribulin for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
  • The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either Eribulin (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 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 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

Peripheral Neuropathy

Liver Function Test Abnormalities

  • Among patients with Grade 0 or 1 ALT levels at baseline, 18% of Eribulin-treated patients experienced Grade 2 or greater ALT elevation. *One Eribulin-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.

Less Common Adverse Reactions

The following additional adverse reactions were reported in ≥5% to <10% of the Eribulin-treated group:

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval of Eribulin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions

Effects of Other Drugs on Eribulin

  • No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when Eribulin was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when Eribulin was administered with or without rifampin (a CYP3A4 inducer).

Effects of Eribulin on Other Drugs

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • There are no adequate and well-controlled studies with Eribulin in pregnant women. Eribulin is a microtubule inhibitor, therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • In a 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 (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.
  • Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eribulin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Eribulin during labor and delivery.

Nursing Mothers

  • It is not known whether Eribulin is excreted into human milk. No studies in humans or animals were conducted to determine if Eribulin is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from Eribulin, a decision should be made whether to discontinue nursing or to discontinue Eribulin taking into account the importance of the drug to the mother.

Pediatric Use

  • The safety and effectiveness of Eribulin in pediatric patients below the age of 18 years have not been established.

Geriatic Use

  • Study 1 did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of Eribulin in clinical studies, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.

Gender

There is no FDA guidance on the use of Eribulin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Eribulin with respect to specific racial populations.

Renal Impairment

  • For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of Eribulin was not studied in patients with severe renal impairment (CrCl < 30 mL/min)

Hepatic Impairment

  • Administration of Eribulin at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin was not studied in patients with severe hepatic impairment (Child-Pugh C)

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Eribulin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Eribulin in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Eribulin Administration in the drug label.

Monitoring

There is limited information regarding Eribulin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Eribulin and IV administrations.

Overdosage

  • Overdosage of Eribulin has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for Eribulin overdose.

Pharmacology

Template:Px
Eribulin
Systematic (IUPAC) name
2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
Identifiers
CAS number 253128-41-5
ATC code L01XX41
PubChem 17755248
Chemical data
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Mol. mass 729.90 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Licence data

US

Pregnancy cat.

D(US)

Legal status

[[Prescription drug|Template:Unicode-only]](US)

Routes Intravenous

Mechanism of Action

  • Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

Structure

  • It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:

Pharmacodynamics

There is limited information regarding Eribulin Pharmacodynamics in the drug label.

Pharmacokinetics

  • The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65% Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration.
Metabolism
  • Unchanged eribulin was the major circulating species in plasma following administration of 14C‑eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.
Elimination
  • Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of Eribulin on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

Clinical Studies

  • Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive Eribulin (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. Eribulin was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. Eribulin-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
  • Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-,PR-,HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the Eribulin and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
  • In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the Eribulin arm compared to the control arm (see Table 3). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to Eribulin, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).

How Supplied

  • Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.

Storage

  • Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Eribulin Patient Counseling Information in the drug label.

Precautions with Alcohol

  • Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Halaven

Look-Alike Drug Names

There is limited information regarding Eribulin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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