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EriBULin

Pronunciation

(er i BUE lin)

Index Terms

  • B1939
  • E7389
  • ER-086526
  • Eribulin Mesylate
  • Halichondrin B Analog

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as mesylate:

Halaven: 1 mg/2 mL (2 mL) [contains alcohol, usp]

Brand Names: U.S.

  • Halaven

Pharmacologic Category

  • Antineoplastic Agent, Antimicrotubular

Pharmacology

Eribulin is a non-taxane microtubule inhibitor which is a halichondrin B analog. It inhibits the growth phase of the microtubule by inhibiting formation of mitotic spindles causing mitotic blockage and arresting the cell cycle at the G2/M phase; suppresses microtubule polymerization yet does not affect depolymerization.

Distribution

Vd: 43 to 114 L/m2

Metabolism

Negligible

Excretion

Feces (~82%, predominantly as unchanged drug); urine (9%, primarily as unchanged drug)

Half-Life Elimination

~40 hours

Protein Binding

49% to 65%

Special Populations: Renal Function Impairment

Patients with moderate or severe renal impairment (CrCl 15 to 49 mL/minute) had systemic exposure increased 1.5-fold.

Special Populations: Hepatic Function Impairment

Exposures increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively.

Use: Labeled Indications

Breast cancer, metastatic: Treatment of metastatic breast cancer in patients who have received at least 2 prior chemotherapy regimens for the treatment of metastatic disease (prior treatment should have included an anthracycline and a taxane in either the adjuvant or metastatic setting)

Liposarcoma, unresectable or metastatic: Treatment of unresectable or metastatic liposarcoma in patients who have received a prior anthracycline-containing regimen

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling (not in US labeling): Hypersensitivity to eribulin mesylate, halichondrin B, or its chemical derivatives.

Dosing: Adult

Note: International Considerations: Some products available internationally may have vial strength and dosing expressed as the base (instead of as the salt). Refer to prescribing information for specific dosing information.

Breast cancer, metastatic: IV: Eribulin mesylate: 1.4 mg/m2 on days 1 and 8 of a 21-day treatment cycle

Liposarcoma, unresectable or metastatic: IV: Eribulin mesylate: 1.4 mg/m2 on days 1 and 8 of a 21-day treatment cycle

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: International Considerations: Some products available internationally may have vial strength and dosing expressed as the base (instead of as the salt). Refer to prescribing information for specific dosing information.

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 49 mL/minute: Reduce dose to eribulin mesylate 1.1 mg/m2.

ESRD (Canadian labeling): Use is not recommended.

Dosing: Hepatic Impairment

Note: International Considerations: Some products available internationally may have vial strength and dosing expressed as the base (instead of as the salt). Refer to prescribing information for specific dosing information.

Mild hepatic impairment (Child-Pugh class A): Reduce dose to eribulin mesylate 1.1 mg/m2.

Moderate hepatic impairment (Child-Pugh class B): Reduce dose to eribulin mesylate 0.7 mg/m2.

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's US labeling (has not been studied); use is not recommended in the Canadian labeling.

Dosing: Adjustment for Toxicity

Note: International Considerations: Some products available internationally may have vial strength and dosing expressed as the base (instead of as the salt). Refer to prescribing information for specific dosing information.

ANC <1,000/mm3 or platelets <75,000/mm3 or grade 3 or 4 nonhematologic toxicity on day 1 or 8: Withhold dose; may delay day 8 dose up to 1 week. If toxicity resolves to ≤ grade 2 by day 15 administer a reduced dose and wait at least 2 weeks before beginning the next cycle. Omit dose if not resolved to ≤ grade 2 by day 15. Do not re-escalate dose after reduction.

Permanently reduce dose from eribulin mesylate 1.4 mg/m2 to 1.1 mg/m2 for the following:

ANC <500/mm3 for >7 days

ANC <1000/mm3 with fever or infection

Platelets <25,000/mm3

Platelets <50,000/mm3 requiring transfusion

Nonhematologic toxicity of grade 3 or 4

Dose omission or delay due to toxicity on day 8 of prior cycle

Permanently reduce dose from eribulin mesylate 1.1 mg/m2 to 0.7 mg/m2 for occurrence of any of the above events; discontinue treatment if the above toxicities occur at the 0.7 mg/m2 dose level.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). No dilution required. May prepare by drawing into a syringe for administration or may dilute in 100 mL normal saline. Discard unused portion of vial.

Administration

IV: Infuse over 2 to 5 minutes. May be administered undiluted or diluted. Do not administer other medications through the same IV line, or through a line containing dextrose.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in normal saline; Incompatible: Dextrose

Storage

Store intact vials at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F); do not freeze. Store in original carton. Undiluted solutions in a syringe and solutions diluted in normal saline for infusion are stable for up to 4 hours at room temperature or up to 24 hours refrigerated at 4°C (40°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Fatigue (≤54%), peripheral neuropathy (35%; grades 3/4: ≤8%), headache (19%)

Dermatologic: Alopecia (45%)

Endocrine & metabolic: Weight loss (21%)

Gastrointestinal: Nausea (35%), constipation (25%), anorexia (20%), diarrhea (18%), vomiting (18%)

Hematologic & oncologic: Neutropenia (82%; grades 3: 28%; grade 4: 29%; nadir: 13 days; recovery: 8 days), anemia (58%; grades 3/4: 2%)

Hepatic: Increased serum ALT (18%)

Neuromuscular & skeletal: Weakness (≤54%), arthralgia (≤22%), myalgia (≤22%), back pain (16%), ostealgia (12%), limb pain (11%)

Respiratory: Dyspnea (16%), cough (14%)

Miscellaneous: Fever (21%)

1% to 10%:

Cardiovascular: Peripheral edema (≥5% to <10%)

Central nervous system: Depression (≥5% to <10%), dizziness (≥5% to <10%), insomnia (≥5% to <10%), myasthenia (≥5% to <10%)

Dermatologic: Skin rash (≥5% to <10%)

Endocrine & metabolic: Hypokalemia (≥5% to <10%)

Gastrointestinal: Mucosal inflammation (9%), abdominal pain (≥5% to <10%), dysgeusia (≥5% to <10%), dyspepsia (≥5% to <10%), stomatitis (≥5% to <10%), xerostomia (≥5% to <10%)

Genitourinary: Urinary tract infection (10%)

Hematologic & oncologic: Febrile neutropenia (5%), thrombocytopenia (grades 3/4: 1%)

Neuromuscular & skeletal: Muscle spasm (≥5% to <10%)

Ophthalmic: Increased lacrimation (≥5% to <10%)

Respiratory: Upper respiratory tract infection (≥5% to <10%)

<1% (Limited to important or life-threatening): Dehydration, drug-induced hypersensitivity, hepatotoxicity, hypomagnesemia, interstitial pulmonary disease, lymphocytopenia, pancreatitis, pneumonia, prolonged Q-T interval on ECG, sepsis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Hematologic toxicity, including severe neutropenia and neutropenic fever, has occurred. Neutropenic sepsis (fatal) has also been reported (case reports). May require treatment delay and dosage reduction. A higher incidence of grade 4 neutropenia and neutropenic fever occurred in patients with ALT or AST >3 x ULN or bilirubin >1.5 x ULN. Monitor complete blood counts prior to each dose; more frequently if severe cytopenias develop. Patients with baseline neutrophils <1,500/mm3 were not included in clinical studies.

• Peripheral neuropathy: Peripheral neuropathy commonly occurs. Peripheral neuropathy may be prolonged (>1 year in 5% of metastatic breast cancer patients and >60 days in close to 60% of liposarcoma patients); over 60% of liposarcoma patients with peripheral neuropathy had not recovered within a median follow-up of ~6 months in one clinical trial. The median time to the first occurrence of peripheral neuropathy (any severity) in liposarcoma patients was 5 months (range: 3.5 to 9 months). Monitor for signs of peripheral motor or sensory neuropathy. May require treatment delay or discontinuation. Some patients may have preexisting neuropathy due to prior chemotherapy; monitor closely for worsening neuropathy.

• QT prolongation: QT prolongation was observed on day 8 of eribulin therapy (in an uncontrolled study). Monitor ECG in patients with heart failure, bradyarrhythmia, with concomitant medication known to prolong the QT interval, or with electrolyte imbalance. Correct hypokalemia and hypomagnesemia prior to treatment; monitor electrolytes periodically during treatment. Avoid use in patients with congenital long QT syndrome.

Disease-related concerns:

• Hepatic impairment: Dosage reduction required in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment; use has not been studied in patients with severe hepatic impairment. Transaminase or bilirubin elevations are associated with a higher incidence of grade 4 neutropenia and neutropenic fever.

• Renal impairment: Dosage reduction required in patients with moderate or severe renal impairment (CrCl 15 to 49 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• International issues: Some products available internationally may have vial strength and dosing expressed as the base (instead of as the salt). Refer to prescribing information for specific dosing information.

Monitoring Parameters

CBC with differential prior to each dose (increase frequency with grades 3/4 cytopenias); renal and liver function tests; serum electrolytes, including potassium and magnesium. Assess for peripheral neuropathy prior to each dose. Monitor ECG in patients with heart failure, bradyarrhythmia, with concomitant medication known to prolong the QT interval, and electrolyte abnormalities (eg, hypokalemia, hypomagnesemia).

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Based on its mechanism of action, eribulin would be expected to cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception to avoid pregnancy during eribulin treatment and for at least 2 weeks following the last eribulin dose; males with female partners of reproductive potential should use effective contraception during eribulin treatment and for 3.5 months following the last dose. The Canadian labeling recommends effective contraception during and for at least 3 months after treatment in women of reproductive potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, hair loss, nausea, vomiting, constipation, diarrhea, mouth sores, lack of appetite, weight loss, joint pain, muscle pain, bone pain, abdominal pain, or back pain. Have patient report immediately to prescriber signs of infection, burning or numbness feeling, painful extremities, tachycardia, arrhythmia, severe dizziness, passing out, shortness of breath, swelling of arms or legs, bruising, bleeding, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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