EriBULin

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]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 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%

Use in Specific Populations

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 the US labeling): Hypersensitivity to eribulin mesylate, halichondrin B, or its chemical derivatives.

Dosage and Administration

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: 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

No dilution required. May prepare by drawing into a syringe for administration or may dilute in 100 mL NS. 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.

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive 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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (≥5% to 12%)

Central nervous system: Fatigue (≤62%), peripheral neuropathy (29% to 35%; grades 3/4: 3% to 8%), headache (18% to 19%)

Dermatologic: Alopecia (35% to 45%)

Endocrine & metabolic: Hypokalemia (≥5% to 30%), hypocalcemia (28%), weight loss (21%), hypophosphatemia (20%)

Gastrointestinal: Nausea (35% to 41%), constipation (25% to 32%), abdominal pain (≥5% to 29%), anorexia (20%), decreased appetite (19%), vomiting (18% to 19%), diarrhea (17% to 18%), stomatitis (≥5% to 14%)

Genitourinary: Urinary tract infection (10% to 11%)

Hematologic & oncologic: Neutropenia (63% to 82%; grade 4: 29% grades 3/4: 12% to 57%; nadir: 13 days; recovery: 8 days), anemia (58% to 70%; grades 3/4: 2% to 4%)

Hepatic: Increased serum ALT (18% to 43%), increased serum AST (36%)

Neuromuscular & skeletal: Weakness (≤62%), arthralgia (≤22%), myalgia (≤22%), back pain (16%), ostealgia (12%), limb pain (11%)

Respiratory: Cough (14% to 18%), dyspnea (16%)

Miscellaneous: Fever (21% to 28%)

1% to 10%:

Cardiovascular: Hypotension (≥5% to <10%)

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

Dermatologic: Skin rash (≥5% to <10%)

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

Gastrointestinal: Dysgeusia (≥5% to <10%), dyspepsia (≥5% to <10%), xerostomia (≥5% to <10%), mucosal inflammation (9%)

Hematologic & oncologic: Thrombocytopenia (≥5% to <10%; grades ≥3: 1%), febrile neutropenia (≤5%)

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

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

Respiratory: Oropharyngeal pain (≥5% to <10%), upper respiratory tract infection (≥5% to <10%)

<1%, postmarketing, and/or case reports: Dehydration, drug-induced hypersensitivity, hepatotoxicity, hypomagnesemia, interstitial pulmonary disease, lymphocytopenia, neutropenic sepsis, pancreatitis, pneumonia, prolonged Q-T interval on ECG, pruritus, sepsis, Stevens-Johnson syndrome, toxic epidermal necrolysis

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.

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

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to eribulin may cause fetal harm.

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.

Patient Education

What is this drug used for?

• It is used to treat breast cancer and soft tissue sarcoma.

Frequently reported side effects of this drug

• Fatigue
• Headache
• Hair loss
• Nausea
• Vomiting
• Constipation
• Diarrhea
• Mouth sores
• Mouth irritation
• Lack of appetite
• Weight loss
• Joint pain
• Muscle pain
• Painful extremities
• Muscle spasm
• Tearing
• Dry mouth
• Change in taste
• Common cold symptoms
• Trouble sleeping
• Anxiety
• Bone pain
• Abdominal pain
• Back pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Burning or numbness feeling
• Depression
• Fast heartbeat
• Abnormal heartbeat
• Severe dizziness
• Passing out
• Shortness of breath
• Swelling of arms or legs
• Bruising
• Bleeding
• Severe loss of strength and energy
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.