eriBULin (Monograph)

Brand name: Halaven
Drug class: Antineoplastic Agents
- Halichondrin B Analogs
- Microtubule Inhibitors
VA class: AN900
Chemical name: (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-[(2S)-3-Amino-2-hydroxypropyl]-3-methoxy-26-methyl-20,27-dimethylidenehexacosahydro-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 methanesulfonate
Molecular formula: C₄₀H₅₉NO₁₁•CH₄O₃S
CAS number: 441045-17-6

Introduction

Antineoplastic agent; a non-taxane microtubule dynamics inhibitor.

Uses for eriBULin

Breast Cancer

Treatment of metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens, including an anthracycline and a taxane, in either the adjuvant or metastatic setting.

There is no generally accepted standard of care for management of advanced and heavily pretreated anthracycline- and taxane-refractory metastatic breast cancer. Some clinicians recommend individualizing therapy based on factors such as patient’s disease stage and tumor type, performance status, quality of life, preferences, treatment history (e.g., toxicity), underlying medical conditions, and expected benefits and risks of each option.

eriBULin Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Assess for peripheral neuropathy and perform CBC prior to each dose of eribulin. Modify or temporarily withhold dose for hematologic and nonhematologic toxicities according to degree of these toxicities. (See Dosage Modification for Toxicity under Dosage and Administration.)

• May cause nausea and vomiting; consider use of prophylactic antiemetics, including corticosteroids. Routine premedication to prevent hypersensitivity reactions not necessary.

Administration

IV Administration

Administer IV, either as an injection or short infusion.

Administer on day 1 and day 8 of a 21-day treatment cycle.

Withdraw appropriate dose from single-use vial and administer either undiluted or diluted in 100 mL of 0.9% sodium chloride injection.

Do not administer in the same IV line with other drugs.

For solution and drug compatibility information, see Compatibility under Stability.

Vials are for single use only.

Rate of Administration

Manufacturer recommends administering undiluted or diluted solution over 2–5 minutes. In clinical trials, the drug was given either undiluted or diluted over 1–60 minutes^{† [off-label]}.

Dosage

Available as eribulin mesylate; dosage expressed in terms of the salt.

Adults

Breast Cancer

IV

1.4 mg/m² on days 1 and 8 of a 21-day treatment cycle.

In principal efficacy study, patients received a median of 5 cycles (range: 1–23 cycles) of therapy.

Dosage Modification for Toxicity

Withhold dose on day 1 or day 8 of treatment cycle if ANC <1000/mm³, platelet counts <75,000/mm³, or grade 3 or 4 nonhematologic toxicities occur. May delay dose on day 8 for a maximum of 1 week. If toxicities resolve or improve to ≤grade 2 by day 15, resume therapy at a reduced dosage (see Table 1) and initiate next treatment cycle ≥2 weeks later. If toxicities do not resolve or improve to ≤grade 2 by day 15, omit dose. Once dosage reduced, do not re-escalate.

If any of the above events occurs while receiving 1.1 mg/m², reduce dosage to 0.7 mg/m².

If any of the above events occurs while receiving 0.7 mg/m², discontinue therapy.

Special Populations

Hepatic Impairment

Reduce dosage to 1.1 mg/m² on days 1 and 8 of a 21-day cycle in patients with mild hepatic impairment (Child-Pugh class A).

Reduce dosage to 0.7 mg/m² on days 1 and 8 of a 21-day cycle in patients with moderate hepatic impairment (Child-Pugh class B).

Not studied in patients with severe hepatic impairment (Child-Pugh class C). Manufacturer does not provide specific dosage recommendations in such patients. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment (Cl_cr 50–80 mL/minute).

Reduce initial dosage to 1.1 mg/m² on days 1 and 8 of a 21-day cycle in patients with moderate renal impairment (Cl_cr 30–50 mL/minute).

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute). Manufacturer does not provide specific dosage recommendations in such patients. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for eriBULin

Contraindications

• None.

Warnings/Precautions

Warnings

Neutropenia

Neutropenia occurs commonly; may be severe (grade 3 or 4) and potentially life-threatening. Higher incidence of grade 4 neutropenia and febrile neutropenia reported in patients with serum AST or ALT concentrations >3 times ULN or serum bilirubin concentrations >1.5 times ULN.

Monitor peripheral blood cell counts prior to each dose and more frequently in patients who develop grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients with febrile neutropenia or grade 4 neutropenia lasting >7 days. (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy is a common dose-limiting adverse effect of microtubule inhibitors, including eribulin. Usually mild to moderate in severity in eribulin-treated patients, but may be severe (grade 3 or 4) in some cases. Peripheral neuropathy of any grade reported in 35% of eribulin-treated patients in main efficacy study; also was most common adverse effect resulting in drug discontinuance. May be prolonged in some cases.

Closely monitor patients for symptoms of peripheral motor and sensory neuropathy prior to each dose. Withhold therapy in patients who experience grade 3 or 4 peripheral neuropathy until resolves to ≤grade 2; may then resume therapy at reduced dosage. (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of fetal hazard. (See Advice to Patients.)

Prolongation of QT interval

QT-interval prolongation observed on day 8 of treatment cycle, but not on day 1, in an open-label study; appears to be a delayed effect of the drug.

Avoid use in patients with congenital long QT syndrome. Monitor serum potassium and magnesium concentrations periodically during therapy; correct hypokalemia or hypomagnesemia prior to initiating therapy. Manufacturer recommends ECG monitoring for QT-interval prolongation in patients with CHF, bradyarrhythmias, or electrolyte abnormalities and in those receiving drugs known to prolong the QT interval (e.g., class Ia and III antiarrhythmic agents). (See Drugs that Prolong QT Interval under Interactions.)

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk; discontinue nursing or the drug.

Pediatric Use

Safety and effectiveness not established in pediatric patients <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. No overall differences in safety observed relative to younger adults.

Hepatic Impairment

Increased exposure to eribulin in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; reduce dosage in such patients. (See Special Populations under Dosage and Administration and also see Special Populations under Pharmacokinetics.) Not studied in patients with severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

A lower initial dosage is recommended in patients with moderate renal impairment (Cl_cr 30–50 mL/minute). Has not been studied in patients with severe renal impairment (Cl_cr <30 mL/minute). (See Special Populations under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Neutropenia, anemia, asthenia or fatigue, alopecia, peripheral neuropathy, nausea, constipation.

Patients with grade 0 or 1 ALT levels at baseline: ≥grade 2 ALT elevation reported.

Drug Interactions

Minimally metabolized by CYP3A4. Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 and; does not induce CYP isoenzymes 1A2, 2C9, 2C19, or 3A4 at clinically relevant concentrations.

Substrate and weak inhibitor of P-glycoprotein in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Clinically important pharmacokinetic interactions not expected.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4: Clinically important pharmacokinetic interactions not expected.

Drugs Affecting the P-glycoprotein Transport System

Clinically important pharmacokinetic interactions not expected with concurrent use of drugs that inhibit P-glycoprotein.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation). Manufacturer recommends ECG monitoring. (See Prolongation of QT Interval under Cautions.)

Specific Drugs

eriBULin Pharmacokinetics

Absorption

Plasma Concentrations

Following IV administration, plasma concentrations decline in a triphasic manner with an initial rapid distribution phase followed by a slower elimination phase.

Special Populations

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure increased approximately 1.8- or 2.5-fold, respectively. (See Hepatic Impairment under Cautions.)

Formal pharmacokinetic studies in patients with renal impairment not conducted. Exposure increased twofold in patients with moderate renal impairment (Cl_cr 30–50 mL/minute). (See Renal Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

49–65%.

Elimination

Metabolism

Primarily metabolized by cytochrome CYP3A4; no major human metabolites detected.

Elimination Route

Eliminated mainly as unchanged drug in feces (82%) and in urine (9%).

Half-life

Terminal elimination half-life approximately 40 hours.

No accumulation observed with weekly administration.

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C) in original carton; do not freeze.

Store undiluted solution in syringe for ≤4 hours at room temperature or ≤24 hours under refrigeration (4°C). Store diluted solution for ≤4 hours at room temperature or ≤24 hours under refrigeration. Discard any unused portions of the vial.

Compatibility

Parenteral

Solution Compatibility1

Actions

• A non-taxane microtubule dynamics inhibitor antineoplastic agent; synthetic analog of halichondrin B, a naturally occurring product isolated from the marine sponge Halichondria okadai.

• Appears to have a distinct mechanism of action from that of other currently available antimicrotubule agents (epothilones, taxanes, vinca alkaloids).

• Like other antimicrotubule agents, binds to tubulin and blocks cell cycle progression at the G₂/M phase, resulting in mitotic arrest and apoptosis.

  Unlike other antimicrotubule agents, inhibits growth of microtubules without affecting shortening phase and causes sequestration of tubulin into nonfunctional aggregates.

• Antitumor activity against paclitaxel-resistant cell lines demonstrated in preclinical studies.

Advice to Patients

• Importance of instructing patients to carefully read manufacturer’s patient information before initiating eribulin therapy and also before receiving each injection of the drug.

• Risk of myelosuppression; importance of patients informing a clinician if they develop any symptoms of an infection (e.g., fever ≥100.5°F, chills, cough, burning or pain upon urination). Necessity of obtaining CBCs periodically.

• Risk of peripheral neuropathy. Importance of patients informing a clinician if they develop any numbness, tingling, or burning in their hands or feet.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., liver and kidney disease, heart problems including congenital long QT syndrome).

• Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving eribulin therapy. Advise pregnant women of potential risk to fetus. Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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