Eribulin Mesylate

Class: Antineoplastic Agents
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
Brands: Halaven

Introduction

Antineoplastic agent; a non-taxane microtubule dynamics inhibitor.1 2 4 5 6 7 10 12 13 17 23

Uses for Eribulin Mesylate

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.1 2 12 23

There is no generally accepted standard of care for management of advanced and heavily pretreated anthracycline- and taxane-refractory metastatic breast cancer.1 2 5 6 13 14 15 16 17 19 23 35 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.14 15 16 35

Slideshow: Flashback: FDA Drug Approvals 2013

Eribulin Mesylate Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.24 25

  • Assess for peripheral neuropathy and perform CBC prior to each dose of eribulin.1 Modify or temporarily withhold dose for hematologic and nonhematologic toxicities according to degree of these toxicities.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

  • May cause nausea and vomiting; consider use of prophylactic antiemetics, including corticosteroids.1 2 33 Routine premedication to prevent hypersensitivity reactions not necessary.1 2 4 7 10 16 26

Administration

IV Administration

Administer IV, either as an injection or short infusion.1 25 27

Administer on day 1 and day 8 of a 21-day treatment cycle.1 12 18 19 23

Withdraw appropriate dose from single-use vial and administer either undiluted or diluted in 100 mL of 0.9% sodium chloride injection.1

Do not administer in the same IV line with other drugs.1

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

Vials are for single use only.1

Rate of Administration

Manufacturer recommends administering undiluted or diluted solution over 2–5 minutes.1 In clinical trials, the drug was given either undiluted or diluted over 1–60 minutes.25

Dosage

Available as eribulin mesylate; dosage expressed in terms of the salt.1

Adults

Breast Cancer
IV

1.4 mg/m2 on days 1 and 8 of a 21-day treatment cycle.1 12 18 19 23

In principal efficacy study, patients received a median of 5 cycles (range: 1–23 cycles) of therapy.1 2

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.1 May delay dose on day 8 for a maximum of 1 week.1 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.1 If toxicities do not resolve or improve to ≤grade 2 by day 15, omit dose.1 Once dosage reduced, do not re-escalate.1

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.

Table 1. Recommended Dosage Reductions for Hematologic and Nonhematologic Toxicities1

Permanently Reduce Dosage in Patients Initially Dosed with 1.4 mg/m2 for Any of the Following Toxicities

Recommended Dosage on Days 1 and 8 of 21-Day Cycle

ANC <500/mm3 for >7 days

1.1 mg/m2

ANC <1000/mm3 with fever or infection

1.1 mg/m2

Platelets <25,000/mm3

1.1 mg/m2

Platelets <50,000/mm3 requiring transfusion

1.1 mg/m2

Nonhematologic grade 3 or 4 toxicities

1.1 mg/m2

Omission or delay of day 8 dose in previous cycle for toxicity

1.1 mg/m2

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).1 23

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).1 23

Not studied in patients with severe hepatic impairment (Child-Pugh class C).1 Manufacturer does not provide specific dosage recommendations in such patients.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment (Clcr 50–80 mL/minute).1

Reduce initial dosage to 1.1 mg/m2 on days 1 and 8 of a 21-day cycle in patients with moderate renal impairment (Clcr 30–50 mL/minute).1 23

Not studied in patients with severe renal impairment (Clcr <30 mL/minute).1 Manufacturer does not provide specific dosage recommendations in such patients.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. 1

Cautions for Eribulin Mesylate

Contraindications

  • None.1

Warnings/Precautions

Warnings

Neutropenia

Neutropenia occurs commonly; may be severe (grade 3 or 4) and potentially life-threatening.1 2 18 19 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.1

Monitor peripheral blood cell counts prior to each dose and more frequently in patients who develop grade 3 or 4 cytopenias.1 Delay administration and reduce subsequent doses in patients with febrile neutropenia or grade 4 neutropenia lasting >7 days.1 (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.1 2 4 7 18 19 21 26 Usually mild to moderate in severity in eribulin-treated patients, but may be severe (grade 3 or 4) in some cases.1 2 19 26 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.1 2 May be prolonged in some cases.1

Closely monitor patients for symptoms of peripheral motor and sensory neuropathy prior to each dose.1 Withhold therapy in patients who experience grade 3 or 4 peripheral neuropathy until resolves to ≤grade 2; may then resume therapy at reduced dosage.1 (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.1

Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of fetal hazard.1 (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.1 3

Avoid use in patients with congenital long QT syndrome.1 Monitor serum potassium and magnesium concentrations periodically during therapy; correct hypokalemia or hypomagnesemia prior to initiating therapy.1 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).1 (See Drugs that Prolong QT Interval under Interactions.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk; discontinue nursing or the drug.1

Pediatric Use

Safety and effectiveness not established in pediatric patients <18 years of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 No overall differences in safety observed relative to younger adults.1

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.1 (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.1

Renal Impairment

A lower initial dosage is recommended in patients with moderate renal impairment (Clcr 30–50 mL/minute).1 Has not been studied in patients with severe renal impairment (Clcr <30 mL/minute).1 (See Special Populations under Dosage and Administration and also see Special Populations under Pharmacokinetics.)1

Common Adverse Effects

Neutropenia,1 2 18 19 anemia,1 2 18 19 asthenia or fatigue,1 2 18 19 26 alopecia,1 2 18 19 peripheral neuropathy,1 2 18 19 nausea,1 2 18 19 26 constipation.1 2

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

Interactions for Eribulin Mesylate

Minimally metabolized by CYP3A4.1 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.1 11

Substrate and weak inhibitor of P-glycoprotein in vitro.1 10 11 13

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Clinically important pharmacokinetic interactions not expected.1 11

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4: Clinically important pharmacokinetic interactions not expected.1 11

Drugs Affecting the P-glycoprotein Transport System

Clinically important pharmacokinetic interactions not expected with concurrent use of drugs that inhibit P-glycoprotein.1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).1 Manufacturer recommends ECG monitoring.1 (See Prolongation of QT Interval under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation1

ECG monitoring recommended1

Antipsychotic agents that prolong QT interval (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)

Increased risk of QT-interval prolongation1 30 31 32

ECG monitoring recommended1

Carboplatin

Pharmacokinetic interaction not observed7 9 10

Gatifloxacin

Increased risk of QT-interval prolongation1 30 31 32

ECG monitoring recommended1

Ketoconazole

No substantial effect on eribulin AUC;1 7 10 pharmacokinetic interaction unlikely1 7 10

Moxifloxacin

Increased risk of QT-interval prolongation1 30 31 32

ECG monitoring recommended1

Palifermin

Possible increased risk of oral mucositis if receive palifermin within 24 hours of myelotoxic chemotherapy administration28

Avoid palifermin during or within 24 hours before or after eribulin administration28

Tetrabenazine

Increased risk of QT-interval prolongation1 29

ECG monitoring recommended1

Eribulin Mesylate 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.4 7 10 13 26 36

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.1 8 (See Hepatic Impairment under Cautions.)

Formal pharmacokinetic studies in patients with renal impairment not conducted.1 Exposure increased twofold in patients with moderate renal impairment (Clcr 30–50 mL/minute).1 (See Renal Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

49–65%.1

Elimination

Metabolism

Primarily metabolized by cytochrome CYP3A4; no major human metabolites detected.1 10 13

Elimination Route

Eliminated mainly as unchanged drug in feces (82%) and in urine (9%).1

Half-life

Terminal elimination half-life approximately 40 hours.1 19 26

No accumulation observed with weekly administration.1

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C) in original carton; do not freeze.1

Store undiluted solution in syringe for ≤4 hours at room temperature or ≤24 hours under refrigeration (4°C).1 Store diluted solution for ≤4 hours at room temperature or ≤24 hours under refrigeration.1 Discard any unused portions of the vial.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Incompatible

Dextrose 5% in water

Actions

  • A non-taxane microtubule dynamics inhibitor antineoplastic agent;1 2 4 5 6 7 10 12 13 17 23 synthetic analog of halichondrin B, a naturally occurring product isolated from the marine sponge Halichondria okadai.1 4 7 13 20 21 22 23

  • Appears to have a distinct mechanism of action from that of other currently available antimicrotubule agents (epothilones, taxanes, vinca alkaloids).2 4 5 6 7 10 13 21 22

  • Like other antimicrotubule agents, binds to tubulin and blocks cell cycle progression at the G2/M phase, resulting in mitotic arrest and apoptosis.1 5 7 10 20

    Unlike other antimicrotubule agents, inhibits growth of microtubules without affecting shortening phase and causes sequestration of tubulin into nonfunctional aggregates.1 2 4 7 10 21 22

  • Antitumor activity against paclitaxel-resistant cell lines demonstrated in preclinical studies.6 7 10 13

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.1

  • 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).1 Necessity of obtaining CBCs periodically.1

  • Risk of peripheral neuropathy.1 Importance of patients informing a clinician if they develop any numbness, tingling, or burning in their hands or feet.1

  • 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).1

  • Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving eribulin therapy.1 Advise pregnant women of potential risk to fetus.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Eribulin Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use only

0.5 mg/mL (1 mg)

Halaven (available in single-use vials)

Eisai

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 3, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Eisai Inc. Halaven (eribulin mesylate) injection prescribing information. Woodcliff Lake, NJ: 2010 Nov.

2. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011; 377:914-23. [PubMed 21376385]

3. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 201532: Summary review for eribulin mesylate. From FDA website.

4. Cigler T, Vahdat LT. Eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother. 2010; 11:1587-93. [PubMed 20450446]

5. Morris PG. Advances in therapy: eribulin improves survival for metastatic breast cancer. Anticancer Drugs. 2010; 21:885-9. [PubMed 20838209]

6. Twelves C, Cortes J, Vahdat LT et al. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2010; 10:160-3. [PubMed 20299316]

7. Cortes J, Montero AJ, Glück S. Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treat Rev. 2011; :[epub ahead of print].

8. Witteveen P, Marchetti S, Roelvink-Mergui M et al. Eribulin mesylate pharmacokinetics in patients with hepatic impairment. J Clin Oncol. 2010; 28 (Suppl. 15): Abstr. No. 2582.

9. Swami U, Petrylak P, Raftopoulos H et al. Phase IB study of eribulin mesylate in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol. 2010; 28 (Suppl. 15): Abstr. No. 2589.

10. Swami U, Chaudhary I, Ghalib MH et al. Eribulin-a review of preclinical and clinical studies. Crit Rev Oncol Hematol. 2011; :[epub ahead of print]. [PubMed 21493087]

11. Zhang ZY, King BM, Pelletier RD et al. Delineation of the interactions between the chemotherapeutic agent eribulin mesylate (E7389) and human CYP3A4. Cancer Chemother Pharmacol. 2008; 62:707-16. [PubMed 18431572]

12. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: breast cancer. Version 2.2011. From NCCN website

13. Mani S, Swami U. Eribulin mesilate, a halichondrin B analogue, in the treatment of breast cancer. Drugs Today (Barc). 2010; 46:641-53. [PubMed 20967296]

14. Murphy CG, Seidman AD. Evolving approaches to metastatic breast cancer previously treated with anthracyclines and taxanes. Clin Breast Cancer. 2009; 9 (Suppl. 2):S58-65. [PubMed 19596644]

15. Moreno-Aspitia A, Perez EA. Treatment options for breast cancer resistant to anthracycline and taxane. Mayo Clin Proc. 2009; 84:533-45. [PubMed 19483170]

16. Gradishar WJ. The place for eribulin in the treatment of metastatic breast cancer. Curr Oncol Rep. 2011; 13:11-6. [PubMed 21104168]

17. Cortes J, Lorca R. Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer. Future Oncol. 2011; 7:355-64. [PubMed 21375468]

18. Cortes J, Vahdat L, Blum JL et al. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2010; 28:3922-8. [PubMed 20679609]

19. Vahdat LT, Pruitt B, Fabian CJ et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009; 27:2954-61. [PubMed 19349550]

20. Kuznetsov G, Towle MJ, Cheng H et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res. 2004; 64:5760-6. [PubMed 15313917]

21. Smith JA, Wilson L, Azarenko O et al. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry. 2010; 49:1331-7. [PubMed 20030375]

22. Jordan MA, Kamath K, Manna T et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005; 4:1086-95. [PubMed 16020666]

23. Anon. Eribulin mesylate (Halaven) for breast cancer. Med Lett Drugs Ther. 2011; 53:30-1. [PubMed 21502935]

24. Institute for Safe Medication Practices. ISMP’s list of high-alert medications. Horsham, PA; 2008. From ISMP website (). Accessed 2011 Jun 10.

25. Eisai Inc. Woodcliff Lake, NJ: Personal communication.

26. . Goel S, Mita AC, Mita M. A phase I study of eribulin mesylate, a mechanicistically novel inhibioty or microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res. 2009; 15:4207-12. [PubMed 19509177]

27. Edwards MS, Solimando DA, Waddell JA. Cancer chemotherapy update: eribulin mesylate and denosumab. Hosp Pharm. 2011; 46:247-50.

28. Amgen Inc. Kepivance (palifermin) for injection, for intravenous use prescribing information. Thousand Oaks, CA; 2009 Apr.

29. Lundbeck Inc. Xenazine (tetrabenazine) tablets prescribing information. Deerfield, IL.; 2009 Sep.

30. Ortho-McNeil-Janssen Pharmaceuticals. Invega (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2009 Jul.

31. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005; 20:243-51. [PubMed 16096514]

32. Schering Corporation, a subsidiary of Merck & Co., Inc. Saphris (asenapine maleate) sublingual tablets prescribing information. Whitehouse Station, NJ; 2011 Jan.

33. Eisai Ltd. Halaven 0.44 mg/ml solution for injection summary of product characteristics. Hertfordshire, UK; 2011 Mar 25.

34. Piekarz RL, Frye AR, Wright JJ et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006; 12:3762-73. [PubMed 16778104]

35. Fornier MN. Approved agents for metastatic breast cancer. Semin Oncol. 2011; 38 (Suppl 2):S3-10. [PubMed 21600382]

36. Tan AR, Rubin EH, Walton DC et al. Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors. Clin Cancer Res. 2009; 15:4213-9. [PubMed 19509146]

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