Eribulin

L01X - Other antineoplastic agents ATC L01XX41 Small molecule approved 2010 Parenteral Natural product

JFDA label: Halaven 1mg/2ml

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.

Indications

Approved

Breast cancer, metastatic
Liposarcoma, unresectable or metastatic

Contraindications

Source: Lexicomp

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 Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Very Common Peripheral edema

Common Hypotension (≥5% to Central nervous system: Anxiety (≥5% to Dermatologic: Skin rash (≥5% to Endocrine & metabolic: Hyperglycemia (≥5% to Gastrointestinal: Dysgeusia (≥5% to Hematologic & oncologic: Th

Nervous system disorders (3)

Very Common Fatigue · headache · peripheral neuropathy

Hepatobiliary disorders (2)

Very Common Increased serum ALT · increased serum AST

Renal and urinary disorders (1)

Very Common Urinary tract infection

Blood and lymphatic system disorders (2)

Very Common anemia · Neutropenia

Metabolism and nutrition disorders (4)

Very Common hypocalcemia · Hypokalemia · hypophosphatemia · weight loss

Gastrointestinal disorders (8)

Very Common abdominal pain · anorexia · constipation · decreased appetite · diarrhea · Nausea · stomatitis · vomiting

Skin and subcutaneous tissue disorders (1)

Very Common Alopecia

Musculoskeletal and connective tissue disorders (6)

Very Common arthralgia · back pain · limb pain · myalgia · ostealgia · Weakness

General disorders and administration site conditions (1)

Very Common Fever

Respiratory, thoracic and mediastinal disorders (2)

Very Common Cough · dyspnea

Dosing

Source: Lexicomp

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

Refer to adult dosing.

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.

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.

Warnings & Precautions

Source: Lexicomp

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 3 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.

Pregnancy & Lactation

Pregnancy

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.

Lactation

Avoid

It is not known if eribulin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, breastfeeding is not recommended by the manufacturer during eribulin treatment and for 2 weeks after the last dose.

Monitoring

Clinical pearl	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).

Clinical pearl

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).

Chemistry & Properties

Formula	C40H59NO11
Molecular weight	729.91 g/mol
IUPAC name	(1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-dimethylidene-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.13,32.13,33.16,9.112,16.018,22.029,36.031,35]hentetracontan-24-one
CAS	253128-41-5
PubChem CID	11354606
InChIKey	`UFNVPOGXISZXJD-JBQZKEIOSA-N`
logP	3.44 (XLogP 1.1)
Polar surface area	146.39 Å²
H-bond acceptors / donors	12 / 2
Drug-likeness (QED)	0.41
Lipinski violations	2

SMILES

C=C1C[C@@H]2CC[C@@]34C[C@H]5O[C@H]6[C@@H](O3)[C@H]3O[C@H](CC[C@@H]3O[C@H]6[C@H]5O4)CC(=O)C[C@@H]3[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]3C[C@H]3O[C@@H](CC[C@@H]1O2)C[C@@H](C)C3=C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.812 h
Volume of distribution	1.647 L/kg
Protein binding	54.0%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
tubulin beta class I (TUBB)	Inhibitor	pIC50 8.2

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP4 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)BSEP (Substrate)MATE1 (Substrate)MDR1 (Substrate)MRP2 (Substrate)OAT1 (Substrate)OAT3 (Substrate)OATP (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OCT1 (Substrate)OCT2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Amiodarone	major
Amisulpride	major
Anagrelide	major
Arsenic trioxide	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Bedaquiline	major
Bepridil	major
Cabozantinib	major
Ceritinib	major
Certolizumab pegol	major
Chloroquine	major
Cisapride	major
Citalopram	major
Cladribine	major
Clozapine	major
Crizotinib	major
Deferiprone	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Dronedarone	major
Droperidol	major
Efavirenz	major
Escitalopram	major
Etanercept	major
Fingolimod	major
Gatifloxacin	major
Golimumab	major
Grepafloxacin	major
Halofantrine	major
Haloperidol	major
Hydroxychloroquine	major
Ibutilide	major
Iloperidone	major
Infliximab	major
Ivabradine	major
Ivosidenib	major
Lefamulin	major

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Halaven	Vial 0.44 mg/ml	1 vial	Nairoukh Drug Store	—