Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
eriBULin
eriBULin is a synthetic form of halichondrin B, an agent isolated from the sea sponge Halichondria okadai. It is a non-taxane microtubule dynamic inhibitor which suppresses the polymerization of microtubules and sequesters tubulin into nonproductive aggregates. Its action is distinct from the vinca alkaloids, taxanes and epothilones that affect both microtubule growth or shortening. The antimitotic action of eriBULin leads to cell apoptosis due to G2/M cell cycle-block.
Pharmacokinetics is dose-proportional and linear. No significant eriBULin accumulation is observed on weekly administration. Gender and race do not have significant effects on eriBULin pharmacokinetics.
Rapid distribution phase
| PPB | 49-65% |
Negligible metabolism by CYP3A4. eriBULin is also a substrate of P-gp, but the contribution of this transporter to the biliary and renal elimination of eriBULin is unknown. No major human metabolites are found.
| Inactive metabolites | Trace (0.6% concentration of parent compound) |
Triphasic drug concentration decline with a long elimination phase. eriBULin is mainly eliminated unchanged.
| Feces | 82% |
| Urine | 9% |
| Half-life | 40 hours |
For the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane administered in either the adjuvant or metastatic setting.
For the treatment of paitents with unresectable or metastatic liposarcoma, a subtype of soft tissue sarcoma. Prior therapy should have included an anthracycline-containing regimen, if clinically appropriate.
Emetogenic Potential:
Extravasation Potential: Minimal
The following adverse effects were reported in the pivotal trial in metastatic breast cancer patients (EMBRACE) or were severe or life-threatening.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Atrial fibrillation (rare) | E | |||
| Hypertension (<10%) | E | ||||
| QT interval prolonged (<10%) | E | ||||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (45%) | D | |||
| Hand-foot syndrome (1%) | E | ||||
| Rash (<10%; may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (<10%) | E | |||
| Anorexia, weight loss (21%) | E | ||||
| Constipation (25%) | E | ||||
| Diarrhea (18%) | E | ||||
| Mucositis (9%) | E | ||||
| Nausea, vomiting (35%) | I | ||||
| General | Edema (<10%) | E | |||
| Fatigue (54%) | E | ||||
| Hematological | Disseminated intravascular coagulation (rare) | E D | |||
| Myelosuppression ± infection, bleeding (58%) (severe) | E | ||||
| Hepatobiliary | ↑ LFTs (73%) (may be severe) | E | |||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (38%) | E | |||
| Hyperglycemia (<10%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (22%) | E | |||
| Nervous System | Anxiety /depression/ insomnia (<10%) | E | |||
| Dizziness (<10%) | E | ||||
| Dysgeusia (<10%) | E | ||||
| Headache (19%) | E | ||||
| Neuropathy (35%) (8% severe) | E D | ||||
| Other - Pharyngolaryngeal pain (<10%) | E | ||||
| Vertigo (<10%) | E | ||||
| Ophthalmic | Conjunctivitis (<10%) | E | |||
| Renal | Creatinine increased (14%) | E | |||
| Respiratory | Cough, dyspnea (16%) | E | |||
| Pneumonitis (rare) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for eriBULin include ↑ lfts, myelosuppression ± infection, bleeding, fatigue, alopecia, abnormal electrolyte(s), nausea, vomiting, neuropathy, constipation, pain, anorexia and weight loss.
Myelosuppression usually manifests as neutropenia, is dose dependent and may be severe in some cases. Patients with elevated LFTs (> 3 x ULN; bilirubin > 1.5 x ULN) had higher incidences of grade 4 neutropenia and febrile neutropenia than patients with normal liver function tests.
Neuropathy was the most common toxicity leading to treatment discontinuation in the pivotal trial. It is dose-limiting and 5% of patients experienced neuropathy that lasted more than one year.
QT prolongation appeared to be a delayed effect as it has been observed on day 8 (maximum 11.4 msec from baseline) in a non-controlled trial, but this was not observed on day 1.
Severe rashes, including SJS and TENS have been reported.
Refer to protocol by which patient is being treated. Do not start the first dose until platelets are > 100 x 109/L and ANC ≥ 1.5 x 109/L. Correct electrolyte abnormalities prior to treatment, especially potassium, calcium and magnesium. Do not re-escalate a dose reduced for toxicity.
|
Starting Dose
|
Dose level -1
|
Dose level -2
|
Dose level -3
|
|
1.4 mg/m2
|
1.1 mg/m2
|
0.7 mg/m2
|
Discontinue
|
Dose adjustments on Day 1 or Day 8:
|
Worst toxicity in previous period / on day of dosing |
Day 1*
|
Day 8 */#
|
|
Platelets < 75-100 x 109/L or ANC <1-1.5 x 109/L on day of dosing |
Do not treat *
|
Delay for one week; if no recovery, omit for that cycle |
|
Grade 4 ANC > 7 days, Grade 4 thrombocytopenia, Febrile neutropenia, Platelets < 50 requiring transfusion or Thrombocytopenic bleeding |
Hold until recovered*, then ↓ 1 dose level |
Delay for one week; if no recovery, omit for that cycle |
|
≥ grade 3 non-hematologic
|
Hold until recovered*, then ↓ 1 dose level |
Delay for one week until ≤ grade 2; if no recovery, omit for that cycle |
|
Delay or dose modification for day 8 in previous cycle |
↓ one dose level for all subsequent doses |
|
| * Do not treat until ANC ≥ 1 x 109/L and platelets ≥ 75 x 109/L and other toxicity ≤ grade 2. # If delay day 8, the cycle length is also increased (next cycle must be ≥2 weeks after the delayed "day 8"). |
||
eriBULin exposure is increased in mild and moderate hepatic impairment. Starting doses should be reduced and patients monitored closely for toxicity.
|
Hepatic function
|
Recommended Dose on Days 1 and 8 (mg/m2)
|
|
Normal (bilirubin < 1.5 x ULN, transaminases ≤ 3 x ULN)
|
1.4
|
|
Mild impairment (Child Pugh A)
|
1.1
|
|
Moderate impairment (Child Pugh B)
|
0.7
|
|
Severe impairment (Child Pugh C)
|
OMIT
|
Mild or moderate renal impairment may decrease eriBULin clearance. Exposure may increase up to 1.5-fold in moderate or severe renal impairment. Monitor for adverse effects, especially myelosuppression.
| Renal impairment | Starting dose |
| Mild (50-80 mL/min) | No change in starting dose |
| Moderate or severe (15-50 mL/min) | Caution; ↓ starting dose to 1.1 mg/m2 |
| End-stage (<15 mL/min) | No data; OMIT |
No dose adjustments required.
Safety and effectiveness in pediatric patients have not been established.
- Give IV over 2 to 5 minutes
- Dose may be administered in a syringe without dilution or may dilute in up to 100mL NS.
- Does not require premedications with steroids and/or antihistamines for hypersensitivity.
- Do not admix eriBULin with other medicinal products.
- Do not dilute or administer with dextrose-containing solutions.
- Store unopened vials at room temperature in their original cartons.
- Diluted solutions may be stored for up to 48 hours refrigerated, or for up to 24 hours at room temperature.
- Patients who have a hypersensitivity to this drug, halichondrin B or any of its components
- Severe hepatic impairment
- End-stage renal disease
Other Warnings/Precautions:
- Avoid use in patients with congenital long QT syndrome.
- Avoid concomitant use of QT-prolonging drugs, where possible (see Drug Interactions).
- Correct any hypocalcemia, hypokalemia and hypomagnesemia prior to starting eriBULin.
- Exercise extreme caution with significant cardiovascular impairment (congestive heart failure > grade 2, unstable angina or myocardial infarction within the last 6 months) as the safety of eriBULin in this population has not been established.
- Use with caution in patients with pre-existing neuropathy as eriBULin may aggravate the condition.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Documented in animals
-
Mutagenicity:
No
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Teratogenicity:
Documented in animals
eriBULin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.
-
Breastfeeding:
Not recommended
-
Fertility effects:
Probable
May be irreversible. Male patients should seek advice on conservation of sperm prior to treatment.
eriBULin is not expected to alter the plasma concentrations of drugs that are substrates of CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. No drug-drug interactions are expected with CYP3A4 inhibitors or inducers.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Inhibitors of transport proteins, such as P-gp (i.e. quinidine, verapamil, cyclosporine) | ↑ eriBULin exposure (theoretical) | ↓ drug efflux | Caution and monitor for toxicity |
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of QT prolongation | Additive | Avoid where possible. Monitor with ECG if used together. |
| Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) | ↑ risk of QT prolongation | electrolyte imbalance | Caution; monitor ECG |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each dose; more frequent in patients who develop severe myelosuppression. |
Liver and renal function tests, including electrolytes |
Baseline and before each dose |
ECG in patients with risk factors for torsade de pointes (i.e. patients with cardiac disease or concomitant QT-prolonging medications) |
Baseline and as clinically indicated |
Clinical toxicity assessment for neuropathy, cardiotoxicity, hepatic, musculoskeletal, fatigue, GI symptoms and thromboembolism |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program ( )
- Eribulin - Metastatic or Incurable Locally Advanced - Breast Cancer
Eribulin: AHFS Drug Information. October 2011. Available from: http://www.ahfsdruginformation.com
Eribulin mesylate. NCI Drug Dictionary - National Cancer Institute. Available from: http://www.cancer.gov/drugdictionary?cdrid=257773
NCCN Clinical Practice Guidelines in Oncology: Antiemesis: Version 1, 2012.
Perry CM. Eribulin. Drugs 2011;71(10):1321-31.
Product Monograph: Halaven® (eribulin). Eisai Limited, August 2017.
Product Monograph: Halaven® (eribulin). Eisai Inc. (US), November 2010.
January 2018 added new indication for liposarcoma; updated adverse effects
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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