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ERIBULIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Eribulin mesylate, a synthetic analog of halichondrin B, is a non-taxane microtubule inhibitor. It is used to treat patients with metastatic breast cancer.

Specific Substances

    1) Eribulin mesylate
    2) E7389
    3) ER-086526
    4) NSC-707389
    5) CAS 253128-41-5
    1.2.1) MOLECULAR FORMULA
    1) C40H59NO11CH4O3S (Prod Info HALAVEN(TM) intravenous injection, 2010)

Available Forms Sources

    A) FORMS
    1) Eribulin is available in the United States as 1 mg/2 mL (0.5 mg/mL) in a single-use vial (Prod Info HALAVEN(R) intravenous injection, 2016).
    B) USES
    1) Eribulin is indicated for the treatment of metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens containing an anthracycline and a taxane. It is also indicated for the treatment of liposarcoma that is metastatic or unresectable in patients who have previously received an anthracycline-containing regimen (Prod Info HALAVEN(R) intravenous injection, 2016).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Eribulin is indicated for the treatment of metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens containing an anthracycline and a taxane. It is also indicated for the treatment of liposarcoma that is metastatic or unresectable in patients who have previously received an anthracycline-containing regimen.
    B) PHARMACOLOGY: Eribulin mesylate is a synthetic analog of halichondrin B, a product that is isolated from the marine sponge Halichondria okadai. Without affecting the shortening phase of microtubules, this non-taxane microtubule inhibitor inhibits the growth phase of microtubules and sequesters tubulin into nonproductive aggregates leading to G2/M cell-cycle block, disruption of mitotic spindles, and eventually apoptotic cell death following prolonged mitotic blockage.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (25% or greater): Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. OTHER EFFECTS: Stomatitis, diarrhea, vomiting, abdominal pain, anorexia, elevated liver enzymes, arthralgia, myalgia, back pain, bone pain, headache, dizziness, cough, dyspnea, rash, thrombocytopenia, and fever.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of eribulin.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients receiving eribulin in clinical trials.
    0.2.20) REPRODUCTIVE
    A) There was evidence of teratogenicity, embryofetal toxicity, and maternal toxicity when rats were given eribulin at doses half of the recommended human dose. At the time of this review, no data were available to assess the potential effects of exposure to eribulin during pregnancy in humans. Because eribulin is a microtubule inhibitor, fetal harm is expected when the drug is administered to a pregnant woman.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for eribulin in humans.

Laboratory Monitoring

    A) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring.
    B) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving eribulin. The mean time to nadir was 13 days, and the mean time for recovery from severe neutropenia was 8 days. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes renal function and liver enzymes.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) No clinical reports available; information derived from experience with other antineoplastics. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as eribulin is moderately protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Decontamination is not necessary as eribulin is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable dysrhythmias develop. Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions, but this is rare.
    F) ANTIDOTE
    1) None.
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    I) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    J) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    K) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    L) STOMATITIS/MUCOSITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with an eribulin overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    M) PERIPHERAL NEUROPATHY
    1) Peripheral neurotoxicity should be anticipated in overdose. Monitor and treat symptoms as indicated.
    N) ENHANCED ELIMINATION
    1) Dialysis, hemoperfusion or plasmapheresis are UNLIKELY to be of benefit due to large volume of distribution.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    P) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity, cardiotoxicity).
    Q) PHARMACOKINETICS
    1) Protein binding: 49% to 65%. Mean Vd: 43 to 114 L/m(2). Excretion: urine: approximately 9% (approximately 91% as unchanged drug); feces: approximately 82%. Mean elimination half-life: about 40 hours.
    R) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause myelosuppression or peripheral neuropathy.

Range Of Toxicity

    A) TOXICITY: Limited date. At the time of this review, a minimum lethal dose has not been established. One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of erbulin.
    B) THERAPEUTIC DOSE: ADULT: 1.4 mg/m(2) IV over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Eribulin is indicated for the treatment of metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens containing an anthracycline and a taxane. It is also indicated for the treatment of liposarcoma that is metastatic or unresectable in patients who have previously received an anthracycline-containing regimen.
    B) PHARMACOLOGY: Eribulin mesylate is a synthetic analog of halichondrin B, a product that is isolated from the marine sponge Halichondria okadai. Without affecting the shortening phase of microtubules, this non-taxane microtubule inhibitor inhibits the growth phase of microtubules and sequesters tubulin into nonproductive aggregates leading to G2/M cell-cycle block, disruption of mitotic spindles, and eventually apoptotic cell death following prolonged mitotic blockage.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (25% or greater): Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. OTHER EFFECTS: Stomatitis, diarrhea, vomiting, abdominal pain, anorexia, elevated liver enzymes, arthralgia, myalgia, back pain, bone pain, headache, dizziness, cough, dyspnea, rash, thrombocytopenia, and fever.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of eribulin.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients receiving eribulin in clinical trials.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In an open-label, randomized, multicenter trial, pyrexia (any grade) occurred in 21% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 13% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) INCREASED LACRIMATION has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In one study (n=26), QT prolongation developed in patients 8 days after receiving eribulin; no QT prolongation was observed on day 1 (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, cough (any grade) occurred in 14% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 9% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, dyspnea (any grade) occurred in 16% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 13% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, any-grade peripheral neuropathy, including neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paresthesia, occurred in 35% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 16% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    b) During clinical trials, peripheral neuropathy was the most common adverse reaction that resulted in discontinuation of therapy (5% of patients; 24/503), and dose reduction was required for 3% (14/503). Peripheral motor neuropathy (any grade) occurred in 4% (20/503) of eribulin-treated patients and grade 3 occurred in 2% (8/503). A new or worsening neuropathy that did not resolve within a median of 269 days occurred in 22% (109/503) of patients, and 5% (26/503) of patients had a neuropathy that lasted more than one year (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, headache (any grade) occurred in 19% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 12% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, asthenia/fatigue (any grade) occurred in 54% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 40% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, constipation (any grade) occurred in 25% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 21% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, diarrhea (any grade) occurred in 18% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 18% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    D) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, nausea (any grade) occurred in 35% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 28% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    E) VOMITING
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, vomiting (any grade) occurred in 18% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 18% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, anorexia (any grade) occurred in 20% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 13% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    G) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ALT (SGPT) LEVEL RAISED
    1) WITH THERAPEUTIC USE
    a) During clinical trials with eribulin, 18% of patients with a grade 0 or 1 ALT level at baseline developed a grade 2 or greater elevation in ALT. One patient without liver metastases (documented) had grade 2 elevations of both bilirubin and ALT, which resolved and did not recur with subsequent therapy (Prod Info HALAVEN(TM) intravenous injection, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, urinary tract infections (any grade) occurred in 10% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 5% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, neutropenia (any grade) occurred in 82% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 53% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days). In eribulin-treated patients, grade 3 neutropenia occurred in 28% (143/503) of patients and grade 4 neutropenia in 29% (144/503) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    b) Patients with elevated aminotransferase levels, defined as an alanine aminotransferase or aspartate aminotransferase of greater than 3 times the ULN, or elevated bilirubin levels (greater than 1.5 times the ULN) had an increased risk for grade 4 neutropenia. Severe neutropenia, defined as an absolute neutrophil count of less than 500/mm(3), lasting more than one week occurred in 12% (62/503) of patients. The mean time to nadir was 13 days, and the mean time for recovery from severe neutropenia was 8 days (Prod Info HALAVEN(TM) intravenous injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of eribulin (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, anemia (any grade) occurred in 58% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 55% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    C) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, febrile neutropenia occurred in 5% (23/503) of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer, and 2 patients (0.4%) died from complications of febrile neutropenia. Patients with elevated aminotransferase levels, defined as an alanine aminotransferase or aspartate aminotransferase of greater than 3 times the ULN, or elevated bilirubin levels (greater than 1.5 times the ULN) had an increased risk for febrile neutropenia (Prod Info HALAVEN(TM) intravenous injection, 2010).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer (Prod Info HALAVEN(TM) intravenous injection, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, alopecia (any grade) occurred in 45% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 10% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, arthralgia or myalgia (any grade) occurred in 22% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 12% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, arthralgia or myalgia (any grade) occurred in 22% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 12% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    C) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, back pain (any grade) occurred in 16% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 7% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    D) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, bone pain (any grade) occurred in 12% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 9% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    E) PAIN
    1) WITH THERAPEUTIC USE
    a) In an open-label, randomized, multicenter trial, pain in an extremity (any grade) occurred in 11% of patients treated with eribulin 1.4 mg/m(2) on days 1 and 8 of a 21-day cycle (n=503; median duration 118 days) as monotherapy for metastatic breast cancer compared with 10% of patients who were treated with single-agent chemotherapy or hormonal therapy (n=247; median duration 63 days) (Prod Info HALAVEN(TM) intravenous injection, 2010).
    F) SPASM
    1) WITH THERAPEUTIC USE
    a) Muscle spasm has been reported in 5% to 10% of eribulin-treated patients (Prod Info HALAVEN(TM) intravenous injection, 2010).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH POISONING/EXPOSURE
    a) One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of eribulin (Prod Info HALAVEN(TM) intravenous injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) There was evidence of teratogenicity, embryofetal toxicity, and maternal toxicity when rats were given eribulin at doses half of the recommended human dose. At the time of this review, no data were available to assess the potential effects of exposure to eribulin during pregnancy in humans. Because eribulin is a microtubule inhibitor, fetal harm is expected when the drug is administered to a pregnant woman.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of eribulin in humans. Because eribulin is a microtubule inhibitor, fetal harm is expected when the drug is administered to a pregnant woman (Prod Info HALAVEN(R) intravenous injection, 2016).
    B) ANIMAL STUDIES
    1) Severe external or soft-tissue anomalies (eg, absence of a lower jaw, tongue, stomach, and/or spleen) were reported in offspring after IV doses administered during organogenesis that were approximately 0.64 times the recommended human dose (based on body surface area). Minor skeletal anomalies were noted after the administration of doses 0.43 times the recommended human dose (Prod Info HALAVEN(R) intravenous injection, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to eribulin during pregnancy in humans. Because eribulin is a microtubule inhibitor, fetal harm is expected when the drug is administered to a pregnant woman (Prod Info HALAVEN(R) intravenous injection, 2016).
    B) RISK SUMMARY
    1) Although no data were available to assess the potential effects of exposure to eribulin during pregnancy in humans, there was evidence of teratogenicity, embryofetal toxicity, and maternal toxicity during animal studies. Avoid eribulin use in pregnancy and advise women of childbearing potential to use effective contraception during treatment. If eribulin therapy is required during pregnancy or if a woman becomes pregnant while receiving the drug, inform her of the possibility of serious fetal harm (Prod Info HALAVEN(R) intravenous injection, 2016).
    C) ANIMAL STUDIES
    1) Increased abortion rates were reported in offspring after IV doses were administered during organogenesis approximately 0.64 times the recommended human dose (based on body surface area). There were adverse effects (eg, increased embryofetal death/resorption, decreased fetal weights) as well as maternal toxicity (eg, enlarged spleen, reduced maternal weight gain, and decreased food consumption) at doses at or above 0.43 times the recommended human dose (Prod Info HALAVEN(R) intravenous injection, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether eribulin is excreted in human breast milk, the effects milk production, or the effects on the breastfed infant. Advise women not to breastfeed during eribulin treatment or for 2 weeks after the final dose (Prod Info HALAVEN(R) intravenous injection, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In repeated-dose toxicology studies, male fertility was compromised by eribulin therapy. Testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) was observed after eribulin doses at or above 0.43 times the recommended human dose (mg/m(2)) were given once weekly for 3 weeks or at or above 0.21 times the recommended human dose (mg/m(2)) for 3 out of 5 weeks and repeated for 6 cycles (Prod Info HALAVEN(R) intravenous injection, 2016).
    2) Testicular toxicity was noted following eribulin doses 0.64 times the recommended human dose (mg/m(2)) weekly for 3 out of 5 weeks and repeated for 6 cycles (Prod Info HALAVEN(R) intravenous injection, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for eribulin in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for eribulin in humans (Prod Info HALAVEN(TM) intravenous injection, 2010).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for eribulin sodium in animals (Prod Info HALAVEN(TM) intravenous injection, 2010).

Genotoxicity

    A) There was no evidence of mutagenicity in in vitro bacterial reverse mutation assays (Ames test). However, mutagenicity and clastogenicity were observed in mouse lymphoma mutagenesis assays and rat bone marrow micronucleus assays (in vivo), respectively (Prod Info HALAVEN(TM) intravenous injection, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring.
    B) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving eribulin. The mean time to nadir was 13 days, and the mean time for recovery from severe neutropenia was 8 days. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes renal function and liver enzymes.
    4.1.2) SERUM/BLOOD
    A) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving eribulin. The mean time to nadir was 13 days, and the mean time for recovery from severe neutropenia was 8 days (Prod Info HALAVEN(TM) intravenous injection, 2010). Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac function, and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor vital signs and serial ECGs; institute continuous cardiac monitoring.
    B) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving eribulin. The mean time to nadir was 13 days, and the mean time for recovery from severe neutropenia was 8 days. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes renal function and liver enzymes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary as eribulin is administered intravenously.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) Dialysis, hemoperfusion or plasmapheresis are UNLIKELY to be of benefit due to large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: Limited date. At the time of this review, a minimum lethal dose has not been established. One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of erbulin.
    B) THERAPEUTIC DOSE: ADULT: 1.4 mg/m(2) IV over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) 1.4 mg/m(2) IV over 2 to 5 minutes on days 1 and 8 of a 21-day cycle (Prod Info HALAVEN(R) intravenous injection, 2014)
    7.2.2) PEDIATRIC
    A) Safety and effectiveness have not been established in pediatric patients (Prod Info HALAVEN(R) intravenous injection, 2014).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) One patient developed Grade 3 neutropenia (lasting 7 days) and Grade 3 hypersensitivity reaction after receiving approximately 4 times the recommended dose of erbulin (Prod Info HALAVEN(TM) intravenous injection, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Eribulin mesylate is a synthetic analog of halichondrin B, a product that is isolated from the marine sponge Halichondria okadai. Without affecting the shortening phase of microtubules, this non-taxane microtubule inhibitor inhibits the growth phase of microtubules and sequesters tubulin into nonproductive aggregates leading to G2/M cell-cycle block, disruption of mitotic spindles, and eventually apoptotic cell death following prolonged mitotic blockage (Prod Info HALAVEN(R) intravenous injection, 2016).

Physicochemical

Physical Characteristics

    A) A clear, colorless, and sterile solution (Prod Info HALAVEN(TM) intravenous injection, 2010).

Molecular Weight

    A) 826 (729.9 for free base) (Prod Info HALAVEN(TM) intravenous injection, 2010)

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