Eribulin Mesylate

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in detail in other sections of the labeling:

• Neutropenia [see WARNINGS AND PRECAUTIONS]
• Peripheral neuropathy [see WARNINGS AND PRECAUTIONS]
• QT prolongation [see WARNINGS AND PRECAUTIONS]

In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%).

The most common adverse reactions ( ≥ 25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies]. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m² on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2: Adverse Reactionsa with a Per-Patient Incidence of at Least 10% in Study 1

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in < 1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia ( < 500/mm³>) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN.

Peripheral Neuropathy: In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.

Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥ 5% to < 10% of the HALAVEN-treated group:

• Eye Disorders: increased lacrimation
• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth
• General Disorders and Administration Site Conditions: peripheral edema
• Infections and Infestations: upper respiratory tract infection
• Metabolism and Nutrition Disorders: hypokalemia
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness
• Nervous System Disorders: dysgeusia, dizziness
• Psychiatric Disorders: insomnia, depression
• Skin and Subcutaneous Tissue Disorders: rash

The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN 1.4 mg/m² on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m² (20%), 1000 mg/m² (64%), or 1200 mg/m² (16%) every 3 weeks. A total of 223 patients received HALAVEN and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens. The trial excluded patients with pre-existing ≥ Grade 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study 2 was 56

years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving HALAVEN [see Clinical Studies].

The most common adverse reactions ( ≥ 25%) reported in patients receiving HALAVEN were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common ( ≥ 5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving HALAVEN were neutropenia (4.9 %) and pyrexia (4.5%). Permanent discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia (0.9% each). Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%).

Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in the HALAVEN-treated arm in Study 2.

Table 3: Adverse Reactionsa Occurring in ≥ 10% (all Grades) of Patients Treated on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥ 5% for All Grades or ≥ 2% for Grades 3 and 4) (Study 2)b

Other clinically important adverse reactions occurring in ≥ 10% of the HALAVEN-treated patients were:

• Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%)
• General Disorders: asthenia/fatigue (62%); peripheral edema (12%)
• Metabolism and Nutrition Disorders: decreased appetite (19%)
• Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%)
• Respiratory Disorders: cough (18%)

Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in ≥ 5% to < 10% of the HALAVEN-treated group:

• Blood and Lymphatic System Disorders: thrombocytopenia
• Eye Disorders: increased lacrimation
• Gastrointestinal Disorders: dyspepsia
• Metabolism and Nutrition Disorders: hyperglycemia
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain
• Nervous System Disorders: dizziness, dysgeusia
• Psychiatric Disorders: insomnia, anxiety
• Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain
• Vascular Disorders: hypotension

Table 4: Laboratory Abnormalities Occurring in ≥ 10% (all Grades) of Patients Treated on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥ 5% forAll Grades or ≥ 2% for Grades 3 and 4)a (Study 2)†

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval of HALAVEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and Lymphatic System Disorders: lymphopenia
• Gastrointestinal Disorders: pancreatitis
• Hepatobiliary Disorders: hepatotoxicity
• Immune System Disorders: drug hypersensitivity
• Infections and Infestations: pneumonia, sepsis/neutropenic sepsis
• Metabolism and Nutrition Disorders: hypomagnesemia, dehydration
• Respiratory, thoracic and mediastinal disorders: interstitial lung disease
• Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis

Read the entire FDA prescribing information for Halaven (Eribulin Mesylate)

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

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

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

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

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

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.

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

Contraindications

• None.1

Warnings/Precautions

Warnings

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 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.)

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.)

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

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

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

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

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

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

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

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

• 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

• 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.)